CN116710156A

CN116710156A - Coated medical product

Info

Publication number: CN116710156A
Application number: CN202180087733.1A
Authority: CN
Inventors: M·霍夫曼; E·霍夫曼; G·马塔尔
Original assignee: Hemoteq AG
Current assignee: Hemoteq AG
Priority date: 2020-11-16
Filing date: 2021-11-16
Publication date: 2023-09-05

Abstract

The present invention relates to a suspension for coating a medical product comprising at least one tri-O-acylglycerol, at least one limus active substance in microcrystalline form and at least one solvent, in which the at least one tri-O-acylglycerol is dissolved and in which the crystallites of the at least one limus active substance are not dissolved. Furthermore, the invention relates to a method for preparing said suspension, to a method for coating a medical product with said suspension, and to a medical product coated with at least one tri-O-acylglycerol and at least one microcrystalline limus active substance.

Description

Coated medical product

Technical Field

The present invention relates to a suspension for coating a medical product comprising at least one tri-O-acylglycerol, at least one micro-crystalline Limus (Limus) active substance and at least one solvent or solvent mixture in which the at least one tri-O-acylglycerol is dissolved, and in which the micro-crystals of the at least one Limus active substance are not dissolved when the at least one tri-O-acylglycerol is present. The invention also relates to a method for preparing said suspension, to a method for coating a medical product and to a medical product coated with at least one tri-O-acylglycerol and at least one active substance of microcrystalline limus.

Background

Medical products are used to take on missing functions in the body, to support the body's own functions or to locally transfer active substances with the aid of it. Depending on the field of application, the medical product is in short-term or long-term contact with the living organism. The contact time may be from a few seconds to several decades. If a medical product is required, the unavoidable inflammatory processes occurring during wound healing must be controlled to prevent an excessive reaction of the immune system during the healing process.

Restenosis (restenosis) occurs as a common complication several weeks after treatment when mechanical or thermal methods are used to treat vascular contractions (stenosis), such as implantation of vascular stents (stents) or balloon angioplasty. To prevent restenosis, stents and catheter balloons have been coated with active substances, in particular anti-restenosis agents. In the past, limus actives such as rapamycin (sirolimus) or taxanes such as paclitaxel have proven to be successful actives. The limus active substance binds reversibly to FKBP12 and inhibits cell division, whereas the taxane, such as paclitaxel, binds irreversibly to microtubules and also inhibits cell division.

"drug eluting stents" (DES) (active substance releasing stents) are known in the art, wherein it is necessary to control the healing of the relevant site by means of a suitable active substance, in addition to vasodilation and associated damage to the vessel wall.

Medical products that cannot be permanently retained in the body, such as biodegradable stents, are also known in the art. Biodegradable stents may additionally have an active coating to provide the benefit of long-term medical products. However, this approach is still under development.

Apart from stents, active substance release catheters, in particular balloon catheters, are also known in the prior art, which have the advantage of only being in short contact with the organism.

However, not only stents and catheters may be coated with active substances, the requirements for coating other medical products naturally vary depending on the field of application.

The requirements for active substance release coatings of catheters are particularly high, since the long-term, good dosing and as quantitative as possible of the active substance, which exceeds the very short residence time of the medical product, is a particular challenge, especially for medical products which are used very short, especially in the vascular region, wherein it must be ensured that on the one hand the active substance is not washed away prematurely on its way to the target site, or is broken up, for example during expansion, and that only an indefinite or insufficient amount of active substance reaches the vascular wall. On the other hand, in the case of coronary "drug coated balloons" (DCB) (active substance coated balloons) as a medical product for short use, a very limited contact time of up to 90 seconds must also be sufficient for the transfer of the active substance from the balloon catheter onto or into the vessel wall in the desired dosage. The peripheral vascular system, for example in the leg arteries, allows for longer contact times of about 120 seconds or more, with an upper limit of contact time in the peripheral blood vessel of up to 5 minutes in superficial femoral artery Arteria Femoralis Superficialis (AFS), depending on the blood vessel being treated.

In the prior art, some active substance coatings of catheter balloons are known, which circumvent these problems by using further adjuvants in the coating to accelerate drug release or to increase the stability of the coating (see WO2010/121840A2, WO 2013/007553 A1, WO2012/146681 A1).

In particular in the case of catheter balloons coated with a limus compound, another reason for low efficacy, besides low active substance transfer, is the short residence time of the limus compound in the vessel wall.

It is known from the prior art that crystals of limus active substance exhibit slower dissolution behaviour than amorphous particles of limus. Thus, a higher concentration of active substance in the vessel wall was observed after one month of treatment with the catheter balloon coated with crystalline limus active substance compared to treatment with the catheter balloon coated with amorphous active substance (Clever et al, circ. Cardiovic. Inter. 2016,9,1-11; e 003543).

Thus, it is desirable to have a coating of crystalline limus active substance to ensure an extended residence time of the limus active substance in the vessel wall. However, the use of crystalline balloon coatings has the risk of embolization (WO 2011/147408 A2), so in the prior art amorphous coatings are still preferred for catheter balloons.

Application of the limus crystals to the tissue to be treated by balloon dilation has the following advantages: the crystals act as a reservoir for the active substance and delay the release of the active substance, whereas for amorphous active substances, release is immediate after expansion. However, it has been shown that coating with crystals of limus directly or with a suspension of pure limus active substance containing crystals has the particular disadvantage that the crystals of limus do not adhere sufficiently to the surface of the medical product. Another problem is that suspensions of particles greater than 1-5 μm tend to precipitate rapidly, which then makes it more difficult to uniformly coat the microcrystalline limus active substance from the suspension.

Active substance coatings with crystalline limus active substances for catheter balloons are known in the art, which attempt to avoid these problems. However, prior art methods for coating catheter balloons with crystalline limus compounds are expensive and complex.

International patent application WO2013/022458A1 discloses a method for converting amorphous Everolimus (Everolimus) into its crystalline form by aging a supersaturated solution (suspension) for several days. Here, the characteristic that the solubility of crystals is lower than that of amorphous forms is utilized.

In the prior art, suspensions of limus crystals are mainly proposed, wherein the size of the limus crystals is in the order of nanometers smaller than 1 μm. However, crystals of this size have the disadvantage of not being able to adequately ensure the prolonged residence time required for the limus active substance in the vessel wall.

International patent application WO2015/039969A1 discloses a method of coating a balloon catheter with crystalline limus active substance. The crystalline limus active substance is prepared in advance and applied as a suspension to the balloon catheter, or crystallization is induced on the balloon by a seed crystal. However, crystallization on the surface has the following disadvantages: in addition to crystallization, a precipitation process occurs which results in amorphous particles or agglomerates of 100-300 μm in size, which cannot be dispersed by sonication. Such agglomerates with a size greater than 100 μm are at risk of causing a vascular occlusion distal to the expansion site during expansion, and thus may pose a considerable risk to the patient. It is therefore particularly desirable to keep the number of such amorphous particles or agglomerates as low as possible.

By coating the catheter balloon with a solution consisting of a solvent and a limus active substance, and by sputtering the limus crystals onto the balloon surface, then optionally enhancing adhesion by "solvent bonding" and by crystallization of the dissolved limus active substance from a solution of the limus active substance in a solvent and a non-solvent, a sufficiently strong, repeatable coating of the catheter balloon with the limus crystals, which exhibits sufficient active substance transfer upon expansion, cannot be obtained.

The object of the present invention is to provide a coating formulation and a coated medical product, wherein the coating is flexible, adheres very well to the surface of the medical product, has an optimal size distribution of the active substance particles, and releases the active substance as quantitatively as possible even in a very short residence time in the body, after which the active substance can diffuse from the vessel wall into the cells over a much longer period of time.

In other words, the object of the present invention is to provide a composition for coating medical products for short-term and long-term use, which adheres as a coating to the surface of the medical product in a stable but flexible manner and, on the other hand, ensures as complete and controlled as possible transfer of the active substance to the vessel wall or tissue in order to optimally support the healing process.

In particular, it is an object of the present invention to provide a coating of a catheter balloon with a crystalline limus compound, wherein the coating adheres to the surface of the catheter balloon in a stable but flexible manner and, on the other hand, ensures as complete and controlled as possible the transfer of the active substance to the vessel wall or tissue during expansion in order to optimally support the healing process.

This object is solved by the technical teaching of the independent claims of the present invention. Further advantageous embodiments of the invention emerge from the dependent claims, the description, the figures and the examples.

Summary of The Invention

Surprisingly, it has been found that a suspension for coating medical products, in particular catheter balloons, balloon catheters, stents and cannulas, comprising a) at least one tri-O-acylglycerol selected from the group consisting of trioctanoylglycerol, trinonoylglycerol, tridecanoylglycerol and triundecanoylglycerol, and b) at least one limus active substance in microcrystalline form, and c) a solvent or a solvent mixture, in which the at least one tri-O-acylglycerol is dissolved and in which the crystallites of the at least one limus active substance are not dissolved or in which the crystallites of the at least one limus active substance are not dissolved when present.

It has now been found that if at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol is present in dissolved form in said suspension, it is possible to provide a particularly advantageous crystalline suspension of microcrystalline limus active substance for coating a medical product, wherein the crystallites of limus active substance are insoluble.

With these tri-O-acylglycerols according to the present invention, it is surprisingly possible to prepare a stable suspension of such microcrystalline limus active substance such that the crystallites of the limus active substance remain "floating" and therefore do not precipitate. This is particularly surprising because suspensions of crystals in the micrometer range, i.e. crystals larger than 1-5 μm, tend to precipitate. The crystalline suspension of the invention is therefore particularly advantageous for preparing a uniform coating of microcrystals of a limus active substance on a medical product.

Another particular advantage of using at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol is that the tri-O-acylglycerol according to the invention is able to retain the crystallites of the limus active substance on the surface of the medical product, as a "flexible binder". The crystalline suspension according to the invention is therefore particularly advantageous for preparing a uniform coating of microcrystals of a limus active substance on a medical product, wherein the microcrystals of a limus active substance also adhere well to the surface of the medical product.

The preparation of the crystal suspensions according to the invention is not possible using other prior art tri-O-acylglycerols which are not according to the invention. It has been shown that the tri-O-acylglycerols not according to the invention cause or promote the dissolution of the microcrystals of the limus active substance in suspension. Furthermore, precipitation of microcrystals of the limus active substance occurs in the case of tri-O-acylglycerols which are not according to the invention.

Furthermore, with other prior art tri-O-acylglycerols not according to the present invention, a uniform coating of the micro-crystals of the active substance of the limus on the medical product could not be produced, in particular insufficient adhesion of the micro-crystals of the active substance of the limus on the surface of the medical product was observed. It has been shown that tri-O-acylglycerols which are not the present invention do not sufficiently "adhere" and retain the microcrystals of the limus active substance on the surface of the medical product.

Thus, only with the use of tri-O-acylglycerols selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol or mixtures of these tri-O-acylglycerols can a crystalline suspension of the microcrystalline limus active substance of the present invention be prepared, wherein the crystallites of the limus active substance remain intact. Another particular advantage is that the crystallites of the at least one limus active substance are floating in the suspension and thus uniformly distributed in the suspension, so that the limus active substance can be applied not only in microcrystalline form but also uniformly on the surface of the medical product.

The medical product which has been coated with the suspension according to the invention has a coating of at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol and crystallites of said at least one limus active substance on the surface of the medical product. The coating is mainly characterized by very good flexibility and excellent adhesion to the surface of the medical product. Furthermore, the coating provides advantageous properties: even in the case of very short residence times in the body, the crystallites of the at least one limus active substance can be released quantitatively, which can then diffuse from the vessel wall into the cells over a longer period of time than the particles of amorphous limus active substance.

The coating according to the invention may be provided on any medical product, preferably herein a catheter balloon, balloon catheter, stent or cannula, particularly preferably a catheter balloon. The amount of limus active and the delivery rate or elution rate of the limus active may vary depending on the desired specifications at the surgical site, while at least one tri-O-acylglycerol selected from trioctanoyl glycerol, trinonoyl glycerol, tridecanoyl glycerol and triundecyl glycerol on the one hand supports optimal transfer of the microcrystalline limus active into the tissue while ensuring high flexibility and stability of the coating, thereby ensuring that the microcrystalline limus active actually reaches the surrounding tissue in optimal concentration without loss.

The very good flexibility and adhesion of the coating according to the invention is particularly important for medical products (e.g. stents and catheter balloons) that have to undergo shape changes. For example, inflation, deflation, folding and crimping place special stability demands on the coating that is also exposed to friction and body fluids and flow during implantation. Setting the desired elution rate of the micro-crystalline limus active substance and the optimal transfer amount of the micro-crystalline limus active substance into the tissue can also be solved with the catheter balloon coating (DCB) according to the invention. Other requirements to be considered for the coating according to the invention to meet without damage relate to sterilization, storage capacity, minimum shelf life, temperature resistance etc. of the medical product.

Thus, the coating on the medical product of the present invention solves an important task that is posed for medical products for use in vivo in both long and short periods of time.

Detailed Description

The present invention relates to a suspension for coating medical products, preferably catheter balloons, balloon catheters, stents and cannulas, said suspension comprising:

a) At least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, and

b) At least one active substance of limus in microcrystalline form, and

c) A solvent or solvent mixture in which the at least one tri-O-acylglycerol is dissolved and in which the crystallites of the at least one limus active substance are not dissolved.

The key to the present invention is the use of a microcrystalline limus active substance and the presence of a microcrystalline limus active substance suspension, wherein the suspension must contain at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol.

The term "coating formulation" or "active agent-containing composition" as used herein refers to a mixture, i.e., a solution, dispersion, suspension or emulsion, of at least one limus active agent and a solvent or solvent mixture and at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol. The term "formulation" is intended to mean that it is a liquid mixture (suspension, emulsion, dispersion, solution). Thus, the term "coating formulation" as used herein represents the generic term of the terms "solution" or "coating solution", "dispersion" or "coating dispersion", "suspension" or "coating suspension" and "emulsion" or "coating emulsion".

The term "solution" or "coating solution" as used herein generally refers to a homogeneous mixture of two or more chemically pure substances. The solutions themselves are not externally identifiable in that by definition they form only a single phase and the dissolved species are uniformly distributed in the solvent.

The term "dispersion" or "coating dispersion" as used herein generally refers to a heterogeneous mixture of at least two substances that are insoluble or hardly soluble or chemically bound to each other. In this case, one or more substances are finely dispersed as a dispersed phase in another continuous substance (so-called dispersion medium).

The term "emulsion" or "coating emulsion" as used herein generally refers to a finely distributed mixture of two generally immiscible liquids, with no visible separation. One liquid forms small droplets that are dispersed in another liquid. Emulsions are a particular form of dispersion.

The term "suspension" or "coating suspension" as used herein generally refers to a heterogeneous mixture of substances consisting of finely divided solids in a liquid. Thus, by definition, a "suspension" is not a homogeneous mixture and is therefore not a solution. Suspensions are a particular form of dispersion.

A "suspension" containing at least one active substance of the limus in microcrystalline form is also referred to herein as "crystalline suspension". According to the invention, the finely divided solid of the suspension herein is at least one microcrystalline limus active substance or at least one microcrystalline limus active substance. The liquid of the suspension herein is a solvent or solvent mixture in which at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol is present in dissolved form in the solvent or solvent mixture.

Thus, the "suspension" according to the invention relates to a heterogeneous mixture of substances containing at least one liquid of tri-O-acylglycerols selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol and solids finely distributed in the liquid, i.e. crystallites of at least one limus active substance. Thus, according to the present invention, the microcrystalline limus active substance is suspended in a liquid containing at least one dissolved tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol.

The suspension according to the invention is characterized in that neither precipitation nor dissolution of the crystallites of the at least one limus active substance takes place in the suspension. The suspension according to the invention is also referred to herein as "stable suspension".

The suspension according to the invention may consist of a solvent or solvent mixture and microcrystalline limus active substance and at least one dissolved tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol. However, the suspension may contain up to 5.0 wt.% of other additives based on the active substance of the limus, i.e. for 95g of active substance of the limus, up to 5g of additives may be contained in the suspension. The amount of antioxidant may be up to 15% by weight only in the case of antioxidant as additive, but the amount of antioxidant and all other additives may still not exceed 15% by weight, i.e. up to 15g of antioxidant may be contained in suspension for 85g of limus active substance. Thus, if 15 wt% of antioxidant is contained in the suspension, no other additives may be present. On the other hand, if 10 wt.% of antioxidant is contained in the suspension, other additives may also be contained up to 5.0 wt.%.

The invention therefore also relates to a suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, consisting of:

b) At least one active substance of limus in microcrystalline form, and

c) A solvent or solvent mixture in which said at least one tri-O-acylglycerol is dissolved and in which said microcrystals of at least one limus active substance are insoluble in the presence of at least one tri-O-acylglycerol, and

d) Up to 5.0 wt% of an additive based on Yu Limo s active, or up to 15.0 wt% of an antioxidant based on limus active as an additive and up to 5 wt% of a non-antioxidant additive based on Yu Limo s active, wherein the total amount of additives does not exceed 15 wt% based on limus active.

Suitable additives are those described below, preferably antioxidants, polyvinylpyrrolidone (PVP) and flocculation inhibitors.

The antioxidant and preferably BHT are preferably contained in the suspension in an amount of up to 12.0 wt% based on Yu Limo s active, more preferably up to 10.0 wt% based on limus active, more preferably up to 9.0 wt% based on limus active, more preferably up to 8.0 wt% based on limus active, and more preferably up to 7.0 wt% based on limus active. Other additives, such as PVP or flocculation inhibitors, which are not antioxidants, may preferably be included in an amount of up to 4 wt.%, based on Yu Limo s active, preferably up to 3.0 wt.%, based on limus active, further preferably up to 2.5 wt.%, based on limus active, further preferably up to 2.0 wt.%, based on limus active, further preferably up to 1.5 wt.% based on limus active and further preferably up to 1.0 wt.% based on limus active.

The term "tri-O-acylglycerol" or simply "triacylglycerol" as used herein refers to glycerol (glycon) compounds esterified with three fatty acids, i.e., tri-esterified glycerol (glycon). Triglycerides or triglycerides are synonyms for tri-O-acylglycerols, the name tri-O-acylglycerols conforming to IUPAC recommendations.

The tri-O-acylglycerols have the following general formula (I):

wherein R is ¹ 、R ² And R is ³ Represents an alkyl or alkenyl residue. Tri-O-acylglycerolsIs diverse in structure because of R ¹ 、R ² And R is ³ Allowing for a number of different fatty acids and thus a large number of possible combinations. All of these are nonpolar, i.e. lipophilic. In the case of tri-O-acylglycerols, a further distinction can be made between medium-and long-chain tri-O-acylglycerols. Medium-chain tri-O-acylglycerols have fatty acids with an average length of 6 to 12 carbon atoms, whereas long-chain tri-O-acylglycerols have fatty acids with a length of 14 to 24 carbon atoms. Here, two types of tri-O-acylglycerols can occur: simple and mixed tri-O-acylglycerols. In simple tri-O-acylglycerols, the fatty acid residue R ¹ 、R ² And R is ³ Are identical; in the mixed tri-O-acylglycerols, the fatty acid residue R ¹ 、R ² And R is ³ At least one of which is different from the other two. Examples of medium length fatty acids are caproic acid (caproic acid), enanthic acid (enanthic acid), caprylic acid (caprylic acid), pelargonic acid (pelargonic acid), capric acid (capric acid), undecanoic acid and lauric acid (lauric acid).

It has been unexpectedly shown that the chemical, physical and biological properties of tri-O-acylglycerols fully esterified with the medium length fatty acids octanoic acid (octanoic acid), decanoic acid (decanoic acid), nonanoic acid (nonanoic acid) or undecanoic acid mainly enable a uniform and well-adhering coating of medical products with microcrystalline limus actives. Furthermore, the crystal suspensions according to the invention can be prepared only with glycerol fully esterified with caprylic acid (caprylic acid), capric acid (capric acid), pelargonic acid (pelargonic acid) or undecanoic acid.

Thus, preferred tri-O-acylglycerols herein have the following general formula (I):

wherein R is ¹ 、R ² And R is ³ Independently of one another selected from-CH ₂ (CH ₂ ) ₅ CH ₃ 、-CH ₂ (CH ₂ ) ₆ CH ₃ 、-CH ₂ (CH ₂ ) ₇ CH ₃ and-CH ₂ (CH ₂ ) ₈ CH ₃ 。

It has been shown that use is made of a composition wherein R ¹ 、R ² And R is ³ Independently selected from-CH ₂ (CH ₂ ) ₅ CH ₃ 、-CH ₂ (CH ₂ ) ₆ CH ₃ 、-CH ₂ (CH ₂ ) ₇ CH ₃ and-CH ₂ (CH ₂ ) ₈ CH ₃ And wherein not all three R' s ¹ 、R ² And R is ³ The same mixed tri-O-acylglycerols can also be used to prepare stable crystalline suspensions of microcrystalline limus active substances. However, these mixed tri-O-acylglycerols are more costly to prepare and are not cost effective, and therefore they are not preferred herein.

Thus, according to the invention, all three residues R ¹ 、R ² And R is ³ Is identical, i.e. R ¹ 、R ² And R is ³ is-CH ₂ (CH ₂ ) ₅ CH ₃ Or R is ¹ 、R ² And R is ³ is-CH ₂ (CH ₂ ) ₆ CH ₃ Or R is ¹ 、R ² And R is ³ is-CH ₂ (CH ₂ ) ₇ CH ₃ Or R is ¹ 、R ² And R is ³ is-CH ₂ (CH ₂ ) ₈ CH ₃ 。

In an attempt to prepare a crystalline suspension containing tri-O-acylglycerols which are fully esterified with other medium length fatty acids than those described above, in particular with shorter medium length fatty acids such as caproic acid (tricarboxylic acid) and shorter monocarboxylic acids such as acetic acid (triacetin), it is not possible to prepare a crystalline suspension according to the invention because dissolution of the limus active substance crystallites in the suspension takes place or is promoted in the presence of these non-inventive tri-O-acylglycerols. Dissolution of the microcrystals of the limus active substance in suspension also occurs in the case of glycerol such as mono-O-acylglycerol or di-O-acylglycerol, which is only partially esterified with medium length fatty acids. In addition, sedimentation of the microcrystals of the limus active substance occurs in those cases of tri-O-acylglycerols which are not according to the invention.

In the complete absence of tri-O-acylglycerols in suspension, the crystallites of at least one of the limus active substances rapidly settle. It is not possible to prepare stable suspensions.

Thus, the presence of dissolved at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol in the suspension is essential for the crystal suspension according to the invention.

Thus, it has been shown that glycerol fully esterified with three octanoic acid molecules, glycerol fully esterified with three decanoic acid molecules, glycerol fully esterified with three nonanoic acid molecules or glycerol fully esterified with three undecanoic acids, i.e. at least one tri-O-acyl glycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, does not partly dissolve or does not dissolve the microcrystalline limus active substance in suspension.

Thus, using the tri-O-acylglycerols according to the present invention, it is possible to provide a crystalline suspension as a coating formulation in which the crystallites of the limus active substance remain intact, float in the suspension and are uniformly distributed in the suspension, and no sedimentation of the crystallites or agglomeration of the particles of the limus active substance occurs, so that the limus active substance can be uniformly applied to the surface of the medical product in the form of crystallites.

Another particular advantage of using at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol is that the tri-O-acylglycerols according to the invention are able to retain the micro-crystals of the limus active substance on the surface of the medical product like a "flexible adhesive" so that a sufficient adhesion of the micro-crystals of the limus active substance to the surface of the medical product can be provided.

The tri-O-acylglycerols selected from the group consisting of trioctacylglycerol, trinonacylglycerol, tridecylglycerol and tri (undecyl) glycerol or the mixtures of said tri-O-acylglycerols according to the invention have the following advantages: their melting point makes them safe for use in vivo. It has also been found that a melting point lower than 37 ℃ is necessary to ensure adequate adhesion of the microcrystals of the limus active substance to the surface of the medical product. Only tri-O-acylglycerols selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol or mixtures of said tri-O-acylglycerols according to the present invention can retain the microcrystalline limus active substance like a "binder", thereby ensuring optimal flexibility and loss-free transport to the target site. The next higher homolog, tris (dodecanoylglycerol), will have the disadvantage of melting at 45-46 ℃.

With the tri-O-acylglycerols, which are not according to the invention, fully esterified with the medium-length fatty acids or long-chain fatty acids (e.g. lauric, myristic or palmitic acid) not according to the invention as described above, it is not possible to provide a crystalline suspension according to the invention in which the crystallites of the limus active substance float in suspension and are homogeneously distributed in the suspension. When using a tri-O-acylglycerol other than the present invention, such as, for example, a tridecylglycerol, it is not possible to uniformly coat the surface of the medical product with the active substance of the limus in microcrystalline form. Catheter balloons coated with a coating of a microcrystalline form of the limus active substance and tri (dodecanoyl) glycerol clearly show a lack of uniform coating, a non-uniform surface and a coating that is easily broken during inflation.

In an attempt to coat a medical product with a suspension containing the microcrystals of the limus active substance and the non-inventive tri-O-acylglycerols in dissolved form in the suspension (which are fully esterified with the non-inventive medium-length fatty acids or long-chain fatty acids such as lauric acid, myristic acid or palmitic acid as described above), it is impossible to prepare a coating in which the microcrystals of the limus active substance are uniformly distributed on the surface of the medical product and sufficiently adhere to the surface of the medical product. For coatings with microcrystals of a limus active substance and a non-inventive tri-O-acyl glycerol (e.g. tridecylglycerol), a higher release of particles is observed in the "break-up test" compared to the microcrystals of a limus active substance and the coating of at least one tri-O-acyl glycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol. This comparison clearly shows that for the coating according to the invention of microcrystals with a limus active substance and of at least one tri-O-acylglycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol, the particle release of all the measured particle sizes is much lower than for the microcrystals with a limus active substance and of the coating of tri-O-acylglycerol (such as, for example, tridecyl glycerol) that is not according to the invention.

It has also surprisingly been shown that excellent adhesion of the microcrystals of a limus active substance to the surface of a medical product is achieved, in particular when the tri-O-acylglycerol according to the invention is present in dissolved form in a crystal suspension according to the invention and is applied to the surface of a medical product together with or simultaneously with microcrystals of at least one limus active substance suspended in the suspension.

This excellent adhesion of the micro-crystals of limus active substance to the surface of a medical product is not possible to be reproduced when the surface of the medical product is first coated with a solution containing at least one tri-O-acylglycerol according to the present invention and when the micro-crystals of limus active substance are subsequently applied to said tri-O-acylglycerol layer. When the surface of a medical product is first coated with crystals of a limus active substance according to the prior art method and then coated with a solution containing tri-O-acylglycerol in which the microcrystalline limus active substance is insoluble, no adequate adhesion of the limus active substance crystallites is found.

The lack of adhesion of the micro-crystalline limus active substance to the surface of the medical product has heretofore been the most significant disadvantage in the prior art of coating medical products with micro-crystalline limus active substances. The present invention overcomes this drawback and provides a solution for providing a coating with a microcrystalline limus active substance on the surface of a medical product.

In the suspension according to the invention, at least one tri-O-acylglycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol is advantageously present in dissolved form, so that when the medical product is coated with the suspension according to the invention, not only a coating is obtained in which the microcrystals of the active substance of limus are uniformly distributed, but also at least one tri-O-acylglycerol is uniformly distributed throughout the coating. This is particularly advantageous if the microcrystalline coating of the limus active substance has a greater layer thickness and wherein the suspension according to the invention is applied a plurality of times in succession. Thus, the tri-O-acylglycerols according to the present invention are uniformly distributed in such a coating and retain the crystallites of the limus active substance on the surface of the medical product as a "flexible binder", but also as a "flexible binder" to each other.

The suspension of the present invention thus provides the further advantage that the adhesion of the crystallites of the at least one limus active substance to each other is increased. If the microcrystals of the at least one limus active substance are first applied without tri-O-acylglycerol dissolved in suspension and are coated with a tri-O-acylglycerol solution in a subsequent step, the tri-O-acylglycerol does not sufficiently penetrate under and between the microcrystals of the limus active substance and thus does not sufficiently exert the technical effect of increasing the adhesion on the surface of the medical product and between the microcrystals of the at least one limus active substance.

The problem of poor adhesion of the microcrystals of a limus active substance to the surface of a medical product is now surprisingly solved by providing a suspension according to the invention comprising dissolved at least one tri-O-acylglycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol and at least one limus active substance in microcrystalline form.

Coating of medical products with a microcrystalline limus active substance in the presence of at least one tri-O-acylglycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol also shows a significantly reduced "crushing behaviour" compared to the medical products currently on the market, since they show a significantly reduced release of particles compared to the medical products currently available on the market, in particular in the field of active substance delivery balloon catheters, thus demonstrating that the stability of the coating of the invention is likewise increased. This is especially due to the advantage that at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol holds the micro crystals of the limus active substance, such as a "flexible binder", firmly on the surface of the medical product, resulting in a stable, non-brittle and flexible coating.

It has furthermore been shown that tri-O-acylglycerols selected from the group consisting of trioctylglycerol, trionoylglycerol, tridecanoylglycerol and trioundecyl glycerol or mixtures of said tri-O-acylglycerols have other advantages. In particular, they enable optimal transfer of the microcrystalline limus active substance into the tissue. The coating prepared with the suspension according to the invention has a smoother, uniform surface and a uniform distribution of the microcrystals of the limus active substance on the medical surface, compared to the case of the known coated medical products available on the market. Thus, these advantageous properties of at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol lead to an optimal transfer and elution of the active substance into the tissue, as well as an optimal distribution of the active substance at the implantation site.

Thus, the tri-O-acylglycerols or mixtures of these tri-O-acylglycerols selected from the group consisting of trioctacylglycerol, trinonacylglycerol, tridecylglycerol and triundecanoyl glycerol, which are critical for the present invention, particularly fulfil the following important tasks: they are carriers of the microcrystalline limus active substance and thus affect the mechanical properties of the coating ("drug carrier"), such as adhesion to the surface of the medical product, ensuring the lowest possible loss of microcrystalline limus active substance ("drug delivery loss") during implantation, but also affect the particle size distribution of the coating and thus the "crushing behaviour" ("particle release"), thus indicating the brittleness or plasticity and conformability of the coating and the associated shape changes before and during implantation. The uniformity of the coating ("uniformity") is considered another important parameter, since a uniform coating can also achieve a uniform distribution of the active substance of the micro-crystalline limus active substance on the surface of the medical product and therefore also in the surrounding tissues. In addition, as "catalysts", they accelerate or promote the transfer of the active substance of the microcrystalline limus active substance into the surrounding tissue without altering the microcrystalline limus active substance and affecting its efficacy ("drug transfer promoting agent").

Thus, the tri-O-acylglycerols according to the invention or the mixture of said tri-O-acylglycerols selected from the group consisting of trioctanoylglycerols, trionoylglycerols, tridecanoylglycerols and trioundecanoylglycerols are particularly advantageous for coating medical products with the limus active substance crystallites, because the resulting coating adheres to the surface of the medical product without loss, undergoes a change in the shape of the substrate, such as elongation, and is free from problems and does not prematurely separate or even dissolve, without prematurely "losing" the embedded or applied at least one microcrystalline limus active substance, but the crystallites of the at least one limus active substance can be released in situ to the intended location without problems. Even in the case of severe shape changes, for example due to folding, inflation and deflation of such coated balloon catheters, the coating is not subject to any damage.

The object of the present invention is thus solved by a suspension according to the invention containing at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol in dissolved form, sufficient active substance adhesion and active substance release of the microcrystalline limus active substance.

As used herein, the term "trioctylglycerol" or "tri-O-octanoyl glycerol" refers to a tri-O-acyl glycerol in which the glycerol is fully esterified with octanoic acid. The synonymous names of trioctyl glycerol known in the prior art are trioctyl glyceride, glycerol trioctanoate, trioctanoyl glycerol, capryl-1, 1',1"- (1, 2, 3-trioyl) ester, glycerol trioctanoate, trioctanoyl glycerol, TG (8:0/8:0/8:0), glycerol trioctanoate, capryl-1, 2, 3-trioyl ester, capryl glycerol, capryl triglyceride, trioctanoyl glycerol ester, trioctanoyl glycerol, capryl-1, 2, 3-trioctyl ester, glycerol trioctanoate, capryl triglyceride, trioctanoyl glycerol, 1,2, 3-trioctanoyl glycerol, glycerol trioctanoate and 1,2, 3-trioctanoyl glycerol. Trioctanoylglycerol has a CAS number of 538-23-8, a molecular weight of 470.68g/mol, and has the following structural formula:

octanoic acid is a carboxylic acid known under the common name octanoic acid and is a saturated fatty acid having the structural formula:

in a preferred embodiment of the invention, the suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprises at least trioctylglycerol. Thus, in a preferred embodiment of the present invention, the at least one tri-O-acylglycerol is preferably selected from trioctylglycerols.

The melting point of trioctylglycerol is in the range of 9-10deg.C. Trioctylglycerol is present under normal conditions (20 ℃,101 hPa) as a clear colorless to amber liquid without taste. Trioctylglycerol is hardly soluble in water.

The term "trisnonoyl glycerol" or "tri-O-nonoyl glycerol" as used herein refers to a tri-O-acyl glycerol in which glycerol is fully esterified with pelargonic acid. Synonymous names of trisnonoyl glycerol known in the prior art are glycerol trisnonoate, 1,2, 3-trisnonoyl glycerol, tripalmitin, 1,2, 3-trisnonoyl glycerol. Trinoneoyl glycerol has a CAS number of 126-53-4, a molecular weight of 512.76g/mol, and the following structural formula:

pelargonic acid is a carboxylic acid known under the common name pelargonic acid and is a saturated fatty acid having the following structural formula:

in a preferred embodiment of the invention, the suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprises at least trisnonoyl glycerol. Thus, in a preferred embodiment of the invention, the at least one tri-O-acylglycerol is preferably selected from the group consisting of trisnonoyl glycerols.

The melting point of the trisnonoyl glycerol is 8-9 ℃. Trinonecylglycerol is present as a liquid under normal conditions (20 ℃,101 hPa). Trinonecylglycerol is hardly soluble in water.

The term "tridecylglycerol" or "tri-O-decylglycerol" as used herein refers to tri-O-acylglycerols in which glycerol is fully esterified with decanoic acid. Synonymous names of tridecyl glycerols known in the prior art are glycerol tri- (decanoate), 1,2, 3-tridecanoyl glycerol, 1,2, 3-tridecanoyl glycerol, glycerol tridecanoate, and tridecanoyl glycerol. The tridecyl glycerol has a CAS number of 621-71-6, a molecular weight of 554.84g/mol and a structural formula as follows:

capric acid is a carboxylic acid known under the common name capric acid and is a saturated fatty acid having the structural formula:

in a preferred embodiment of the invention, the suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprises at least tridecyl glycerol. Thus, in a preferred embodiment of the invention, the at least one tri-O-acylglycerol is preferably selected from the group consisting of tridecylglycerols.

The melting point of tridecyl glycerol is in the range of 31-33 ℃. Tridecyl glycerol exists as a pale yellow solid under normal conditions (20 ℃,101 hPa). Tridecyl glycerol is practically insoluble in water.

The term "tri (undecyl) glycerol" or "tri-O-undecyl glycerol" as used herein refers to tri-O-acyl glycerols in which glycerol is fully esterified with undecanoic acid. Synonymous names of tri (undecyl) glycerol known in the prior art are glycerol triundecanoate, glycerol triacontanoate, 1,2, 3-tri (undecyl) glycerol, glycerol triundecanoate. IUPAC name is 1, 3-bis (undecyloxy) propan-2-yl-undecanoate. Triundecyl glycerol has a CAS number of 13552-80-2, a molecular weight of 596.9g/mol, and the following structural formula:

Undecanoic acid is a saturated fatty acid having the following structural formula:

in a preferred embodiment of the invention, the suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprises at least tri (undecyl) glycerol. Thus, in a preferred embodiment of the invention, the at least one tri-O-acylglycerol is preferably selected from the group consisting of tri (undecyl) glycerol.

The melting point of the tri (undecyl) glycerol is in the range of 30-32 ℃. Triundecyl glycerol is present as a solid under normal conditions (20 ℃,101 hPa). Triundecyl glycerol is hardly soluble in water.

Thus, the suspension of the invention for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, contains at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol according to the invention.

In other words, according to the invention, the suspension according to the invention for coating a medical device, preferably selected from a catheter balloon, a balloon catheter, a stent or a cannula, contains at least one tri-O-acylglycerol selected from the group consisting of tri-O-octanoylglycerol, tri-O-nonanoylglycerol, tri-O-decanoylglycerol and tri-O-undecanoylglycerol.

In other words, according to the invention, the suspension of the invention for coating a medical product, preferably selected from a catheter balloon, a balloon catheter, a stent or a cannula, contains tri-O-acylglycerols selected from trioctacylglycerols, trinonacylglycerols, tridecanoylglycerols and tri (undecanoyl) glycerols, or a mixture of at least two tri-O-acylglycerols selected from trioctacylglycerols, trinonacylglycerols, tridecanoylglycerols and tri (undecanoyl) glycerols.

In other words, according to the invention, the suspension according to the invention for coating a medical product, preferably selected from a catheter balloon, a balloon catheter, a stent or a cannula, contains tri-O-acylglycerols selected from trioctacylglycerols, trinonacylglycerols, tridecanoylglycerols and tri (undecanoyl) glycerols, or a mixture of two, three or four tri-O-acylglycerols selected from trioctacylglycerols, trinonacylglycerols, tridecanoylglycerols and tri (undecanoyl) glycerols.

Thus, the phrase "at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol" also refers herein to a mixture of tri-O-acylglycerols selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol. Thus, the phrase "at least one tri-O-acylglycerol" includes expressions such as "at least two tri-O-acylglycerols", "at least three tri-O-acylglycerols", "two tri-O-acylglycerols", "three tri-O-acylglycerols" and "four tri-O-acylglycerols".

In some embodiments of the invention, the suspension for coating a medical product (preferably selected from the group consisting of catheter balloons, balloon catheters, stents or catheters) contains at least two tri-O-acylglycerols selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol.

In some embodiments of the invention, the suspension for coating a medical product (preferably selected from the group consisting of catheter balloons, balloon catheters, stents or catheters) contains at least three tri-O-acylglycerols selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol.

In some embodiments of the invention, the suspension used to coat the medical product (preferably selected from the group consisting of catheter balloons, balloon catheters, stents or cannulas) contains trioctyl glycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol.

The tri-O-acylglycerols selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol according to the invention have a melting point below 37 ℃ such that they are present in molten form at body temperature or melt or soften at body temperature.

In some embodiments of the invention, it is preferred to use tri-O-acylglycerols, such as trioctylglycerol or trionoyl glycerol, particularly preferably trioctylglycerol, which are present in liquid form under normal conditions (20 ℃ C., 101 hPa) for the preparation of the suspensions according to the invention. In particular, excellent stable, non-brittle and flexible coatings can be obtained using trioctanoyl glycerol. In some embodiments, mixtures of trioctyl glycerol, trionoyl glycerol, tridecyl glycerol and trioundecyl glycerol are also preferred, which contain at least trioctyl glycerol and/or trionoyl glycerol, with trioctyl glycerol being particularly preferred, since the resulting mixture is present as a liquid under normal conditions (20 ℃,101 hPa). Particularly preferred mixtures of tri-O-acylglycerols herein are mixtures of trioctanoylglycerols and tridecanoylglycerols.

In some further embodiments of the invention, it is preferred to use tri-O-acylglycerols, such as tridecylglycerol or tri (undecyl) glycerol, which are present as solids under normal conditions (20 ℃,101 hPa), for preparing the suspension according to the invention. In particular, with tridecyl glycerol, excellent stable, nonfriable and flexible coatings can be obtained. Since body temperature is still above the melting point of these tri-O-acylglycerols, the tridecyl glycerol or tri (undecyl) glycerol is present in molten form at body temperature during implantation, so that there are no disadvantages in terms of particle release and friability, especially during inflation of medical products such as catheter balloons or stents, compared to tri-O-acylglycerols (e.g. trioctylglycerol or trinonyl glycerol) which are present in liquid form under normal conditions (20 ℃,101 hPa). Furthermore, if needed or desired, the coated medical product may also be heated prior to implantation such that the tridecyl or tri (undecyl) glycerol has melted or softened prior to implantation and thus is already in molten form at the beginning of implantation.

In some preferred embodiments of the invention, the suspension for coating a medical product, preferably selected from the group consisting of catheter balloons, balloon catheters, stents or catheters, thus contains at least one tri-O-acyl glycerol selected from the group consisting of trioctylglycerol, trioonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, more preferably at least one tri-O-acyl glycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol and tridecyl glycerol, still more preferably at least one tri-O-acyl glycerol selected from the group consisting of trioctylglycerol or at least one tri-O-acyl glycerol selected from the group consisting of tridecyl glycerol.

In some further preferred embodiments of the invention, the suspension for coating a medical product, preferably selected from the group consisting of catheter balloons, balloon catheters, stents or cannulas, contains a mixture of tri-O-acylglycerols selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol. In some of these preferred embodiments, the suspension for coating a medical product (preferably selected from a catheter balloon, balloon catheter, stent or cannula) contains trioctanoyl glycerol, a mixture of trionoyl glycerol and trioctanoyl glycerol, or a mixture of trioctanoyl glycerol and trioundecyl glycerol, or a mixture of trioctanoyl glycerol, trioctanoyl glycerol and trioctanoyl glycerol, further preferably a mixture of trioctanoyl glycerol, trioctanoyl glycerol and trioctanoyl glycerol, or a mixture of trioctanoyl glycerol, trioctanoyl glycerol and trioctanoyl glycerol, still more preferably a mixture of trioctanoyl glycerol, trioctanoyl glycerol and trioctanoyl glycerol.

In some preferred embodiments, the suspension for coating a medical product (preferably selected from catheter balloons, balloon catheters, stents or catheters) contains a mixture of trioctanoyl glycerol and tridecanoyl glycerol, or a mixture of trioctanoyl glycerol and trinonoyl glycerol, or a mixture of trinonoyl glycerol and trinonoyl glycerol.

In some preferred embodiments of the invention, the suspension for coating a medical product (preferably selected from a catheter balloon, balloon catheter, stent or cannula) contains a mixture of tridecyl glycerol and trinonyl glycerol, or a mixture of tridecyl glycerol and trinonyl glycerol, further preferably a mixture of tridecyl glycerol and trinonyl glycerol, or a mixture of tridecyl glycerol and trioctyl glycerol, most preferably a mixture of tridecyl glycerol and trioctyl glycerol.

In some preferred embodiments of the invention, the suspension for coating a medical product (preferably selected from a catheter balloon, balloon catheter, stent or cannula) contains a mixture of trioctyl glycerol and trionoyl glycerol, or a mixture of trioctyl glycerol and trioundecyl glycerol, or a mixture of trioctyl glycerol and trionoyl glycerol, further preferably a mixture of trioctyl glycerol and trionoyl glycerol, or a mixture of trioctyl glycerol and trionoyl glycerol, most preferably a mixture of trioctyl glycerol and trionoyl glycerol.

In a most preferred embodiment of the invention, the suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, contains at least one tri-O-acyl glycerol selected from trioctylglycerol and tridecyl glycerol, or a mixture of trioctylglycerol and tridecyl glycerol.

In some preferred embodiments of the invention, the suspension for coating a medical product (preferably selected from catheter balloons, balloon catheters, stents or catheters) contains at least one tri-O-acyl glycerol selected from trioctylglycerol, or a mixture of trioctylglycerol and at least one tri-O-acyl glycerol selected from trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, preferably trinonyl glycerol and tridecyl glycerol, even more preferably tridecyl glycerol.

In some preferred embodiments of the invention, the suspension for coating a medical product (preferably selected from catheter balloons, balloon catheters, stents or catheters) contains trioctanoyl glycerol, or a mixture of trioctanoyl glycerol and at least one further tri-O-acyl glycerol selected from trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, preferably trinonyl glycerol and tridecyl glycerol, even more preferably tridecyl glycerol.

In some preferred embodiments of the invention, the suspension for coating a medical product (preferably selected from catheter balloons, balloon catheters, stents or catheters) contains at least one tri-O-acyl glycerol selected from tridecyl glycerol, or a mixture of tridecyl glycerol and at least one further tri-O-acyl glycerol selected from trisnonoyl glycerol, trioctyl glycerol and tris (undecyl) glycerol, preferably trisnonoyl glycerol and trioctyl glycerol, even more preferably trioctyl glycerol.

In some preferred embodiments of the invention, the suspension for coating a medical product (preferably selected from catheter balloons, balloon catheters, stents or cannulas) contains tridecyl glycerol or a mixture of tridecyl glycerol and at least one further tri-O-acyl glycerol selected from the group consisting of trisnonoyl glycerol, trioctyl glycerol and tri (undecyl) glycerol, preferably trisnonoyl glycerol and trioctyl glycerol, even more preferably trioctyl glycerol.

The at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol preferably has a purity of at least 90%, preferably 95% and more preferably 99%. The mixture of tri-O-acylglycerols selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol preferably consists of at least 90%, preferably 95%, more preferably 99% of the tri-O-acylglycerols selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol.

It is particularly preferred that the suspension according to the invention does not contain any other tri-O-acylglycerols other than at least one tri-O-acylglycerol selected from the group consisting of trioctacylglycerol, trinonacylglycerol, tridecanoyl glycerol and triundecyl glycerol.

For example, trioctylglycerol and tridecylglycerol are also present as natural ingredients in various vegetable oils such as soybean oil, olive oil or coconut shell oil or animal oils. However, these natural vegetable or animal oils also contain other saturated and unsaturated tri-O-acylglycerols or other substances such as mono-O-acylglycerols, di-O-acylglycerols, fatty acids and lipids in various proportions which are not according to the invention, making the natural vegetable or animal oils unsuitable for producing the crystal suspensions according to the invention. Vegetable or animal oils can be used for the preparation of the crystal suspensions according to the invention, provided that they consist of at least more than 90%, preferably more than 95%, particularly preferably more than 99%, of at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol.

Thus, the mixture of tri-O-acylglycerols not according to the present invention is herein an oil, such as linseed oil, hemp oil, corn oil, walnut oil, rapeseed oil, soybean oil, sunflower oil, poppy seed oil, safflower oil, wheat germ oil, safflower oil, grape seed oil, evening primrose oil, borage oil, cumin oil, algae oil, fish oil, cod liver oil, coconut oil, linseed cotton seed oil and/or mixtures of the above.

For the preparation of the suspension according to the invention containing at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, the at least one tri-O-acylglycerol is used as chemically pure substance for the preparation of the crystal suspension according to the invention, or a mixture is used which has at least > 90%, preferably > 95%, more preferably > 99% of the tri-O-acylglycerol consisting of at least one member selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol. At least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol may of course also be obtained from natural vegetable or animal oils, for example tri-O-acylglycerol is a mixture of such trioctylglycerol and tridecyl glycerol and trioctylglycerol and tridecyl glycerol, which are available under the trade name8000 (trioctanoyl glycerol),>1000 (tridecyl glycerol), ->300 (trioctylglycerol/tridecylglycerol), -j>355 (trioctylglycerol/tridecylglycerol), -j>810 (trioctylglycerol: tridecylglycerol, about 70:30) and +.>812 (trioctylglycerol: tridecylglycerol, about 50:50) are commercially available. Such commercially available mixtures can be used to prepare the suspensions of the present invention.

In some preferred embodiments of the invention, the suspension for coating a medical product, preferably selected from a catheter balloon, a balloon catheter, a stent or a cannula, thus contains a mixture of at least two tri-O-acylglycerols selected from trioctacylglycerols, trionoylglycerols, tridecanoylglycerols and tri (undecanoylglycerols, wherein said mixture consists of at least 90%, preferably 95%, more preferably 99% or more of at least two tri-O-acylglycerols selected from trioctacylglycerols, trionoylglycerols, tridecanoylglycerols and tri (undecanoylglycerols).

The term "weight percent" (abbreviation: wt%) as used herein refers to the proportion of a substance in a mixture or solution, in grams per 100 grams of the mixture. The term weight percent as used herein is the name of the mass fraction of the mixture.

The term "parts by mass" as used herein refers to the physical and chemical quantities used to quantitatively describe the composition of a mixture of substances. The mass of the mixture component considered is expressed as the relative proportion of the mass of the mixture component considered in the total mass of the mixture, calculated as the sum of the masses of all the mixture components.

In a preferred embodiment, the mass fraction of tri-O-acylglycerol in the suspension relative to the total mass of tri-O-acylglycerol and microcrystalline limus active substance (m/m; [ g ]/[ g ]; m=mass) is preferably 5-40%, more preferably 10-30% and most preferably 20%. Here, the mass of tri-O-acylglycerol refers to the total mass of tri-O-acylglycerols selected from trioctanoylglycerol, trionoylglycerol, tridecanoylglycerol and tri (undecanoylglycerol, that is, in the case of a mixture of tri-O-acylglycerols selected from trioctanoylglycerol, tridecanoylglycerol and tri (undecanoylglycerol, the mass fraction of the mixture mass is calculated from the total mass of the mixture of tri-O-acylglycerols and microcrystalline limus active substance.

Thus, in order to calculate the mass fraction of tri-O-acylglycerol relative to the total mass of tri-O-acylglycerol and microcrystalline limus active substance in suspension, the quotient of the mass of tri-O-acylglycerol and the total mass of tri-O-acylglycerol and microcrystalline limus active substance is formed. For example, the mass fraction of tri-O-acylglycerol in a mixture of 4g of limus active substance and 1g of tri-O-acylglycerol is 20%.

In a preferred embodiment, the mass fraction of tri-O-acylglycerol in suspension relative to the total mass of tri-O-acylglycerol and microcrystalline limus active substance (m/m; [ g ]/[ g ]; m = mass) is preferably 0.1-50%, further preferably 1-40%, more preferably 10-30%, most preferably 20%.

In a preferred embodiment, the mass fraction of the limus active substance in suspension relative to the total mass of tri-O-acylglycerol and microcrystalline limus active substance (m/m; [ g ]/[ g ]; m=mass) is preferably 99.9 to 50%, more preferably 99 to 60%, still more preferably 90 to 70%, and most preferably 80%.

Therefore, the parts by mass of the tri-O-acylglycerol and the microcrystalline limus active substance relative to the total mass of the tri-O-acylglycerol and the microcrystalline limus active substance are preferably 0.1 to 50% of the tri-O-acylglycerol and 99.9 to 50% of the limus active substance, more preferably 1 to 40% of the tri-O-acylglycerol and 99 to 60% of the limus active substance, still more preferably 10 to 30% of the tri-O-acylglycerol and 90 to 70% of the limus active substance, most preferably 20% of the tri-O-acylglycerol and 80% of the limus active substance.

If a mixture of tri-O-acylglycerols is used, the mass fraction of the tri-O-acylglycerol mixture relative to the total mass of the tri-O-acylglycerol mixture and the microcrystalline limus active substance is determined. For example, the mass fraction of the tri-O-acylglycerol mixture in a mixture of 4g of limus active substance and 1g of tri-O-acylglycerol mixture is 20%.

In a preferred embodiment, the amount of tri-O-acylglycerol is preferably 0.1 to 50 wt%, more preferably 1 to 40 wt%, more preferably 10 to 30 wt%, most preferably 20 wt%, relative to the limus active substance.

In a preferred embodiment, the amount of limus active substance in suspension is preferably 99.9-50 wt%, further preferably 99-60 wt%, more preferably 90-70 wt%, most preferably 80 wt% relative to the amount of tri-O-acylglycerol.

Thus, the tri-O-acylglycerol and microcrystalline limus active in the suspension are preferably present as 0.1 to 50 wt.% tri-O-acylglycerol to 99.9 to 50 wt.% limus active, more preferably as 1 to 40 wt.% tri-O-acylglycerol to 99 to 60 wt.% limus active, particularly preferably as 10 to 30 wt.% tri-O-acylglycerol to 90 to 70 wt.% limus active, and most preferably as 20 wt.% tri-O-acylglycerol to 80 wt.% limus active.

In a preferred embodiment, the parts by mass of antioxidant (m/m, [ g ]/[ g ], m=mass) in the suspension relative to the total mass of antioxidant and microcrystalline limus active substance is preferably 0.001 to 15.0%, more preferably 0.01 to 10.0%, still more preferably 0.05 to 5.0%.

In a preferred embodiment, the parts by mass (m/m; [ g ]/[ g ]; m=mass) is preferably 0.001 to 1.0%, more preferably 0.01 to 2.5%, still more preferably 0.05 to 5.0%.

In a preferred embodiment, the total mass of antioxidants and additives in suspension and microcrystalline limus active substance, the parts by mass of antioxidants together with other additives than antioxidants (m/m; [ g ]/[ g ]; m=mass) is preferably 0.001 to 15.0%, more preferably 0.01 to 10.0%, particularly preferably 0.05 to 5.0%.

In a preferred embodiment, the parts by mass of the antioxidant and the other additives than the antioxidant (m/m; [ g ]/[ g ]; m=mass) in the total mass of the antioxidant and the additive and the active substance of micro-crystalline limus in the suspension are preferably 0.001 to 15.0%, more preferably 0.01 to 10.0%, particularly preferably 0.05 to 5.0%, wherein the parts by mass of the additive other than the antioxidant (m/m; [ g ];) m=mass) are preferably 0.001 to 1.0%, more preferably 0.01 to 2.5%, more particularly preferably 0.05 to 5.0%, relative to the total mass of the additive and the active substance of micro-crystalline limus in the suspension.

The term "mass ratio" as used herein refers to the physical and chemical quantity of a quantitative description of the composition of a mixture of substances. The mass ratio refers to the mass ratio of the two mixture components considered to each other.

The mass ratio (m/m; [ g ]/[ g ];m=mass) of tri-O-acylglycerol to microcrystalline limus active substance is preferably 1:1000-1:1, more preferably 1:100-1:1.5, further preferably 1:10-1:3, and more preferably 1:5-1:4, most preferably 1:4. here, the mass of the tri-O-acylglycerol is based on the total mass of the tri-O-acylglycerols selected from the group consisting of trioctacylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, i.e., for the tri-O-acylglycerol mixture selected from the group consisting of trioctacylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, the mass of the tri-O-acylglycerol mixture is used to calculate the mass ratio.

Thus, to calculate the mass ratio of tri-O-acylglycerol to microcrystalline limus active, a quotient of the mass of tri-O-acylglycerol to the mass of limus active is formed. For example, in a mixture of 1g of tri-O-acylglycerol and 4g of limus active substance, the mass ratio of tri-O-acylglycerol to microcrystalline limus active substance is 1:4.

The mass ratio of tri-O-acylglycerol to the active substance of micro-crystalline limus is further preferably 0.1 to 50%, more preferably 1 to 40%, more preferably 10 to 30%, and further preferably 20 to 25%, most preferably 25%. In some preferred embodiments, the mass ratio of tri-O-acylglycerol to microcrystalline limus active is preferably 5-40%, more preferably 10-30%, most preferably 20-25%.

Thus, to calculate the mass ratio of tri-O-acylglycerol to microcrystalline limus active, a quotient of the mass of tri-O-acylglycerol to the mass of limus active is formed. For example, in a mixture of 1g of tri-O-acylglycerol and 4g of limus active substance, the mass ratio of tri-O-acylglycerol to microcrystalline limus active substance is 25%.

In a preferred embodiment, the mass ratio of microcrystalline limus active substance to 100ml suspension volume (m/V; [ g ]/[100ml ]; m=mass; v=volume) is between 0.5 and 6%, more preferably between 1 and 5%, even more preferably between 2 and 4%, most preferably 3%.

Thus, to calculate the mass ratio of the microcrystalline limus active to the volume of 100ml of suspension, a quotient of the mass of microcrystalline limus active to the volume of 100ml of suspension was formed. For example, in a suspension of 3g of limus active substance to a volume of 100ml of suspension, the mass ratio of microcrystalline limus active substance to the volume of 100ml of suspension is 3%.

The mass ratio of the microcrystalline limus active substance to the 1L suspension volume (m/V; [ g ]/[ L ]; m = mass; V = volume) of 0.5-6%, more preferably 1-5%, still more preferably 2-4%, most preferably 3%.

Thus, to calculate the mass ratio of the microcrystalline limus active to the 1L suspension volume, a quotient of the microcrystalline limus active to the mass of the 1L suspension volume was formed. For example, in a suspension of 30g of limus active substance and a volume of 1L of suspension, the mass ratio of microcrystalline limus active substance to the volume of 1L of suspension is 3%.

In a preferred embodiment, the mass ratio of tri-O-acylglycerol to 100mL suspension volume (m/V; [ g ]/[100mL ]; m = mass; V = volume) is from 0.13 to 1.5%, more preferably from 0.25 to 1.25%, even more preferably from 0.5 to 1%, and most preferably 0.75%.

Thus, to calculate the mass ratio of tri-O-acylglycerol to the volume of 100mL suspension, a quotient of the mass of tri-O-acylglycerol to the volume of 100mL suspension was formed. For example, in a suspension of 0.75g of tri-O-acylglycerol and a volume of 100mL of suspension, the mass ratio of tri-O-acylglycerol to the volume of 100mL of suspension is 0.75%.

In other words, the mass ratio of tri-O-acylglycerol to 1L suspension volume (m/V; [ g ]/[ L ]; m = mass; V = volume) is 0.13 to 1.5%, more preferably 0.25 to 1.25%, even more preferably 0.5 to 1%, and most preferably 0.75%. Thus, to calculate the mass ratio of tri-O-acylglycerol to 1L suspension volume, a quotient of the mass of tri-O-acylglycerol to 1L suspension volume was formed. For example, in a suspension of 7.5g of limus active substance and a volume of 1L of suspension, the mass ratio of tri-O-acylglycerol to the volume of 1L of suspension is 0.75%.

The term "mass concentration" as used herein refers to the physical and chemical quantity used to quantitatively describe the composition of a substance mixture/mixed phase. The mass of the mixture components considered here is related to the total volume of the mixture phase.

In a preferred embodiment, the mass concentration of the active substance of micro-crystalline limus in the suspension (m/V; [ mg ]/[ mL ]; m=mass; v=volume) is preferably between 5 and 60mg/mL, more preferably between 20 and 40mg/mL, even more preferably between 20 and 30mg/mL. In some preferred embodiments, the mass concentration of the microcrystalline limus active substance in the suspension is 20-25mg/mL. In some preferred embodiments, the mass concentration of the microcrystalline limus active substance in the suspension is 25-30mg/mL. In some preferred embodiments, the mass concentration of the microcrystalline limus active substance in the suspension is 20mg/mL. In some preferred embodiments, the mass concentration of the microcrystalline limus active substance in the suspension is 25mg/mL. In some preferred embodiments, the mass concentration of the microcrystalline limus active substance in the suspension is 30mg/mL.

In other words, microcrystalline limus activesMass concentration of the mass in suspension (m/V; [. Kg)]/[m ³ ]The method comprises the steps of carrying out a first treatment on the surface of the m = mass; v=volume) is preferably 5-60kg/m ³ More preferably 20-40kg/m ³ More preferably 20-30kg/m ³ . In some preferred embodiments, the mass concentration of the microcrystalline limus active substance in the suspension is between 20 and 25kg/m ³ . In some preferred embodiments, the mass concentration of the microcrystalline limus active substance in the suspension is between 25 and 30kg/m ³ . In some preferred embodiments, the mass concentration of the microcrystalline limus active substance in the suspension is 20kg/m ³ . In some preferred embodiments, the mass concentration of the microcrystalline limus active substance in the suspension is 25kg/m ³ . In some preferred embodiments, the mass concentration of the microcrystalline limus active substance in the suspension is 30kg/m ³ 。

In a preferred embodiment, the mass concentration of tri-O-acylglycerols in the suspension (m/V; [ mg ]/[ ml ]; m=mass; V=volume) is preferably from 1.3 to 15mg/ml, more preferably from 2.5 to 12.5mg/ml, more preferably from 5 to 10mg/ml.

In some preferred embodiments, the mass concentration of tri-O-acylglycerol in the suspension is 6-9mg/ml. In some preferred embodiments, the mass concentration of tri-O-acylglycerol in the suspension is from 5.5 to 9.5mg/ml. In some preferred embodiments, the mass concentration of tri-O-acylglycerol in the suspension is 7.5mg/ml. In some preferred embodiments, the mass concentration of tri-O-acylglycerol in the suspension is 7mg/ml. In some preferred embodiments, the mass concentration of tri-O-acylglycerol in the suspension is 6.5mg/ml.

In some preferred embodiments, the mass concentration of tri-O-acylglycerol in the suspension is 4-6mg/ml. In some preferred embodiments, the mass concentration of tri-O-acylglycerol in the suspension is 4.5-5.5mg/ml. In some preferred embodiments, the mass concentration of tri-O-acylglycerol in the suspension is 4.5mg/ml. In some preferred embodiments, the mass concentration of tri-O-acylglycerol in the suspension is 5mg/ml. In some preferred embodiments, the mass concentration of tri-O-acylglycerol in the suspension is 5.5mg/ml.

In a preferred embodiment, the mass concentration of the microcrystalline limus active substance in the suspension (m/V; [ mg ]/[ ml ]; m = mass; V = volume) is 5-60mg/ml, the mass concentration of the tri-O-acylglycerol is 1.3-15mg/ml, more preferably the mass concentration of the microcrystalline limus active substance in the suspension is 20-40mg/ml, the mass concentration of the tri-O-acylglycerol is 2.5-12.5mg/ml, still more preferably the mass concentration of the microcrystalline limus active substance in the suspension is 20-30mg/ml, and the mass concentration of the tri-O-acylglycerol is 5-10mg/ml.

As used herein, the term "concentration of an amount of a substance" refers to a physical chemical quantity used to quantitatively describe the composition of a substance mixture/mixed phase. The amounts of substances of the mixture components considered here relate to the total volume of the mixed phase.

In a preferred embodiment, the concentration of the substance of the active substance of the microcrystalline limus in suspension (n/V; [ mmol ]/[ L ]; n=the amount of substance; v=volume) is preferably between 5 and 60mmol/L, more preferably between 20 and 40mmol/L, more preferably between 25 and 35mmol/L.

In other words, the concentration of the active substance of microcrystalline limus in the suspension (n/V; [ mmol ]]/[L]The method comprises the steps of carrying out a first treatment on the surface of the n = amount of substance; v=volume) is preferably 5 to 60mol/m ³ More preferably 20 to 40mol/m ³ More preferably 25 to 35mol/m ³ 。

In some preferred embodiments, the concentration of the tri-O-acylglycerol material in the suspension in an amount of 2-35mmol/L (n/V; [ mmol ]/[ L ]; n=amount of material; V=volume), more preferably 4-25mmol/L, more preferably 10-20mmol/L, more preferably 12-18mmol/L.

In some preferred embodiments, the concentration of the substance in suspension of the tri-O-acylglycerol (n/V; [ mmol ]]/[L]The method comprises the steps of carrying out a first treatment on the surface of the n = amount of substance; v=volume) of 2-35mol/m ³ More preferably 4 to 25mol/m ³ More preferably 10 to 20mol/m ³ More preferably 12 to 18mol/m ³ 。

The term "limus active substance" refers to macrolides comprising the active substances rapamycin (sirolimus) and rapamycin derivatives, such as everolimus, lamimus Deforolimus, mepimox, noose Wo Mosi, pimecrolimus, diphosprolimus, tacrolimus, temsirolimus and zotarolimus.

According to the invention, the following substances can be used as limus active substances: rapamycin, deforolimus, microlimus, nor Wo Mosi, 28-O-methyl rapamycin, C-22-methyl rapamycin C-49-methyl rapamycin, 42-O- (2-ethoxyethyl) -rapamycin (Ulmoseltamium, fulmoseltamium,Or bailimus->) 40-O- (2-hydroxyethyl) rapamycin (everolimus), 40-O-benzyl rapamycin, 40-O- (4 '-hydroxymethyl) benzyl rapamycin, 40-O- [4' - (1, 2-dihydroxyethyl)]Benzyl rapamycin, 40-O-allyl rapamycin, 40-O- [3' - (2, 2-dimethyl-1, 3-dioxolan-4 (S) -yl) -prop-2 ' -en-1 ' -yl]-rapamycin, (2 ': E,4' S) -40-O- (4 ',5' -dihydroxypent-2 '-en-1' -yl) -rapamycin, 40-O- (2-hydroxy) ethoxycarbonylmethyl rapamycin, 40-O- (3-hydroxy) propylrapamycin, 40-O- (6-hydroxy) hexyl rapamycin, 40-O- [2- (2-hydroxy) ethoxy]Ethyl rapamycin, 40-O- [ (3S) -2, 2-dimethyldioxolan-3-yl]Methyl rapamycin, 40-O- [ (2S) -2, 3-dihydroxypropan-1-yl]-rapamycin, 40-O- (2-acetoxy) ethyl rapamycin, 40-O- (2-nicotinoyloxy) ethyl rapamycin, 40-O- [2- (N-morpholino) acetoxy]Ethyl rapamycin, 40-O- (2-N-imidazolyl) ethyl-rapamycin, 40-O- [2- (N-methyl-N' -piperazinyl) acetoxy ]Ethyl rapamycin, 39-O-desmethyl-39, 40-O, O-ethylene rapamycin, (26R) -26-dihydro-40-O- (2-hydroxy) ethyl rapamycin, 40-O- (2-aminoethyl) rapamycin, 40-O- (2-acetaminoethyl) rapamycin, 40-O- (2-nicotinamide ethyl) rapamycin, 40-O- (2- (N-methyl-mi) miAzole-2 ' -ylcarbonylethoxy amido) ethyl) rapamycin, 40-O- (2-ethoxycarbonylaminoethyl) rapamycin, 40-O- (2-toluenesulfonamido ethyl) rapamycin, 40-O- [2- (4 ',5' -dicarbonylethoxy-1 ',2',3' -triazol-1 ' -yl) -ethyl]-rapamycin, 42-epi- (tetrazolyl) rapamycin (tacrolimus), 42- [ 3-hydroxy-2- (hydroxymethyl) -2-methylpropionate]Rapamycin (temsirolimus), (42S) -42-deoxy-42- (1H-tetrazol-1-yl) rapamycin (zotarolimus), (3S, 4r,5S,8r,9E,12S,14S,15r,16S,18r,19r,26 as) -3- { (E) -2- [ (1 r,3r, 4S) -4-chloro-3-methoxycyclohexyl]-1-methylvinyl } -8-ethyl-5, 6,8,11,12,13,14,15,16,17,18,19,24,25,26 a-hexadecyl-5, 19. Dihydroxy-14, 16-dimethoxy-4,10,12,18-tetramethyl-15, 19-epoxy-3H-pyrido [2,1-c ]][1,4]Oxaazacyclotridecane-1,7,20,21 (4H, 23H) -tetraone (pimecrolimus), (1R, 2R, 4S) -4- [ (2R) -2- [ (1R, 9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S, 35R) -1, 18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11, 36-dioxa-4-azatricyclo [30.3.1.04,9 ]Trihexadecan-16,24,26,28-tetraen-12-yl]Propyl group]-2-methoxycyclohexyldimethyl phosphinate (ground phosphorus limus).

Preferably, the active substance of limus is used, which may be in microcrystalline form, such as the active substances rapamycin (sirolimus), everolimus, zotarolimus, ulimoraxel, deforolimus, meolimus, noose Wo Mosi, pimecrolimus, sirolimus, tacrolimus and temsirolimus. Particularly preferred are everolimus and rapamycin.

The limus active substance is preferably selected from the group comprising or consisting of: rapamycin (sirolimus), everolimus, zotarolimus, lamimus, deforolimus, meolimus, noose Wo Mosi, pimecrolimus, sirolimus, tacrolimus and temsirolimus, with rapamycin (sirolimus) and everolimus being further preferred. In an even more preferred embodiment, the active substance of limus is rapamycin (sirolimus). In a particularly preferred embodiment, the active substance of limus is everolimus.

Rapamycin is also known as rapamycin or international non-patent name (INN) sirolimus and IUPAC name [3S- [3R ] [ E (1S, 3S, 4S) ],4S, 5R, 8S, 9E,12R, 14R, 15S, 16R, 18S, 19S, 26aR ] ] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26 a-hexadecane-hydrogen-5, 19-dihydroxy-3- [2- (4-hydroxy-3-methoxy-cyclohexyl) -1-methylvinyl ] -14, 16-dimethoxy-4,10,12,18-tetramethyl-8- (2-propenyl) -15, 19-epoxy-3H-pyrido [2,1-c ] [1,4] -oxazacyclo-ditridec-1,7,20,21 (H, 234H) -tetrahydrate.

Rapamycin has the following structural formula:

everolimus is a derivative of rapamycin having the IUPAC name dihydroxy-12- [ (2R) -1- [ (1 s,3R, 4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl ] prop-2-yl ] -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11, 36-dioxa-4-azatricyclo [30.3.1.04,9] thirty-hexa-carbon-16,24,26,28-tetraen-2,3,10,14,20-dione.

Everolimus has the following structural formula:

the term "crystallites" as used herein refers to solids whose structural units are regularly arranged in a crystal structure and whose dimensions are in the micrometer range. The term "micrometer range" as used herein corresponds to a range of 1 μm to 300 μm, where 1 μm corresponds to 10 ^-6 m、10 ^-3 mm or 1000nm. Thus, the term "crystallites" as used herein refers to crystals having a crystal size in the range of 1 μm to 300 μm.

The term "crystal size" as used herein refers to the length of the crystal along its largest dimension, i.e. along its longitudinal axis in the case of rod-like or needle-like crystals. Thus, the crystallites as defined herein have a length along their largest dimension of 1-300 μm.

As used herein, the term "crystallinity" is the crystalline content of a compound, i.e., the ratio of crystals of a compound to the total amount of the compound in crystalline and other forms.

The term "microcrystalline limus active" as used herein refers to a microcrystalline form of a limus active. Thus, the terms "microcrystalline limus active" and "microcrystalline form of the limus active" are used interchangeably herein.

Crystallization processes for preparing limus active substances are known in the art. In general, in order to crystallize the limus active substance, a limus active substance solution may be prepared and the solubility of the limus active substance in the solution may be reduced. Common methods of reducing solubility include, for example, cooling, addition of antisolvents, and evaporation.

Crystallization is carried out by cooling: the limus active substance may be dissolved in a solvent at room temperature or higher until saturated and crystallized at a lower temperature, for example 0 ℃. The crystal size distribution can be influenced by a controlled cooling rate. Polar and nonpolar organic solvents such as toluene, acetonitrile, ethyl formate, isopropyl acetate, isobutyl acetate, ethanol, dimethylformamide, anisole, ethyl acetate, methyl ethyl ketone, methyl isopropyl ketone, tetrahydrofuran, nitromethane, propionitrile are all suitable solvents for crystallization of the limus active substance.

Crystallization is performed by adding seed crystals: the limus active is dissolved to saturation in a solvent and crystallization is initiated by seeding to achieve a controlled reduction in supersaturation.

Crystallization is carried out by adding an antisolvent: the active material is dissolved in a solvent and then a non-solvent or water is added. Two-phase mixtures are also possible here. Polar organic solvents such as acetone, acetonitrile, ethyl acetate, methanol, ethanol, isopropanol, butanol, butyl methyl ether, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide may be used as a solvent for dissolving the limus active substance. Suitable non-solvents include pentane, hexane, cyclohexane or heptane. The solvent mixture may be allowed to crystallize on standing, stirred or slowly concentrated or evaporated in vacuo. The crystal size and crystallinity of the active material can be affected by controlling the addition of the nonpolar solvent. Satiety is slower to produce large crystals and faster to produce small crystals. It is well known to control the rate of addition of antisolvent to control crystal size.

For the production of crystallites, crystallization may also be assisted by ultrasound. It is generally known that crystal size can be influenced by ultrasound. Ultrasound can be used to initiate crystallization and nucleation at the beginning of crystallization, and further crystal growth then proceeds unimpeded so that larger crystals can be grown. On the other hand, continuous ultrasonic treatment with supersaturated solutions results in smaller crystals, because many nuclei are formed in the process, thereby resulting in the growth of numerous small crystals. Another option is to use pulsed mode ultrasound to affect crystal growth, thereby achieving custom crystal sizes.

In this context, the preferred crystallization method for preparing the microcrystalline limus active substance is controlled crystallization to obtain crystallites in the natural and intact state and avoid possible damage, for example by grinding or micronization.

Other methods known in the art, such as micronization, grinding or sieving, may also be used to provide the desired crystal size. One possibility is to grind the crystals, which can also be done by wet grinding during crystallization. Grinding may be advantageous to obtain different crystal sizes, i.e. a wider crystal size distribution. Milling allows all desired sizes within the crystal size range. The separation and drying may be followed by, for example, special sieving methods to provide a more uniform crystal size. Special screening devices known in the art may be used for this purpose. In the sieving method, the crystals of limus active substance may be sieved through, for example, a stack of sieves, and divided into different size ranges.

Fig. 2 to 9 show example images of the microcrystalline forms of the active substances rapamycin and everolimus. FIGS. 2 and 3 show rapamycin in stick form having a very narrow particle size distribution in the range of 10 μm to 30 μm. FIGS. 4 and 5 show rapamycin in the form of rod-like crystallites having a very narrow particle size distribution in the range of 15 μm to 30 μm. FIGS. 7 and 8 show rapamycin having a particle size distribution in the range of 20 μm to 40 μm. Fig. 6 and 7 show acicular everolimus having a particle size distribution in the range of 20 μm to 40 μm. In fig. 2-9, it is apparent that larger crystals or agglomerates are not present. It is also apparent that everolimus is acicular, whereas rapamycin is in the form of diamond prisms.

It has been shown that particularly stable suspensions can be prepared with microcrystalline limus active substances if the suspension contains at least one tri-O-acylglycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol. According to the invention, the at least one active substance of limus is in microcrystalline form. Thus, the limus active substance is present in microcrystalline form, with a crystal size in the range of 1 μm to 300 μm. Thus, the crystallite size of the at least one limus active substance is between 1 μm and 300 μm.

The microcrystals of the limus active are not encapsulated and coated, for example with a polymer, and are not modified on the surface. Furthermore, the crystallites of the limus active substance are free of polymers, polymer particles, metals, metal particles, ceramics or ceramic particles. They also do not contain any other pharmaceutically active substances or peptides, proteins, amino acids, fatty acid esters or nucleotides or other biopolymers.

The present invention therefore relates to a suspension comprising at least one microcrystalline limus active substance as defined herein. In this suspension, at least one active substance of limus is present in microcrystalline form. The amount of the limus active substance dissolved in the solvent or solvent mixture in the suspension is less than 10%, preferably less than 5%, further preferably less than 2%, most preferably less than 1% based on the mass of the limus active substance in microcrystalline form used to prepare the suspension. It is therefore preferred that at most 10%, preferably at most 5%, and further preferably at most 2%, most preferably at most 1% of the crystallites of the at least one limus active substance are dissolved in the suspension.

According to the invention, the suspension for coating the medical product (preferably selected from catheter balloons, balloon catheters, stents or cannulas) contains a solvent or a solvent mixture in which the at least one tri-O-acylglycerol is dissolved and in which the crystallites of the at least one limus active substance are not dissolved.

As used herein, the expression "wherein the crystallites of the at least one limus active substance are insoluble" means that preferably at most 10%, preferably at most 9%, further preferably at most 8%, further preferably at most 7%, further preferably at most 6%, further preferably at most 5%, still more preferably at most 3%, further preferably at most 2% and most preferably at most 1% of the crystallites of the at least one limus active substance are dissolved in the suspension. Preferably, of course, 100% of the crystallites of the at least one limus active substance are insoluble in the suspension.

It is further preferred that the solubility of the microcrystals of the at least one limus active substance in the solvent or solvent mixture of the suspension is <20mg/ml, more preferably <15mg/ml, more preferably <10mg/ml, more preferably <9mg/ml, more preferably <8mg/ml, more preferably <7mg/ml, more preferably <6mg/ml, more preferably <5mg/ml, more preferably <4mg/ml, more preferably <3mg/ml, more preferably <2mg/ml, more preferably <1mg/ml.

It has surprisingly been found that the microcrystals of the active substance of limus are insoluble in solutions containing at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol. Thus, the crystalline suspension may be prepared as a coating formulation wherein the microcrystals of the limus active substance remain intact.

The crystals of the limus active substance should have a size of at least 1 μm. Crystals smaller than 1 μm are too small, so they dissolve relatively quickly. In preparing the suspensions of the present invention, it has been found that stable suspensions are obtained only when at least one of the limus active substances is substantially free of crystals having a crystal size of less than 1 μm. In other words, the limus active substance is particularly preferably not in the form of nanocrystals. As used herein, the term nanocrystal refers to crystals having a crystal size in the range of 1nm to less than 1000 nm.

Preferably, at least 95% to 97% of the at least one limus active substance is present in the form of crystallites having a crystal size of at least 1 μm, more preferably at least 95% to 99%, even more preferably at least 97% to 99%, particularly preferably at least 98% to 99.9%. In a further preferred embodiment, 100% of the at least one limus active substance is present in microcrystalline form having a crystal size of at least 1 μm.

It has also been shown to be advantageous if the active substance of limus in microcrystalline form has a crystal size of at least 10 μm. Therefore, it is preferred that at least one of the limus active substances has a small proportion of crystallites having a crystal size of 1 μm to 10 μm. It is particularly preferred that only a few crystals, i.e. significantly less than 10% of all crystals, are smaller than 10 μm. In a preferred embodiment, less than 10% of all crystallites of the limus active substance are present in a crystal size of less than 10 μm.

It is therefore preferred that at least 90% of said at least one limus active substance, preferably at least 90% -95% of said at least one limus active substance, more preferably at least 93% -98% of said at least one limus active substance, more preferably at least 95% -99% of said at least one limus active substance, and particularly preferably at least 98% -99.9% of said at least one limus active substance is present in the form of crystallites having a crystal size of at least 10 μm.

It is further preferred that the crystallites of the at least one limus active substance have a crystal size of at least 5 μm. It is therefore preferred that at least 90% of the at least one limus active, preferably at least 90% -95% of the at least one limus active, more preferably at least 93% -98% of the at least one limus active, even more preferably at least 95% -99% of the at least one limus active, and particularly preferably at least 98% -99.9% of the at least one limus active is present in the form of crystallites having a crystal size of at least 5 μm. Crystallites having a crystal size in the range of less than 5 μm can dissolve more rapidly and are thus less preferred.

It is still further preferred that the crystallites of the at least one limus active substance have a crystal size of at least 20 μm. Thus, preferably at least 90% of said at least one limus active substance, preferably at least 90% -95% of said at least one limus active substance, more preferably at least 93% -98% of said at least one limus active substance, even more preferably at least 95% -99% of said at least one limus active substance, and particularly preferably at least 98% -99.9% of said at least one limus active substance are present in the form of crystallites having a crystal size of at least 20 μm.

Furthermore, it is preferred that only a small amount of microcrystals of the active substance of limus is present, i.e. less than 40%, more preferably less than 30% or even less than 25%, with a crystal size of 50 μm to 300 μm. Therefore, preferably at most 40% of the at least one limus active substance, preferably at most 30% of the at least one limus active substance, more preferably at most 25% of the at least one limus active substance is present in the form of crystallites having a particle size of 50 μm to 300 μm. In a further embodiment, preferably at most 20% of said at least one limus active substance, preferably at most 15% of said at least one limus active substance, further preferably at most 10% of said at least one limus active substance is present in the form of crystallites having a particle size of 50 μm to 300 μm. In a particularly preferred embodiment, the crystallites of the at least one limus active substance are substantially present in a crystal size of at most 50 μm.

More preferably, very few microcrystals of the active substance of the limus are present, i.e. less than 10%, more preferably less than 5% or even less than 2%, most preferably less than 1% of the crystals have a size ranging from 100 μm to 300 μm. Crystallites having a crystal size in the range of 100 μm to 300 μm may form agglomerates and coalesce into larger particles, which may pose a risk of vascular occlusion. Therefore, it is particularly preferable that the proportion of crystallites having a particle size in the range of 100 μm to 300 μm is as low as possible.

Thus, preferably at most 10% of said at least one limus active substance, preferably at most 5% of said at least one limus active substance, further preferably at most 2% of said at least one limus active substance, still more preferably at most 1% of said at least one limus active substance is present in the form of crystallites having a particle size of 100 μm-300 μm. In a further embodiment, preferably at least 99%, preferably 99.5%, further preferably at least 99.7%, even more preferably at least 99.9% and most preferably 100% of the at least one limus active substance is present in a particle size of less than or equal to 100 μm. In a preferred embodiment, the crystallites of the at least one limus active substance are present substantially with a crystallite size of at most 100 μm. In a particularly preferred embodiment, the crystallites of the at least one limus active substance are present substantially with a crystallite size of at most 100 μm.

Thus, preferably, the limus active substance is in the form of crystallites having a crystal size of 1 μm to 100 μm.

Crystallites of the limus active substance having a crystal size in the range of 10 μm to 50 μm have been shown to be very suitable for providing the suspension of the invention for coating medical products. Thus, preferably at least 70% of said at least one limus active substance, preferably at least 70% -80% of said at least one limus active substance, further preferably at least 80% -90% of said at least one limus active substance, further preferably at least 90% -95% of said at least one limus active substance, and particularly preferably at least 95% -99% of said at least one limus active substance is present in the form of crystallites having a crystal size of 10 μm to 50 μm.

Microcrystals of limus active substances having a particle size in the range of 5 μm to 35 μm have been shown to be suitable for providing stable suspensions for coating medical products. Therefore, it is preferred that at least 70% of the microcrystals of the limus active substance are present in a crystal size ranging from 5 μm to 35 μm. Thus, preferably at least 70% of the limus active substance, preferably at least 70-80% of the limus active substance, further preferably at least 80% -90% of one of the limus active substances is present in the form of crystallites having a particle size in the range of 5 μm to 35 μm. It is further preferred that at least 70% of said at least one limus active substance, preferably at least 70% -80% of said at least one limus active substance, further preferred at least 80% -90% of said at least one limus active substance, further preferred at least 90% -95% of said at least one limus active substance, and especially preferred at least 95% -99% of said at least one limus active substance is present in the form of crystallites having a particle size of 5 μm to 35 μm.

In a particularly preferred embodiment, the crystallites of the limus active substance are present in a crystal size of 20-40 μm. Thus, preferably, at least 70% of said at least one limus active substance, preferably at least 70% -80% of said at least one limus active substance, further preferably at least 80% -90% of said at least one limus active substance, further preferably at least 90% -95% of said at least one limus active substance. And particularly preferably at least 95% -99% of the at least one limus active substance is present in microcrystalline form with a crystal size of 20 μm to 40 μm.

Preferably, the crystallinity of the limus active substance is at least 90 wt%, more preferably at least 92.5 wt%, more preferably at least 95 wt%, more preferably at least 97.5 wt%, most preferably at least 99 wt%.

The microcrystals of the at least one limus active substance are preferably microcrystals of at least one limus active substance selected from the group comprising or consisting of: rapamycin, everolimus, zotarolimus, lamimus, deforolimus, meolimus, noose Wo Mosi, pimecrolimus, diphospolimus, tacrolimus and temsirolimus.

The crystallites of at least one of the limus active substances are preferably rapamycin crystallites or everolimus crystallites. Preferred herein are microcrystalline rapamycin and microcrystalline everolimus. Microcrystalline everolimus is particularly preferred herein.

Crystals having prismatic to acicular habit are one-dimensional elongated forms in which the length of the crystal is significantly greater than its diameter.

In a preferred embodiment, at least one of the limus active substances is rapamycin. Rapamycin is crystallized in the form of diamond prisms. Accordingly, preferably at least 90%, more preferably at least 92.5%, more preferably at least 95%, more preferably at least 97.5% and most preferably at least 99% of the rapamycin crystallites are in the form of diamond prisms. Accordingly, preferably at least 90%, more preferably at least 92.5%, more preferably at least 95%, more preferably at least 97.5%, most preferably at least 99% of the rapamycin crystallites are prismatic. Accordingly, preferably at least 90%, more preferably at least 92.5%, more preferably at least 95%, more preferably at least 97.5% and most preferably at least 99% of the rapamycin is in the form of prismatic crystallites.

In a preferred embodiment, the at least one active substance of limus is everolimus. Everolimus is crystallized in needles. Thus, preferably at least 90%, more preferably at least 92.5%, more preferably at least 95%, more preferably at least 97.5% and most preferably at least 99% of the everolimus crystallites are needle-like. Thus, it is preferred that at least 90%, more preferably at least 92.5%, more preferably at least 95%, more preferably at least 97.5%, most preferably at least 99% of the everolimus is needle-like in shape. It is therefore preferred that at least 90%, more preferably at least 92.5%, more preferably at least 95%, more preferably at least 97.5% and most preferably at least 99% of the everolimus crystallites are in needle-like form.

The term "solvent" as used herein refers to a substance that exists in a liquid aggregated state at normal temperature (20 ℃) and normal pressure (101 hPa;1 bar, 1 atm) and that can dissolve or dilute a gas, liquid or solid without a chemical reaction occurring between the dissolved substance and the substance being dissolved. Liquids such as water and liquid organic substances are used as solvents to dissolve other substances.

As used herein, the term "non-solvent" refers to a solvent that is incapable of dissolving the microcrystalline limus active substance, i.e., a solvent in which the microcrystalline limus active substance is practically insoluble, but in which a tri-O-acylglycerol selected from the group consisting of trioctanoylglycerol, trinonoylglycerol, tridecanoylglycerol and tri (undecanoylglycerol, or a mixture of said tri-O-acylglycerols, is soluble.

The solubility of the microcrystalline limus active substance in the non-solvent should be at most 1mg/mL. Examples of solvents in which the solubility of the microcrystalline limus active substance is at most 1mg/mL are water and some non-polar organic solvents such as saturated aliphatic hydrocarbons.

Examples of solvents in which tri-O-acylglycerols, trioctylglycerols, trinonyl glycerols, tridecyl glycerols and tri (undecyl) glycerols or mixtures of said tri-O-acylglycerols are soluble include, but are not limited to, non-polar organic solvents such as hexane, heptane, cyclohexane, toluene, and polar organic solvents such as diethyl ether, ethyl acetate, acetone, isopropanol and ethanol.

tri-O-acylglycerols are nonpolar, i.e. lipophilic, and are difficult or practically insoluble in very polar solvents, such as water or glycerol. Thus, suspensions containing as solvent only very polar solvents, for example water or glycerol, are not according to the invention, since the tri-O-acylglycerols selected from trioctanoylglycerol, trionoylglycerol, tridecanoylglycerol and tri (undecanoyl) glycerol or the mixtures of said tri-O-acylglycerols do not exist in dissolved form in very polar solvents, for example water or glycerol.

Thus, the term "non-solvent" as used herein refers to non-polar organic solvents, particularly saturated aliphatic hydrocarbons. Thus, a "non-solvent" may also be referred to as a "non-polar organic non-solvent". Thus, the non-polar organic solvents referred to herein as "non-solvents" include saturated aliphatic hydrocarbons which are liquid at normal temperature (20 ℃) and normal pressure (101 hPa;1 bar, 1 atm), i.e., having the general formula C _n H _2n+2 (n=5-16) a non-branched (linear) saturated hydrocarbon of the general formula C _n H _2n+2 (n=4-16) branched saturated hydrocarbons or of the general formula C _n H _2n (n=5-16). Examples of non-solvents include, but are not limited to, unbranched C _5-16 Alkanes, e.g. pentane, hexane, heptane, octane, nonane, decane, petroleum ether, branched C _5-16 Alkanes (isoalkanes), e.g. isopentane, isooctane, 2-methylpentane, 3-methylpentane, 2-dimethylbutane, 2, 3-dimethylbutane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, 2-methyloctane, 2-methylheptane, 3-methylheptane, 4-methylheptane, tetraethylmethane, C _5-16 Cycloalkanes such as cyclopentane, cyclohexane, methylcyclopentane, tert-butylcyclohexane, methylcyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, 2, 3-dimethylcyclobutane, 1, 2-dimethylcyclobutane, decalin, pinane, hexylcyclohexane, heptylcyclopentane, 1, 4-dimethylcyclohexane, 1-dimethylcyclohexane, spiro-pentane, spiro-hexane, spiro-heptane. Of course, mixtures of non-solvents may also be used.

The non-solvents suitable for use in the present invention are present in liquid aggregated form at normal temperature (20 ℃) and normal pressure (101 hPa;1bar,1 atm). The melting point of the preferred non-solvent is <20 ℃, more preferably <15 ℃, even more preferably <10 ℃. Preferred non-solvents also have a boiling point of <200 ℃, further preferably <150 ℃, even more preferably <100 ℃. Preferred non-solvents also have a boiling point of >25 ℃, further preferably >30 ℃, even more preferably >40 ℃. Thus, the boiling point of the preferred non-solvent is from 25 ℃ to 200 ℃, further preferably from 30 ℃ to 150 ℃, still more preferably from 40 ℃ to 100 ℃. The data at the melting point and boiling point are referred to herein as normal pressure (101 hPa;1bar,1 atm).

Preferred non-solvents also have a vapor pressure of <600hPa, more preferably <300hPa, even more preferably <200hPa, at room temperature (20deg.C). Preferred non-solvents also have a vapor pressure of >1hPa, more preferably >10hPa, even more preferably >30hPa at 20 ℃. Therefore, the preferred non-solvent has a vapor pressure of 1hPa to 600hPa, more preferably 10hPa to 300hPa, still more preferably 30hPa to 200hPa, at room temperature (20deg.C).

Preferred non-solvents do not have a permanent dipole moment, i.e. a dipole moment of 0.0 to a maximum of 0.1D (0.0-0.3.10) ^- ³⁰ Cm)。

Preferred non-solvents have a dielectric constant ε of 2.5 or less, more preferably 2.2 or less, even more preferably 2.0 or less at room temperature (20deg.C) _r . Preferred non-solvents exhibit>2.0, more preferably not less than 2.5, even more preferably not less than 3.0. Thus, the preferred non-solvent is one having a dielectric constant ε of 2.5 or less at ordinary temperature (20 ℃ C.) _r And>log Kow of 2.0, more preferably a dielectric constant ε of 2.2 or less _r And a logKow of 2.5 or more, still more preferably 2.0 or less _r And logKow.gtoreq.3.0.

Preferred non-solvents also have a density of <0.95g/mL, more preferably <0.9g/mL, even more preferably <0.8g/mL at ambient temperature (20 ℃). Preferred non-solvents also have a viscosity of <2.0 mPas, more preferably <1.5 mPas, even more preferably <1.0 mPas at ambient temperature (20 ℃).

Therefore, it is preferred herein thatA non-solvent like a liquid in a state of aggregation at normal temperature (20 ℃) and normal pressure (101 hPa;1 bar, 1 atm), and having<20 ℃, more preferably<15 ℃ and still more preferably<A melting point of 10 c,<200 ℃ and more preferably<150℃and still more preferably<Boiling point at 100℃, or>25 ℃, more preferably>30℃and even more preferably>Boiling point at 40 ℃ at 20 DEG C<600hPa, more preferably<300hPa, even more preferably<Vapor pressure of 200hPa, or at 20deg.C>1hPa, more preferably>10hPa, still more preferably>The vapor pressure of 30hPa,<0.95g/mL, more preferably<0.9g/mL, still more preferably<A density of 0.8g/mL, 0.0-0.1D (0.0-0.3.10) ^-30 Cm) at 20 c<2.0 mPas, still more preferably<1.5 mPas, even more preferred<A viscosity of 1.0 mPas and in particular a dielectric constant ε of 2.5 or less, more preferably 2.2 or less, even more preferably 2.0 or less at 20 ℃ _r ，>N-octanol-water partition coefficient logKow of 2.0, more preferably not less than 2.5, even more preferably not less than 3.0.

An overview of the dielectric constants and orientation values (given as rounded values) of the non-solvents suitable for use herein are shown in table 1. An overview of other parameters for some specific non-solvents is shown in table 2 (the values given are rounded values).

TABLE 1 overview of dielectric constant and logKow values of the non-solvents (rounded values)

Solvent(s)	Dielectric constant epsilon _r (20℃)	logK _OW
			N-alkane	About 1.80 to 2.00	About 3 to 8
Isoalkanes	About 1.80 to 1.95	About 3 to 8
			Cycloalkane (CNS)	About 1.90 to 2.20	About 3 to 8

Table 2 overview of some physical parameters of some non-solvents (rounded values).

Melting point<Dielectric constant ε at 15℃and 20 DEG C _r Not more than 2.5, logKow not less than 3.0, boiling point<200 ℃, boiling point>Preferred non-solvents having vapor pressures between 1hPa and 600hPa at 20 ℃ include, but are not limited to, pentane, hexane, heptane, octane, nonane, decane, petroleum ether, isooctane, 2-methylpentane, 3-methylpentane, 2-dimethylbutane, 2, 3-dimethylbutane, 2-dimethylbutane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, 2-methyloctane, 2-methylheptane, 3-methylheptane, 4-methylheptane, tetraethylmethane, cyclopentane, cyclohexane, methylcyclopentane, t-butylcyclohexane, methylcyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, 2, 3-dimethylcyclobutane, 1, 2-dimethylcyclobutane, decalin, pinane. Melting point and boiling point data given herein refer to data at normal pressure (101 hPa;1 bar, 1 atm).

Preferred non-solvents herein include pentane, cyclopentane, hexane, cyclohexane, heptane, octane, nonane, and decane.

Melting point<Dielectric constant ε at 10deg.C and 20deg.C _r Not more than 2.0, logKow not less than 3.0, boiling point<150 ℃, boiling point>Further preferred non-solvents having a vapor pressure between 10 and 600hPa at 20deg.C include, but are not limited to, pentane, hexane, heptane, octane, petroleum ether, isooctane, 2-methylpentane, 3-methylpentane, 2-dimethylbutane, 2, 3-dimethylbutane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, 2-methyloctane, 2-methylheptane, 3-methylheptane, 4-methylheptane, tetraethylmethane, cyclopentane, cyclohexane, methylcyclopentane, methylcyclohexane, cycloheptane, 2, 3-dimethylcyclobutane, 1, 2-dimethylcyclobutane. The melting point and boiling point data given here refer to those at normal pressure (10 lhpa;1 bar, 1 atm).

Melting point<Dielectric constant ε at 10deg.C and 20deg.C _r Not more than 2.0, logKow not less than 3.0, boiling point<100 ℃, boiling point>Still further preferred non-solvents having a vapor pressure between 30hPa and 300hPa at 20deg.C include, but are not limited to, hexane, heptane, 2-methylpentane, 3-methylpentane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, cyclohexane, cycloheptane, 2, 3-dimethylcyclobutane, 1, 2-dimethylcyclobutane. The melting point and boiling point data given here refer to those at normal pressure (10 lhpa;1 bar, 1 atm).

Particularly preferred non-solvents herein are hexane, cyclohexane and heptane.

The term "nonpolar organic solvent" as used herein refers to a carbon-based solvent that is liquid at normal temperature (20 ℃) and normal pressure (10 lhpa;1 bar, 1 atm), i.e., has at least a melting point <20 ℃. Examples of nonpolar organic solvents include, but are not limited to, carbon tetrachloride, pure hydrocarbon solvents such as pentane, cyclopentane, hexane, cyclohexane, heptane, octane, nonane, or decane, aromatic solvents such as toluene, benzene, and xylene.

As defined herein, the non-polar organic solvent has a dielectric constant epsilon at 20 deg.c _r 10 or less, more preferably 5.0 or less, more preferably 3.0 or less, even more preferably 2.0 or less, with a n-octanol-water partition coefficient logKow>2.0, more preferably not less than 2.5, even more preferably not less than 3.0. Thus, the dielectric constant ε is at 20 ℃ _r Solvents of 10 or less and logKow 2.0 or less, in particular 1.5 or less, do not constitute the nonpolar organic solvents herein. For example, the dielectric constant ε of 1, 4-dioxane at 20deg.C _r About 2.3, but log K _OW About-0.4, and thus does not represent a non-polar organic solvent herein.

Therefore, it is preferable that the dielectric constant ε be at ordinary temperature (20deg.C) _r Less than or equal to 10 and logKow>2.0, more preferably dielectric constant ε _r Less than or equal to 5 and logKow less than or equal to 2.5, and still more preferably dielectric constant epsilon _r A nonpolar organic solvent of 3.0 or less and logKow of 3.0 or more. In particular, it is preferable that the dielectric constant ε be at ordinary temperature (20 ℃ C.) _r Less than or equal to 2.0 and logKow>3.0.

The nonpolar organic solvents suitable for use in the present invention are present in the liquid state of aggregation at normal temperature (20 ℃) and normal pressure (101 hPa;1 bar, 1 atm). The preferred non-polar organic solvents have a melting point of <20 ℃, more preferably <15 ℃, still more preferably <10 ℃. Preferred non-polar organic solvents also have a boiling point of <200 ℃, further preferably <150 ℃, even more preferably <100 ℃. Preferred non-polar organic solvents also have a boiling point of >25 ℃, more preferably >30 ℃, even more preferably >40 ℃. Thus, the boiling point of the preferred nonpolar organic solvent is from 25 ℃ to 200 ℃, further preferably from 30 ℃ to 150 ℃, still more preferably from 40 ℃ to 100 ℃. Melting point and boiling point data are referred to herein as normal pressure (101 hPa;1 bar, 1 atm).

Preferred non-polar organic solvents also have a vapor pressure of <600hPa, more preferably <300hPa, even more preferably <200hPa at room temperature (20deg.C). Preferred non-polar organic solvents also have a vapor pressure of >1hPa, more preferably >10hPa, even more preferably >30hPa at 20 ℃. Thus, the preferred nonpolar organic solvents exhibit vapor pressures of from 1hPa to 600hPa, more preferably from 10hPa to 300hPa, and even more preferably from 30hPa to 200hPa, at ambient temperature (20deg.C).

Dielectric constant ε at normal temperature (20 ℃ C.) _r Less than or equal to 10 and logKow>Examples of non-polar organic solvents of 2 include, but are not limited to, unbranched C _5-16 Alkanes, such as pentane, hexane, heptane, octane, nonane, decane, petroleum ether; branched C _5-16 Alkanes, e.g. isopentane, isooctane, 2-methylpentane, 3-methylpentane, 2-dimethylbutane, 2, 3-dimethylbutane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, 2-methyloctane, 2-methylheptane, 3-methylheptane, 4-methylheptane, tetraethylmethane or C _5-16 Cycloalkanes such as cyclopentane, cyclohexane, methylcyclopentane, tert-butylcyclohexane, methylcyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, 2, 3-dimethylcyclobutane, 1, 2-dimethylcyclobutane, decalin, pinane, 1, 4-dimethylcyclohexane, 1-dimethylcyclohexane, spiropentane, spirohexane, spiroheptane, light petroleum oils, haloalkanes such as carbon tetrachloride, tetradecane, aromatic hydrocarbons such as benzene, aromatic hydrocarbons having saturated aliphatic substituents such as toluene, o-xylene, m-xylene, p-xylene, mesitylene, 1-phenylbutane, 2-methyl-1-phenylpropane, 2-phenylbutane, cumene, isobutylbenzene, propylbenzene, hexylbenzene, isobutylbenzene, halogenated aromatic hydrocarbons such as chlorobenzene, fluorobenzene, p-dichlorobenzene, o-dichlorobenzene, hexafluorobenzene, bromobenzene, benzyl chloride, benzyl bromide or other substituted aromatic hydrocarbons such as anisole and ethoxybenzene.

Therefore, preferred herein are nonpolar organic solvents which are in the liquid aggregate state at normal temperature (20 ℃) and normal pressure (101 hPa;1 bar, 1 atm) and which have<20 ℃, more preferably<15℃and even more preferably<A melting point of 10 c,<200 ℃ and more preferably<150℃and even more preferably<A boiling point of 100 ℃,>25 ℃, more preferably>30℃and even more preferably>Boiling point at 40 ℃ at 20 DEG C<600hPa, more preferably<300hPa, even more preferably<Vapor pressure of 200hPa at 20deg.C>1hPa, more preferably>10hPa, still more preferably>Vapor pressure of 30hPa, 0.0-0.5D (0.0-1.7.10) ^-30 Cm, youSelecting 0.0-0.1D (0.0-0.3.10) ^-30 Cm), and in particular a dielectric constant epsilon of 10 or less, more preferably 5.0 or less, even more preferably 3.0 or less, even more preferably 2.0 or less at 20 deg.c _r A kind of electronic device>N-octanol-water partition coefficient logKow of 2.0, more preferably not less than 2.5, even more preferably not less than 3.0.

The term "nonpolar organic solvent" as used herein preferably refers to aprotic-nonpolar solvents which are nonpolar due to small differences in electronegativity between carbon and hydrogen and have no permanent dipole moment, so less preferred are halogenated aromatic compounds, such as chlorobenzene, fluorobenzene, p-dichlorobenzene, o-dichlorobenzene, bromobenzene, benzyl chloride, benzyl bromide or further substituted aromatic compounds, such as anisole, ethoxybenzene, having a molecular weight of at least 1.0D (3.3 _* 10 ^-30 Cm) or dielectric constant epsilon of 3 or more at 20 DEG C _r 。

Thus, the preferred nonpolar organic solvents have 0.0-0.5D (0.0-1.7.10) ^-30 Cm), and further preferred non-polar organic solvents do not have a permanent dipole moment, i.e. have a dipole moment of 0.0-0.1D (0.0-0.3.10) ^-30 Cm) of the magnetic field.

Aprotic-nonpolar solvents are very lipophilic and very hydrophobic and are therefore preferred here as nonpolar organic solvents. Representative of aprotic-nonpolar solvents preferred herein are alkanes, benzene, and aromatic compounds with aliphatic and aromatic substituents, perhalogenated hydrocarbons, such as carbon tetrachloride, hexafluorobenzene.

Other representatives of aprotic-nonpolar solvents are olefins, alkynes, aromatic compounds with unsaturated aliphatic substituents and other molecules with completely symmetrical structures, such as tetramethylsilane or carbon disulphide. Aprotic-nonpolar solvents such as alkenes, alkynes, aromatic compounds with unsaturated aliphatic substituents, and other molecules with fully symmetrical structures, such as tetramethylsilane or carbon disulfide, may be used as the nonpolar organic solvent herein, but are less preferred. If such aprotic-nonpolar solvents are used, it must be ensured that they do not react chemically with the microcrystalline limus active substance and the at least one tri-O-acylglycerol. One skilled in the art can readily assess whether a chemical reaction can take place between a particular solvent and the microcrystalline limus active or tri-O-acylglycerol, and whether a particular solvent is suitable for preparing a crystal suspension. Thus, the selection of a suitable solvent is part of the routine work of those skilled in the art.

Thus, preferred nonpolar organic solvents herein are unbranched, branched and cyclic saturated aliphatic hydrocarbons, aromatic hydrocarbons and perhalogenated hydrocarbons having saturated aliphatic substituents.

Thus, preferred nonpolar organic solvents have a dielectric constant ε of 3 or less, more preferably 2.5 or less, more preferably 2.2 or less, even more preferably 2.0 or less at normal temperature (20deg.C) and normal pressure (101 hPa;1 bar, 1 atm) _r And>n-octanol-water partition coefficient logKow of 2.0, more preferably not less than 2.5, even more preferably not less than 3.0.

Thus, particularly preferred herein are non-polar organic solvents which are in the liquid aggregated state at normal temperature (20 ℃) and normal pressure (101 hPa;1 bar, 1 atm) and which have<20 ℃, more preferably<15 ℃ and still more preferably<A melting point of 10 c,<200 ℃ and more preferably<150℃and still more preferably<Boiling point at 100℃, or>25 ℃, more preferably>30℃and even more preferably>Boiling point at 40 ℃ at 20 DEG C<600hPa, more preferably<300hPa, even more preferably<Vapor pressure of 200hPa, or at 20deg.C>1hPa, more preferably>10hPa, still more preferably>Vapor pressure of 30hPa, 0.0-0.5D (0.0-1.7.10) ^-30 Cm), preferably 0.0 to 0.1D (0.0 to 0.3.10) ^-30 Cm) and a dielectric constant epsilon of 3 or less, more preferably 2.5 or less, even more preferably 2.2 or less, even more preferably 2.0 or less at 20 deg.c _r And (2) and>n-octanol-water partition coefficient logKow of 2.0, more preferably not less than 2.5, even more preferably not less than 3.0.

An overview of the dielectric constants of the nonpolar organic solvents and the orientation values of logKow (the values given are rounded values) is shown in table 3.

TABLE 3 overview of dielectric constant and logKow values of nonpolar organic solvents (rounded values).

Solvent(s)	Dielectric constant epsilon _r (20℃)	logK _OW
			N-alkanes	About 1.8 to 2.0	About 3 to 8
Iso-alkanes	About 1.8 to 1.9	About 3 to 8
			Cycloalkane (CNS)	About 1.9 to 2.2	About 3 to 8
Benzene	About 2.3	About 2.1
			Aromatic compounds having aliphatic groups	About 2.2 to 2.5	About 2 to 6
Carbon tetrachloride	About 2.3	About 2.8
			Halogen aromatic compounds	About 5 to 10	About 2 to 4
Aromatic compounds having other groups	About 4 to 5	About 2 to 3

An overview of some physical parameters of some specific examples of non-polar organic solvents, in addition to those already shown in table 2, is shown in table 4 below (the values given are rounded values).

Table 4 overview of some physical parameters of some examples of non-polar organic solvents.

Melting point<Dielectric constant ε at 20deg.C _r ≤3，logKow>2.0 boiling point<200 ℃, boiling point>30 ℃, preferred nonpolar organic solvents having a vapor pressure between 1hPa and 600hPa at 20deg.C include, but are not limited to, pentane, hexane, heptane, octane, nonane, decane, petroleum ether, isooctane, 2-methylpentane, 3-methylpentane, 2-dimethylbutane, 2, 3-dimethylbutane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, 2-methyloctane, 2-methylheptane, 3-methylheptane, 4-methylheptane, tetraethylmethane, cyclopentane, cyclohexane, methylcyclopentane, tert-butylcyclohexane, methylcyclohexane, 2, 3-dimethylcyclobutane, cycloheptane, cyclooctane, cyclononane, cyclodecane, 1, 2-dimethylcyclobutane, decalin, pinane, carbon tetrachloride, tetradecane, hexafluorobenzene, benzene, toluene, o-xylene, m-xylene, p-xylene, mesitylene, ethylbenzene, 1-phenylbutane, 2-methyl-1-phenylpropane, 2-phenylbutane, isopropyl Benzene, isobutylbenzene, propylbenzene. Of course, mixtures of nonpolar organic solvents may also be used.

Even more preferred melting point<Dielectric constant epsilon at 10 deg.C and 20 deg.C _r ≤3，logK _OW >2.0 boiling point<150 ℃, boiling point>Non-polar organic solvents having a vapor pressure of between 10hPa and 600hPa at 20deg.C include, but are not limited to, pentane, hexane, heptane, octane, petroleum ether, isooctane, 2-methylpentane, 3-methylpentane, 2-dimethylbutane, 2, 3-dimethylbutane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, 2-methyloctane, 2-methylheptane, 3-methylheptane, 4-methylheptane, tetraethylmethane, cyclopentane, cyclohexane, methylcyclopentane, cycloheptane, 2, 3-dimethylcyclobutane, 1, 2-dimethylcyclobutane, carbon tetrachloride, tetradecane, hexafluorobenzene, benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene. Of course, mixtures of nonpolar organic solvents may also be used.

Even more preferred melting point<Dielectric constant epsilon at 10 deg.C and 20 deg.C _r ≤2.5，logK _OW >2.0 boiling point<100 ℃, boiling point>Non-polar organic solvents having a vapor pressure of between 10hPa and 300hPa at 20deg.C include, but are not limited to, hexane, heptane, 2-methylpentane, 3-methylpentane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, cyclohexane, cycloheptane, 2, 3-dimethylcyclobutane, 1, 2-dimethylcyclobutane, carbon tetrachloride, tetradecylfluorohexane, hexafluorobenzene, benzene. Of course, mixtures of nonpolar organic solvents may also be used.

Even more preferred melting point<Dielectric constant epsilon at 10 deg.C and 20 deg.C _r ≤2.5，logK _OW Not less than 3.0, boiling point<100 ℃, boiling point>Non-polar organic solvents having a vapor pressure of between 10hPa and 300hPa at 20deg.C include, but are not limited to hexane, heptane, 2-methylpentane, 3Methyl pentane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, cyclohexane, cycloheptane, 2, 3-dimethylcyclobutane, 1, 2-dimethylcyclobutane, carbon tetrachloride. Of course, mixtures of nonpolar organic solvents may also be used.

The preferred non-polar organic solvents are also anhydrous, i.e., dry non-polar organic solvents.

Preferred non-polar organic solvents also have a density of <0.95g/mL, more preferably <0.9g/mL, even more preferably <0.8g/mL at room temperature (20 ℃). Thus, particularly preferred non-polar organic solvents represent the non-solvents defined herein. Thus, particularly preferred non-polar organic solvents herein are hexane, cyclohexane and heptane.

Oils such as coconut oil, palm oil, peanut oil, cottonseed oil, rapeseed oil, fish oil, soybean oil, linseed oil, olive oil are generally non-polar and have a dielectric constant epsilon of about 2-5 at 20 DEG C _r . Such oils as castor oil, coconut oil, palm oil, peanut oil, cottonseed oil, rapeseed oil, fish oil, soybean oil, linseed oil, olive oil are less preferred herein as non-polar organic solvents. These oils are viscous and have a viscosity of about 30-160mPas at 20 ℃. The preferred nonpolar organic solvents herein have a molecular weight at room temperature (20 ℃ C.)<2.0mPas, more preferably<1.5mPas, even more preferred<A viscosity of 1.0 mPas.

The term "polar organic solvent" as used herein refers to carbon-based solvents that are liquid at normal temperature (20 ℃) and normal pressure (101 hPa;1 bar, 1 atm), i.e., have a melting point of at least <20 ℃. Examples of common polar organic solvents include, but are not limited to, acetonitrile, dimethylsulfoxide, ethers such as dioxane, tetrahydrofuran (THF), diethyl ether, methyl tert-butyl ether (MTBE), ketones such as acetone, butanone or pentanone, alcohols such as methanol, ethanol, propanol, isopropanol, carboxylic acids such as formic acid, acetic acid, propionic acid, amides such as Dimethylformamide (DMF) or dimethylacetamide, halogenated solvents such as chloroform, dichloromethane and carboxylic esters such as methyl acetate and ethyl acetate.

The polar organic solvent as defined herein preferably has an n-octanol-water partition coefficient logKow of +.2.0, preferably-1.0 to +2.0, more preferably-0.5 to +1.5, even more preferably-0.4 to +1.4, even more preferably-0.4 to +0.9. Further preferred polar organic solvents have a temperature of 20 DEG C>3, more preferably ∈ of 5.0 or more _r . Preferred polar organic solvents also have a water content of 20 DEG C<50, more preferably<40, still more preferably<35, most preferably<Dielectric constant ε of 30 _r 。

Thus, the preferred organic solvents herein have n-octanol-water partition coefficients logKow of less than or equal to +2.0, and>3 dielectric constant epsilon at 20 DEG C _r Still more preferably from-1.0 to +2.0 and ≡5.0 at 20℃and<40 dielectric constant epsilon _r More preferably from-0.5 to +1.5 and ≡5.0 at 20 ℃ and<dielectric constant ε of 30 _r And most preferably-0.4 to +1.4 log K _OW And at 20 ℃ not less than 5.0<Dielectric constant ε of 30 _r . Thus, preferred organic solvents have n-octanol-water partition coefficients logKow and of-1.0 to +2.0>Dielectric constant ε at 20 ℃ of 3.0 to 40 _r Even more preferably-1.0 to +2.0 and a dielectric constant epsilon at 20 ℃ of 5.0 to 40 _r Even more preferably-1.0 to +2.0 and a dielectric constant epsilon of 5.0 to 35 at 20 DEG C _r And most preferably-0.5 to +1.5 logKow and a dielectric constant epsilon at 20 ℃ of 5.0 to 30 _r . Thus, the dielectric constant ε at 20 ℃ is _r >3 and logKow>The solvent of 2.0 is not a polar organic solvent herein. For example, chlorobenzene has a dielectric constant epsilon at 20 DEG C _r Is about 5.6, but log kow is about 2.9, and thus does not constitute a polar organic solvent herein.

The polar organic solvents suitable for use in the present invention are present in the liquid aggregate state at normal temperature (20 ℃) and normal pressure (101 hPa;1 bar, 1 atm). The preferred polar organic solvents have a melting point of <20 ℃, more preferably <15 ℃, still more preferably <10 ℃. Preferred polar organic solvents also have a boiling point of <200 ℃, further preferably <150 ℃, even more preferably <100 ℃. Preferred polar organic solvents also have a boiling point of >25 ℃, more preferably >30 ℃, even more preferably >40 ℃. Thus, preferred polar organic solvents have a boiling point of 25 ℃ to 200 ℃, further preferably 30 ℃ to 150 ℃, still more preferably 40 ℃ to 100 ℃. Melting point and boiling point data are referred to herein as normal pressure (101 hPa;1 bar, 1 atm).

Preferred polar organic solvents also have a vapor pressure of <600hPa, more preferably <300hPa, even more preferably <200hPa, at room temperature (20deg.C). Preferred polar organic solvents also exhibit a vapor pressure of >1hPa, more preferably >10hPa, even more preferably >30hPa at 20 ℃. Thus, the preferred polar organic solvents exhibit vapor pressures of 1hPa to 600hPa at normal temperature (20deg.C), more preferably 10hPa to 300hPa, and even more preferably 30hPa to 200 hPa.

Preferred polar organic solvents have a D of 1.0 (3.3.10) ^-30 Cm), further preferred polar organic solvents have a dipole moment of 3.0D (9.9.10) ^-30 Cm), even more preferably ∈2.0D (6.6.10) ^-30 Cm) of the magnetic field.

As used herein, the term "polar organic solvent" refers to aprotic polar solvents and protic solvents. In aprotic polar solvents, the molecules are asymmetrically substituted such that the molecules have dipole moments. Examples of aprotic polar solvents include ethers, esters, anhydrides, ketones such as acetone, tertiary amines, pyridine, furan, thiophene, asymmetric halogenated hydrocarbons, nitromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethyl carbonate, tetramethylurea, tetraethylurea, dimethylpropyleneurea (DMPU), 1, 3-dimethyl-2-imidazolidinone (DMEU). The most important protic solvent is water. Examples of other protic solvents are alcohols, aldehydes and carboxylic acids. Thus, protic solvents are water, methanol, ethanol and other alcohols, primary and secondary amines, formamides and carboxylic acids such as formic acid and acetic acid.

Preferred polar organic solvents are in particular aprotic polar solvents, as they are generally miscible with the non-polar organic solvents as defined herein, in particular the non-solvents as defined herein, in any mixing ratio.

An overview of the dielectric constants of some polar organic solvents and orientation values of logKow (given as rounded values) is shown in table 5.

Table 5: overview of dielectric constant and logKow of some polar organic solvents (rounded values)

Solvent(s)	Dielectric constant epsilon _r (20℃)	logK _OW
			Halogenated alkanes	About 3 to 11	About +1.0 to +1.98
Alkyl ethers	About 4 to 8	About-0.4 to +1.98
			Alkyl ketones	About 15 to 25	About-0.5 to +1.5
Pyridine compound	About 9 to 13	About +0.6
			Alkylnitriles	About 25 to 38	About-0.3 to +0.5
Alkyl amines	About 3 to 7	About-0.8
			Alkyl diols	About 30 to about 50	About-0.9
Higher alkyl alcohols	About 5 to 17	About +0.8- > +2.0
			Lower alkyl alcohols	ca.19-32	About-0.7 to +0.3
Aldehydes	About 9 to 18	About-4.0
			Formic acid	About 50	About-0.5
Higher carboxylic acids	About 2 to 6	About-0.2
			Alkyl esters	About 3 to 9	About +0.0- > +2.0%
Water and its preparation method	About 80	About-1.4
			DMF	About 37	About-1.0
DMSO	About 47	About-1.4

An overview of some of the physical parameters of some of the polar organic solvents (given as rounded values) is shown in table 6 below.

Table 6: overview of some physical parameters of some examples of polar organic solvents.

Preferred polar organic solvents are tetrahydrofuran, acetone, methanol, ethanol, n-propanol, isopropanol, chloroform, methylene chloride (dichloromethane) and ethyl acetate (ethyl acetate).

Further preferred polar organic solvents are tetrahydrofuran, acetone, ethanol, n-propanol, isopropanol and ethyl acetate.

Most preferred are the physiologically substantially harmless solvents ethanol, isopropanol and ethyl acetate. Ethyl acetate is particularly preferred.

Of course, mixtures of polar organic solvents may also be used.

Water is considered a very polar organic solvent, but should be avoided because the aqueous coating is difficult to dry. Furthermore, the tri-O-acylglycerols according to the invention are poorly soluble or hardly soluble in very polar solvents such as water. Suspensions containing only water as solvent are not according to the invention, since the tri-O-acylglycerols selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol cannot be present in dissolved form in water. However, it is also possible to provide an aqueous solvent mixture of water-miscible polar organic solvents, wherein at least one tri-O-acylglycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol is present in dissolved form, for example a solvent mixture such as water/methanol (25:75), water/isopropanol (35:65) or water/acetonitrile (15:85). However, anhydrous solvent mixtures are preferred herein.

Thus, particularly preferred are anhydrous suspensions for coating medical products (preferably catheter balloons, balloon catheters, stents and cannulas) containing at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol and at least one limus active substance in microcrystalline form; and a solvent or solvent mixture, wherein the at least one tri-O-acylglycerol is dissolved in the at least one solvent or solvent mixture, and wherein the crystallites of the at least one limus active substance are not dissolved in the solvent or solvent mixture containing the dissolved at least one tri-O-acylglycerol.

As used herein, an "anhydrous suspension" contains no more than 20% by volume of water, preferably less than 20% by volume, more preferably less than 10% by volume, more preferably less than 5% by volume, more preferably less than 3% by volume, more preferably less than 2% by volume, more preferably less than 1.5% by volume, still more preferably less than 1% by volume, still more preferably less than 0.5% by volume, and most preferably less than 0.1% by volume of water, based on the total volume of the suspension.

In some preferred embodiments, the suspension of the present invention comprises a solvent mixture in which at least one tri-O-acylglycerol will dissolve and at least one microcrystal of a limus active substance will not dissolve. Preferred solvent mixtures herein are mixtures of at least one non-polar organic solvent, preferably a mixture of at least one non-solvent and at least one polar organic solvent. The nonpolar organic solvent or the non-solvent and the polar organic solvent must be miscible with each other and preferably with each other in any proportion to obtain a homogeneous mixture.

The non-polar organic solvents as defined herein are generally not miscible with water and other highly polar organic solvents such as short chain alcohols, e.g. methanol, in any proportion. Non-polar organic solvents that are not miscible with water include, but are not limited to, benzene, carbon tetrachloride, cyclohexane, heptane, hexane, isooctane, pentane, toluene, and xylene. Thus, in particular, the non-solvent as defined herein is not miscible with water. Thus, solvent mixtures containing at least one non-solvent are particularly preferably free of water as a mixture component. In addition, some nonpolar organic solvents such as xylene, cyclohexane, heptane, hexane, isooctane, and pentane are not miscible in any proportion even with very polar organic solvents such as dimethyl sulfoxide and dimethylformamide. In addition, non-solvents as defined herein, such as cyclohexane, heptane, hexane, isooctane and pentane, are also immiscible with polar organic solvents, such as acetonitrile and methanol.

Thus, the solvent mixture of at least one non-solvent as defined herein and at least one polar organic solvent particularly preferably contains a dielectric constant ε having a logKow of-0.5 to +1.5 and at 20 DEG C _r <30, further preferably a logKow of-0.4 to +1.4 and a dielectric constant ε at 20 DEG C _r <30.

In some embodiments, the volume ratio between the non-polar organic solvent and the polar organic solvent in the suspension is 25:75 to 75:25, preferably 30:70 to 70:30, more preferably 35:65 to 65:35.

preferably, the volume ratio between the non-polar organic solvent and the polar organic solvent in the suspension is 99:1 to 65:35, preferably 95:5 to 70:30, more preferably 80:20 to 65:35, more preferably 90:10 to 80:15, most preferably 85:15.

further preferred are solvent mixtures containing at least 50% by volume of a non-polar organic solvent, more preferably at least 55% by volume of a non-polar organic solvent, more preferably at least 60% by volume of a non-polar organic solvent, more preferably at least 65% by volume of a non-polar organic solvent, more preferably at least 70% by volume of a non-polar organic solvent, more preferably at least 75% by volume of a non-polar organic solvent, and most preferably at least 80% by volume of a non-polar organic solvent.

Further preferred are solvent mixtures containing at least 50% by volume of non-solvent, more preferably at least 55% by volume of non-solvent, more preferably at least 60% by volume of non-solvent, more preferably at least 65% by volume of non-solvent, more preferably at least 70% by volume of non-solvent, more preferably at least 75% by volume of non-solvent and most preferably at least 80% by volume of non-solvent.

In a preferred embodiment, the solvent mixture thus contains at least one nonpolar organic solvent having a dielectric constant ε at 20 ℃ _r N-octanol-water distribution coefficient logKow less than or equal to 10>2.0, more preferably a dielectric constant ε at 20 DEG C _r A n-octanol-water distribution coefficient logKow of 2.5 or more, more preferably a dielectric constant ε at 20 ℃ of 5.ltoreq.0 _r A n-octanol-water distribution coefficient logKow of 3.0 or more, most preferably a dielectric constant epsilon at 20 DEG C _r ≤2.0。

In a further preferred embodiment, the solvent mixture contains at least 50% by volume, more preferably at least 55% by volume, more preferably at least 60% by volume, more preferably at least 65% by volume, more preferably at least 70% by volume, more preferably at least 75% by volume and most preferably at least 80% by volume of a non-polar organic solvent having a dielectric constant ε at 20 ℃ of 10 or less _r And>n-octanol-water partition coefficient logKow of 2.0, more preferably having a dielectric constant ε at 20 ℃ of 5.0 or less _r And n-octanol-water distribution coefficient logKow.gtoreq.2.5, more preferably having a dielectric constant ε at 20 ℃ of 3.0 or less _r And n-octanol-water distribution coefficient logKow.gtoreq.3.0, and most preferably has a dielectric constant ε at 20 ℃ of 2.0 or less _r 。

Preferred combinations of polar and non-polar organic solvents are for example ethanol and cyclohexane or ethyl acetate and heptane.

Preferred are solvent mixtures of at least one polar organic solvent and a nonpolar organic solvent, the polar organic solvent having a logKow of from-1.0 to +2.0 and a dielectric constant epsilon at 20 ℃ of from 3.0 to 40 _r Even more preferably-1.0 to +2.0 logKow and a dielectric constant epsilon at 20 ℃ of 5.0 to 40 _r Even more preferably-1.0 to +2.0 logKow and a dielectric constant epsilon at 20 ℃ of 5.0 to 35 _r More preferably-0.5 to +1.5 and a dielectric constant epsilon at 20 ℃ of 5.0 to 30 _r And most preferably-0.4 to +0.9 logKow and a dielectric constant epsilon at 20 ℃ of 5.0 to 30 _r The method comprises the steps of carrying out a first treatment on the surface of the The non-polarity is provided withThe organic solvent has a dielectric constant epsilon at 20 ℃ of less than or equal to 10 _r And>n-octanol-water partition coefficient logKow of 2.0, more preferably having a dielectric constant ε at 20 ℃ of 5.0 or less _r And n-octanol-water distribution coefficient logKow of 2.5 or more, more preferably having dielectric constant ε at 20 ℃ of 3.0 or less _r And n-octanol-water partition coefficient logKow of 3.0 or more, and most preferably has a dielectric constant ε at 20 ℃ of 2.0 or less _r 。

Preferred are solvent mixtures of at least one polar organic solvent and a non-polar organic solvent, the polar organic solvent being selected from the group comprising or consisting of: tetrahydrofuran, acetone, methanol, ethanol, n-propanol, isopropanol, chloroform, dichloromethane, ethyl acetate, preferably tetrahydrofuran, acetone, ethanol, n-propanol, isopropanol, and ethyl acetate, further preferably ethanol, isopropanol, and ethyl acetate; the non-polar organic solvent has a dielectric constant epsilon at 20 DEG C _r N-octanol-water distribution coefficient logKow less than or equal to 10>2.0, more preferably having a dielectric constant ε at 20deg.C of 5.0 or less _r And n-octanol-water distribution coefficient logKow of 2.5 or more, more preferably having dielectric constant ε at 20 ℃ of 3.0 or less _r And n-octanol-water distribution coefficient logKow of 3.0 or more, and most preferably having a dielectric constant ε at 20 ℃ of 2.0 or less _r 。

A particularly preferred combination of a polar organic solvent and a non-polar organic solvent is a solvent mixture of ethyl acetate and a non-polar organic solvent as defined herein, said non-polar organic solvent having a dielectric constant epsilon at 20 deg.c _r N-octanol-water distribution coefficient logKow less than or equal to 10>2.0, more preferably a dielectric constant ε at 20 DEG C _r A n-octanol-water distribution coefficient logKow of 2.5 or more, more preferably a dielectric constant ε at 20 ℃ of 5.ltoreq.0 _r Not more than 3.0 and n-octanol-water distribution coefficient logKow not less than 3.0, and most preferably having a dielectric constant ε at 20 ℃ not more than 2.0 _r 。

An even more preferred combination of a polar organic solvent and a non-polar organic solvent is a solvent mixture of ethyl acetate and a non-solvent as defined herein, said non-solvent having a dielectric constant epsilon at 20 DEG C _r ≤2.0。

Preferred combinations of polar organic solvents and non-polar organic solvents are ethyl acetate and non-polar organic solvents selected from the group comprising or consisting of: pentane, hexane, heptane, octane, nonane, decane, petroleum ether, isooctane, 2-methylpentane, 3-methylpentane, 2-dimethylbutane, 2, 3-dimethylbutane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, 2-methyloctane, 2-methylheptane, 3-methylheptane, 4-methylheptane, tetraethylmethane, cyclopentane, cyclohexane, methylcyclopentane, tert-butylcyclohexane, methylcyclohexane, 2, 3-dimethylcyclobutane, cycloheptane, cyclooctane, cyclononane, cyclodecane, 1, 2-dimethylcyclobutane, decalin, pinane, carbon tetrachloride, tetradecane, hexafluorobenzene, benzene, toluene, o-xylene, m-xylene, p-xylene, mesitylene, ethylbenzene, 1-phenylbutane, 2-methyl-1-phenylpropane, 2-phenylbutane, cumene, isobutylbenzene, propylbenzene, preferably pentane, hexane, heptane, octane, petroleum ether, isooctane, 2-methylpentane, 3-methylpentane, 2-dimethylbutane, 2, 3-dimethylbutane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, 2-methyl octane, 2-methyl heptane, 3-methyl heptane, 4-methyl heptane, tetraethyl methane, cyclopentane, cyclohexane, methylcyclopentane, methylcyclohexane, cycloheptane, 2, 3-dimethylcyclobutane, 1, 2-dimethylcyclobutane, carbon tetrachloride, tetradecahydrohexane, hexafluorobenzene, benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, further preferably hexane, heptane, 2-methylpentane, 3-methylpentane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, cyclohexane, cycloheptane, 2, 3-dimethylcyclobutane, 1, 2-dimethylcyclobutane, carbon tetrachloride, tetradecahydrohexane, hexafluorobenzene, benzene, still further preferred are hexane, heptane, 2-methylpentane, 3-methylpentane, 2-dimethylpentane, 2-methylhexane, 3-methylhexane, 2, 3-dimethylpentane, 2, 4-dimethylpentane, 3-dimethylpentane, 3-ethylpentane, 2, 4-trimethylpentane, 2, 4-trimethylbutane, cyclohexane, cycloheptane, 2, 3-dimethylcyclobutane, 1, 2-dimethylcyclobutane, carbon tetrachloride and most preferred are hexane, heptane and cyclohexane.

Kow is the n-octanol-water partition coefficient. Thus Kow is the partition coefficient of a substance in a two-phase system of n-octanol and water. logKow is the decimal logarithm of Kow. logKow is also known as log P in the english world. The Kow is used as a measure of the relationship between lipophilicity and hydrophilicity of a substance. If the substance is more soluble in a lipophilic solvent such as n-octanol, this value is greater than 1, if it is more soluble in water, this value is less than 1.

n-Octanol-water partition coefficient log kow for various solvents is well known to those skilled in the art, see, e.g., james Sangster, "Octanol-Watter Partition Coefficients of Simple Organic Compounds," j.Phys.chem. Ref.data 1989, vol.18, no.3, pp.1111-1227, which is incorporated herein by reference in its entirety. Polar organic solvents are defined herein as those having a logKow of from-1.0 to +2.0, preferably from-0.5 to +1.5. Non-solvents or non-polar organic solvents are defined herein as those having a logkow.gtoreq.2.8, preferably logkow.gtoreq.3.3 or logKow from +2.8 to +7.5, preferably +3.3 to +7.0.

Measurement methods for determining the n-Octanol-water partition coefficient are also well known to the person skilled in the art, see for example James Sangster, "Octanol-Watter Partition Coefficients of Simple Organic Compounds", J.Phys.chem. Ref. Data 1989, vol.18, no.3, pp.1111-1227, content in the "measurement methods (Methods of Measurement)" section. The actual determination of the logKow value can be performed as follows: will have a known concentration c _0b ^{Water and its preparation method} Corresponding solvent of (2) is in a known volume V ^{Water and its preparation method} Introducing into aqueous solution, the upper layer being covered with octanol V of precisely measured volume ^{Octanol (octanol)} And mixed vigorously. The phases are then awaited to separate and separate the octanol phase. To ensure that no further volume changes occur during phase mixing, the octanol used is pre-treated with waterThe water used was saturated beforehand with octanol. logKow is positive for lipophilic solvents and negative for hydrophilic solvents.

Table 7: overview of logKow values for some polar organic solvents

TABLE 8 LogK of some non-polar organic solvents _OW Overview of values

Solvent(s)	logK _OW	Solvent(s)	logK _OW
				Toluene (toluene)	2.73	Pentane	3.45
Benzene	2.13	Cyclopentane process	3.00
				Cyclohexane	2.86	Hexane	4.00
Nonane (nonane)	5.65	Heptane (heptane)	4.50
				Decane	6.25	Octane (octane)	5.15
O-xylene	3.12	Mesitylene	3.42
				m-xylene	3.20	Petroleum ether	4.20
P-xylene	3.15

Between the logKow value of the polar organic solvent and the logKow value of the non-polar organic solvent, there should be a difference of at least 1.0, preferably at least 1.5, and more preferably at least 2.0.

To determine the Kow of the mixture of nonpolar organic solvents, the Kow values of the respective nonpolar organic solvents are weighted according to the volume fraction of the mixture, and an average value is determined from the weighted Kow values.

Dielectric constant (relative dielectric constant, formula symbol ε) _r ) Is a physical substance constant that may be used to describe certain properties of a solvent. Solvents with high dielectric constants are good solvents for ionic and other polar compounds, solvents with low dielectric constants are better solvents for non-polar compounds. The term "dielectric constant" is also known in the art as dielectric constant, dielectric conductivity, dielectric property or dielectric function. Relative dielectric constant ε of medium _r Also known as dielectric constant or permittivity, is the dielectric constant ε and the dielectric constant ε of vacuum ₀ Is a dimensionless ratio of (c). Epsilon for gaseous, liquid and solid substances _r >1. Measurement methods for determining the relative permittivity are well known to those skilled in the art. Many methods for measuring dielectric constants have been developed. For example, the open coaxial probe method is applicable to liquids. In this method, the probe is immersed in a liquid, and the reflectance is measured and used to determine the dielectric constant.

According to the invention, the suspension according to the invention contains a solvent or a solvent mixture. According to the invention, at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol is dissolved in a solvent or a solvent mixture. According to the invention, the suspension thus contains a solvent or a mixture of solvents in which at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol is dissolved, wherein the crystallites of the at least one limus active substance are not dissolved or are not dissolved any more in the presence of the at least one tri-O-acylglycerol.

Thus, by definition, the solvent or solvent mixture forms a solution with the dissolved at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, and thus constitutes a homogeneous mixture. Thus, the solution of at least one tri-O-acyl glycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol in the solvent or solvent mixture has only one phase, and the dissolved at least one tri-O-acyl glycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol is homogeneously distributed in the solvent or solvent mixture.

The suspension according to the invention is thus a combination of:

1) A solution of at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol in a solvent or solvent mixture, and

2) At least one active substance of the limus in microcrystalline form, wherein the microcrystals of said at least one active substance of the limus are insoluble in the solution according to 1).

At least one active substance of the limus in microcrystalline form is finely distributed as a solid, i.e. "suspended" in a solution of at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol in at least one solvent or solvent mixture. Thus, according to the present invention, the microcrystals of at least one limus active substance are "suspended" in a solution of at least one tri-O-acylglycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol in a solvent or mixture of solvents.

The invention therefore also relates to a suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprising:

a) At least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol;

b) At least one active substance of limus in microcrystalline form; and

c) A solvent or a mixture of solvents is used,

wherein the at least one tri-O-acylglycerol is dissolved in the solvent or solvent mixture and

wherein the microcrystals of the at least one limus active substance are insoluble in a solvent or solvent mixture containing dissolved at least one tri-O-acylglycerol.

In other words, the present invention relates to a suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprising:

a) A solution of at least one of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol;

b) At least one active substance of limus in microcrystalline form, said microcrystalline being suspended in said solution.

In still other words, the present invention relates to a suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprising:

a) Solutions of at least one of trioctyl glycerol, dinonyl glycerol, tridecyl glycerol and triundecyl glycerol, and

b) Microcrystals of at least one limus active substance suspended in said solution.

The present invention thus relates to a suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprising:

a) At least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol,

b) At least one active substance of limus in microcrystalline form, and

c) A solvent or solvent mixture in which said at least one tri-O-acylglycerol is dissolved and in which said microcrystals of at least one limus active substance are not dissolved,

wherein the crystallites of the at least one limus active substance have a crystal size in the range of 1 μm to 300 μm.

The present invention relates to a suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprising:

b) At least one active substance of limus in microcrystalline form, and

wherein the at least one limus active substance has a crystallinity of at least 90% by weight.

b) At least one active substance of limus in microcrystalline form, and

wherein the at least one limus active substance is selected from rapamycin (sirolimus), everolimus, zotarolimus, lamimus, deforolimus, mepimox, noose Wo Mosi, pimecrolimus, sirolimus, tacrolimus and temsirolimus.

b) At least one active substance of limus in microcrystalline form, and

wherein the at least one limus active substance is selected from rapamycin (sirolimus) and everolimus.

b) At least one active substance of limus in microcrystalline form, and

Wherein the crystallites of the at least one limus active substance have a crystal size in the range of 1 μm to 300 μm,

b) At least one active substance of limus in microcrystalline form, and

wherein the crystallinity of the at least one limus active agent is at least 90% by weight,

b) At least one active substance of limus in microcrystalline form, and

wherein the at least one tri-O-acylglycerol and the at least one limus active are present in a mass ratio of 10% to 30% tri-O-acylglycerol to 90% to 70% limus active.

b) At least one active substance of limus in microcrystalline form, and

wherein the at least one limus active substance is selected from rapamycin (sirolimus), everolimus, zotarolimus, lamimus, deforolimus, meolimus, noose Wo Mosi, pimecrolimus, dipholimus, tacrolimus and temsirolimus,

b) At least one active substance of limus in microcrystalline form, and

wherein the at least one limus active substance is selected from rapamycin (sirolimus) and everolimus,

b) At least one active substance of limus in microcrystalline form, and

wherein the solvent is a dielectric constant ε at 20 DEG C _r 2.0 or less, or said solvent mixture having at least 50% by volume of a dielectric constant epsilon at 20 DEG C _r A non-solvent content of less than or equal to 2.0.

b) At least one active substance of limus in microcrystalline form, and

c) A solvent mixture in which the at least one tri-O-acylglycerol is dissolved and in which the crystallites of the at least one limus active substance are not dissolved,

wherein the solvent mixture is a mixture of at least one polar organic solvent having-0.5 to +1.5 n-octyl and at least one non-polar organic solventAlcohol-water distribution coefficient logKow and dielectric constant ε at 20 ℃ of 5.0 to 30 _r The nonpolar organic solvent has a dielectric constant epsilon of 3.0 or less at 20 DEG C _r And n-octanol-water partition coefficient logKow of 3.0 or more.

b) At least one active substance of limus in microcrystalline form, and

Wherein the solvent mixture is a mixture of at least one polar organic solvent and at least one non-polar organic solvent, the polar organic solvent having an n-octanol-water partition coefficient log Kow of-0.5 to +1.5 and a dielectric constant ε at 20 ℃ of 5.0 to 30 _r The nonpolar organic solvent has a dielectric constant epsilon of 3.0 or less at 20 DEG C _r And n-octanol-water partition coefficient logKow of 3.0 or more.

b) At least one active substance of limus in microcrystalline form, and

Wherein the solvent is a dielectric constant ε at 20 DEG C _r 2.0 or less, or the solvent mixture contains at least 50% by volume of a dielectric constant epsilon at 20 DEG C _r A non-solvent of less than or equal to 2.0.

b) At least one active substance of limus in microcrystalline form, and

wherein the solvent mixture is a mixture of at least one polar organic solvent and at least one non-polar organic solvent, the at least one polar organic solvent having an n-octanol-water partition coefficient log Kow of-0.5 to +1.5 and a dielectric constant ε at 20 ℃ of 5.0 to 30 _r The at least one nonpolar organic solvent has a dielectric constant ε of 20 ℃ of 3.0 or less _r And n-octanol-water partition coefficient logKow of 3.0 or more.

b) At least one active substance of limus in microcrystalline form, and

wherein the solvent mixture is a mixture of at least one polar organic solvent and at least one non-polar organic solvent, the polar organic solvent havingN-octanol-water distribution coefficient log Kow of 0.5 to +1.5 and dielectric constant ε of 5.0 to 30 at 20 DEG C _r The nonpolar organic solvent has a dielectric constant epsilon of 3.0 or less at 20 DEG C _r And n-octanol-water partition coefficient logKow of 3.0 or more.

b) At least one active substance of limus in microcrystalline form, and

wherein the solvent mixture is selected from ethanol and cyclohexane or ethyl acetate and heptane.

b) At least one active substance of limus in microcrystalline form, and

wherein the at least one tri-O-acylglycerol and the at least one limus active are present in a mass ratio of 10% to 30% tri-O-acylglycerol to 90% to 70% limus active,

b) At least one active substance of limus in microcrystalline form, and

Wherein the solvent mixture is a mixture of at least one polar organic solvent and at least one non-polar organic solvent, the polar organic solvent having an n-octanol-water partition coefficient log Kow of-0.5 to +1.5 and a dielectric constant ε at 20 ℃ of 5.0 to 30 _r The nonpolar organic solvent has a dielectric constant epsilon of 3.0 or less at 20 DEG C _r And n-octanol-water distribution coefficient log K not less than 3.0ow。

b) At least one active substance of limus in microcrystalline form, and

Wherein the solvent is a dielectric constant ε at 20 DEG C _r 2.0 or less, or the solvent mixture contains at least 50% by volume of a medium at 20 DEG CElectric constant epsilon _r A non-solvent of less than or equal to 2.0.

b) At least one active substance of limus in microcrystalline form, and

The invention thus preferably relates to a suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprising:

b) At least one active substance of limus in microcrystalline form, and

c) A solvent or a mixture of solvents in which said at least one tri-O-acylglycerol is dissolved and in which said at least one microcrystal of a limus active substance is insoluble or in which said at least one microcrystal of a limus active substance is insoluble when said at least one tri-O-acylglycerol is present

Wherein,,

wherein the suspension contains 1-6% of the active substance of limus.

In some further embodiments, the coating suspension may consist of only three components: a) At least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol; b) At least one active substance of limus in microcrystalline form; and c) at least one solvent or solvent mixture in which said at least one tri-O-acylglycerol is dissolved and in which the crystallites of the at least one limus active substance are insoluble.

Additive agent

The suspension according to the invention may contain one or more additives in addition to the above-mentioned at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol, and tri (undecyl) glycerol or a mixture of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and/or tri (undecyl) glycerol. In particular, the one or more additives are preferably dissolved in the suspension.

In a preferred embodiment, the suspension according to the invention is free of polymers, oligomers, metals or metal particles, organometallic compounds and salts. Thus, in some embodiments, the suspension for coating a medical product according to the present invention is free of polymers, oligomers, metals or metal particles, organometallic compounds and salts.

In a preferred embodiment, antioxidants may be present as additives in the suspension according to the invention. The antioxidant may be added to the suspension for the purpose of durability of the at least one limus active substance.

Suitable antioxidants include Butylhydroxytoluene (BHT), butylhydroxyanisole, ascorbyl palmitate, ascorbyl stearate, tocopheryl acetate, ascorbic acid, tocopherols, and tocotrienols (e.g., alpha-tocopherol), carotenoids such as beta-carotene, zeaxanthin, lycopene and lutein, vitamin C, nordihydroguar acid, probucol, propyl gallate, secondary plant compounds (flavonoids) such as catechin, gallocatechin, epicatechin, epigallocatechin, gallate, taxifolin, isoliquiritigenin, xanthohumol, morin, quercetin (rutin and methyl ether isorhamnetin), kaempferol, myricetin, feissuenone, jin Siding, luteolin, apigenin, hesperetin, ioglycol, genistein, soy bean, licorice, anthocyanin, garlicin, astaxanthin, glutathione, resveratrol, derivatives thereof, and combinations thereof.

Thus, the preferred antioxidant is Butyl Hydroxy Toluene (BHT) which prevents or delays rancidity (Ranzig) in particular in the fatty phase after contact with air, butyl Hydroxy Anisole (BHA), tocopherols, carotenoids, flavonoids, and of course mixtures of said antioxidants.

Butyl Hydroxy Toluene (BHT) is particularly preferred as an antioxidant.

If one or more antioxidants are added to the suspension, the total content thereof is from 0.001 to 15.0% by weight, preferably from 0.01 to 10.0% by weight, particularly preferably from 0.05 to 5.0% by weight, relative to the active substance of the limus.

In some embodiments, flocculation inhibitors may be present in the suspensions of the present invention as additives that may prevent the microcrystalline settling of at least one limus active substance in the suspension. Suitable flocculation inhibitors include, but are not limited to, polysorbates, such as tween 80. The flocculation inhibitors are preferably used in the preparation of crystal suspensions at very low active substance levels.

For example, a 3% everolimus-containing suspension with uniformly distributed crystals can be prepared without flocculation inhibitors; the addition of flocculation inhibitors from about 1.5-1% suspension (w/v) and below may be advantageous, as these additionally prevent sedimentation of the crystallites and thus also allow a uniform coating.

If one or more flocculation inhibitors are added to the suspension, the amount of addition capable of maintaining the microcrystalline suspension must be determined for each limus active substance alone. The total amount of microcrystalline limus active substance in the suspension is preferably very low, between 1.0 and 0.001 wt.%, more preferably 0.5 to 0.005 wt.%, particularly preferably 0.1 to 0.01 wt.%.

Another non-polymeric additive may also be added to the solution as a matrix. For example, contrast agents or contrast agent analogues are suitable, as well as biocompatible organic substances, which likewise improve or do not negatively alter the coating properties.

In some embodiments, the suspensions of the invention may also contain one or more polymers as additives, such as polyvinylpyrrolidone (PVP). Suitable polymer additives are polymers which are soluble in organic solvents, in particular in nonpolar solvents. Very hydrophilic water-soluble polymers which are poorly soluble or hardly soluble in organic solvents are not preferred. Furthermore, care must be taken to ensure that the crystallites of the at least one limus active substance do not dissolve in the presence of the polymer dissolved in the suspension. Polymers for use in the coating of medical products are known in the art. Thus, a person skilled in the art can easily select a suitable polymer as additive.

However, polymer-free suspensions for coating medical products are particularly preferred herein.

The present invention thus relates to a suspension for coating a medical device, preferably selected from a catheter balloon, balloon catheter, stent or cannula, consisting of:

a) At least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol; and

b) At least one active substance of the type in microcrystalline form, wherein the active substance of the type is selected from the group consisting of rapamycin (sirolimus), everolimus, zotarolimus, aconitum, deforolimus, meolimus, no Wo Mosi, pimecrolimus, dipholimus, tacrolimus and temsirolimus, and

c) A solvent or solvent mixture in which the at least one tri-O-acylglycerol is dissolved and in which the crystallites of the at least one limus active substance are not dissolved when the at least one tri-O-acylglycerol is present, and

d) An additive of up to 5.0 wt% based on Yu Limo st active substance or an antioxidant of up to 15.0 wt% based on limus active substance as additive and an additive of up to 5.0 wt% based on Yu Limo st active substance that is not an antioxidant, wherein the total amount of additives is not more than 15.0 wt% based on limus active substance.

Suitable additives are the substances mentioned below, preferably antioxidants, polyvinylpyrrolidone (PVP) and flocculation inhibitors.

d) An additive of up to 5.0 wt% based on Yu Limo st active substance or an antioxidant of up to 15.0 wt% based on limus active substance as an additive and an additive of up to 5.0 wt% based on Yu Limo st active substance that is not an antioxidant, wherein the total amount of additives is not more than 15.0 wt% based on limus active substance,

b) At least one active substance of limus in microcrystalline form, wherein the active substance of limus is selected from rapamycin (sirolimus), everolimus, zotarolimus, aconitum, deforolimus, meolimus, no Wo Mosi, pimecrolimus, dipholimus, tacrolimus and temsirolimus, and

The invention therefore preferably relates to a suspension for coating a medical product, preferably selected from catheter balloons, balloon catheters, stents or cannulas, consisting of:

d) Up to 5.0 wt% of additive based on Yu Limo st active substance or up to 15.0 wt% of antioxidant based on limus active substance as additive and up to 5.0 wt% of additive not being antioxidant based on Yu Limo st active substance, wherein the total amount of additives is not more than 15.0 wt% based on limus active substance,

wherein the solvent mixture is a mixture of at least one polar organic solvent and at least one non-polar organic solventThe polar organic solvent has an n-octanol-water distribution coefficient logKow of-0.5 to +1.5 and a dielectric constant epsilon at 20 ℃ of 5.0 to 30 _r The nonpolar organic solvent has a dielectric constant epsilon of 3.0 or less at 20 DEG C _r And n-octanol-water partition coefficient logKow of 3.0 or more.

wherein the at least one tri-O-acylglycerol and the at least one limus active substance are present in a mass fraction of 10% -30% tri-O-acylglycerol to 90% -70% limus active substance,

Method for producing a suspension

The invention also relates to a method for preparing a suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprising the steps of:

a) Dissolving at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol in a solvent or solvent mixture;

b) Adding at least one active substance of the micro-crystalline form of the limus to the solution of step a), or adding the solution of step a) to at least one active substance of the micro-crystalline form of the limus,

Wherein the crystallites of the at least one limus active substance are insoluble in the solution of step a).

In other words, the invention also relates to a method for preparing a suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprising the steps of:

b) Preparing a suspension of at least one active substance of the limus in microcrystalline form and the solution of step a),

Preferably, the crystallinity of the at least one limus active substance is at least 90% by weight. Preferably, the crystallites of the at least one limus active substance have a crystal size in the range of 1 μm to 300 μm, more preferably a crystal size of at most 100 μm, more preferably a crystal size in the range of 10 μm to 50 μm. More preferably, the at least one limus active substance is selected from rapamycin (sirolimus), everolimus, zotarolimus, lamimus, deforolimus, meolimus, no Wo Mosi, pimecrolimus, sirolimus, tacrolimus and temsirolimus. Even more preferably, the at least one limus active substance is selected from rapamycin (sirolimus) and everolimus. Particularly preferably, the at least one active substance of limus is everolimus. Preferably, the solvent is a dielectric constant ε at 20deg.C _r 2.0 or less, or the solvent mixture contains at least 50% by volume of a dielectric constant epsilon at 20 DEG C _r A non-solvent of less than or equal to 2.0. Preferably, the solvent mixture is a mixture of at least one polar organic solvent and at least one non-polar organic solvent, the polar organic solvent having an n-octanol-water partition coefficient log Kow of from-0.5 to +1.5 and a dielectric constant ε at 20 ℃ of from 5.0 to 30 _r The nonpolar organic solvent has a dielectric constant epsilon at 20 ℃ of 3.0 or less _r And n-octanol-water partition coefficient logKow of 3.0 or more.

In other words, the present invention relates to a method for preparing a suspension for coating a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, comprising the steps of:

a) Providing a solution of at least one tri-O-acyl glycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol in a solvent or solvent mixture;

b) Providing at least one active substance of limus in microcrystalline form,

c) Preparing a suspension by combining the solution according to step a) with at least one active substance of the limus in microcrystalline form according to step b),

Wherein the microcrystals of said at least one limus active substance according to step b) are insoluble in the solution according to step a).

Preferably, the crystallinity of the at least one limus active substance is at least 90% by weight. Preferably, the crystallites of the at least one limus active substance have a crystal size in the range of 1 μm to 300 μm, more preferably a crystal size of at most 100 μm, more preferably a crystal size in the range of 10 μm to 50 μm. More preferably, the at least one limus active substance is selected from rapamycin (sirolimus), everolimus, zotarolimus, lamimus, deforolimus, meolimus, no Wo Mosi, pimecrolimus, diltiazem, tacrolimus and temsirolimus. Even more preferably, the at least one limus active substance is selected from rapamycin (sirolimus) and everolimus. More preferably, the at least one active substance of limus is everolimus. Preferably, the solvent is a dielectric constant ε at 20deg.C _r 2.0 or less, or the solvent mixture contains at least 50% by volume of a dielectric constant epsilon at 20 DEG C _r A non-solvent of less than or equal to 2.0. Preferably, the solvent mixture is a mixture of at least one polar organic solvent and at least one non-polar organic solvent, the polar organic solvent having an n-octanol-water partition coefficient log Kow of from-0.5 to +1.5 and a dielectric constant ε at 20 ℃ of from 5.0 to 30 _r The nonpolar organic solvent has a dielectric constant epsilon at 20 ℃ of 3.0 or less _r And n-octanol-water partition coefficient logKow of 3.0 or more.

It has proven important to provide at least one active substance of the limus in microcrystalline form and to combine it with a solution of at least one tri-O-acylglycerol in a solvent or solvent mixture, so as to form a stable crystalline suspension. If, on the contrary, the microcrystals of the limus active substance are first added to a solvent or solvent mixture and then the at least one tri-O-acylglycerol is added, a suspension of microcrystals of the limus active substance according to the invention is not formed, resulting in a firmly adhering coating on the medical product. Thus, the order of the steps for preparing the crystalline suspensions of limus active substance is important and not interchangeable. Likewise, improper coatings may be formed when attempting to prepare crystals of the limus active substance from a solution of the limus active substance in a solvent or solvent mixture containing at least one tri-O-acylglycerol after application to the surface of a medical product.

a') dissolving at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol in a solvent, preferably in a polar organic solvent,

a ") adding a non-polar organic solvent, preferably a non-solvent, to the solution from step a'); and optionally homogenizing and filtering the mixture,

b) Adding at least one active substance of the micro-crystalline form of the limus to the solution from step a '), or adding the solution from step a') to at least one active substance of the micro-crystalline form of the limus,

wherein the crystallites of the at least one limus active substance are insoluble in the solution of step a ").

b) Providing at least one active substance of limus in microcrystalline form,

c) Preparing a suspension by combining the solution according to step a ") with at least one active substance of the limus in microcrystalline form according to step b),

wherein the microcrystals of said at least one limus active substance according to step b) are insoluble in the solution according to step a ").

Preferably, the crystallinity of the at least one limus active substance is at least 90% by weight. Preferably, the crystallites of the at least one limus active substance have a crystal size in the range of 1 μm to 300 μm, more preferably a crystal size of at most 100 μm, more preferably a crystal size in the range of 10 μm to 50 μm. More preferably, the at least one limus active substance is selected from rapamycin (sirolimus), everolimus, zotarolimus, lamimus, deforolimus, meolimus, no Wo Mosi, pimecrolimus, diltiazem, tacrolimus and temsirolimus. Even more preferably, the at least one limus active substance is selected from rapamycin (sirolimus) and everolimus. More preferably, the at least one active substance of limus is everolimus. Preferably, the non-solvent has a dielectric constant ε at 20deg.C _r Less than or equal to 2.0. Preferably, the solvent contains at least 50% by volume of a dielectric constant ε at 20 DEG C _r A non-solvent of less than or equal to 2.0. Preferably, the solvent mixture is a mixture of at least one polar organic solvent and at least one non-polar organic solvent, the polar organic solvent having an n-octanol-water partition coefficient log Kow of from-0.5 to +1.5 and a dielectric constant ε at 20 ℃ of from 5.0 to 30 _r The nonpolar organic solvent has a dielectric constant epsilon at 20 ℃ of 3.0 or less _r And n-octanol-water partition coefficient logKow of 3.0 or more.

Coating method

The invention also relates to a method for coating a medical product, preferably a catheter balloon, balloon catheter, stent or cannula, with a suspension comprising the steps of:

a) A medical product is provided having a medical product surface,

b) Providing a suspension comprising at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, at least one limus active in microcrystalline form, and a solvent or solvent mixture in which the at least one tri-O-acylglycerol is dissolved and in which the crystallites of the at least one limus active are insoluble or in which the at least one tri-O-acylglycerol is insoluble when present; and

c) The suspension is applied to the surface of the medical product by injection, pipetting, capillary, fold spraying, dipping, spraying, dragging (schleppfafahren), wire dragging, drop dragging or rolling.

a) Providing a medical product having a medical product surface, optionally with a pre-treated surface (conditioning of the surface), wherein the medical product surface is uncoated or coated;

c) The suspension is applied to the surface of the medical product by injection, pipetting, capillary, fold spraying, dipping, spraying, dragging, wire dragging, drop dragging or rolling.

In a preferred embodiment, the method further comprises a step d) of drying the coating after step c).

Preferred herein are special coating methods for coating a medical product, wherein the medical product can be coated with a defined amount of a microcrystalline limus active substance, wherein in said coating method preferably a coating device with a volumetric measuring device is used for directional delivery of a defined amount of the coating suspension of the invention onto the surface of the medical product by means of a dispensing device.

Any device capable of providing a defined amount of coating suspension or measuring or indicating the delivered amount of coating suspension may be used as a volume measuring device. The volume measuring device is thus in the simplest case a scale, a graduated pipette, a graduated burette, a graduated container, a graduated chamber as well as a pump, a valve, a syringe or other piston-shaped container, which is capable of providing or delivering or dispensing a defined amount of coating suspension. Thus, the volume measuring device is used for providing or delivering a defined amount of coating suspension or for measuring and/or displaying the delivered amount of coating suspension. The volume measuring device is thus used to determine or measure the amount of coating suspension and thus the amount of microcrystalline limus active substance transferred from the dispensing device to the surface of the medical product.

However, the most important aspect of the coating device is the dispensing device, which may be designed as a nozzle, a plurality of nozzles, a wire, a net, a piece of fabric, a strip, a sponge, a ball, a syringe, a needle, a cannula or a capillary tube. Depending on the design of the dispensing device, slightly modified coating methods are produced, all of which are based on the basic principle of the loss-free transfer of a measurable or defined amount of microcrystalline limus active substance to the surface of a medical product. In this way, a coating of microcrystalline limus active substance having a defined active substance concentration or active substance quantity is provided, thereby providing a repeatable coating. Various terms are used herein to distinguish between these methods, i.e., injection, pipetting, capillary, fold spraying, dipping, spraying, dragging, wire dragging, drop dragging, or rolling, which are preferred embodiments of the present invention.

As a particularly preferred coating method for medical products with crystal suspensions, droplet delivery techniques using microdose methods, such as pipetting or drop drag methods, are used herein. These methods can be used to obtain a particularly uniform coating of microcrystalline limus active substance on the surface of a medical product with the same uniform concentration of active substance, as long as it is ensured that the crystallites of the limus active substance remain uniformly distributed.

Studies of active material recovery (wiederfindngrate) on balloon catheters divided into equal segments confirmed the uniformity of the coating and thus the success of using a crystal suspension (see example 7) and 100% recovery.

Furthermore, in order to ensure a uniform distribution of crystals, pneumatic rotation may be used during the coating process to agitate the suspension to prevent possible sedimentation, which may be advantageous as a precaution against a crystal content of less than 2% (w/v).

On the other hand, other common coating methods, such as spraying, dipping, brushing, pipetting, droplet drag, roll coating, rotation, in situ deposition, screen printing, vapor deposition or spraying, may also be used for possible pretreatment of the surface of the medical product, such as conditioning or applying a primer coating. The above methods may also be combined.

Coated medical product

The suspensions of the invention are particularly suitable for providing coated medical products with an active substance release coating comprising at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, and at least one limus active substance in microcrystalline form.

The invention therefore also relates to a coated medical product, particularly preferably selected from a catheter balloon, balloon catheter, stent or cannula, having a coating comprising at least one tri-O-acylglycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol and at least one limus active substance in microcrystalline form.

The invention therefore further relates to a coated medical product, in particular a medical product selected from a catheter balloon, a balloon catheter, a stent or a cannula, having a coating consisting of at least one tri-O-acylglycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol and at least one active substance of the limus in microcrystalline form.

The term "coating" shall include not only coatings on the surface of medical products, but also folds, cavities, holes, microneedles or other filling or coating of fillable spaces on or between or within materials, and in the case of expandable, folded or collapsed medical products, deflation, partial inflation and full inflation or deployment or partial deployment of medical products.

As used herein, the term "on (onto) the surface of a medical product" preferably means directly applied to the surface of the medical product, i.e. directly applied to the material of the medical product. For example, if the medical product is made of polyamide, this means applied to the polyamide from which the medical device is made. If the medical product is made of, for example, polyamide and is subsequently coated with a polymer, no application will take place on the surface of the medical product.

Preferably uniformly coating the entire surface of the medical product. Furthermore, it is preferred that the microcrystalline limus active substance is evenly distributed over the surface of the medical product. However, the surface may also be coated only partially or differently at different points (e.g. different coating thicknesses, different coatings, different active substance concentrations, only selected defined areas, etc.).

As used herein, the term "medical product" refers to an article or material that is used to detect, prevent, monitor, treat or ameliorate a disease, but that does so primarily by physical means, rather than by pharmacological/immunological means or by metabolic action ("predetermined primary effect"). However, the physical effects of the medical product may be fully supported by pharmacological, immunological or metabolic effects. Medical products can be classified into medical products for long-term use and medical products for short-term use, depending on whether the medical product is in short-term or long-term contact with an organism. All medical products intended to remain in the body are considered to be long-term use. Medical products that are not too long-to-very short-term are medical products that can be removed after a period of time and used for a limited period of time.

Examples of long-term medical products include, but are not limited to, non-biodegradable biostable stents, implants, joint implants, vascular prostheses, brain pacemakers (e.g., those for parkinson's disease), artificial hearts, port catheters, vision implants, ocular lens substitutes, retinal substitutes, vitreous substitutes, cornea substitutes, dental implants, cochlear implants, reconstructive implants, cranial reconstructive implants, bone substitutes, penile prostheses, sphincter prostheses, and the like.

Examples of less long-to very short-term medical products include, but are not limited to, catheters of all forms and types, balloon catheters, angioplasty catheters, bladder catheters, respiratory tubes, venous catheters, all types of cannulas, needles, winged cannulas (Butterflies), active substance reservoirs, fixtures (e.g., for surgical treatment of bone fractures), artificial pathways, tubes, suture materials, clips, and the like.

The term "balloon" or "catheter balloon" refers in principle to any inflatable and recompressible and temporarily implantable medical product, which is commonly used in connection with catheters. The term "catheter balloon" as used herein refers to an expandable portion, i.e., a balloon of a balloon catheter. "balloon catheter" refers to an expanding balloon catheter. Balloon catheters are medical terms for catheters having a balloon attached thereto. Examples of balloon catheters include, but are not limited to, angioplasty balloon catheters for percutaneous transluminal angioplasty to dilate and open narrowed or occluded vessels, bladder catheters, thrombectomy catheters for vascular surgery, neuroradiology and cardiology to treat embolism and secondary thrombosis, and thrombectomy catheters for neurothrombectomy in stroke therapy, embolectomy catheters in vascular surgery to remove fresh and soft emboli in the peripheral arterial system, fogarty catheters, double balloon catheters, balloon catheters for use in respirations, balloon catheters.

In some embodiments of the invention, the medical product is selected from the group comprising or consisting of: catheter balloon, balloon catheter, angioplasty catheter, bladder catheter, stent, implant, joint implant, vascular prosthesis, port catheter, visual prosthesis, ocular implant, dental implant, cochlear implant, reconstructive implant, penile prosthesis, sphincter prosthesis, cardiac pacemaker, brain pacemaker, respiratory tube, venous catheter, cannula, needle, winged cannula (butterfly body), artificial channel, tube, suture material, and medical clip.

In a particularly preferred embodiment of the invention, the medical device is preferably selected from the group comprising or consisting of: catheter balloon, balloon catheter, stent, cannula. Thus, in these embodiments, the medical device is preferably selected from the group comprising or consisting of: catheter balloons, balloon catheters, angioplasty catheters, bladder catheters, port catheters, venous catheters, peripheral catheters, coronary catheters, embolectomy catheters, thrombectomy catheters, neurothrombectomy catheters, stents, bioresorbable stents, cannulas, hypodermic needles, winged tubes (butterfly bodies), peripheral venous indwelling tubes, and epidural cannulas. Further preferably, the medical product is selected from the group comprising or consisting of: catheter balloons, balloon catheters, angioplasty catheters and stents. Still further preferably, the medical product is selected from the group consisting of or consisting of a catheter balloon, a balloon catheter, and an angioplasty catheter. More preferably, the medical device is a catheter balloon.

Regardless of the field of application, the catheter balloon may be made of common biocompatible flexible materials, particularly polymers as described further below, particularly polyamides, such as PA12, polyesters, polyurethanes, polyacrylates, polyethers, pebax, and the like, as well as combinations of suitable polymers, such as superimposed layers of these materials, and blends and combinations of copolymers, embodiments of layers and copolymers, and blends thereof.

The implant may be made of common biocompatible materials such as medical stainless steel, titanium, chromium, vanadium, tungsten, molybdenum, gold, iron, nitinol, magnesium, iron, zinc, alloys of the foregoing metals, ceramics, and polymeric biostable or bioresorbable materials such as PTFE, polysulfone, polyvinylpyrrolidone, polyamide (e.g., PA 12), polyester, polyurethane, polyacrylate, polyether, silicone, PMMA, combinations thereof, and the like. The material is either bio-inert, bio-stable and/or biodegradable, and the implant is expandable, compressible or of a constant shape.

The present invention preferably relates to a medical product selected from the group consisting of catheter balloons, balloon catheters, stents or cannulas coated with at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol and at least one active substance of limus in microcrystalline form,

Wherein the at least one limus active substance is selected from rapamycin (sirolimus), everolimus, zotarolimus, lamimus, defronomitis, mepimox, noose Wo Mosi, pimecrolimus, diphosolimus, tacrolimus and temsirolimus.

Wherein at least 70% of the limus active substance is in the form of crystallites having a crystal size of 10 μm to 50 μm.

For the preparation of the coating, a suspension according to the invention is used which contains the active substance of limus in microcrystalline form and at least one dissolved tri-O-acylglycerol selected from trioctylglycerol, trinonyl glycerol, tridecyl glycerol and triundecyl glycerol in a solvent or solvent mixture.

The present invention thus relates to a medical product selected from a catheter balloon, balloon catheter, stent or cannula coated with a suspension comprising:

b) At least one active substance of limus in microcrystalline form; and

c) A solvent or solvent mixture in which the at least one tri-O-acylglycerol is dissolved and in which the crystallites of the at least one limus active substance are not dissolved or in which the at least one tri-O-acylglycerol is not dissolved when present.

The present invention thus relates to a medical product, preferably selected from a catheter balloon, balloon catheter, stent or cannula, obtainable according to a method comprising the steps of:

a) Providing a medical product selected from a catheter balloon, balloon catheter, stent, or cannula having a medical product surface;

b) Providing a suspension comprising a tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol and at least one active substance of limus in microcrystalline form dissolved in a solvent or solvent mixture, wherein the crystallites of the at least one active substance of limus are insoluble in the solvent or solvent mixture or are insoluble in the presence of the at least one tri-O-acylglycerol;

c) Applying the suspension to the surface of the medical product by injection, pipetting, capillary, fold spraying, dipping, spraying, dragging, wire dragging, drop dragging or rolling,

d) And (5) drying the coating.

In some embodiments of the present invention, a medical product having a medical product surface with a base coating on the medical product surface may be provided. In such an embodiment, a suspension according to the invention comprising at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol and at least one active substance of limus in microcrystalline form is applied on the base coating.

For example, the medical product surface may additionally be provided with a hemocompatible thrombogenic layer as a base coating applied by covalent immobilization of semisynthetic heparin derivatives (e.g. desulphated, re-acetylated heparin) or chitosan derivatives (e.g. N-carboxymethylated, partially N-acetylated chitosan).

If desired or advantageous, the implant surface may be pretreated, for example by surface activation, for example by plasma processes, temperature treatment, wetting with a suitable solvent, DLC coating ("diamond-like carbon"), teflon coating or siliconizing, etc. It can be shown that wetting with a suitable solvent has a positive effect on adhesion.

Likewise, it is possible to achieve a polymer base coating that is biodegradable and/or biostable. These polymer coatings may of course also contain additives, such as further active substances or mixtures of active substances, metals, salts, etc. Suitable actives or combinations of actives include anti-inflammatory, cytostatic, cytotoxic, antiproliferative, antimicrotubular, anti-angiogenic, anti-restenosis (anti-restenosis), antifungal, antitumor, anti-migratory, antithrombotic, and antithrombotic agents.

If the active substance of limus in microcrystalline form is not directly applied to the surface of a medical product or to the surface of a medical device, suitable biocompatible substances of synthetic, semi-synthetic and/or natural origin, biostable and/or biodegradable polymers or polysaccharides can be used as a carrier or matrix on the surface of a medical product or as the surface of a medical product.

As polymers which are generally biostable and only slowly biodegradable, the following may be mentioned: polyacrylic acids and polyacrylates such as polymethyl methacrylate, polybutyl methacrylate, polyacrylamide, polyacrylonitrile, polyamide, polyether amide, polyvinylamine, polyimide, polycarbonate, polyurethane, polyvinyl ketone, polyvinyl halide, polyvinylidene halide, polyvinyl ether, polyvinyl aromatic, polyvinyl ester, polyvinylpyrrolidone, polyoxymethylene, polyethylene, polypropylene, polytetrafluoroethylene, polyurethane, polyolefin elastomer, polyisobutylene, EPDM-rubber, fluorosilicone, carboxymethyl chitosan, polyethylene terephthalate, polypentanoate, carboxymethyl cellulose, rayon triacetate, nitrocellulose, cellulose acetate, hydroxyethyl cellulose, cellulose butyrate, cellulose acetate butyrate, ethyl vinyl acetate copolymer, polysulfone, polyethersulfone, epoxy resin, ABS resin, EPDM rubber, silicone prepolymers, e.g., polysiloxanes, polyvinyl halides and copolymers, cellulose ethers, cellulose triacetate, chitosan derivatives, polymerizable oils such as linseed oil and copolymers, and/or copolymers thereof.

As generally biodegradable, biodegradable or resorbable polymers, for example the following may be used: poly valerolactone, poly-epsilon-decalactone, polylactide, polyglycolide, copolymers of polylactide and polyglycolide, poly-epsilon-caprolactone, polyhydroxy butyric acid, polyhydroxy butyrate, polyhydroxy valerate, polyhydroxy butyrate-co-valerate, poly (1, 4-dioxane-2, 3-dione), poly (1, 3-dioxane-2-one), polydioxanone, polyanhydrides such as polymaleic anhydride, polyhydroxy methacrylate, fibrin, polycyanoacrylate, polycaprolactone dimethacrylate, poly-b-maleic acid, polycaprolactone butyl acrylate, multiblock polymers such as, for example, polyether ester multiblock polymers such as PEG and polybutylene terephthalate from oligomeric caprolactone diols and oligomeric dioxane diols Polypivalolactone, poly (trimethylene glycolate), poly (caprolactone glycolide), poly (g-ethyl glutamate), poly (DTH-iminocarbonate), poly (DTE-co-DT-carbonate), poly (bisphenol A-iminocarbonate), polyorthoesters, polyethylene glycol acid trimethylcarbonate, poly (trimethylene carbonate), polyurethane iminocarbonates, poly (N-vinyl) pyrrolidone, polyvinyl alcohol, polyesteramide, glycolated polyester, polyphosphoester, polyphosphazene, poly [ p-carboxyphenoxy) propane ], polyhydroxyvaleric acid, polyethylene oxide-propylene oxide, soft polyurethane, polyurethane having amino acid residues in the backbone, polyether esters such as polyethylene oxide, polyalkylene oxalate, polyorthoesters and copolymers thereof, carrageenan, fibrinogen, starch, collagen, protein-based polymers, polyamino acids, synthetic polyamino acids, zein, modified zein, polyhydroxyalkanoates, pectic acids, photochemical acids, modified and unmodified fibrin and casein, carboxymethyl sulphate, albumin, hyaluronic acid, heparan sulphate, heparin, chondroitin sulphate, dextran, beta-cyclodextrin, copolymers with PEG and polypropylene glycol, gum arabic, guar gum, gelatin, collagen-N-hydroxysuccinimide, lipids and lipids, polymerizable oils with low degree of cross-linking, modifications and copolymers and/or mixtures of the above.

Drawings

FIG. 1 a) is a cross-sectional view of a circumferentially coated and partially folded balloon; b) Is the microcrystalline structure of the everolimus coating at 1000x magnification under SEM.

FIG. 2 shows rapamycin in the form of rod-like crystallites at 200 Xmagnification, having a very narrow particle size distribution, mainly in the range of 10 μm to 30. Mu.m.

FIG. 3 shows rapamycin in the form of crystallites in the form of regular rods at 1000 Xmagnification, with a very narrow particle size distribution, mainly in the range of 10 μm to 30. Mu.m.

FIG. 4 shows rapamycin at 200 x magnification in microcrystalline form, almost identical rod-like, with an extremely narrow particle size distribution, mainly in the range of 15 μm to 30. Mu.m. Larger crystals or agglomerates are not visible.

FIG. 5 shows rapamycin in the form of almost entirely regular rod-like crystallites at 1000x magnification with a very narrow particle size distribution, mainly in the range of 15 μm to 30. Mu.m. The shape of the diamond prism can be seen very clearly.

Fig. 6 shows everolimus in the form of needle-like crystallites with a very narrow particle size distribution, mainly in the range of 20 μm to 40 μm, at 200 x magnification. Larger crystals or agglomerates are not visible.

Fig. 7 shows everolimus in the form of needle-like crystallites with a very narrow particle size distribution, mainly in the range of 20 μm to 40 μm, at 1000 x magnification. The needle shape can be seen very clearly.

FIG. 8 shows rapamycin in the form of almost identical rod-like crystallites at 1000 x magnification, with an extremely narrow particle size distribution, mainly in the range of 20 μm to 40. Mu.m. Larger crystals or agglomerates are not visible.

FIG. 9 shows rapamycin in the form of almost entirely regular rod-like crystallites at 1000 Xmagnification, with a very narrow particle size distribution, mainly in the range of 20 μm to 40. Mu.m. The shape of the diamond prism can be seen very clearly.

FIG. 10 shows the crystallite structure of a rapamycin coating at 1000 Xmagnification REM, wherein the rapamycin crystallites are essentially diamond prisms.

FIG. 11 shows the crystallite structure of a rapamycin coating with abrasive crystallites at REM at 1000 x magnification.

Fig. 12 shows a model formed by a silicone tube, which simulates the natural distribution of blood vessels in an organism: a) Simulating a peripheral catheter; b) Simulating the femoral artery.

FIG. 13 a) shows a bending test to determine particle release of a coated catheter balloon; b) An edge impact test to determine particle release of the coated catheter balloon is shown.

FIG. 14 shows a rapamycin coating not according to the present invention prepared in accordance with WO 2015/039969 A1 at 1000 times magnification. It can be seen that the crystal is oversized, almost circular, surrounded by a number of very small irregularly shaped and broad size distribution crystals.

FIG. 15 shows a rapamycin coating not according to the present invention prepared in accordance with WO 2015/039969 A1 at 1200 magnifications. It can be seen that many very large crystals are surrounded by many very small irregularly shaped and broad particle size distribution crystals.

FIG. 16 a) shows a rapamycin crystal coating having dry crystals that is not in accordance with the present invention; b) Showing the coating from a) after "solvent bonding". The crystal is no longer intact.

FIG. 17 a) shows a rapamycin crystal coating having a base coating of dry crystals and binder and a top coating with trioctylglycerol, not according to the present invention. b) A rapamycin crystal coating not according to the present invention is shown having a dry crystal and a base coating and a top coating with trioctanoyl glycerol. c) An enlarged view of figure b is shown. It can clearly be seen that the coating is not uniform and has areas on which no crystallites are present.

Examples

Example 1

Preparation of microcrystalline rapamycin and microcrystalline everolimus

To prepare the crystalline suspension of the present invention, crystallites of rapamycin and everolimus are first provided. Crystallization methods for preparing crystalline sirolimus (rapamycin) and crystalline everolimus are known in the art. Crystallization methods well known in the art include:

crystallization is carried out by cooling: the limus active substance may be dissolved in a solvent at room temperature or higher until saturated and crystallized at a lower temperature, such as 0 ℃. The crystal size distribution can be influenced by the controlled cooling rate. Polar and non-polar organic solvents such as toluene, acetonitrile, ethyl formate, isopropyl acetate, isobutyl acetate, ethanol, dimethylformamide, anisole, ethyl acetate, methyl ethyl ketone, methyl isopropyl ketone, tetrahydrofuran, nitromethane, propionitrile are suitable solvents for crystallization for the limus active substance.

Crystallization is carried out by adding an antisolvent: the active material is dissolved in a solvent and then a non-solvent or water is added. Two-phase mixtures are also possible here. Polar organic solvents such as acetone, acetonitrile, ethyl acetate, methanol, ethanol, isopropanol, butanol, butyl methyl ether, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide may be used as a solvent for dissolving the limus active substance. Suitable non-solvents are, for example, pentane, hexane, cyclohexane or heptane. The solvent mixture may be left to crystallize, stirred or slowly concentrated in vacuo or evaporated. The crystal size and crystallinity of the active material can be affected by controlling the addition of the nonpolar solvent. Satiety is slower to produce large crystals and faster to produce small crystals. It is well known to control the rate of addition of antisolvent to control crystal size.

For the production of crystallites, crystallization may also be assisted by ultrasound. It is generally known that crystal size can be influenced by ultrasound. In this context, ultrasound can be used at the beginning of crystallization to initiate crystallization and nucleation, and further crystal growth then proceeds unimpeded, so that larger crystals can be grown. In contrast, continuous sonication of supersaturated solutions using ultrasound results in smaller crystals, as many nuclei are formed in the process, thereby resulting in the growth of many small crystals. Another option is to sonicate with ultrasound in a pulsed mode to affect crystal growth in a manner that achieves a customized crystal size.

Other methods known in the art, such as micronization, grinding or sieving, may also be used to provide the desired crystal size. One possibility is to grind the crystals, which can also be done by wet grinding during crystallization. Grinding may be advantageous to obtain different crystal sizes, i.e. a wider crystal size distribution. Milling allows any desired size within the crystal size range. A more uniform crystal size can be provided by, for example, performing a special sieving process after separation and drying. Special screening devices known in the art may be used for this purpose. During sieving, the crystals of limus active substance may be sieved through, for example, a stack of sieves, and separated into different size ranges.

To prepare microcrystalline rapamycin and microcrystalline everolimus, a crystallization procedure with controlled crystallization is performed. Rapamycin and everolimus are therefore available directly in microcrystalline form, avoiding subsequent grinding or micronisation. Crystallization was performed by adding antisolvent (ethyl acetate/heptane). After crystallization, the crystallites of rapamycin or everolimus are isolated, washed with (heptane) and dried. Optionally, then further separated into different crystal sizes by a sieving method to provide a narrower crystal size distribution of crystallites.

To evaluate crystal size, crystal size distribution, and crystal shape, samples were placed on the foil of REM sample plates. Representative images were taken at 200, 1000 and 3000 magnifications for evaluation, with 200 magnifications being suitable for good detection of so-called oversized particles (coarse particles). The scale of the REM image is used for size estimation.

Example images of rapamycin in microcrystalline form and everolimus in microcrystalline form as used herein are shown in fig. 2-9. In fig. 2 and 3, rapamycin in microcrystalline form is shown as a rod with a very narrow particle size distribution, mainly in the range of 10 μm to 30 μm. In fig. 4 and 5, rapamycin is shown in the form of almost identical rod-like crystallites having a very narrow particle size distribution mainly in the range of 15 μm to 30 μm. In FIGS. 7 and 8, rapamycin is shown in microcrystalline form having a particle size distribution predominantly in the range of 20 μm to 40 μm. In fig. 6 and 7, everolimus is shown in the form of needle-like crystallites, the particle size distribution of which is mainly in the range of 20 μm to 40 μm. In all of fig. 2 to 9, it can be seen that no larger crystals or agglomerates are present. It is also clear that everolimus is acicular, whereas rapamycin is in the form of diamond prisms.

The rapamycin or everolimus microcrystals obtained are used to prepare the crystal suspensions in the examples below.

Example 2

Preparation of crystalline suspensions with tri-O-acylglycerols and microcrystalline rapamycin (SIR) and Everolimus (EVR)

In the first step, a solution of tri-O-acylglycerol is first prepared in a solvent mixture. Subsequently, the solution was combined with crystallites of rapamycin and everolimus and investigated which tri-O-acylglycerols were used to obtain stable crystal suspensions. The composition of the solvent and solvent mixture varies depending on the active substance used. The solutions and solvent mixtures prepared in the examples are suitable for rapamycin (SIR) and Everolimus (EVR). For the preparation of the solution, ethyl acetate/heptane solvent mixtures are used here as examples.

1. Preparation of solutions with tri-O-acylglycerols

To prepare a solution, the corresponding tri-O-acylglycerols are first dissolved in a polar organic solvent and then the nonpolar solvent is added. In addition, solutions were prepared with the addition of antioxidants (BHT) as an alternative.

To prepare a solution 770mg of the corresponding tri-O-acylglycerol and optionally 150mg of BHT were dissolved in 14g of ethyl acetate (15.6 ml). 57.4g of n-heptane (84.4 ml) were then added. Followed by homogenization and filtration. The total volume of the solvent mixture was 100mL.

Solution 1 a)

Tri-O-acylglycerols trioctanoylglycerols

Antioxidant-

Solution 1 b)

Tri-O-acylglycerols trioctanoylglycerols

Antioxidant BHT

Solution 1 c)

Tri-O-acylglycerols tridecylglycerols

Antioxidant-

Solution 1 d)

Tri-O-acylglycerols tridecylglycerols

Antioxidant BHT

Solution 1 e)

Tri-O-acylglycerols Trihexanoyl glycerols

Antioxidant-

Solution 1 f)

Tri-O-acylglycerols Trihexanoyl glycerols

Antioxidant BHT

Solution 1 g)

Tri-O-acylglycerols tributyl acylglycerol

Antioxidant-

Solution 1 h)

Tri-O-acylglycerols tributyl acylglycerol

Antioxidant BHT

Solution 1 i)

Tri-O-acylglycerols 770mg glyceryl triacetate

Antioxidant-

Solution 1 j)

Tri-O-acylglycerols glyceryl triacetate

Antioxidant BHT

Solution 1 k)

Tri-O-acylglycerols Tridodecanoyl glycerol

Antioxidant-

Solution 1 l)

Tri-O-acylglycerols Tridodecanoyl glycerol

Antioxidant BHT

Solution 1 m)

tri-O-acylglycerols lemon/lactyl/linoleyl/oleyl-O-glycerols

Antioxidant-

Solution 1 n)

tri-O-acylglycerols lemon/lactyl/linoleyl/oleyl-O-glycerols

Antioxidant BHT

Solution 1 o)

Tri-O-acylglycerols dioctyl glycerol

Antioxidant-

Solution 1 p)

Tri-O-acylglycerols dioctyl glycerol

Antioxidant BHT

Solution 1q

Tri-O-acylglycerols mono-octanoylglycerols

Antioxidant-

Solution 1 r)

Tri-O-acylglycerols mono-octanoylglycerols

Antioxidant BHT

Solution 1 s)

Tri-O-acylglycerols-tetracosacylglycerols

Antioxidant-

Solution 1 t)

Tri-O-acylglycerols-tetracosacylglycerols

Antioxidant BHT

2. Redispersion of rapamycin or everolimus crystallites

To a precisely weighed amount of dry microcrystals of a pre-prepared limus active substance, a defined amount of a solution containing tri-O-acylglycerol and optionally an antioxidant is carefully added. It was investigated whether the microcrystals of the limus active substance are insoluble in the solution or form a suspension.

To check if a crystal suspension can be prepared, 10ml of one of solutions 1 a) to 1 t) were carefully added to 200mg of rapamycin in microcrystalline form or 200mg of everolimus in microcrystalline form each at room temperature. Three feeds of 10ml of solution were prepared for each solution. After mixing, it was tested whether the microcrystals of the limus active substance were directly dissolved in the solution. For solutions in which the microcrystals of the limus active substance are not immediately dissolved, the suspension of the solution without antioxidant is left for 100 hours and it is again tested whether the microcrystals of the limus active substance are dissolved. For suspensions of antioxidant-containing solutions, the mixture was heated to 50 ℃ to check if the suspension remained stable even under sterilization conditions.

Table 9: results overview of preparation of crystal suspensions with solutions containing different tri-O-acylglycerols (+++ = stable crystal suspension, the crystallites are uniformly distributed, the complete crystallites are "floating"; ++ = suspension, the crystallites did not dissolve completely; ++ = microcrystalline sedimentation or partial dissolution, no intact crystals, - - - - = no suspension, -/- = no study).

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Results:

stable crystal suspensions can be prepared with tri-O-acylglycerols, trioctanoylglycerols and tridecanoylglycerols, which remain stable even after 100 hours and at elevated temperatures. The presence of antioxidants does not affect the stability of the crystal suspension. Stable crystal suspensions were obtained with tri-O-acylglycerol trioctylglycerol and tridecylglycerol in the presence and absence of BHT. In solutions containing trioctylglycerol and tridecylglycerol, no sedimentation of the crystallites occurs, the crystallites "float" in the crystal suspension and are homogeneously distributed.

To evaluate the crystal size, the particle size distribution (i.e. the crystal size distribution) and the crystal shape, samples were taken in each case with a Pasteur pipette and the droplets were placed on the foil of the REM sample plate. REM images were taken at 200x and 1000x magnification for evaluation.

REM images show that crystallites of the crystal suspensions containing tri-O-acylglycerol trioctylglycerol and tridecylglycerol remain intact. The crystallites of everolimus are always needle-like, while the crystallites of rapamycin continue to be in the form of rhombohedral prisms. The crystal size distribution also continues to correspond to that of the initially used microcrystalline everolimus or rapamycin. Thus, no crystal growth or crystallite aggregation occurs in these crystal suspensions.

In solutions containing trihexanoyl glycerol, the crystallites of everolimus and rapamycin do not dissolve directly. In these suspensions, crystallites are unevenly present compared to crystalline suspensions containing trioctylglycerol and tridecylglycerol. In the case of trihexanoyl glycerol, the crystallites of everolimus and rapamycin dissolve almost completely after 100 hours, and when the temperature rises, the crystallites of everolimus and rapamycin dissolve rapidly.

In solutions containing tri (dodecanoyl) glycerol and tri (tetradecanoyl) glycerol, the crystallites of everolimus and rapamycin do not dissolve directly. However, these "suspensions" were also found to be unstable. In the case of tri (dodecanoyl) and tri (tetradecanoyl) glycerols, the crystallites of everolimus and rapamycin do not dissolve completely after 100 hours. However, in contrast to the crystal suspensions containing trioctylglycerol and tridecylglycerol, the crystallites are not uniformly distributed and crystal precipitation occurs. The increase in temperature accelerates the process.

To evaluate the crystal size, particle size distribution (i.e., crystal size distribution), and crystal shape, a droplet was placed on the foil of the REM sample plate using a baster pipette to sample each sample. Additional samples were taken from the bottom (Bodensatz) and a drop was placed on the foil of the REM sample plate. REM images were taken at 200 and 1000 magnifications for evaluation.

REM images showed that crystallites of the crystal suspensions containing tri (dodecanoyl) glycerol and tri (tetradecanoyl) glycerol did not remain intact. The crystal size distribution no longer corresponds to that of the microcrystalline everolimus or rapamycin originally used and larger crystals are detected, especially in samples taken from the bottoms.

The crystal suspension cannot be prepared with other tri-O-acylglycerol solutions. Thus, stable crystal suspensions can only be prepared with trioctyl glycerol and tridecyl glycerol.

Example 3

Preparation of crystalline suspensions with additional tri-O-acylglycerols and microcrystalline rapamycin (SIR) and Everolimus (EVR)

Based on the results of example 2, other solutions of three tri-O-acylglyceroheptoyl glycerol, trinonyl glycerol and tri (undecyl) glycerol were prepared to investigate whether these could be used to obtain stable crystal suspensions. Ethyl acetate/heptane solvent mixtures were also used here to prepare the solutions.

1. Preparation of solutions with tri-O-acylglycerols

Solution 2 a)

Tri-O-acylglycerols Triheptanoylglycerols

Antioxidant-

Solution 2 b)

Tri-O-acylglycerols Triheptanoylglycerols

Antioxidant BHT

Solution 2 c)

Tri-O-acylglycerols Trinonoylglycerols

Antioxidant-

Solution 2d

Tri-O-acylglycerols Trinonoylglycerols

Antioxidant BHT

Solution 2 e)

Tri-O-acylglycerols Triundecyl glycerol

Antioxidant-

Solution 2 f)

Tri-O-acylglycerols Triundecyl glycerol

Antioxidant BHT

2. Redispersion of rapamycin and everolimus crystallites

To prepare a crystal suspension, 200mg of rapamycin in microcrystalline form or 200mg of everolimus in microcrystalline form were each carefully added to 10mL of solutions 2 a) to 2 f) at room temperature, as described in example 2. Three feeds of 10mL of solution were prepared for each solution. After combining, it was tested whether the microcrystals of the limus active substance were directly dissolved in these solutions. For solutions that did not immediately dissolve the microcrystals of the limus active, the suspension of the solution without antioxidant was left for 100 hours and tested again for dissolution of microcrystals of the limus active. For suspensions of antioxidant-containing solutions, the mixture was heated to 50 ℃ to check if the suspension remained stable under sterilization conditions.

For direct comparison, the results from solutions 1 a) to 1 d) of example 2 are listed in the table below.

Table 10: overview results of crystal suspensions prepared with solutions containing different tri-O-acylglycerols (+++ = excellent stable crystal suspensions, the crystallites are uniformly distributed, the complete crystallites are "floating"; ++ +++ = stable crystal suspension, uniform distribution of crystallites, intact crystallites, "floating" the crystallites; the complete crystallites are formed in a state, the crystallites "float".

Results:

the use of tri-O-acylglycerinum trisnonoyl glycerol and tri (undecoyl) glycerol allows the preparation of stable crystal suspensions which remain stable even after 100 hours and at elevated temperatures. The presence of the antioxidant has no effect on the stability of the crystal suspension. In the solution containing trisnonoyl glycerol and tris (undecoyl) glycerol, no microcrystalline precipitation occurred; the crystallites "float" in the crystal suspension and are uniformly distributed.

REM images show that crystallites of the crystal suspensions containing tri-O-acylglycerol trinonyl glycerol and tri (undecyl) glycerol remain intact. The crystallites of everolimus are always needle-like, while the crystallites of rapamycin continue to be in the form of rhombohedral prisms. The crystal size distribution also continues to correspond to that of the initially used microcrystalline everolimus or rapamycin.

In solutions containing triheptanoyl glycerol, the crystallites of everolimus and rapamycin are not directly dissolved. However, the crystallites of everolimus and rapamycin are partially dissolved after 100 hours, and at elevated temperatures, the crystallites of everolimus and rapamycin are dissolved.

REM images showed that the crystallites of the crystal suspension containing triheptanoyl glycerol did not remain intact. The crystal size distribution no longer corresponds to that of the microcrystalline everolimus or rapamycin originally used.

Thus, stable crystal suspensions can be prepared with additional tri-O-acylglycerinum trisnonoyl glycerol and tri (undecoyl) glycerol.

Example 4

Preparation of 3% and 1% crystalline suspensions containing trioctylglycerol and microcrystalline Everolimus (EVR)

I. Preparation of trioctylglycerol solution

Ia)

Examples of solvent mixtures for 100ml batches with 3% evr crystal content. 770mg of trioctylglycerol were dissolved in 14g of ethyl acetate. To this solution was added 57.4g of n-heptane, homogenized and filtered.

Ib) solvent mixture example for a 100ml batch with 3% evr crystal content and BHT. 770mg of trioctylglycerol and 150mg of BHT were dissolved in 14g of ethyl acetate. To this solution was added 57.4g of n-heptane, homogenized and filtered.

Ic) solution mixture example for a 100ml batch with 1% evr crystal content. 250mg of trioctylglycerol and 20mg of Tween 80 were dissolved in 14g of ethyl acetate. To this solution was added 57.4g of n-heptane, homogenized and filtered.

Id) for 100ml of the solution mixture example for a batch with a 1% EVR crystal content. 250mg of trioctylglycerol, 50mg of BHT and 20mg of Tween 80 were dissolved in 14g of ethyl acetate. To this solution was added 57.4g of n-heptane, homogenized and filtered.

Preparation of crystal suspensions

Defined amounts of the solvent mixture are carefully added to precisely weighed amounts of pre-prepared crystals of dry active substance. The crystals insoluble in the solvent mixture form a suspension with the solvent mixture. For solutions la) and lb) 3g of everolimus in microcrystalline form was used, and for solutions lc) and ld) 1g of everolimus in microcrystalline form was used.

Example 5

Preparation of crystalline suspensions containing microcrystals of Everolimus (EVR) and rapamycin with varying proportions of tri-O-acylglycerols

In examples 2 and 3, it is shown that for tri-O-acylglycerol trioctanoyl glycerol, tridecanoyl glycerol, trinonyl glycerol and tri (undecyl) glycerol, it is possible to use a catalyst in the form of a catalyst in the range of 20:80 to the mass ratio of micro crystals of the active substance of the limus.

For this purpose, further studies were carried out using solutions of trioctanoyl glycerol or tridecanoyl glycerol with different proportions of tri-O-acyl glycerol to find the optimal mass ratio of tri-O-acyl glycerol to microcrystalline limus active substance. To prepare the solutions, the corresponding amounts of each tri-O-acylglycerol were dissolved in 14g of ethyl acetate (15.6 ml). 57.4g of n-heptane (84.4 ml) were then added. Followed by homogenization and filtration. The total volume of the solvent mixture was 100ml.

Solution 3 a)

Tri-O-acylglycerols trioctanoylglycerols

Weighing: 300mg of

Solution 3 b)

Tri-O-acylglycerols trioctanoylglycerols

Weighing: 450mg

Solution 3 c)

Tri-O-acylglycerols trioctanoylglycerols

Weighing: 600mg

Solution 3d

Tri-O-acylglycerols trioctanoylglycerols

Weighing: 900mg

Solution 3 e)

Tri-O-acylglycerols trioctanoylglycerols

Weighing: 1200mg

Solution 3 f)

Tri-O-acylglycerols trioctanoylglycerols

Weighing: 1500mg

Solution 4 a)

Tri-O-acylglycerols tridecylglycerols

Weighing: 300mg of

Solution 4 b)

Tri-O-acylglycerols tridecylglycerols

Weighing: 450mg

Solution 4 c)

Tri-O-acylglycerols tridecylglycerols

Weighing: 600mg

Solution 4d

Tri-O-acylglycerols tridecylglycerols

Weighing: 900mg

Solution 4 e)

Tri-O-acylglycerols tridecylglycerols

Weighing: 1200mg

Solution 4 f)

Tri-O-acylglycerols tridecylglycerols

Weighing: 1500mg

Table 11: overview results of crystal suspensions prepared with solutions containing different amounts of tri-O-acylglycerol (+++ = excellent stable crystal suspension, the crystallites are uniformly distributed, the complete crystallites are "floating"; +++++ = stable crystal suspension, uniform distribution of crystallites, complete crystallites, crystallites "floating"; the complete crystallites of the glass will be, the crystallites "float".

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Results:

stable crystalline suspensions of microcrystalline everolimus and microcrystalline rapamycin may be prepared with varying proportions of triacylglycerol, trioctanoylglycerol and tridecanoylglycerol. For solutions with different proportions of trioctylglycerol and tridecylglycerol, in particular, a crystal suspension with a 20:80 proportion still has excellent stability after 100 hours.

Example 6

Preparation of crystalline suspensions containing microcrystalline rapamycin (SIR) and Everolimus (EVR) in different solvent mixtures

Based on the results of the previous examples, different solvent mixtures were tested for preparing crystalline suspensions of microcrystalline rapamycin and everolimus. The ratio of ethyl acetate/heptane solvent mixture used in the previous examples was about 85:15 (heptane: ethyl acetate).

To investigate other solvent mixtures for preparing the crystal suspensions, solvent mixtures of the polar organic solvents acetone, ethanol, isopropanol and ethyl acetate and the nonpolar organic solvents hexane, heptane and cyclohexane were prepared in different proportions.

To prepare the solution 770 mg trioctylglycerol was dissolved in a polar solvent. Then adding nonpolar solvent, homogenizing and filtering. The total volume of the solvent mixture was in each case 100ml.

To test whether a crystal suspension can be prepared, 10 ml solutions each were carefully added to 200 mg microcrystalline form of everolimus at room temperature. After mixing, it was tested whether a stable crystal suspension was obtained.

Table 12 overview of the results of various solvent mixtures for preparing crystal suspensions (+ ++ = good +/- = average; -poor;)

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Various solvent mixtures can be used to prepare stable crystalline suspensions with microcrystalline everolimus. It has been shown that a nonpolar solvent content of at least 50% by volume results in a very stable crystal suspension.

Example 7

Coating balloon catheter with crystalline suspension of microcrystalline everolimus

A 4 x 40mm balloon catheter was coated with a 2% EVR suspension containing trioctyl glycerol (20 wt% based on EVR) in a microdose method (e.g., pipetting or drop draging) using a microdroplet technique. A uniform coating can be prepared with an equivalent uniform concentration of active substance over the balloon surface, with crystals uniformly distributed. Studies of active material recovery on balloon catheters divided into equally sized segments confirmed the uniformity of the coating, thus successfully using a crystalline suspension and having 100% recovery (see table 13).

Table 13: balloon catheter 4 x 40mm coated with 2% evr suspension (3 incisions divided into 4 segments as equally as possible)

A 7 x 150mm balloon catheter was coated with a 2% EVR suspension containing trioctyl glycerol (20 wt% based on EVR) in a microdose process (e.g., a pipetting process or a drop drag process) using a microdroplet technique. A uniform coating can be prepared with an equivalent uniform concentration of active substance over the balloon surface, wherein a uniform distribution of crystals is ensured. Studies of active material recovery on balloon catheters divided into equally sized segments confirmed the uniformity of the coating, thus successfully using a crystalline suspension and having 100% recovery (see table 14).

Table 14: balloon catheter 7×150mm, coated with 2% evr suspension (14 sections, as equal in size as possible, divided into 15 segments).

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SEM image of the coating. Fig. 1 a) shows a cross-sectional view of a circumferentially coated and partially folded balloon and b) shows the microcrystalline structure of the everolimus coating at 1000x magnification under SEM.

Example 8

Coating balloon catheter with crystalline suspension of microcrystalline rapamycin (SIR)

Rapamycin (SIR) crystal suspensions containing trioctanoyl glycerol

To coat the balloon catheter with a crystalline suspension of microcrystalline rapamycin (SIR) containing trioctylglycerol (20 wt%, based on EVR), two different 2% crystalline suspensions were provided.

The first crystal suspension was prepared with rapamycin in microcrystalline form having a particle size distribution in the range of 20 μm to 40 μm. Rapamycin is present here substantially entirely in the form of diamond prisms.

A second crystal suspension was prepared with rapamycin in microcrystalline form, wherein the rapamycin crystals were pre-ground to provide a broader crystal size distribution.

Using the drop delivery technique, 4 x 40mm balloon catheters were each coated with a 2% sir suspension containing trioctyl glycerol (20 wt% based on EVR) in a microdose method such as a pipetting method or a microdroplet blotting method. A uniform coating with the same uniform active concentration can be produced on the balloon surface. Studies of the recovery of active substance on balloon catheters divided into equally sized fragments confirm the uniformity of the coating, thus using a crystalline suspension successfully, as well as 100% recovery.

REM image of the coating. In fig. 10, the microcrystalline structure of the rapamycin coating is shown at 1000 x magnification REM to be substantially entirely in the form of diamond prisms of rapamycin crystallites (unground).

FIG. 11 shows the crystallite structure of a rapamycin coating with milled rapamycin crystallites at 1000 Xmagnification REM.

These coated balloon catheters were then impacted against the edge of the appropriate object on the black pad (edge impact test). The particles collected on the pad were then determined microscopically and the size distribution of the exfoliated coating was determined. The inflated balloon was then immersed in a PBS solution so that any remaining particles that were still loosely adhered were also shed and included in the evaluation. In further studies, additional coated balloon catheters were inflated as prescribed on black pads and bent in different directions (bending test). The particles collected on the pad were then determined microscopically and the size distribution of the exfoliated coating was determined. The inflated balloon was then immersed in the PBS solution so that any remaining loosely adhered particles could also fall off and be included in the evaluation.

Crystalline suspensions of rapamycin (SIR) containing triacylglycerols not according to the invention

In example 2, it has been found that the microcrystalline active substance is not completely dissolved in the solution containing tri (dodecanoyl) glycerol or tri (tetradecanoyl) glycerol. Suspensions containing tri (dodecanoyl) glycerol or tri (tetradecanoyl) glycerol proved to be unstable. To investigate the stability, flexibility and adhesion of balloon catheter coatings containing microcrystalline rapamycin, suspensions containing microcrystalline rapamycin (SIR) other than the tri (dodecanoyl) glycerol or tri (tetradecanoyl) glycerol of the present invention (20 wt% based on EVR) were freshly prepared and used directly in the coating. For this purpose, rapamycin is provided in microcrystalline form with a particle size distribution in the range of 20 μm to 40 μm.

A balloon catheter of 4 x 40mm was coated with a 2% sir suspension containing tri (dodecanoyl) glycerol or tri (tetradecanoyl) glycerol (20 wt% based on EVR) in a microdose method such as a pipetting method or a droplet drag method using a droplet delivery technique. These suspensions were found to be unable to apply the coating sufficiently uniformly.

Results of edge impact test and bending test of coatings according to the invention and coatings not according to the invention Comparison of

The edge impact test and the bending test clearly show that the total particle loss and the particle size distribution/balloon surface area of the coating with trioctylglycerol according to the invention are much lower than the total particle loss and the particle size distribution/balloon surface area of the coating with tri (dodecanoyl) glycerol or tri (tetradecanoyl) glycerol not according to the invention. Particle release of the coating with rapamycin microcrystals and trioctanoyl glycerol according to the present invention shows little particle exfoliation. Balloon catheters coated according to the present invention have a well-defined particle count that is far lower than the prior art.

Example 9

Particle release ("crush test"), determination of loss of active substance or coating during implantation, prewetting of implant surface, determination of uniform coating according to in vitro model

1. Particle release ("crush test")

As an examination of the mechanical adhesion of the coating on the surface, particle release ("crush test") was measured, in which it was determined how many particles and what size were released from the surface and thus lost when the coated medical product impacted the edge and bent (during and after balloon inflation). For this purpose, up to three mechanical tests were performed on the coated implants. The coated implants of a specific weight were weighed before and after testing.

a) Edge impact test

The coated balloon catheter was gently impacted against the hard (sharp) edge of the appropriate object on the black pad. The particles collected on the pad were then determined microscopically and the size distribution of the exfoliated coating was determined. The inflated balloon was then immersed in PBS solution. This results in any remaining loosely adhered particles also falling off and can be included in the evaluation.

b) Bending test

The coated balloon catheter was inflated as prescribed over a black pad and bent by hand in various directions. The particles collected on the pad were then determined microscopically and the size distribution of the exfoliated coating was determined. The inflated balloon was then immersed in a PBS solution. This results in any remaining loosely adhered particles also falling off and can be included in the evaluation.

c) Adhesion test

To this end, especially in the case of longer balloon catheters, peripheral balloons, for example 150mm in length, are deflated and inflated, wrapped around a circular container (for example a test tube, upstanding cylinder or the like) of suitable diameter, and it is checked whether on the one hand no debris is formed, and on the other hand whether the coating is detached from the balloon catheter and adheres to the container surface. The balloon is curved around the hydrolytic tube so that it is in contact with the wall, lubrication wear on the glass is tolerable, and broken material is intolerable.

The "crush test" clearly shows that the total particle loss, and particle size distribution/balloon surface area, for all samples is well below the FDA guidelines. Using trioctylglycerol, it can be clearly seen in Table 15 that there is no matter how much of a trioctylglycerol is 1. Mu.g/mm ² The EVR crystallite loading was also 3. Mu.g/mm ² The loading of EVR crystallites, which release significantly fewer particles, is well below the values obtained for commercially available and thus allowable coated balloon catheters. For the coating according to the invention with everolimus crystallites and trioctylglycerol (here on different BMT catheter balloons), at all measured particle size rangesRelease of particles within the enclosure shows that virtually no particles will flake off. All balloon catheters coated according to the invention have a well-defined particle count well below the state of the art.

Thus, it can be seen that the flexibility and stability of the crystalline coating of the microcrystals of the everolimus coated balloon according to the present invention is much higher than the standard and prior art allowed.

TABLE 15 EVR/mm at 1. Mu.g ² And 3 μg EVR/mm ² With different active loading of trioctanoylglycerol (HTQ =hemoteq, trioctanoylglycerol 20wt%, relative to EVR) and particle size dependent particle loss per mm ² Balloon surface

During and after inflation, the crystalline coating with trioctylglycerol/EVR showed a uniform coating with a uniform surface structure when visually observed. The coating does not break during balloon inflation.

In addition to excellent flexibility and almost non-destructive adhesion, the crystalline coating according to the invention also exhibits the required and necessary temperature stability, sterilizability (ETO sterilization is preferred) and storage capacity (shelf life).

2. Determination of loss of active substance or coating during implantation based on in vitro model

In order to simulate the natural, often tortuous path through the blood vessel that the balloon catheter must travel to the implantation site, a model is made of silicone tubing (see fig. 12a and 12 b), which simulates the natural course of the blood vessel in the organism.

The catheter was inserted into a silicone tube simulating an artery and inflated. The silicone tube is pre-filled with a defined volume of pyrogen-free water. After 60 seconds, the balloon was deflated (evacuated) and carefully pulled out. Care was taken to ensure that the liquid from the tube was completely collected in the container. Then rinsed with a defined amount of water and collected as such. Particle analysis (particle size distribution and quantification) was performed by LPC (liquid particle counter).

Table 16 release of particles of different coatings of crystalline suspensions of everolimus containing 20% trioctylglycerol relative to everolimus during expansion in PBS after in vitro determination by means of LPC.

3. Determination of uniform coating

For this purpose, the coated weighed balloon is fixed and inflated. The balloon is then cut into small pieces of as equal a size as possible with a scalpel, for example a 40mm long balloon is cut into 4 pieces and a 120mm long balloon is divided into 6 pieces. First the balloon was cut in half longitudinally and the layer thickness was measured with a micrometer. The balloons were then separated, the small pieces were weighed and the layer thickness was measured with a micrometer.

The coatings were each dissolved in a defined amount of acetone and the amount of active substance was determined by HPLC. The results were compared with each other, taking into account the balloon cross-sectional area.

In all cases, it has been found that the presence of trioctylglycerol or tridecylglycerol gives rise to particularly stable and flexible coatings, in which the active substance also adheres very well in crystalline form, which is released only during the contact time with the target site.

Example 10

Comparison with a crystalline coating according to the invention

Crystal coating according to WO 2015/039969 A1

FIG. 14 shows a coating according to WO 2015/039969 A1 with rapamycin crystals at a magnification of 1000. It can be seen that the crystal is oversized, almost circular, surrounded by a number of very small irregularly shaped and broad size distribution crystals. FIG. 15 shows a coating according to WO 2015/039969 A1 with rapamycin crystals at a magnification of 1200. It can be seen that many very large crystals are surrounded by many very small irregularly shaped and broad size distribution crystals.

Crystalline coating of rapamycin microcrystals with "solvent bonding"

The degree of application of the limus crystals as dry matter (powder) to balloon catheters was tested. Wherein the adhesion of the crystals was evaluated in particular. Rapamycin crystals produced by Hemoteq were used in the experiments. For application of the coating, a PTA catheter with balloon dimensions of 4.0X10 mm was used.

First, the application of pure crystalline powder is performed. For this purpose, the powder is filled into custom dishes and brought into contact with the balloon. In this process, the rotating balloon picks up crystals that adhere to the surface. The solvent is then carefully sprayed to slightly dissolve the crystals so that they adhere better to the balloon surface after subsequent drying. In fig. 16 a), a coating with rapamycin crystals that is not according to the invention is shown at 200 x magnification. FIG. 16 b) clearly shows that the crystallites of rapamycin do not remain intact and dissolved. The "crush test" clearly shows that the total particle loss and particle release are very high. The coating has poor adhesion to the balloon surface.

Base coating with a commercially available binder or trioctylglycerol solution and optionally with a trioctylglycerol solution Crystal coating of rapamycin crystallites of the topcoat

The extent to which the limus crystals can be applied as a dry substance (powder) to balloon catheters was tested. Among them, the adhesiveness of the crystals was evaluated in particular. Sirolimus crystals made by Hemoteq were used for the experiment. For application of the coating, a PTA catheter with balloon dimensions of 4.0X10 mm was applied.

First, a base coat (primer) is applied to ensure adhesion of the crystals to the balloon. In order to test the suitability of the experimental apparatus, a commercially available medical adhesive (Henkel corporation) was used first.

Base coat of commercially available adhesive (Uhu): the adhesive is applied thinly directly from the tube and evenly distributed over the rotating balloon. The crystals are then coated.

In addition, trioctylglycerol was used as a base coating. The base coating is applied by pipetting onto the rotating catheter. After the base coating has dried for about 10 minutes, the pure crystalline powder is applied. For this purpose, the powder is filled into custom dishes and brought into contact with the balloon. In this process, the rotating balloon picks up crystals that adhere to the surface.

Composition of the solution:

84.4% n-heptane (vol%)

15.6% ethyl acetate (vol%)

0.05% butylhydroxytoluene (mass/volume)

200. Mu.L of trioctylglycerol was dissolved in 2mL of solution. 2X 50. Mu.L of base coating solution was applied.

When trioctylglycerol is used, it has been shown that although crystals adhere to the balloon surface, the crystals do not adhere sufficiently to each other.

In the third coating step, a top coat with trioctylglycerol is thus applied with a pipette to increase adhesion. Adhesion was evaluated by the "bend test". The bending test is a method in which the coated balloon is bent 2 times around a glass tube having a diameter of about 14 mm. Adhesion was rated as insufficient if many and/or taught fragments detached from the coating during the process.

Composition of the topcoat solution:

84.4% n-heptane (vol%)

15.6% ethyl acetate (vol%)

0.25% trioctanoyl glycerol (mass/volume)

0.05% butylhydroxytoluene (mass/volume)

2X 30. Mu.L of the top coat solution was removed separately.

When using a top coating solution, it has been found that the crystals adhere better to the balloon surface and that the adhesion of the crystals to each other is also improved, so that less particle release occurs in the edge impact test. However, the bending test and inflation of the balloon showed insufficient adhesion of the crystals to each other.

Figures 17a-c show images of balloon coating with a top coating. Fig. 17c is an enlarged view of fig. 17 b. The coating was clearly visible to the naked eye as non-uniform and had a large area without crystallites. Furthermore, the reproducibility of these coatings is very poor. Thus, particularly uniform, flexible and very good adhesion coatings with rapamycin crystallites cannot be produced in this way.

Example 11

In vivo studies with sirolimus (SIR, crystalline) and everolimus (EVR, crystalline) and trioctyl glycerol (GTC, 20wt% on active substance) on PTA catheter

This study was used to determine the local pharmacokinetics of sirolimus and everolimus in the presence of trioctanoyl glycerol. Three commercially available sirolimus and everolimus eluting stents and balloon catheters were used for comparison. For comparison, the study included a commercially available sirolimus coated balloon catheter (Concept Medical's Magic Touch) and a sirolimus eluting stent (Biotronik's Orsiro). Because there is no commercially available everolimus coated balloon catheter, only everolimus eluting stents (Promus of Boston Scientific) can be included in the study for comparison.

For this purpose, EVR crystal suspension/GTC (3. Mu.g/mm ² EVR, 20wt% based on EVR) and SIR crystal suspension/GTC (3. Mu.g/mm ² SIR, 20wt% based on SIR) was used to coat balloon catheters of different sizes. Thirty healthy pigs (pub, castrated) were used as laboratory animals.

After implantation, the remaining active substance residues were measured on the surface of both embodiments, wherein it is clear that the transfer to the vessel wall is very good and only small residues remain on the balloon, so that the transfer to the vessel wall can be considered very effective (see table 17).

Table 17 average residual active substance content on PTA catheters after implantation.

Sample of	Average active substance content	SD
			SCB-2
3.5-4.0mm	7.4％	2.8％
			5.0-6.0mm	3.9％	2.4％
ECB-4
			3.5-4.0mm	3.0％	1.0％
5.0-6.0mm	17.1％	5.6％

* Average active substance residue on balloon after implantation%

The complementary active substance concentrations in the vessel wall after implantation and after 7 and 28 days also showed successful active substance delivery effects-also compared to the control samples. Thus, as a direct DCB comparison, magic Touch delivered significantly less sirolimus to the vessel wall than SCB-2 according to the present invention. After 7 days, the concentration of sirolimus in SBC-2 was more comparable to that of Magic Touch for scaffolds, and this difference continued after 28 days. Therefore, SCB-2 according to the present invention certainly outperforms Magic Touch as DCB and superior to Des Orsiro.

Table 18 follow-up values for active concentration in arteries after 1-2h, 7d and 28d for sirolimus/three Xin Xiangan oil group (SCB) are as follows.

For everolimus/trioctyl glycerol balloon catheters (ECB), the delivery values are still significantly increased and better. Optimally increasing the delivery of the active substance to the vessel wall. Comparison with everolimus eluting stents shows that balloon catheters according to the invention are also superior to stents that remain even in the body until explanted.

Table 19 follow-up values for active substance concentrations in arteries after 1-2h, 7d and 28d for everolimus/three Xin Xiangan oil group (ECB) are as follows.

Furthermore, it can be seen that the recovery of the active substances clearly indicates that the active substances have actually reached their destination and are in the vessel wall (HPLC measurement). A small amount of missing residue remained on the balloon catheter (see table 20). These data further demonstrate the stability and flexibility of the active substance upon target expansion and very good usability.

TABLE 20 recovery of active substances Sirolimus (SCB) and Everolimus (ECB) after 28 days (HPLC).

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Claims

1. A suspension for coating a medical product selected from a catheter balloon, balloon catheter, stent or cannula, the suspension comprising:

b) At least one active substance of limus in microcrystalline form, and

2. The suspension according to claim 1, wherein the at least one limus active substance is selected from rapamycin, everolimus, zotarolimus, lamimus, deforolimus, meolimus, no Wo Mosi, pimecrolimus, sirolimus, tacrolimus and temsirolimus.

3. The suspension of claim 1 or 2, wherein the at least one tri-O-acylglycerol and the limus active are present in a mass ratio of 10% -30% tri-O-acylglycerol to 90% -70% limus active.

4. A suspension according to any one of claims 1 to 3, wherein the at least one limus active substance is in the form of crystallites having a crystal size in the range of 1 μιη to 300 μιη.

5. The suspension according to any one of claims 1-4, wherein at least 70% of the at least one limus active substance is in the form of crystallites having a crystal size ranging from 10 μm to 50 μm.

6. Suspension according to any one of claims 1 to 5, wherein the at least one limus active substance has a crystallinity of at least 90% by weight.

7. The suspension of any one of claims 1-6, wherein the solvent is a dielectric constant epsilon at 20 °c _r 2.0 or less, or the solvent mixture contains at least 50% by volume of a dielectric constant epsilon at 20 DEG C _r A non-solvent of less than or equal to 2.0.

8. The suspension of any one of claims 1-7, wherein the solvent mixture is a mixture of at least one polar organic solvent and at least one non-polar organic solvent, the polar organic solvent having an n-octanol-water partition coefficient log kow of-0.5 to +1.5 and a dielectric constant epsilon at 20 ℃ of 5.0 to 30 _r The nonpolar organic solvent has a dielectric constant epsilon of 3.0 or less at 20 DEG C _r And n-octanol-water partition coefficient logKow of 3.0 or more.

9. A method of preparing a suspension according to any one of claims 1 to 8, the method comprising the steps of:

b) Preparing a suspension of at least one active substance of limus in microcrystalline form and the solution from step a),

10. The method according to claim 9, wherein the at least one limus active substance is selected from rapamycin, everolimus, zotarolimus, lamimus, deforolimus, meolimus, no Wo Mosi, pimecrolimus, sirolimus, tacrolimus and temsirolimus.

11. The method according to claim 9 or 10, wherein the at least one limus active substance is in the form of crystallites having a crystal size in the range of 1 μιη to 300 μιη.

12. The method of any one of claims 9 to 11, wherein at least 70% of the at least one limus active substance is in the form of crystallites having a crystal size in the range of 10 μιη to 50 μιη.

13. The method of any one of claims 9 to 12, wherein the at least one limus active substance has a crystallinity of at least 90% by weight.

14. The method of any one of claims 9-13, wherein the solvent is a dielectric constant epsilon at 20 °c _r 2.0 or less, or the solvent mixture contains at least 50% by volume of a dielectric constant epsilon at 20 DEG C _r A non-solvent of less than or equal to 2.0.

15. The method according to any one of claims 9 to 14, wherein the solvent mixture is a mixture of at least one polar organic solvent and at least one non-polar organic solvent, the polar organic solvent having an n-octanol-water partition coefficient log kow of-0.5 to +1.5 and a dielectric constant epsilon at 20 ℃ of 5.0 to 30 _r The nonpolar organic solvent has a dielectric constant epsilon of 3.0 or less at 20 DEG C _r And n-octanol-water partition coefficient logKow of 3.0 or more.

16. A method for coating a medical product selected from a catheter balloon, balloon catheter, stent or cannula, the method comprising the steps of:

a) A medical product is provided having a medical product surface,

b) Providing a suspension comprising at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol, at least one limus active substance in microcrystalline form, and a solvent or solvent mixture in which the at least one tri-O-acylglycerol is dissolved and in which the crystallites of the at least one limus active substance are insoluble, and

c) The coating suspension is applied to the surface of the medical product by injection, pipetting, capillary, fold spraying, dipping, spraying, dragging, wire dragging, drop dragging or rolling.

17. The method of claim 16, further comprising the step of: d) Drying the coating.

18. A medical product selected from a catheter balloon, balloon catheter, stent or cannula obtainable by the method according to claim 16 or 17.

19. A medical product selected from a catheter balloon, balloon catheter, stent or cannula, which is coated with the suspension according to any one of claims 1 to 8, and subsequently drying the coating.

20. A medical product selected from the group consisting of a catheter balloon, balloon catheter, stent or cannula coated with at least one tri-O-acylglycerol selected from the group consisting of trioctylglycerol, trinonyl glycerol, tridecyl glycerol and tri (undecyl) glycerol and at least one active substance of limus in microcrystalline form.

21. The medical product of claim 20, wherein the limus active substance is selected from the group comprising or consisting of: rapamycin, everolimus, biolimus A9, pimecrolimus, zotarolimus, tacrolimus, deforolimus, meolimus, noose Wo Mosi, dipholimus and temsirolimus.

22. The medical product of claim 20 or 21, wherein the at least one tri-O-acylglycerol and the at least one limus active are present in a mass ratio of 10% -30% tri-O-acylglycerol to 90% -70% limus active.

23. The medical product of any one of claims 20 to 22, wherein the at least one limus active substance is in the form of crystallites having a crystal size in the range of 1 μιη to 300 μιη.

24. The medical product according to any one of claims 20 to 23, wherein at least 70% of the at least one limus active substance is in microcrystalline form with a crystal size ranging from 10 μιη to 50 μιη.

25. The medical product according to any one of claims 20 to 24, wherein said at least one limus active substance has a crystallinity of at least 90% by weight.

26. The medical product according to any one of claims 20 to 25, wherein a biostable or biodegradable, bioactive or bioinert polymeric, metallic or ceramic layer is present below the layer of the at least one tri-O-acylglycerol and the at least one limus active substance.