KR101705033B1 - Self-assembled nanovesicles with multi-walls for stepwise drug-release and manufacturing method thereof - Google Patents
Self-assembled nanovesicles with multi-walls for stepwise drug-release and manufacturing method thereof Download PDFInfo
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Abstract
Description
The present invention relates to a self-assembled multi-layered nanoparticle elastomer capable of stepwise drug release and a method for preparing the same, and more particularly, to an amphipathic polymer-based elastomer having a plurality of layers laminated by inducing chemical instability occurring at an emulsion droplet interface Self-assembled nano-particles are prepared, and a water-soluble or poorly soluble drug is loaded on these layers. Then, a degradation reaction is induced to proceed under physiological conditions to apply the drug to a drug delivery system It is.
Recently, the usefulness of the development of functional materials using nano-level structures has been gaining attention, and studies have been focused on controlling various self-assembled nanostructures of amphipathic polymers having both hydrophobic blocks and hydrophilic blocks. The amphipathic polymer in the aqueous solution can maintain the thermodynamically stable structure in the aqueous solution because the hydrophobic block attempts to lower the free energy of the system and associate the hydrophilic blocks with each other to avoid water, and the hydrophilic block is to be uniformly dissolved in the aqueous solution . Thus, amphipathic polymers can be prepared by various core-shells such as spherical, rod-shaped, and ribbon-type micelles by controlling molecular weight, hydrophilic / hydrophobic block ratio, stiffness of the block, affinity between the blocks, molecular structure of the block, core-shell type self-assembled nanostructure, and it is easy to manufacture a functional material based on the nanostructure through the introduction of a functional block exhibiting a specific action.
For example, amphipathic polymers incorporating biocompatible and biodegradable blocks have potential applications in many biomedical applications and surface modification of the core-shell nanostructures formed can be achieved by simple introduction or replacement of blocks It is possible to apply it to a target-oriented drug delivery system and a gene delivery system, as well as to solubilization of a poorly soluble drug.
Among the various nanostructures that can be self-assembled, since the internally empty nanospores have a hydrophilic center and a hydrophobic membrane space, it is possible to carry out treatment and diagnostic agents having various surface properties at the same time, It is a very interesting nanostructure because it can be applied as a nanomedicine. However, for example, in the case of nanostructures formed by directly dissolving PEO- b- PCL, an amphipathic polymer composed of a biocompatible biodegradable block that has been approved by FDA, in water, linear micelles or a plate-like structure It is very difficult to form the endoplasmic reticulum.
In addition, in the conventional drugs, it is difficult to carry the hydrophobic drug itself to the transporter with high efficiency, and there are many cases where the release of the drug occurs immediately or the loss of the physiologically active substance occurs in the process of manufacturing the transporter. Therefore, in the development of nano-carriers, it is urgently required to develop a sustained-release preparation capable of suppressing the loss of physiologically active substance or drug, effectively delivering the drug to a desired lesion, and releasing a therapeutic dose of drug for a long time.
SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned problems, and an object of the present invention is to provide a self-assembled multi-layered nanosepposite in which a plurality of layers are stacked on the basis of an amphipathic polymer comprising at least one hydrophilic block and a hydrophobic block will be.
Another object of the present invention is to provide a hydrophilic and hydrophobic layer in which a decomposition reaction of a plurality of hydrophilic and hydrophobic layers undergoes a decomposition reaction and a layer containing a hydrophilic or hydrophobic drug is gradually decomposed to gradually release the drug contained in the layer, Assembled multi-layered drug nanosepsicles and a method of manufacturing the same.
It is still another object of the present invention to provide a self-assembled multi-layer which can produce an endoplasmic reticulum without chemical modification of an amphipathic polymer by utilizing chemical instability occurring at an emulsion droplet interface, And to provide a method for processing a drug nanoseposite solution.
It is a further object of the present invention to provide a process for the preparation of a hydrophobic layer which is capable of destroying binding by a certain temperature and pH by supporting or bonding hydrophobic components via hydrophobic interactions with a hydrophobic component, in particular a drug such as doxorubicin, The present invention also provides a self-assembled multi-layer drug nanoparticle and a method of manufacturing the same, which can sequentially release drug by decomposition of a hydrophobic layer continuously stacked on a lesion.
It is another object of the present invention to provide a self assembled multilayer drug nanostructured body capable of drastically increasing the amount of a supported component carried through a multilayer structure in which a plurality of layers form a water channel and a method of manufacturing the same.
The present invention relates to a self-assembled multilayer drug nano-sieve and a method of manufacturing the same.
One aspect of the present invention is a crystalline amphipathic polymer having at least one hydrophilic block and a hydrophobic block polymerized, wherein the hydrophobic block is self-assembled using an amphipathic polymer having a molecular weight significantly larger than that of the hydrophilic block, And a multilayered ellipsoid in which a hydrophilic layer and a hydrophobic layer produced therefrom are alternately laminated in plural layers.
The multilayered endoplasmic reticulum of the present invention also relates to multilayer nanospores.
In the present invention, the multi-layered vesicle may comprise at least three layers each of the hydrophilic layer and the hydrophobic layer. The multi-layered structure of the present invention has a multi-layered nanospores structure having a structure in which amphipathic polymer layers are laminated via a water channel.
In addition, the hydrophobic layer of the multilayered vesicle of the present invention can be hydrolyzed in an acidic atmosphere, and more preferably decomposition can proceed at a pH of 2 to 6 or lower.
Further, the decomposition reaction of the present invention may more preferably proceed at a temperature of from 2 to 5.5 and at a temperature of 37 < 0 > C or more.
In the present invention, the above-mentioned supportable hydrophobic component (e.g., drug, etc.) can be carried or bonded to the hydrophobic layer through hydrophobic interaction, and it should be small compared to the size of the hydrophobic layer. More specifically, the hydrophobic drug doxorubicin or surface The hydrophobic nature of the modified diagnostic contrast agent Fe 3 O 4 The nanoparticles can be, but are not limited to, nanoparticles.
The multilayered microcapsule of the present invention is an amphipathic polymer comprising a hydrophobic block and a hydrophilic block. The amphipathic polymer should have self-assembling ability because the hydrophobic portion has crystallinity. Also, the hydrophobic block should be prepared by using a polymer having a significantly high molecular weight of the hydrophobic block The hydrophobic block preferably has a molecular weight of at least 2 times, preferably at least 3 times, and more preferably at least 5 times the molecular weight of the hydrophilic block. The molecular weight may be a weight average molecular weight or a number average molecular weight measured by gel permeation chromatography using a styrene standard material.
Wherein the amphipathic polymer of the present invention is introduced into a mixed solvent of a hydrophilic solvent and a hydrophobic solvent to induce self-assembly.
The present invention also provides a method of making the multilayered vesicle.
The method of the present invention
a) preparing an emulsion containing at least one hydrophobic block and a hydrophilic block, wherein the hydrophobic block is at least twice the molecular weight of the hydrophilic block, and the crystalline amphiphilic polymer is added to a mixed solvent of a hydrophilic solvent and a hydrophobic solvent and stirred; And
b) removing the organic solvent from the emulsion;
Wherein the crystalline amphiphilic polymer has a molecular weight of 2 times, preferably 3 times, more preferably 5 times or more, the hydrophobic block relative to the hydrophilic block, and the hydrophobic block has a pH 6 or less.
In the present invention, the hydrophilic block is at least one selected from the group consisting of polyethylene oxide, polyethyleneimine, polyalkylene oxide, polyoxazoline, polyvinylpyrrolidone, polyacrylamide, polyvinyl alcohol, amino acid, sugar, The hydrophobic block may be selected from the group consisting of polycaprolactone, poly (D, L-lactide), poly (L-lactide) But are not necessarily limited to, one or more selected from the group consisting of polyanhydrides (polyanhydrides), poly (glycolide), poly (anhydride) and poly (hydroxyalkanoate).
In the present invention, the weight average molecular weight of the hydrophobic block or the hydrophilic block may be, for example, 1,000 to 50,000, and the weight average molecular weight ratio of the hydrophobic block (Mw o ) and the hydrophilic block (Mw i ) (Mw o / Mw i ) may be from 2 to 20, preferably from 3 to 15, more preferably from 5 to 10, but not limited as long as the molecular weight of the hydrophobic block is at least two times the molecular weight of the hydrophilic block, It is possible to form a multi-layered structure in the form of the most excellent endoplasmic reticulum close to a sphere
The hydrophilic solvent may be at least one selected from the group consisting of water, methanol, propanol, ethylene glycol, acetone and butane. The hydrophobic solvent may be at least one selected from the group consisting of pentane, hexane, decane, cyclohexane cyclohexane, 1-pentene, isobutylene, benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl May be one or more selected from the group consisting of diethyl sulfide, dimethyl sulfoxide, diethylamine, methylene chloride, chloroform, dimethyl formamide and pyridine, But is not limited to.
In the present invention, it is also possible to add to the above-mentioned organic solvent an effective amount of at least one selected from the group consisting of paclitaxel, ketoconazole, itraconazole, cyclosporine, sissapride, acetaminophen, aspirin, acetylsalicylic acid, indomethacin, naprose, wararin, papaverine, thioabendazole, , Doxorubicin, omeprazole, cholecalciferol, melphalan, nifedipine, digoxin, benzoic acid tryptophan, tyrosine, phenylalanine, aztreonam, ibuprofen, phenoxymethylpenicillin, thalidomide, methyl testosterone, prochlorperazine, hydrocortisone, dideoxy But are not limited to, purine nucleoside, vitamin D2, sulfonamide, sulfonylurea, paraaminobenzoic acid, melatonin, benzylpenicillin, chlorambucil, diazepine, digethoxine, hydrocortisone bureate, metronidazole benzoate, tolbutamide, Dean, fluodurocotisone, griseofulvin, myconazole nitrate, The antioxidant is preferably selected from the group consisting of an antioxidant, an antioxidant inhibitor, a propranolol, a theophylline, a flabopropene, a sodium benzoate, benzoic acid, riboflavin, benzodiazepine, phenobarbital, glidrolide, sulfiazine, sulfaethyl thiadiazole, diclofenac sodium, But is not limited to, at least one hydrophobic component selected from bromipyrimidine, hydrochlorothiazide, and florconazole.
The embodiment described above is not limited to the contents described above, and includes all matters that can be easily changed by a person engaged in the field. As an example, there may be cases where other types of devices are used for the purpose of implementing the same technique.
The self-assembled multilayered vesicle according to the present invention preferably has a form in which the amphipathic polymer is laminated by a plurality of layers of three or more layers via a water channel. Therefore, by interacting with the water-soluble or poorly soluble components (drug) in the layers, it is possible to remarkably improve the efficiency of supporting water-soluble or poorly soluble components (drugs), as opposed to a general monolayer.
That is, in the case of the endoplasmic reticulum of the present invention, when the drug is injected into the body, the hydrophobic layer of the outer layer in the lesion part is decomposed under proper pH and temperature conditions, the drug is gradually released, And then the inner layer is decomposed again to slowly release the drug, whereby the drug action is sustained over a long period of time.
Also, since the hydrophobic block of the amphipathic layer has a property of decomposing at a specific temperature or pH condition, the components can be selected such that the components supported at the sites different in temperature and pH from the normal site can be released.
In addition, the self-assembled multilayered vesicle according to the present invention has a multi-layered structure capable of containing water-soluble or poorly-adherent congestion, and degradation occurs from the outermost layer under certain conditions, It can be used as a sustained-release preparation.
FIG. 1 illustrates the morphology and self-assembled multilayer nanofiber expanded body according to one embodiment of the present invention and the phased release principle of the complimentary body.
FIG. 2 illustrates a method of fabricating a general self-assembled nanostructure according to an embodiment of the present invention and a method of manufacturing a chemically instable multilayered endoplasmic reticulum at an emulsion droplet interface.
FIG. 3 is a transmission electron microscope image showing the process of forming an endoplasmic reticulum (ES) according to an organic solvent evaporation process of an emulsion droplet prepared according to Example 1 of the present invention.
FIG. 4 is a graph showing the results of measurement of layer thickness and inter-layer distance of the nanofibers produced according to Example 1 of the present invention, where a is the thickness of the hydrophobic layer, b is the thickness of the hydrophilic layer, It is.
FIG. 5 illustrates a 3D structure of a self-assembling endoplasmic reticulum fabricated in an emulsified liquid form according to an embodiment of the present invention.
FIG. 6 shows Nile red, Fe 3 O 4 supported on a self-assembled monolayer prepared in the form of an emulsion according to an embodiment, wherein a is a fluorescence microscope of a conjugate containing Nile red (λ ex = 530 nm) (B) shows a transmission electron microscope photograph of a self-assembled ER containing Nile red, and (c) shows a fluorescence spectrum graph of a Nile red-containing aggregate.
FIG. 7 shows the amount of doxorubicin released over time of the nanospores prepared according to Example 4 of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Reference will now be made in detail to the preferred embodiments of the present invention, examples of which are illustrated in the accompanying drawings. It should be understood, however, that the invention is not limited thereto and that various changes and modifications may be made without departing from the spirit and scope of the invention.
Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In addition, the following drawings are provided by way of example so that those skilled in the art can fully understand the spirit of the present invention. Therefore, the present invention is not limited to the following drawings, but may be embodied in other forms, and the drawings presented below may be exaggerated in order to clarify the spirit of the present invention. Also, throughout the specification, like reference numerals designate like elements.
Also, the singular forms as used in the specification and the appended claims are intended to include the plural forms as well, unless the context clearly indicates otherwise.
Throughout the specification, when an element is referred to as "including" an element, it does not exclude other elements unless specifically stated to the contrary.
The term " polymer " in the present invention may include an oligomer in a form in which one or more monomers are combined.
In the present invention, the term 'amphipathic polymer' refers to an amphiphilic block copolymer and refers to a polymer composed of a hydrophobic block and a hydrophilic block.
The term " self-assembled nanostructure " in the present invention refers to a unique morphology formed by self-alignment between molecules or between blocks of the amphipathic polymer, Micelles, ribbons, vesicles, and the like, which have a size of about 1 micrometer.
The term " nanocarrier " in the present invention means any substance capable of carrying one or more drugs or diagnostic agents in self-assembly, and capable of transferring the carried drugs and diagnostic agents to a desired site in the body.
In general, the nano-transporter technology used in the drug delivery system is a technology for carrying a desired substance to a nano-sized transporter and releasing it to the lesion at a desired rate. The nano-transporter technology should be ① not toxic so that it can be used in the human body, (2) the amount of the carrier to be loaded, such as drug, should be high; (3) the amount of the carrier to be loaded must be controlled; and (4) the size of the carrier must be effectively controlled.
The amphipathic polymer is advantageous in that it can self-assemble between blocks by selectively polymerizing hydrophilic and hydrophobic blocks which are not toxic, and can maintain a thermodynamically stable structure in solution. However, in the case of an amphipathic block copolymer containing a crystalline polymer such as polycaprolactone, it is difficult to produce various types of nanostructures due to high crystallinity in an aqueous solution.
DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted intensive studies to solve such problems. When the hydrophobic block has a remarkably high molecular weight as a crystalline amphipathic polymer, when the hydrophobic block forms an endoplasmic reticulum through emulsification using the hydrophobic block, Using the interfacial instability of the derived polymer, the crystallinity of the polymer is lowered, and a multilayered vesicle having onion-like multi-layered shells is formed to carry the supported components to various layers, .
Also, it has been found that each layer of the self-assembled multilayered nanospores can be decomposed sequentially under certain conditions to control the amount of the supported component.
The self-assembled multilayer nanofibers according to the present invention is to provide a multilayered ellipsoidal structure in which one or more amphipathic polymer layers are stacked in a plurality of layers, and one or more water-soluble or insoluble congestion bodies are carried on any one of the multilayered structures.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a pictorial representation of the endoplasmic reticulum produced by the present invention. As shown in FIG. 1, the amphipathic polymer is separated in the emulsion self-assembling condition to form a circular vesicle having a plurality of amphipathic polymer layers of a multi-layer structure, and each layer forms a layer with a water channel as shown in blue Each layer shows a state in which water-soluble or poorly soluble drugs are supported, and the endoplasmic reticulum is decomposed at a proper pH and temperature so that the supported drug gradually releases and the process continues until the completion of the process in each layer .
Also, the self-assembled multilayer nanofibers according to the present invention may comprise a) an amphipathic polymer comprising at least one hydrophobic block and a hydrophilic block, wherein the hydrophobic block is at least twice the molecular weight of the hydrophilic block, and the crystalline amphipathic polymer is dissolved in a mixed solvent of a hydrophilic solvent and a hydrophobic solvent Adding and stirring to prepare an emulsion; And b) removing the organic solvent from the emulsion.
Figure 2 is a schematic representation of a method of making the multilayered umbrella structure of the present invention. That is, a method is disclosed in which an amorphous polymer is prepared in the form of a solution, followed by emulsification with an emulsifying agent and water to emulsify the emulsion, thereby producing an endoplasmic reticulum structure having a multi-layer structure in the form of an endoplasmic reticulum. If the emulsion is not used or the weight average molecular weight of the hydrophobic block is not more than 2 times the hydrophilic block, it is difficult to form a spherical multi-layered vesicle structure.
In the present invention, the hydrophilic layer is composed of a hydrophilic block of an amphiphilic block copolymer. The hydrophilic block is typically used as an amphiphilic block copolymer block in the art, and is not limited to a water-soluble polymer, It is preferable to use one which does not exhibit toxicity to human body.
Examples of the hydrophilic block that can be used in the present invention include polyethyleneimines, polyalkylene oxides, polyoxazolines, polyvinylpyrrolidones, polyacrylamides, polyvinyl alcohols, amino acids, sugars and monomers thereof Or more, and it is preferable that the use of polyethylene oxide does not react with molecules in living body.
In the present invention, the hydrophobic layer is composed of a hydrophobic block of an amphipathic block copolymer. Like the hydrophilic block, a conventional hydrophobic polymer that does not exhibit toxicity in the human body can be used. Further, a substance which can exhibit hydrolysis at a pH of 6 or less, preferably at a pH of 2 to 5.5 or less is preferable.
Examples of the hydrophobic block that can be used in the present invention include poly (D, L-lactide) (Poly (D, L-lactide) ), Poly (dioxanone), poly (glycolide), poly (anhydride) and poly (hydroxyalkanoate), and preferably polycaprolactone Is preferable because it is excellent in biocompatibility and the decomposition reaction can proceed well under the condition of pH 6 or less.
In the present invention, the morphology of the self-assembled multi-layered nanostructure can be determined by controlling the physical properties of each block constituting the amphipathic polymer, for example, the molecular weight of each block, the molecular weight ratio of the block, and the total molecular weight.
In the self-assembled nanostructure according to the present invention, the molecular weight of the hydrophobic block or the hydrophilic block is not limited. However, when the extracorporeal release is considered, the molecular weight of the hydrophobic block or the hydrophilic block may be 1,000 to 5,000. When the weight average molecular weight is less than 1,000, the amount of the concealed support can be reduced. When the weight average molecular weight is more than 50,000, the size of the conglomerate becomes too large and the transferability to the affected part is greatly reduced. The structural aspect of forming the endoplasmic reticulum does not have to be such low molecular weight. More preferably, the molecular weight of the hydrophobic block is at least 2 times, more preferably at least 5 times, depending on the molecular weight of the hydrophilic block, since the hydrophilic block has a molecular weight of 1,000 to 5,000, It is possible to form an endoplasmic reticulum having a multilayer structure close to a circle
In the self-assembled nanostructure according to the present invention, the weight average molecular weight ratio between the hydrophobic block and the hydrophilic block can be adjusted. Through this, the shape of the nanostructure produced through self-assembly can be determined.
More specifically, in the present invention, the weight average molecular weight ratio (M wo / M wi ) of the hydrophobic block (M wo ) and the hydrophilic block (M wi ) can be 2 or more, preferably 2 to 30, and more preferably 3 to 15 , And the range of 5 to 10 is preferable. In this range, a precise nanostructure can be obtained, and the interfacial curvature of the hydrophobic block and the hydrophilic block in the solvent can be reduced, so that the shape of the self-assembled nanostructure can be changed into a water channel between each layer in the cylinder, May have the form of a derived layer, for example a multilayered vesicle with several layers of shells.
In the present invention, when inducing emulsification during the production of the self-assembled nano-sister-form structure, it is preferable to mix at least one hydrophilic solvent with a non-immiscible hydrophobic solvent.
In the present invention, the hydrophilic solvent is not limited as long as the hydrophilic solvent can be prepared in the form of a vesicle having several layers of self-assembled amphipathic polymers, and examples thereof include water, methanol, propanol, ethylene glycol, It is preferable to use at least one selected from acetone and butane, more preferably water.
In the present invention, the hydrophobic solvent is not limited as long as it is a substance capable of dissolving or dispersing the hydrophobic block in the amphipathic polymer, and includes, but not limited to, pentane, hexane, decane, cyclohexane cyclohexane, 1-pentene, isobutylene, benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl At least one or more selected from the group consisting of diethyl sulfide, dimethyl sulfoxide, diethylamine, methylene chloride, chloroform, dimethyl formamide and pyridine. Preferably methylene chloride or chloroform.
In the present invention, the mixing ratio of the solvent and the amphipathic polymer is not limited in the case of preparing the self-assembled nanostructure using the emulsification reaction. However, in one embodiment of the present invention, 1 to 50 mg, More preferably 5 to 20 mg. When mixing a hydrophilic solvent and a hydrophobic solvent, the mixing ratio of the hydrophilic solvent and the hydrophobic solvent is not limited to the present invention. However, if the hydrophilic solvent and the hydrophobic solvent are mixed, it is preferable to use 1 to 30 parts by volume of the hydrophilic solvent It is preferable to mix the hydrophilic solvent at a ratio of 5 to 15 parts by volume relative to one part by volume of the hydrophobic solvent.
Further, when a hydrophilic solvent and a hydrophobic solvent are used together, they may further include a surfactant. The surfactant acts as a dispersant in the turbidity of the polymer. In the present invention, the type and content of the surfactant are not limited, but polyvinyl alcohol is preferably used. As an example, it is preferable to add 1 to 50 mg, more preferably 5 to 20 mg, to 1 mL of the hydrophilic solvent.
In the present invention, when preparing a self-assembled nanostructure using an emulsion as described above, the emulsion obtained in step b) may be prepared in an emulsion droplet, and then the solvent may be removed.
When the self-assembled nanostructure is prepared using the emulsion as described above, the nanostructure of the present invention has the form of a multi-layered nanospores.
The emulsified liquid prepared as described above can evaporate the hydrophobic organic solvent in the air. At this time, interfacial instability occurs due to the high concentration of the polymer at the interface between the hydrophilic solvent and the hydrophobic solvent at the same time as the evaporation of the solvent Self assembled multilayered endoplasmic reticulum is formed. More specifically, as shown in FIG. 3, in the case of the amphipathic polymer having a large proportion of the hydrophobic block, the hydrophobic solvent of the emulsion containing the droplet form slowly evaporates, and the interfacial instability causes the self-assembled multilayered endoplasmic reticulum (A multi-layered vesicle of d is formed and separated from the surface of the droplet of a). As the hydrophobic solvent continues to evaporate, these self-assembled multilayered vesicles are separated from the droplets and have a spherical shape with several layers inside as shown in d of FIG.
The dispersed self-assembled multilayered vesicle can remove residual surfactant and hydrophobic solvent using ultrapure water. At this time, the removal method is not limited to the present invention, but may be preferably performed using a high molecular weight cut-off device.
The self-assembled multilayered vesicle produced according to the present invention may be composed of three or more layers in order to increase the amount of conveying of the congested body.
The self-assembled multilayered vesicle according to the present invention may further comprise a structure for supporting the concealed body on any one or all layers of each layer. For example, when a hydrophobic component is selected as the carrier to be supported, one or more hydrophobic blocks may be bonded with hydrophobic interactions with one or more hydrophobic components.
In the present invention, the congestus body may be a hydrophilic or hydrophobic component, and it is preferable to use a poorly water soluble drug having low solubility in water because bioavailability of the self-assembled multilayered vesicle can be increased .
In the present invention, the hydrophilic component congestion retardant may be any one or more selected from camptothecin, doxorubicin hydrochloride and verapamil hydrochloride, for example.
In the present invention, the poorly soluble component concealer may be, for example, at least one selected from the group consisting of paclitaxel, ketoconazole, itraconazole, cyclosporine, sissapride, acetaminophen, aspirin, acetylsalicylic acid, indomethacin, naproxen, warfarin, , Meconazole, cinarizine, doxorubicin, omeprazole, cholecalciferol, melphalan, nifedipine, digoxin, tryptophan tyrosine, tyrosine, phenylalanine, aztreonam, ibuprofen, phenoxymethylpenicillin, thalidomide, methyl testosterone, prochlorperazine , Hydrocortisone, dideoxypurine nucleoside, vitamin D2, sulfonamide, sulfonylurea, paraaminobenzoic acid, melatonin, benzylpenicillin, chlorambucil, diazepine, digethoxine, hydrocortisone buretate, metronidazole benzoate, Butadiene, prostaglandine, fuudro cortisone, griseofulvin, mykona But are not limited to, nitrate, leucotriene non-inhibitor, propranolol, theophylline, flabiprofen, sodium benzoate, benzoic acid, riboflavin, benzodiazepine, phenobarbital, glidrolide, sulfiazine, sulfaethyl thiadiazole, diclofenac sodium, But is not limited to, any one or more selected from the group consisting of cholinesterase, cholinergic hydrochloride, buppyrimine, hydrochlorothiazide, and floroconazole. In addition to the above components, an analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics including antibiotics, penicillins, anticoagulants, antidepressants, antidiabetic agents, , Antiepileptics, antihistamines, antihypertensive agents, anti-cancer drugs antimicrobial agents, neoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, antimuscarinic agents, antifungal agents, Antimycobacterial agents, beta-adrenoreceptor blocking agents, cardiac inotropic agents, contrasting agents, corticosteroids, diagnostic agents, diagnostic agents, Dopaminergics, dopaminergics, hemostatics, immunological agents, lipid regulating agents, muscle relaxants, coughs, diuretics, anti-Parkinson drugs, Cough suppressants, parasympathomimetics, calcitonin (parathyroid calcitonin), prostaglandins, radio-phar sex hormones, anti-allergic agents, stimulants, anorexics, sympathomimetics, thyroid drugs (including thyroid hormones, maceuticals), steroids thyroid agents, vasodilators, nutritional agents, xanthines and physiologically active peptides, proteins, carbohydrates, nucleic acids, nucleic acids, lipids, polysaccharides, and the like. However, it is preferable that the size of the drug is smaller than the size of the vesicle hydrophobic layer.
The hydrophobic component may preferably include doxorubicin, adriamycin, Adriamycin). The material may be combined with hydrophobic interaction with the hydrophobic layer and may be separated from the poorly soluble component by hydrolysis of the hydrophobic PCL block layer at certain temperature and pH conditions. It is acidic with a pH below 5.5 such as in the lesion, especially cancer, different in temperature and pH from normal tissue of our body, and when there is a tissue having a high temperature of 37 DEG C or higher, more preferably 37 to 42 DEG C, The multi-layered nanomaterial transporter carries hydrophobic components in other normal tissues, and reacts with the pH conditions of the lesion to sequentially decompose the hydrophobic layer to enable the drug to be transported to a desired site of the body.
In the present invention, various methods can be applied to carry the hydrophilic or hydrophobic fragile concealer onto the self-assembled multilayered vesicle. For example, methods such as stirring, heating, ultrasonic irradiation, solvent evaporation using an emulsion method, matrix formation, and dialysis using an organic solvent can be used alone or in combination.
The self-assembled multilayered vesicles prepared by the above method can be obtained after filtration of a solution containing an endoplasmic reticulum.
The self-assembled multilayered endoplasmic reticulum produced according to the present invention may comprise the hydrophilic component or the poorly soluble drug of the hydrophobic component. Accordingly, it can be usefully used as a medicinal preparation capable of selectively delivering a drug to a malignant tumor such as a lesion, particularly a cancer.
In addition, the self-assembled multilayered vesicles produced may comprise an insoluble MRI diagnostic imaging material of said hydrophilic or hydrophobic component. Thus, malignant tumors such as cancer, especially cancer, can be selectively diagnosed and used as medicinal preparations capable of simultaneous treatment and diagnosis.
In addition, since the self-assembled multilayered vesicle according to the present invention does not need to introduce functional groups or adhesive substances for bonding the concealed bodies, unnecessary processes can be shortened.
Hereinafter, the self-assembled multilayered vesicle according to the present invention and the method for producing the same will be described in more detail with reference to Examples and Comparative Examples. However, the following examples and comparative examples are merely examples for explaining the present invention in more detail, and the present invention is not limited by the following examples and comparative examples.
The specifications of the raw materials used in Examples and Comparative Examples, the equipment for measuring physical properties, and the methods are as follows.
(Raw material)
① block copolymer
The PEO (1k) -b-PCL (1k), PEO (1k) -b-PCL (5k), PEO (5k) -b-PCL (5k), all of which are manufactured by Polysciences Inc.
However,
Iron (III) acetylacetonate was used for Alfa-Aesar, diphenyl ether was used for titanochemistry, doxorubicin hydrochloride was used for Boryeong pharmaceutical, and Nile red dye was used for Acros Organics.
③ Other
Polyvinyl alcohol (98% hydrolyzed, weight average molecular weight 27000), 1,2-hexadecanediol, oleylamine and oleyl acid were all Sigma-Aldrich products.
(measuring equipment)
Fluorescence spectra were measured using an FS-2 fluorescence spectrometer (Scinco, Republic of Korea).
Fluorescence microscopy: Measured using an Eclipse Ti-E microscope (Nikon, Japan).
Scanning electron microscope: CX-100S (COXEM, Republic of Korea) was used to measure electron beams accelerated to 20 kV.
Cross-sectional scanning electron microscopy was performed using a Helios NanoLab 660 (FEI, USA) and a dual beam focused ion beam (FIB) / SEM system.
Transmission electron microscopy (TEM) was performed using electron beams of 300 kV (JEM-3011 HR) and 120 kV (JEM-1400).
TEM Tomography: Synthesis with JEM-2100F (JEOL), 200 kV, 137 images
(Drug loading capacity and drug loading efficiency)
The self-assembled nanostructures prepared through the following examples were treated with 10% (v / v) Triton X-100. Then, the measurement was carried out using a fluorescence measuring apparatus (λ ex = 470 nm,
[Formula 1]
Drug loading capacity (DLC, wt%) = drug loading / total weight of self-assembled nanostructure × 100
[Formula 2]
Drug loading efficiency (DLE, wt%) = drug loading /
(Example 1)
A solution of 10 mg / ml of PEO (1 k) -b-PCL (5 k) (block copolymer of poly (ethylene oxide) and polycaprolactone) as an amphipathic polymer was dissolved in polyvinyl alcohol (10 mg / ml) 1/10 by volume ratio.
The stirred solution was transferred to a glass box and chloroform was evaporated to prepare a self-assembled nanostructure. The resulting self-assembled nanostructures were filtered with ultrapure water through a high molecular weight cut-off MWCO (14 kDa) device to remove residual polyvinyl alcohol and chloroform.
As shown in FIG. 4, the self-assembled nano-form of multilayer was analyzed by a Cryo-TEM image to find that the hydrophobic layer had a thickness of about 17.7 nm and the hydrophilic layer formed between the hydrophobic layers had a size of 16.2 nm Could know.
Also, in order to confirm the multi-layer structure, it was confirmed that the 3B image measured by the electron-tomography method had a perfect multilayered nanosecomposite structure as shown in FIG.
(Comparative Examples 1 and 2)
The PEO- b- PCL copolymer was prepared from the amphipathic polymer. B- PCL (5k) (Comparative Example 2) PEO (1k) -b- PCL (1k) (Comparative Example 1) and PEO (5k) -b- PCL (Comparative Example 2). The fabricated structure was obtained as a fibrous form rather than an endoplasmic reticulum form.
(Example 2)
As a result of conducting the same experiment except that PEO (1k) -g-PCL (2.5k) was used in Example 1, it was formed into a multilayered vesicle form, but it was found to have a distorted form.
(Example 3)
Except that 10 μl of hexane containing Fe 3 O 4 (Nile Red) was mixed with 100 μl of the PEO- b- PCL block copolymer dissolved in chloroform in Example 1, and the mixture was stirred. In the production method of 10 μl of hexane containing Fe 3 O 4 , 2 nmol of Fe (acac) 3 , 20 ml of phenyl ether, 10 mmol of 1,2-hexadecanediol, 6 mmol of oleic acid and 6 mmol of oleylamine were mixed and stirred The reaction was carried out at 200 ° C for 30 minutes and then again at 265 ° C for 30 minutes. The black brown mixture was cooled and precipitated in ethanol. The precipitate was collected and dissolved in 20 ml of hexane containing 0.05 ml of oleic acid and oleylamine, Filtered, again precipitated in ethanol and dispersed in hexane.
As a result of fluorescence analysis of the prepared multi-layered endoplasmic reticulum, it can be confirmed by image analysis that nyled was carried by fluorescence analysis as shown in FIG. 6 (a), TEM image analysis shows that the original endoplasmic reticulum maintains its shape b), and Nile red shifts to 622 nm through fluorescence spectrum analysis. (c) It can be seen that the ER of the present invention is very compactly packed.
(Example 4)
A solution of 100 μl of PEO (1 k) -g-PCL (5 k) (10 mg / ml) in chloroform and 10 μl of Doxlubicin (10 mg / ml) in chloroform was added to 1 ml of water (containing PVOH). To remove the undissolved Dox and PVOH, dialysis was performed using a dialysis membrane (MWCO, 14 kDa) for 48 hours and then centrifuged. And filtered to obtain a multi-layered fibrous structure having the same structure as the onion skin.
Drug release test was carried out using the obtained Dox-loaded vesicle structure. In the test method, the content of Dox dialyzed and eluted was measured using a dialysis tube (1 ml) suspended in a 20 ml acetate buffer (50x10-3M, pH 5.5) constantly shaking at 100 rpm at 37 ° C. That is, each time the dialysis progressed for a predetermined time, the Triton X-100 solution was injected into the nanostructure solution and the cumulative leakage amount was measured by performing fluorescence spectrum analysis (λ ex = 470 nm,
As a result, it can be seen that the present invention slowly releases 49% at 5 days, 60% at 10 days, and 81% at 20 days, indicating that it is very well controlled as a sustained-release preparation.
FIG. 7 shows the amount of doxorubicin released over time in the nanostructure prepared according to Example 4. The amount of doxorubicin released till the end of 12 hours after the nanostructure was injected increased sharply, This shows a tendency to decrease suddenly. This is because doxorubicin carried on the hydrophobic layer meets the appropriate decomposition temperature and decomposition pH of the hydrophobic layer, decomposition proceeds, and doxorubicin is released. When the hydrophobic layer decomposition is completed, the release of doxorubicin is suppressed until the next hydrophilic layer decomposes .
In FIG. 4, the release of doxorubicin tends to increase rapidly around 10 days and 18 days. Thus, the nanofibers prepared according to the present invention have a plurality of hydrophilic layers and hydrophobic layers alternately formed, , The release of doxorubicin can be controlled by decomposition of the hydrophilic layer and the hydrophobic layer, and it can be confirmed that doxorubicin is continuously released even after a long time after the nanoparticle is injected.
While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
Claims (14)
Wherein the hydrophilic block is at least one selected from the group consisting of polyethylene oxide, polyethyleneimine, polyalkylene oxide, polyoxazoline, polyvinylpyrrolidone, polyacrylamide, polyvinyl alcohol, amino acid, sugar and monomers thereof, Polycaprolactone, poly (D, L-lactide), poly (L-lactide), poly (dioxanone), poly Wherein the at least one selected from the group consisting of poly (glycolide), poly (anhydride) and poly (hydroxyalkanoate).
Wherein the multi-layer nanospores are three or more layers.
Wherein the hydrophobic block is hydrolyzed in an acidic atmosphere.
Wherein the hydrophobic layer undergoes a decomposition reaction at a pH of 2 to 6 at 37 占 폚 or higher.
The hydrophobic layer may comprise one or more incompatible concealers.
The insoluble congestion regimen is selected from the group consisting of paclitaxel, ketoconazole, itraconazole, cyclosporine, sisaferide, acetaminophen, aspirin, acetylsalicylic acid, indomethacin, naprose, warfarin, papaverine, thioabendazole, myconazole, cinarizine, doxorubicin , Omeprazole, cholecalciferol, melphalan, nifedipine, digoxin, tryptophan benzoate, tyrosine, phenylalanine, aztreonam, ibuprofen, phenoxymethylpenicillin, thalidomide, methyl testosterone, prochlorperazine, hydrocortisone, dideoxypurine But are not limited to, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, creosides, vitamin D2, sulphonamides, sulphonylureas, paraaminobenzoic acid, melatonin, benzylpenicillin, chlorambucil, diazepine, digethoxine, hydrocortisone, Fluodurocotisson, griseofulvin, myconadol nitrate, leucotriene nono Or a pharmaceutically acceptable salt or solvate thereof. The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of propranolol, thiopyrine, flabipropene, sodium benzoate, riboflavin, benzodiazepine, phenobarbital, glidrolide, Min, hydrochlorothiazide, and floroconazole.
b) removing the organic solvent after preparing the emulsion;
To produce multi-layered nanoseposites having multiple layers of shells,
Wherein the hydrophilic block is at least one selected from the group consisting of polyethylene oxide, polyethyleneimine, polyalkylene oxide, polyoxazoline, polyvinylpyrrolidone, polyacrylamide, polyvinyl alcohol, amino acid, sugar and monomers thereof, Polycaprolactone, poly (D, L-lactide), poly (L-lactide), poly (dioxanone), poly Wherein the at least one selected from the group consisting of poly (glycolide), poly (anhydride) and poly (hydroxyalkanoate).
Wherein the hydrophilic block has a weight average molecular weight of 1,000 to 50,000.
The hydrophilic solvent may be at least one selected from water, methanol, propanol, ethylene glycol, acetone, and butane, and the hydrophobic solvent may be at least one selected from the group consisting of pentane, hexane, decane, cyclohexane, It is also possible to use one or more of the following compounds: 1-pentene, isobutylene, benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl sulfide A method for producing a self-assembled multilayered vesicle having at least one selected from the group consisting of dimethyl sulfoxide, diethylamine, methylene chloride, chloroform, dimethyl formamide and pyridine .
Wherein the solvent can further comprise a hydrophilic or scarcely congested body.
Wherein the congestive body is selected from the group consisting of diagnostic contrast agents, doxorubicin, paclitaxel, ketoconazole, itraconazole, cyclosporine, sissapride, acetaminophen, aspirin, acetylsalicylic acid, indomethacin, naprose, wararin, papaverine, thioabendazole, Or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of lysine, doxorubicin, omeprazole, cholecalciferol, melphalan, nifedipine, digoxin, benzoic acid tryptophan, tyrosine, phenylalanine, aztreonam, ibuprofen, phenoxymethylpenicillin, thalidomide, methyl testosterone, But are not limited to, oxuridine nucleoside, oxydurine nucleoside, vitamin D2, sulfonamide, sulfonylurea, paraaminobenzoic acid, melatonin, benzylpenicillin, chlorambucil, diazepine, digethoxine, hydrocotisone buyrate, metronidazole benzoate, tolbutamide, Glucan, fluodurocotisson, griseofulvin, myconazole nitrate, A prodrug, a cholesterol, a cholesterol, a cholesterol, a cholesterol, a cholesterol, a cholesterol, a cholesterol, a cholesterol, a cholesterol, a cholesterol, , Bromipyrimine, hydrochlorothiazide, and florconazole. The method of producing a self-assembled multilayer nanosome according to claim 1,
Wherein the congested body is at least one selected from camptothecin, doxorubicin hydrochloride and verapamil hydrochloride.
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| CN113384527A (en) * | 2020-03-11 | 2021-09-14 | 江苏恒瑞医药股份有限公司 | A pharmaceutical composition containing papaverine or its salt and its preparation method |
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| KR20190038033A (en) | 2017-09-29 | 2019-04-08 | 영남대학교 산학협력단 | Manufacturing device of nanocomposites, method of preparing nanocomposites and nanocomposite prepared therefrom |
| CN113384527A (en) * | 2020-03-11 | 2021-09-14 | 江苏恒瑞医药股份有限公司 | A pharmaceutical composition containing papaverine or its salt and its preparation method |
| CN113384527B (en) * | 2020-03-11 | 2023-01-24 | 江苏恒瑞医药股份有限公司 | A pharmaceutical composition containing papaverine or its salt and its preparation method |
| KR20220146107A (en) * | 2021-04-23 | 2022-11-01 | 한국세라믹기술원 | Multiple emulsion for sequential release of functional component and cosmetic composition comprising thereof |
| KR102548433B1 (en) | 2021-04-23 | 2023-06-28 | 한국세라믹기술원 | Multiple emulsion for sequential release of functional component and cosmetic composition comprising thereof |
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