CN115518044A - Composition for improving solubility of everolimus and freeze-drying process thereof - Google Patents
Composition for improving solubility of everolimus and freeze-drying process thereof Download PDFInfo
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- CN115518044A CN115518044A CN202210973059.3A CN202210973059A CN115518044A CN 115518044 A CN115518044 A CN 115518044A CN 202210973059 A CN202210973059 A CN 202210973059A CN 115518044 A CN115518044 A CN 115518044A
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- Prior art keywords
- everolimus
- composition
- carrier material
- beta
- solubility
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/02—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of powders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to a composition for improving the solubility of everolimus and a freeze-drying process thereof, wherein the composition comprises 0.1-10% of everolimus and 10-95% of carrier material in parts by weight; the carrier material comprises a beta-CD; the carrier material comprises one or more surfactants; the carrier material includes a water-soluble polymer. The freeze drying process comprises the following three stages: 1) A pre-freezing stage; 2) A sublimation drying stage; 3) And (4) resolving and drying. According to the invention, the SBE-beta-CD is used for solubilizing the everolimus, the solubility of the everolimus in an aqueous solution is obviously improved, and compared with a spray-dried product, a freeze-dried product of the everolimus has a higher dissolution rate.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a composition for improving the solubility of everolimus and a freeze-drying process thereof.
Background
Everolimus is a derivative of sirolimus (also known as rapamycin), so everolimus is also known as 40-O- (2-hydroxyethyl) -rapamycin, or 40-O- (2-hydroxyethyl) -sirolimus. Everolimus (everolimus) was developed by nova, switzerland and approved by the FDA for marketing in 2010 for rejection after adult renal and cardiac surgery. The european commission of 8/6 th 2009 so far approved the drug for european marketing for the treatment of ineffective patients with advanced renal cancer.
Rapamycin and its derivatives have very low solubility in water, and belong to highly hydrophobic compounds, such as everolimus, which has a solubility in water of less than 0.0l% (g/ml) at 25 ℃. The extremely low solubility results in the failure of rapamycin derivatives to be absorbed in significant amounts in the blood after oral administration, and the simple rapamycin mixtures prepared with conventional pharmaceutical excipients have unpredictable dissolution rates and irregular bioavailability.
In order to overcome the problem of solubility of the drug, patent ZL96196788.9 adopts the steps of firstly preparing the drug into a solid dispersion, and using cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate or polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) and the like as carrier materials for spray drying, however, the method is mainly used for improving the dissolution rate of everolimus during preparation of the solid dispersion, and is difficult to directly improve the solubility of everolimus;
beta-cyclodextrin (beta-CD) and derivatives thereof (beta-CDD) are novel drug inclusion materials developed in recent years, after hydrophilic methylated and hydroxypropylated cyclodextrin of beta-CD forms an inclusion compound with a poorly soluble drug, the solubility, dissolution rate and bioavailability of the drug can be improved, and after hydrophobic ethylated beta-CD forms an inclusion compound with a water soluble drug, the release rate of the drug can be controlled;
sulfobutyl beta-cyclodextrin (SBE-beta-CD) is an anionic and highly water-soluble beta-CD derivative successfully developed by Cydex corporation in the 90 th century in the United states, and can be well included with drug molecules to form a non-covalent compound, so that the stability, water solubility and safety of the drug are improved, the nephrotoxicity is reduced, the hemolysis of the drug is alleviated, the drug release rate is controlled, bad odors are covered, and the like. Compared with beta-CD, the beta-CD has better water solubility, small hemolytic effect and low nephrotoxicity, and is a novel pharmaceutic adjuvant with very wide application prospect.
Disclosure of Invention
The invention aims to solve the technical problem of providing a composition for improving the solubility of everolimus and a freeze-drying process thereof, wherein the everolimus is solubilized by using SBE-beta-CD, the solubility of the everolimus in an aqueous solution is remarkably improved, and compared with a spray-dried product, a freeze-dried product of the composition can have a higher dissolution rate.
In order to solve the technical problems, the invention adopts the following technical scheme:
a composition for increasing the solubility of everolimus, comprising 0.1-10% by weight of everolimus and 10-95% by weight of a carrier material; the carrier material comprises a beta-CD; the carrier material comprises one or more surfactants; the carrier material includes a water-soluble polymer.
Preferably, the beta-CD, preferably SBE-beta-CD.
Preferably, the surfactant is a nonionic, anionic or amphiphilic surfactant, preferably Poloxamer188.
Preferably, the water-soluble polymer is a derivative of cellulose, preferably hypromellose.
Preferably, the carrier material is prepared from the following components in parts by weight: SBE-beta-CD 10% -25%, poloxamer 188% 1% -5%, hydroxypropyl methylcellulose 1% -5% and purified water for dissolving carrier material 60% -80%.
Preferably, the composition may be administered in any convenient form, such as tablets, capsules, granules or powders in sachets.
The freeze-drying process of the composition for improving the solubility of everolimus comprises the following three stages:
1) A pre-freezing stage: under the non-vacuum condition, starting a Ramp mode, rapidly cooling to 2-7 ℃ within 1min, and keeping for 30min; starting the Ramp mode again, reducing the temperature to minus 40-50 ℃ at a constant speed within 60min, and keeping the temperature for 120min;
2) A sublimation drying stage: starting a Ramp mode to heat to minus 8-12 ℃ at a constant speed within 120min under the condition that the vacuum degree is 100mT, and keeping the temperature for 1800min; starting the Ramp mode again, raising the temperature to minus 2-7 ℃ at a constant speed within 60min, and keeping the temperature for 120min; finally, starting a Ramp mode to uniformly heat up to 30-40 ℃ within 60 min;
3) And (3) an analysis drying stage: keeping the above temperature for 240min under the condition of vacuum degree of 0, and drying to obtain the final product powder.
The invention has the beneficial effects that:
according to the invention, the SBE-beta-CD is used for solubilizing the everolimus, the solubility of the everolimus in an aqueous solution is obviously improved, and compared with a spray-dried product, a freeze-dried product of the everolimus has a higher dissolution rate. The composition may be administered in any convenient form, such as tablets, capsules, granules or powders in sachets.
Detailed Description
The present invention will be further described with reference to the following examples for facilitating understanding of those skilled in the art, and the description of the embodiments is not intended to limit the present invention.
Example 1
Preparing an aqueous solution containing the following components (parts by weight):
| components | Is in percentage by weight |
| API | 5 |
| SBE-β-CD | 10 |
| Poloxamer188 | 3 |
| HPMC | 3 |
| Purified water | 79 |
The support material in the table was dissolved in purified water in the table, and everolimus (API) was added after complete dissolution of the support material to make composition 1.
Example 2
Preparing an aqueous solution containing the following components (parts by weight):
the support material in the table was dissolved in purified water in the table, and everolimus (API) was added after complete dissolution of the support material to make composition 2.
Example 3
Preparing an aqueous solution containing the following components (parts by weight):
| components | Is in percentage by weight |
| API | 5 |
| SBE-β-CD | 20 |
| Poloxamer188 | 3 |
| HPMC | 3 |
| Purified water | 69 |
Table support material was dissolved in purified water and everolimus (API) was added after complete dissolution of the support material to produce composition 3.
Example 4
Preparing an aqueous solution containing the following components (parts by weight):
| components | Is in percentage by weight |
| API | 5 |
| SBE-β-CD | 25 |
| Poloxamer188 | 3 |
| HPMC | 3 |
| Purified water | 64 |
The support material in the table was dissolved in purified water in the table, and everolimus (API) was added after complete dissolution of the support material to obtain composition 4.
Example 5
The compositions 1 to 4 prepared in the above examples 1 to 4 were made into powders by freeze-drying, and the freeze-drying process was as follows:
according to the invention, the SBE-beta-CD is used for solubilizing the everolimus, the solubility of the everolimus in an aqueous solution is obviously improved, and compared with a spray-dried product, a freeze-dried product of the everolimus has a higher dissolution rate. The composition may be administered in any convenient form, such as tablets, capsules, granules or powders in sachets.
All technical features in the embodiment can be subjected to appearance modification according to actual needs.
The above embodiments are preferred implementations of the present invention, and besides, the present invention can be implemented in other ways, and any obvious substitutions without departing from the concept of the present invention are within the protection scope of the present invention.
Claims (7)
1. A composition for increasing solubility of everolimus, characterized by: the composition comprises 0.1 to 10 weight percent of everolimus and 10 to 95 weight percent of carrier material;
the carrier material comprises a beta-CD;
the carrier material comprises one or more surfactants;
the carrier material includes a water-soluble polymer.
2. The composition for increasing solubility of everolimus according to claim 1, wherein: the beta-CD is preferably SBE-beta-CD.
3. The composition for increasing solubility of everolimus according to claim 1, wherein: the surfactant is a nonionic, anionic or amphiphilic surfactant, preferably Poloxamer188.
4. The composition for increasing solubility of everolimus according to claim 1, wherein: the water-soluble polymer is a cellulose derivative, preferably hydroxypropyl methylcellulose.
5. The composition for increasing the solubility of everolimus according to any one of claims 1 to 4, wherein: the carrier material is prepared from the following components in parts by weight: SBE-beta-CD 10% -25%, poloxamer1881% -5%, hydroxypropyl methylcellulose 1% -5% and purified water for dissolving carrier materials 60% -80%.
6. A composition for increasing solubility of everolimus according to claim 1, wherein: the composition may be administered in any convenient form, such as tablets, capsules, granules or powders in sachets.
7. The process of claim 1, wherein the lyophilization of the composition for increasing solubility of everolimus comprises: the method comprises the following three stages:
1) A pre-freezing stage: under the non-vacuum condition, starting a Ramp mode to rapidly cool to 2-7 ℃ within 1min, and keeping for 30min; starting the Ramp mode again, reducing the temperature to minus 40-50 ℃ at a constant speed within 60min, and keeping the temperature for 120min;
2) A sublimation drying stage: starting a Ramp mode to heat to minus 8-12 ℃ at a constant speed within 120min under the condition that the vacuum degree is 100mT, and keeping the temperature for 1800min; starting the Ramp mode again, raising the temperature to minus 2-7 ℃ at a constant speed within 60min, and keeping the temperature for 120min; finally starting a Ramp mode to uniformly heat up to 30-40 ℃ within 60 min;
3) And (3) analysis and drying stage: maintaining the above temperature for 240min under the condition of vacuum degree of 0, and drying to obtain the final product powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210973059.3A CN115518044A (en) | 2022-08-15 | 2022-08-15 | Composition for improving solubility of everolimus and freeze-drying process thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210973059.3A CN115518044A (en) | 2022-08-15 | 2022-08-15 | Composition for improving solubility of everolimus and freeze-drying process thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115518044A true CN115518044A (en) | 2022-12-27 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210973059.3A Pending CN115518044A (en) | 2022-08-15 | 2022-08-15 | Composition for improving solubility of everolimus and freeze-drying process thereof |
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| Country | Link |
|---|---|
| CN (1) | CN115518044A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1939302A (en) * | 2005-09-29 | 2007-04-04 | 福建省微生物研究所 | Siromosi medicinal composition and its making method |
| CN104039370A (en) * | 2011-11-16 | 2014-09-10 | W.L.戈尔及同仁股份有限公司 | Eluting medical devices |
| CN107823136A (en) * | 2017-11-27 | 2018-03-23 | 郭丽颖 | A kind of sirolimus self-assembled micelle and preparation method thereof |
-
2022
- 2022-08-15 CN CN202210973059.3A patent/CN115518044A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1939302A (en) * | 2005-09-29 | 2007-04-04 | 福建省微生物研究所 | Siromosi medicinal composition and its making method |
| CN104039370A (en) * | 2011-11-16 | 2014-09-10 | W.L.戈尔及同仁股份有限公司 | Eluting medical devices |
| CN107823136A (en) * | 2017-11-27 | 2018-03-23 | 郭丽颖 | A kind of sirolimus self-assembled micelle and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| D.S.KIM ET AL: "Influence of Hydroxypropylmethylcellulose and Sodium Lauryl Sulfate on the Solubility and Dissolution of Sirolimus in Solvent-evaporated Solid Dispersions", BULL.KOREAN CHEM.SOC, vol. 39, pages 778 - 783 * |
| S.W.JANG ET AL: "Improved oral absorption and chemical stability of everolimus via preparation of solid dispersion using solvent wetting technique", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 473, pages 187 - 193 * |
| SEOK, ET AL: "Formulation of Nanoparticle Containing Everolimus Using Microfluidization and Freeze-Drying", CHEM. PHARM. BULL, vol. 64, no. 10, pages 1445 - 1449 * |
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