CN114376994A - Rapamycin sustained-release medicinal film and preparation method thereof - Google Patents
Rapamycin sustained-release medicinal film and preparation method thereof Download PDFInfo
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- CN114376994A CN114376994A CN202210208385.5A CN202210208385A CN114376994A CN 114376994 A CN114376994 A CN 114376994A CN 202210208385 A CN202210208385 A CN 202210208385A CN 114376994 A CN114376994 A CN 114376994A
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- rapamycin
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- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229960002930 sirolimus Drugs 0.000 title claims abstract description 68
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 title claims abstract description 68
- 238000013268 sustained release Methods 0.000 title claims abstract description 39
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000003960 organic solvent Substances 0.000 claims abstract description 34
- 239000003814 drug Substances 0.000 claims abstract description 21
- 239000002002 slurry Substances 0.000 claims abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- 229920000642 polymer Polymers 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 239000000693 micelle Substances 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 239000011248 coating agent Substances 0.000 claims abstract description 5
- 238000000576 coating method Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 5
- 238000004108 freeze drying Methods 0.000 claims abstract description 5
- 230000001954 sterilising effect Effects 0.000 claims abstract description 5
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 125000005456 glyceride group Chemical group 0.000 claims description 12
- 150000003904 phospholipids Chemical class 0.000 claims description 12
- 239000003381 stabilizer Substances 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 4
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical group C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 claims description 4
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 238000000855 fermentation Methods 0.000 claims description 4
- 230000004151 fermentation Effects 0.000 claims description 4
- 229920001427 mPEG Polymers 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 230000000813 microbial effect Effects 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 229920001992 poloxamer 407 Polymers 0.000 claims description 4
- 229940044476 poloxamer 407 Drugs 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 229940083466 soybean lecithin Drugs 0.000 claims description 4
- 239000006228 supernatant Substances 0.000 claims description 4
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 claims description 4
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 3
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 claims description 3
- 229940117972 triolein Drugs 0.000 claims description 3
- 239000000463 material Substances 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 7
- 230000003409 anti-rejection Effects 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 229930000044 secondary metabolite Natural products 0.000 description 2
- AFSHUZFNMVJNKX-UHFFFAOYSA-N 1,2-di-(9Z-octadecenoyl)glycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCC=CCCCCCCCC AFSHUZFNMVJNKX-UHFFFAOYSA-N 0.000 description 1
- AFSHUZFNMVJNKX-LLWMBOQKSA-N 1,2-dioleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-LLWMBOQKSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
Classifications
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- 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
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Transplantation (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a rapamycin sustained-release drug film, which comprises the following components: rapamycin, a soluble high molecular polymer carrier and an organic solvent; the preparation method of the rapamycin sustained-release medicine film comprises the following steps of S1: preparing rapamycin; s2: dissolving; s3: stirring for sterilization; s4: recovering the organic solvent under reduced pressure; s5: centrifuging and filtering; s6: freeze-drying the micelle solution to obtain a rapamycin sustained release agent; s7: preparing slurry; s7: pouring the film-making slurry on a smooth and flat plate, coating the film-making slurry into a film by using a push rod with a fixed thickness, and drying and demoulding to form a rapamycin sustained-release medicinal film; the sustained-release medicinal film prepared by the invention is nontoxic, nonirritant, stable in property, non-functional with medicaments and safe to use; when the invention is prepared, the dosage of the film forming material is less; after the preparation is finished, the slow-release medicine film does not fly when in use; the content is accurate; the stability is good; has quick action.
Description
Technical Field
The invention relates to the field of rapamycin sustained-release medicinal film preparation, in particular to a rapamycin sustained-release medicinal film and a preparation method thereof.
Background
Rapamycin, also known as Sirolimus (Rapamycin), is a novel anti-rejection drug for macrolides, is the latest potent immunosuppressant in the world at present, and is clinically used for the anti-rejection reaction of organ transplantation and the treatment of autoimmune diseases. Its immunosuppressive activity is tens times stronger than that of currently clinically widely used cyclosporin, toxicity is low and dosage is small. It is a secondary metabolite secreted by streptomyces cutaneus and found by scientists in 1975 for the first time from soil of Easter Chilean, and the chemical structure of the secondary metabolite belongs to a 'triene macrolide' compound. The prior rapamycin is generally prepared into a slow release agent for injection or other medicaments, and a preparation process of a medicine film is not available.
Disclosure of Invention
The invention aims to provide a rapamycin sustained-release medicinal film and a preparation method thereof, and solves the problem of the preparation method of the rapamycin sustained-release medicinal film.
In order to achieve the purpose, the invention provides the following technical scheme:
a rapamycin sustained release drug film comprises the following components: rapamycin, a soluble high molecular polymer carrier and an organic solvent; the preparation method of the rapamycin sustained-release medicine film comprises the following steps:
s1: preparing rapamycin;
s2: adding rapamycin and a soluble high molecular polymer carrier into an organic solvent to form an organic phase;
s3: dripping the organic phase into the aqueous phase liquid at a speed of 5 drops per minute, and stirring at 23 ℃ for 35min-3 h; the stirring speed is 1000 rpm; and filtering for sterilization;
s4: recovering the organic solvent under reduced pressure;
s5: centrifuging for 130min at 8500rpm, collecting supernatant, and filtering with 0.5 μm filter membrane to obtain micelle solution;
s6: freeze-drying the micelle solution to obtain a rapamycin sustained release agent;
s7: evaporating the rapamycin sustained release agent for 1 hour at the temperature of 40 ℃ and the pressure of 0.09MPa, and evaporating the rapamycin sustained release agent for 12-18 min at the temperature of 58-62 ℃ and the pressure of 0.085-0.095 MPa to form film-forming slurry;
s7: and pouring the film preparation slurry on a smooth flat plate, coating the film preparation slurry into a film by using a push rod with a fixed thickness, and drying and demolding the film preparation slurry to form the rapamycin sustained-release drug film.
Further, the preparation method of rapamycin in step S1 includes a microbial fermentation method and a chemical purification method.
Further, in step S2, the organic solvent is one or more of absolute ethyl alcohol, dichloromethane, acetone and methanol; the soluble high-molecular polymer carrier is mPEG-PLA copolymer, wherein the molecular weight of mPEG is 2000, the molecular weight of PLA is 2000, and the total molecular weight is 4000; the water phase liquid is distilled water.
Further, the organic solvent further comprises phospholipid, glyceride and a stabilizer, wherein the phospholipid is one or two of soybean lecithin or egg yolk lecithin, and the glyceride comprises one or more selected from glycerol dioleate, glycerol trioleate or glycerol stearate; the stabilizer is poloxamer 407 or polyethylene glycol.
Further, the rapamycin and the organic solvent comprise 1 part by weight of rapamycin and 2000 parts by weight of organic solvent, wherein the organic solvent comprises 200 parts by weight of ethanol, 700 parts by weight of phospholipid, 1000 parts by weight of glyceride and 100 parts by weight of stabilizer.
Compared with the prior art, the invention has the beneficial effects that:
the slow-release medicinal film prepared by the invention is non-toxic, non-irritant, stable in property, non-functional with medicaments and safe to use.
Secondly, when the invention is prepared, the dosage of film forming materials is less; after the preparation is finished, the slow-release medicine film does not fly when in use; the content is accurate; the stability is good; has quick action.
The specific implementation mode is as follows:
in order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It is to be understood that the following description is only illustrative of the present invention and is not to be construed as limiting the present invention.
Example 1:
a rapamycin sustained release drug film comprises the following components: rapamycin, a soluble high molecular polymer carrier and an organic solvent; the organic solvent is one or more than two of absolute ethyl alcohol, dichloromethane, acetone and methanol; the soluble high-molecular polymer carrier is mPEG-PLA copolymer, wherein the molecular weight of mPEG is 2000, the molecular weight of PLA is 2000, and the total molecular weight is 4000; the organic solvent further comprises phospholipid, glyceride and a stabilizer, wherein the phospholipid is one or two of soybean lecithin or egg yolk lecithin, and the glyceride comprises one or more selected from diglycerol dioleate, triolein or stearin; the stabilizer is poloxamer 407 or polyethylene glycol; the water phase liquid is distilled water.
The preparation method of the rapamycin sustained-release medicine film comprises the following steps:
s1: preparing rapamycin;
s2: adding rapamycin and a soluble high molecular polymer carrier into an organic solvent to form an organic phase;
s3: dripping the organic phase into the aqueous phase liquid at a speed of 5 drops per minute, and stirring at 23 ℃ for 35min-3 h; the stirring speed is 1000 rpm; and filtering for sterilization;
s4: recovering the organic solvent under reduced pressure;
s5: centrifuging for 130min at 8500rpm, collecting supernatant, and filtering with 0.5 μm filter membrane to obtain micelle solution;
s6: freeze-drying the micelle solution to obtain a rapamycin sustained release agent;
s7: evaporating the rapamycin sustained release agent for 1 hour at the temperature of 40 ℃ and the pressure of 0.09MPa, and evaporating the rapamycin sustained release agent for 12-18 min at the temperature of 58-62 ℃ and the pressure of 0.085-0.095 MPa to form film-forming slurry;
s7: and pouring the film preparation slurry on a smooth flat plate, coating the film preparation slurry into a film by using a push rod with a fixed thickness, and drying and demolding the film preparation slurry to form the rapamycin sustained-release drug film.
In this example, the rapamycin preparation method in step S1 includes a microbial fermentation method and a chemical purification method.
In this embodiment, the rapamycin and the organic solvent are calculated according to parts by weight, and the rapamycin is 1 part by weight, and the organic solvent is 2000 parts by weight, wherein the organic solvent comprises 200 parts by weight of ethanol, 700 parts by weight of phospholipid, 1000 parts by weight of glyceride, and 100 parts by weight of a stabilizer.
Example 2:
a rapamycin sustained release drug film comprises the following components: rapamycin, a soluble high molecular polymer carrier and an organic solvent; the organic solvent is one or more than two of absolute ethyl alcohol, dichloromethane, acetone and methanol; the soluble high-molecular polymer carrier is mPEG-PLA copolymer, wherein the molecular weight of mPEG is 2000, the molecular weight of PLA is 2000, and the total molecular weight is 4000; the organic solvent further comprises phospholipid, glyceride and a stabilizer, wherein the phospholipid is one or two of soybean lecithin or egg yolk lecithin, and the glyceride comprises one or more selected from diglycerol dioleate, triolein or stearin; the stabilizer is poloxamer 407 or polyethylene glycol; the water phase liquid is distilled water.
The preparation method of the rapamycin sustained-release medicine film comprises the following steps:
s1: preparing rapamycin;
s2: adding rapamycin and a soluble high molecular polymer carrier into an organic solvent to form an organic phase;
s3: dripping the organic phase into the aqueous phase liquid at a speed of 5 drops per minute, and stirring at 23 ℃ for 35min-3 h; the stirring speed is 1000 rpm; and filtering for sterilization;
s4: recovering the organic solvent under reduced pressure;
s5: centrifuging for 130min at 8500rpm, collecting supernatant, and filtering with 0.5 μm filter membrane to obtain micelle solution;
s6: freeze-drying the micelle solution to obtain a rapamycin sustained release agent;
s7: evaporating the rapamycin sustained release agent at 40 ℃ and 0.09MPa for 1h, and evaporating the rapamycin sustained release agent at 6 ℃ and 0.9MPa for 20min to form film-forming slurry;
s7: and pouring the film preparation slurry on a smooth flat plate, coating the film preparation slurry into a film by using a push rod with a fixed thickness, and drying and demolding the film preparation slurry to form the rapamycin sustained-release drug film.
In this example, the rapamycin preparation method in step S1 includes a microbial fermentation method and a chemical purification method.
In this embodiment, the rapamycin and the organic solvent are calculated according to parts by weight, and the rapamycin is 1 part by weight, and the organic solvent is 2000 parts by weight, wherein the organic solvent comprises 200 parts by weight of ethanol, 700 parts by weight of phospholipid, 1000 parts by weight of glyceride, and 100 parts by weight of a stabilizer.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (5)
1. The rapamycin sustained-release medicine film is characterized by comprising the following components: rapamycin, a soluble high molecular polymer carrier and an organic solvent; the preparation method of the rapamycin sustained-release medicine film comprises the following steps:
s1: preparing rapamycin;
s2: adding rapamycin and a soluble high molecular polymer carrier into an organic solvent to form an organic phase;
s3: dripping the organic phase into the aqueous phase liquid at a speed of 5 drops per minute, and stirring at 23 ℃ for 35min-3 h; the stirring speed is 1000 rpm; and filtering for sterilization;
s4: recovering the organic solvent under reduced pressure;
s5: centrifuging for 130min at 8500rpm, collecting supernatant, and filtering with 0.5 μm filter membrane to obtain micelle solution;
s6: freeze-drying the micelle solution to obtain a rapamycin sustained release agent;
s7: evaporating the rapamycin sustained release agent for 1 hour at the temperature of 40 ℃ and the pressure of 0.09MPa, and evaporating the rapamycin sustained release agent for 12-18 min at the temperature of 58-62 ℃ and the pressure of 0.085-0.095 MPa to form film-forming slurry;
s7: and pouring the film preparation slurry on a smooth flat plate, coating the film preparation slurry into a film by using a push rod with a fixed thickness, and drying and demolding the film preparation slurry to form the rapamycin sustained-release drug film.
2. The sustained-release rapamycin pharmaceutical film according to claim 1, characterized in that: the preparation method of rapamycin in the step S1 comprises a microbial fermentation method and a chemical purification method.
3. The sustained-release rapamycin pharmaceutical film according to claim 1, characterized in that: in the step S2, the organic solvent is one or more than two of absolute ethyl alcohol, dichloromethane, acetone and methanol; the soluble high-molecular polymer carrier is mPEG-PLA copolymer, wherein the molecular weight of mPEG is 2000, the molecular weight of PLA is 2000, and the total molecular weight is 4000; the water phase liquid is distilled water.
4. The sustained-release rapamycin pharmaceutical film according to claim 3, characterized in that: the organic solvent also comprises phospholipid, glyceride and a stabilizer, wherein the phospholipid is one or two of soybean lecithin or egg yolk lecithin, and the glyceride comprises one or more selected from diglycerol dioleate, triolein or stearin; the stabilizer is poloxamer 407 or polyethylene glycol.
5. The sustained-release rapamycin pharmaceutical film according to claim 4, wherein: the rapamycin-containing organic solvent comprises 1 part of rapamycin and 2000 parts of organic solvent by weight, wherein the organic solvent comprises 200 parts of ethanol, 700 parts of phospholipid, 1000 parts of glyceride and 100 parts of stabilizer by weight.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210208385.5A CN114376994A (en) | 2022-03-04 | 2022-03-04 | Rapamycin sustained-release medicinal film and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210208385.5A CN114376994A (en) | 2022-03-04 | 2022-03-04 | Rapamycin sustained-release medicinal film and preparation method thereof |
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| CN114376994A true CN114376994A (en) | 2022-04-22 |
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| CN202210208385.5A Pending CN114376994A (en) | 2022-03-04 | 2022-03-04 | Rapamycin sustained-release medicinal film and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634046A (en) * | 2004-10-29 | 2005-07-06 | 山东省眼科研究所 | Use of rapamycin in preparation of intraocularly embedded drug |
| WO2017047618A1 (en) * | 2015-09-18 | 2017-03-23 | 日本化薬株式会社 | Medicinal composition comprising rapamycin or derivative thereof |
| CN108771656A (en) * | 2018-07-10 | 2018-11-09 | 白晓春 | Rapamycin sustained-release dosage type and preparation method, rapamycin it is slow-release injected and application |
| CN110623925A (en) * | 2019-09-26 | 2019-12-31 | 严鹏科 | Rapamycin nanometer sustained release agent and preparation method thereof |
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2022
- 2022-03-04 CN CN202210208385.5A patent/CN114376994A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634046A (en) * | 2004-10-29 | 2005-07-06 | 山东省眼科研究所 | Use of rapamycin in preparation of intraocularly embedded drug |
| WO2017047618A1 (en) * | 2015-09-18 | 2017-03-23 | 日本化薬株式会社 | Medicinal composition comprising rapamycin or derivative thereof |
| CN108771656A (en) * | 2018-07-10 | 2018-11-09 | 白晓春 | Rapamycin sustained-release dosage type and preparation method, rapamycin it is slow-release injected and application |
| CN110623925A (en) * | 2019-09-26 | 2019-12-31 | 严鹏科 | Rapamycin nanometer sustained release agent and preparation method thereof |
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