CN114376994A - A kind of rapamycin sustained-release medicinal film and preparation method thereof - Google Patents
A kind of rapamycin sustained-release medicinal film and preparation method thereof Download PDFInfo
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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 64
- 229960002930 sirolimus Drugs 0.000 title claims abstract description 64
- 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 64
- 238000013268 sustained release Methods 0.000 title claims abstract description 35
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000003960 organic solvent Substances 0.000 claims abstract description 34
- 239000003814 drug Substances 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 14
- 229920000642 polymer Polymers 0.000 claims abstract description 13
- 239000002002 slurry Substances 0.000 claims abstract description 12
- 239000000693 micelle Substances 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract 3
- 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
- 238000000034 method Methods 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-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
- 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
- 239000012153 distilled water Substances 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
- 230000000813 microbial effect Effects 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
- 230000001954 sterilising effect Effects 0.000 claims description 4
- 238000004659 sterilization and disinfection Methods 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
- 229940117972 triolein Drugs 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 239000008346 aqueous phase Substances 0.000 claims 1
- 239000011248 coating agent Substances 0.000 claims 1
- 238000000576 coating method Methods 0.000 claims 1
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 claims 1
- 238000004108 freeze drying Methods 0.000 claims 1
- 239000012528 membrane Substances 0.000 claims 1
- 239000012071 phase Substances 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 2
- 231100000344 non-irritating Toxicity 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 239000000843 powder Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 8
- 239000003405 delayed action preparation Substances 0.000 description 4
- 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 3
- 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 3
- 229940075529 glyceryl stearate Drugs 0.000 description 3
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- 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
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 230000003409 anti-rejection Effects 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
- 230000000694 effects Effects 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
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
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- 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
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- 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
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- 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
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- 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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Abstract
本发明公开了一种雷帕霉素缓释药膜，包括以下组分：雷帕霉素、可溶性高分子聚合物载体以及有机溶剂；该雷帕霉素缓释药膜的制备方法包括以下步骤S1：制备雷帕霉素；S2：溶解；S3：搅拌除菌；S4：减压回收有机溶剂；S5：离心过滤；S6：将胶束溶液冷冻干燥，得到雷帕霉素缓释剂；S7：制备浆料；S7：将上述制膜浆料倾倒在光洁、平整的平板上，用固定厚度的推杆涂铺成膜后，干燥、脱膜形成雷帕霉素缓释药膜；本发明通过制备成缓释药膜后无毒、无刺激性、性质稳定、与药物不起作用，使用安全；本发明制备时，成膜材料用量少；制备完成后缓释药膜使用时无粉末飞扬；含量准确；稳定性好；起效快。The invention discloses a rapamycin sustained-release medicinal film, comprising the following components: rapamycin, a soluble high molecular polymer carrier and an organic solvent; the preparation method of the rapamycin sustained-release medicinal film comprises the following steps S1: prepare rapamycin; S2: dissolve; S3: stir and sterilize; S4: recover organic solvent under reduced pressure; S5: centrifugal filtration; S6: freeze-dry the micelle solution to obtain rapamycin sustained-release agent; S7 : prepare slurry; S7: pour the above-mentioned film-making slurry on a smooth and flat plate, spread it with a push rod of a fixed thickness to form a film, dry and remove the film to form a rapamycin sustained-release drug film; the present invention After being prepared into a sustained-release medicinal film, it is non-toxic, non-irritating, stable in nature, ineffective with drugs, and safe to use; during the preparation of the present invention, the amount of film-forming materials is small; after the preparation is completed, the sustained-release medicinal film is used without powder Flying; accurate content; good stability; fast onset.
Description
技术领域technical field
本发明涉及雷帕霉素缓释药膜制备领域，具体涉及一种雷帕霉素缓释药膜及其制备方法。The invention relates to the field of preparation of a rapamycin sustained-release medicinal film, in particular to a rapamycin sustained-release medicinal film and a preparation method thereof.
背景技术Background technique
雷帕霉素又名西罗莫司(Sirolimus、Rapamycin)，是新型大环内酯的抗排斥药物，是目前世界上最新的强效免疫抑制剂，临床上用于器官移植的抗排斥反应和自身免疫性疾病的治疗。它的免疫抑制活性比现行临床广泛使用的环孢素强数十倍，毒性低，用量小。它是科学家于1975年首次从智利复活节岛的土壤中发现的一种由土壤链霉菌分泌的次生代谢物，其化学结构属于“三烯大环内酯类”化合物。现有的雷帕霉素一般是做成注射的缓释剂或其他药剂，没有药膜的制备工艺。Rapamycin, also known as Sirolimus (Rapamycin), is a new type of macrolide anti-rejection drug. It is the latest potent immunosuppressant in the world. Treatment of autoimmune diseases. Its immunosuppressive activity is dozens of times stronger than that of cyclosporine, which is widely used in clinical practice, with low toxicity and small dosage. It is a secondary metabolite secreted by soil Streptomyces that was first discovered by scientists in the soil of Easter Island, Chile in 1975, and its chemical structure belongs to the "triene macrolide" compound. The existing rapamycin is generally made into a sustained-release preparation for injection or other medicaments, and there is no preparation process for the drug film.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一种雷帕霉素缓释药膜及其制备方法，本发明解决了雷帕霉素缓释剂的药膜制备方法。The purpose of the present invention is to provide a rapamycin sustained-release drug film and a preparation method thereof, and the invention solves the preparation method of the drug film of a rapamycin sustained-release agent.
为实现上述目的，本发明提供如下技术方案：To achieve the above object, the present invention provides the following technical solutions:
一种雷帕霉素缓释药膜，包括以下组分：雷帕霉素、可溶性高分子聚合物载体以及有机溶剂；该雷帕霉素缓释药膜的制备方法包括以下步骤：A rapamycin sustained-release medicinal film, comprising the following components: rapamycin, a soluble high molecular polymer carrier and an organic solvent; the preparation method of the rapamycin sustained-release medicinal film comprises the following steps:
S1：制备雷帕霉素；S1: preparation of rapamycin;
S2：把雷帕霉素和可溶性高分子聚合物载体加入到有机溶剂中，形成有机相；S2: adding rapamycin and a soluble polymer carrier into an organic solvent to form an organic phase;
S3：将有机相按5滴每分钟的速度滴加入水相液中，在23摄氏度下搅拌 35min-3h；搅拌速度为1000rpm；并进行过滤除菌；S3: drop the organic phase into the aqueous liquid at a rate of 5 drops per minute, and stir at 23 degrees Celsius for 35min-3h; the stirring speed is 1000rpm; and filter sterilization;
S4：减压回收有机溶剂；S4: the organic solvent is recovered under reduced pressure;
S5：离心130min，离心速率为8500rpm，取上清，0.5μm滤膜过滤后得到胶束溶液；S5: Centrifuge for 130 min, the centrifugal speed is 8500 rpm, take the supernatant, and filter it with a 0.5 μm filter to obtain a micelle solution;
S6：将胶束溶液冷冻干燥，得到雷帕霉素缓释剂；S6: freeze-dry the micelle solution to obtain a rapamycin sustained-release preparation;
S7：得到雷帕霉素缓释剂在温度为40℃和压强为0.09MPa下蒸发1h，再在温度为58～62℃和压强为0.085～0.095MPa下蒸发12～18min成膜浆料；S7: the obtained rapamycin sustained-release agent is evaporated at a temperature of 40°C and a pressure of 0.09MPa for 1 hour, and then evaporated at a temperature of 58-62°C and a pressure of 0.085-0.095MPa for 12-18min to form a film-forming slurry;
S7：将上述制膜浆料倾倒在光洁、平整的平板上，用固定厚度的推杆涂铺成膜后，干燥、脱膜形成雷帕霉素缓释药膜。S7: Pour the above-mentioned film-forming slurry on a smooth and flat plate, spread it with a push rod of a fixed thickness to form a film, then dry and remove the film to form a rapamycin sustained-release drug film.
进一步的，步骤S1中雷帕霉素的制备方法包括微生物发酵法、化学方纯化法。Further, the preparation method of rapamycin in step S1 includes a microbial fermentation method and a chemical purification method.
进一步的，步骤S2中机溶剂为无水乙醇、二氯甲烷、丙酮和甲醇中的一种或两种以上；所述可溶性高分子聚合物载体为mPEG-PLA共聚物，其中，mPEG的分子量为2000，PLA的分子量为2000，总分子量为4000；所述水相液为蒸馏水。Further, in step S2, the organic solvent is one or more of anhydrous ethanol, dichloromethane, acetone and methanol; the soluble 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 aqueous liquid is distilled water.
进一步的，所述有机溶剂还包括磷脂、甘油酯、稳定剂，所述所述磷脂为大豆卵磷脂或蛋黄卵磷脂中的一种或两种，所述甘油酯包括选自二油酸甘油酯、三油酸甘油酯或硬脂酸甘油酯中的一种或多种；所述稳定剂为泊洛沙姆407或聚乙二醇。Further, the organic solvent also includes phospholipids, glycerides, and stabilizers, the phospholipids are one or both of soybean lecithin or egg yolk lecithin, and the glycerides include glycerol dioleate selected from the group consisting of , one or more of glyceryl trioleate or glyceryl stearate; the stabilizer is poloxamer 407 or polyethylene glycol.
进一步的，所述雷帕霉素、有机溶剂按重量份计，雷帕霉素1份、有机溶剂 2000份，其中有机溶剂中按重量份计乙醇200份、磷脂700份、甘油酯1000份、稳定剂100份。Further, the rapamycin and organic solvent are 1 part by weight of rapamycin and 2000 parts of organic solvent, wherein in the organic solvent 200 parts by weight of ethanol, 700 parts of phospholipids, 1000 parts of glycerides, 100 parts of stabilizer.
与现有技术相比，本发明的有益效果是：Compared with the prior art, the beneficial effects of the present invention are:
一、本发明通过制备成缓释药膜后无毒、无刺激性、性质稳定、与药物不起作用，使用安全。1. The present invention is non-toxic, non-irritating, stable in nature, and does not work with drugs after being prepared into a sustained-release drug film, and is safe to use.
二、本发明制备时，成膜材料用量少；制备完成后缓释药膜使用时无粉末飞扬；含量准确；稳定性好；起效快。2. During the preparation of the present invention, the dosage of the film-forming material is small; after the preparation is completed, the sustained-release medicinal film is used without powder flying; the content is accurate; the stability is good; and the effect is fast.
具体实施方式：Detailed ways:
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，以下描述仅仅用以解释本发明，并不用于限定本发明。In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the following description is only used to explain the present invention, but not to limit the present invention.
实施例1：Example 1:
一种雷帕霉素缓释药膜，包括以下组分：雷帕霉素、可溶性高分子聚合物载体以及有机溶剂；机溶剂为无水乙醇、二氯甲烷、丙酮和甲醇中的一种或两种以上；所述可溶性高分子聚合物载体为mPEG-PLA共聚物，其中，mPEG的分子量为 2000，PLA的分子量为2000，总分子量为4000；所述所述有机溶剂还包括磷脂、甘油酯、稳定剂，所述所述磷脂为大豆卵磷脂或蛋黄卵磷脂中的一种或两种，所述甘油酯包括选自二油酸甘油酯、三油酸甘油酯或硬脂酸甘油酯中的一种或多种；所述稳定剂为泊洛沙姆407或聚乙二醇；所述水相液为蒸馏水。A rapamycin sustained-release drug film, comprising the following components: rapamycin, a soluble high molecular polymer carrier and an organic solvent; the organic solvent is one of absolute ethanol, dichloromethane, acetone and methanol or two or more; 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 also includes phospholipids, glycerides , stabilizer, the phospholipid is one or both of soybean lecithin or egg yolk lecithin, and the glyceride comprises glycerol dioleate, glyceryl trioleate or glyceryl stearate selected from the group consisting of one or more of ; the stabilizer is poloxamer 407 or polyethylene glycol; the aqueous liquid is distilled water.
一种雷帕霉素缓释药膜的制备方法包括以下步骤：A preparation method of a rapamycin sustained-release medicinal film comprises the following steps:
S1：制备雷帕霉素；S1: preparation of rapamycin;
S2：把雷帕霉素和可溶性高分子聚合物载体加入到有机溶剂中，形成有机相；S2: adding rapamycin and a soluble polymer carrier into an organic solvent to form an organic phase;
S3：将有机相按5滴每分钟的速度滴加入水相液中，在23摄氏度下搅拌 35min-3h；搅拌速度为1000rpm；并进行过滤除菌；S3: drop the organic phase into the aqueous liquid at a rate of 5 drops per minute, and stir at 23 degrees Celsius for 35min-3h; the stirring speed is 1000rpm; and filter sterilization;
S4：减压回收有机溶剂；S4: the organic solvent is recovered under reduced pressure;
S5：离心130min，离心速率为8500rpm，取上清，0.5μm滤膜过滤后得到胶束溶液；S5: Centrifuge for 130 min, the centrifugal speed is 8500 rpm, take the supernatant, and filter it with a 0.5 μm filter to obtain a micelle solution;
S6：将胶束溶液冷冻干燥，得到雷帕霉素缓释剂；S6: freeze-dry the micelle solution to obtain a rapamycin sustained-release preparation;
S7：得到雷帕霉素缓释剂在温度为40℃和压强为0.09MPa下蒸发1h，再在温度为58～62℃和压强为0.085～0.095MPa下蒸发12～18min成膜浆料；S7: the obtained rapamycin sustained-release agent is evaporated at a temperature of 40°C and a pressure of 0.09MPa for 1 hour, and then evaporated at a temperature of 58-62°C and a pressure of 0.085-0.095MPa for 12-18min to form a film-forming slurry;
S7：将上述制膜浆料倾倒在光洁、平整的平板上，用固定厚度的推杆涂铺成膜后，干燥、脱膜形成雷帕霉素缓释药膜。S7: Pour the above-mentioned film-forming slurry on a smooth and flat plate, spread it with a push rod of a fixed thickness to form a film, then dry and remove the film to form a rapamycin sustained-release drug film.
本实施例中，步骤S1中雷帕霉素的制备方法包括微生物发酵法、化学方纯化法。In this embodiment, the preparation method of rapamycin in step S1 includes a microbial fermentation method and a chemical purification method.
本实施例中，所述雷帕霉素、有机溶剂按重量份计，雷帕霉素1份、有机溶剂2000份，其中有机溶剂中按重量份计乙醇200份、磷脂700份、甘油酯1000 份、稳定剂100份。In this example, the rapamycin and organic solvent are 1 part by weight of rapamycin and 2000 parts of organic solvent, wherein 200 parts by weight of ethanol, 700 parts of phospholipid and 1000 parts of glyceride are in the organic solvent. parts, 100 parts of stabilizer.
实施例2：Example 2:
一种雷帕霉素缓释药膜，包括以下组分：雷帕霉素、可溶性高分子聚合物载体以及有机溶剂；机溶剂为无水乙醇、二氯甲烷、丙酮和甲醇中的一种或两种以上；所述可溶性高分子聚合物载体为mPEG-PLA共聚物，其中，mPEG的分子量为 2000，PLA的分子量为2000，总分子量为4000；所述所述有机溶剂还包括磷脂、甘油酯、稳定剂，所述所述磷脂为大豆卵磷脂或蛋黄卵磷脂中的一种或两种，所述甘油酯包括选自二油酸甘油酯、三油酸甘油酯或硬脂酸甘油酯中的一种或多种；所述稳定剂为泊洛沙姆407或聚乙二醇；所述水相液为蒸馏水。A rapamycin sustained-release drug film, comprising the following components: rapamycin, a soluble high molecular polymer carrier and an organic solvent; the organic solvent is one of absolute ethanol, dichloromethane, acetone and methanol or two or more; 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 also includes phospholipids, glycerides , stabilizer, the phospholipid is one or both of soybean lecithin or egg yolk lecithin, and the glyceride comprises glycerol dioleate, glyceryl trioleate or glyceryl stearate selected from the group consisting of one or more of ; the stabilizer is poloxamer 407 or polyethylene glycol; the aqueous liquid is distilled water.
一种雷帕霉素缓释药膜的制备方法包括以下步骤：A preparation method of a rapamycin sustained-release medicinal film comprises the following steps:
S1：制备雷帕霉素；S1: preparation of rapamycin;
S2：把雷帕霉素和可溶性高分子聚合物载体加入到有机溶剂中，形成有机相；S2: adding rapamycin and a soluble polymer carrier into an organic solvent to form an organic phase;
S3：将有机相按5滴每分钟的速度滴加入水相液中，在23摄氏度下搅拌 35min-3h；搅拌速度为1000rpm；并进行过滤除菌；S3: drop the organic phase into the aqueous liquid at a rate of 5 drops per minute, and stir at 23 degrees Celsius for 35min-3h; the stirring speed is 1000rpm; and filter sterilization;
S4：减压回收有机溶剂；S4: the organic solvent is recovered under reduced pressure;
S5：离心130min，离心速率为8500rpm，取上清，0.5μm滤膜过滤后得到胶束溶液；S5: Centrifuge for 130 min, the centrifugal speed is 8500 rpm, take the supernatant, and filter it with a 0.5 μm filter to obtain a micelle solution;
S6：将胶束溶液冷冻干燥，得到雷帕霉素缓释剂；S6: freeze-dry the micelle solution to obtain a rapamycin sustained-release preparation;
S7：得到雷帕霉素缓释剂在温度为40℃和压强为0.09MPa下蒸发1h，再在温度为6℃和压强为0.9MPa下蒸发20min成膜浆料；S7: The obtained rapamycin sustained-release agent is evaporated at a temperature of 40°C and a pressure of 0.09MPa for 1 hour, and then evaporated at a temperature of 6°C and a pressure of 0.9MPa for 20min to form a film-forming slurry;
S7：将上述制膜浆料倾倒在光洁、平整的平板上，用固定厚度的推杆涂铺成膜后，干燥、脱膜形成雷帕霉素缓释药膜。S7: Pour the above-mentioned film-forming slurry on a smooth and flat plate, spread it with a push rod of a fixed thickness to form a film, then dry and remove the film to form a rapamycin sustained-release drug film.
本实施例中，步骤S1中雷帕霉素的制备方法包括微生物发酵法、化学方纯化法。In this embodiment, the preparation method of rapamycin in step S1 includes a microbial fermentation method and a chemical purification method.
本实施例中，所述雷帕霉素、有机溶剂按重量份计，雷帕霉素1份、有机溶剂2000份，其中有机溶剂中按重量份计乙醇200份、磷脂700份、甘油酯1000 份、稳定剂100份。In this example, the rapamycin and organic solvent are 1 part by weight of rapamycin and 2000 parts of organic solvent, wherein 200 parts by weight of ethanol, 700 parts of phospholipid and 1000 parts of glyceride are in the organic solvent. parts, 100 parts of stabilizer.
对于本领域技术人员而言，显然本发明不限于上述示范性实施例的细节，而且在不背离本发明的精神或基本特征的情况下，能够以其他的具体形式实现本发明。因此，无论从哪一点来看，均应将实施例看作是示范性的，而且是非限制性的，本发明的范围由所附权利要求而不是上述说明限定，因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。It will be apparent to those skilled in the art that the present invention is not limited to the details of the above-described exemplary embodiments, but that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments are to be regarded in all respects as illustrative and not restrictive, and the scope of the invention is defined by the appended claims rather than the foregoing description, which are therefore intended to fall within the scope of the appended claims. All changes within the meaning and scope of the equivalents of , are included in the present invention.
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| 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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| 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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