CN108066311B - Gemasecan capsule and preparation method thereof - Google Patents
Gemasecan capsule and preparation method thereof Download PDFInfo
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- CN108066311B CN108066311B CN201711434625.9A CN201711434625A CN108066311B CN 108066311 B CN108066311 B CN 108066311B CN 201711434625 A CN201711434625 A CN 201711434625A CN 108066311 B CN108066311 B CN 108066311B
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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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
Abstract
The invention provides a germactecan capsule and a preparation method thereof, the capsule is a hot melt capsule, and the raw materials of the capsule comprise 0.091% of germactecan, 0.2% -5% of antioxidant and 94.909% -99.709% of carrier by mass percentage. A process for preparing a gemmacetan capsule comprising the steps of: heating 94.909-99.709% of carrier to be completely melted to obtain hot melt liquid; firstly, 0.2 to 5 percent of antioxidant is added into hot melt liquid, the mixture is stirred uniformly, and then the gimatecan is added into the hot melt liquid, and the mixture is stirred uniformly; filling the hot melt liquid into the capsule, and smearing and sealing the capsule by using the gelatin sealing liquid; cooling and solidifying the sealed capsule to obtain the product. The preparation has simple prescription, and does not need to add auxiliary materials such as a lubricant, a glidant, an adhesive, a disintegrant and the like; the preparation process is simple, and the medicine and the auxiliary materials are directly filled after being hot-melted and mixed.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a gemmacetan capsule and a preparation method thereof.
Background
Gemmacetan is a lipophilic semi-synthetic cytotoxic agent of Camptothecin (CPT). CPTs, including Sigma-tau products, Irinotecan (IRT) and topotecan (hypocamptin, TPT), exhibit anti-tumor activity primarily through inhibition of the drug target topoisomerase i (topo i). Topo I is an enzyme responsible for modulating DNA topology, playing a key role in DNA repair, transcription and replication.
CPT, a cytotoxic alkaloid, was isolated from the plant Camptotheca acuminata in the 50's of the 20 th century. Early studies found that CPT caused severe hemorrhagic cystitis and bone marrow toxicity, preventing its further development. Until the 80's of the 20 th century, CPT was discovered to be a specific inhibitor of topoisomerase I which plays an important role in relaxing DNA supercoiling structure and in DNA replication and translation, and was not again widely noted. CPT binds to the topoisomerase I-DNA complex and inhibits the re-ligation step during relaxation of the supercoiled structure of DNA, resulting in single-and double-stranded DNA breaks, triggering apoptosis.
The unique topoisomerase I inhibition property of CPT promotes people to synthesize CPT derivatives with higher antitumor activity and lower toxicity, topotecan, irinotecan, hydroxycamptothecin and the like are obtained by structural modification of CPT, and the CPT derivatives are used for clinically treating colon cancer, ovarian cancer and small cell lung cancer.
CN201110151869.2 discloses a gel sustained-release injection, which uses block copolymer as a carrier material of temperature-sensitive in-situ gel, and the preparation process of the carrier material is complex and difficult to control. CN200710203200.7 discloses a liquid preparation containing gemmacetan, which provides a plurality of different polyethylene glycol end groups and solutions composed of different polyethylene glycols, and the carrier synthesis or preparation process is not easy to control. Many have limited the commercial production of gemmacetan formulations.
The solid dispersion technology is a dispersion technology which is formed by highly dispersing a medicament in a solid carrier and exists in a solid form, and can remarkably improve the solubility and bioavailability of a difficultly soluble medicament. But the problems of difficulty in production and stability have limited early commercial applications due to the immaturity of industrial conditions. In recent years, on the basis of a solid dispersion technology, a hot melt filling hard capsule technology is continuously developed, wherein a medicine is dispersed in a molten material, a hot melt liquid is directly filled into a gelatin hard capsule, and a plug is formed in the capsule at room temperature, namely a semisolid skeleton preparation or a capsule plug. With the successful research and development of the full-automatic liquid capsule filling machine, the commercial application of the hot melt filling hard capsule technology is realized.
The means for improving the solubility or dissolution rate of a poorly soluble drug is generally a salt formation, solubilization, particle size reduction, polymorphism, solvate, or the like, and the means for improving the solubility and bioavailability of a poorly soluble drug is not general, and an API is required to have certain conditions. For neutral compounds and certain weak acids, weak bases, it is impractical to make salts, and even if salts are available, in many cases the dissolution of the drug in the gastrointestinal tract is not necessarily increased because the salts are converted to the respective acid or base upon entry into the gastrointestinal tract. Solutions made with organic solvents or added surfactants have reduced patient compliance and commercialization. The conventional solubilization method is to reduce the particle size, but the wettability of the powder is reduced due to problems such as the reduction limit of the particle size and the reaggregation of the powder. Polymorphs or solvates may convert from a metastable state to a stable state upon dissolution. The CPT common preparation is generally administrated by continuous instillation or multiple injections, which brings pain to patients on one hand and has the defects of high toxicity and the like on the other hand, such as neutropenia, thrombocytopenia, anemia and non-blood system toxic reaction, so a new preparation is required to be developed to overcome the defects of poor water solubility and high toxicity.
The invention provides a solid dispersion technology for preparing the gemmacetan capsule, which not only solves most technical problems of the solubilization method, but also can remarkably improve the solubility and bioavailability of the medicine, and can ensure that the medicine which can only be prepared into injection for use because of poor oral absorption and low bioavailability can also be orally taken.
Disclosure of Invention
Gemaotecan is an insoluble camptothecin drug, is poor in oral absorption and low in bioavailability, and most camptothecin drugs are unstable due to easy ring-opening hydrolysis under neutral and alkaline conditions. Generally, the administration method of continuous instillation or multiple injections is adopted, which not only brings the pain of administration to patients, but also has great toxicity. The invention provides an oral administration preparation, which increases the solubility and bioavailability of the germactecan, improves the stability of the medicine and the compliance of patients, and reduces the toxicity of the medicine.
The germactecan capsule is characterized in that the capsule is a hot-melt capsule, and the raw materials of the capsule comprise, by mass, 0.091% of germactecan, 0.2% -5% of an antioxidant and 93.409% -99.109% of a carrier.
Preferably, the antioxidant in the capsule is one or more of meglumine, tocopherol, vitamin C, vitamin E, fumaric acid, citric acid, tartaric acid, sodium ascorbate, tert-butyl hydroxy anisole, dibutyl hydroxy toluene, sodium metabisulfite, sodium thiosulfate, sodium bisulfite, disodium edetate or sodium dodecanoate.
Further preferably, the carrier in the capsule is one or more of polyethylene glycol fatty acid glyceride G44/14, polyethylene glycol fatty acid glyceride G50/13, polyethylene glycol fatty acid glyceride G46/07, poloxamer 188, lauroyl polyoxyethylene 32 glyceride, glyceryl monostearate, stearic acid polyoxyl 40, hydrogenated castor oil, beeswax, PEG 4000 or PEG 6000.
A process for preparing a gemmacetan capsule comprising the steps of:
(1) 93.409-99.109% of carrier is heated to 50-70 ℃ and completely melted to obtain hot melt liquid;
(2) firstly, 0.8 to 6.5 percent of antioxidant is added into hot melt, the mixture is stirred uniformly, and then the gimatecan is added into the hot melt and stirred uniformly, wherein the percentage is the mass percentage of each component in the raw materials;
(3) filling the hot melt liquid into the capsule, and smearing and sealing the capsule by using the gelatin sealing liquid;
(4) cooling and solidifying the sealed capsule to obtain the product.
Further optimizing, wherein the stirring temperature in the step (2) is 50-70 ℃.
Further optimized, D90 of the gimatecan in the step (2) is less than or equal to 80 mu m.
Further optimizing, wherein the weight of each capsule filled in the step (3) is 150-300 mg.
Further optimizing, wherein the time for cooling and solidifying the capsule in the step (4) is 10-30 hours.
The invention has the beneficial effects that:
the technology provided by the invention is to fill hot melt into hard capsules to prepare a semisolid skeleton preparation. The method is characterized in that:
(1) the preparation has simple prescription, and does not need to add auxiliary materials such as a lubricant, a glidant, an adhesive, a disintegrant and the like;
(2) the preparation process is simple, and the medicine and the auxiliary materials are directly filled after being hot-melted and mixed.
Detailed Description
The following detailed description of embodiments of the present invention is given in conjunction with examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention.
Example 1
| Prescription composition | Unit dose (%) |
| Gemadecan | 0.091 |
| Gelucire44/14 | 97.409 |
| Tert-Butyl Hydroxyanisole (BHA) | 0.50 |
| Vitamin C | 2.0 |
The preparation process comprises the following steps:
(1) pre- formation: putting Gelucire 44/14 into a liquid preparation tank, heating to 50 ℃ and completely melting;
(2) preparing liquid: putting tert-butyl hydroxy anisol and vitamin C into a liquid preparation tank, setting the temperature at 50 ℃, starting a high-speed homogenizing head, uniformly stirring, putting the gemmacetan raw material (D90 is less than or equal to 60 mu m), keeping the temperature, and continuously homogenizing at high speed to uniformly stir;
(3) and (3) filling capsules: the filling amount was set to 300mg for filling, and the capsule weight difference was controlled to within. + -. 5%.
(4) And (3) sealing the capsule: coating and sealing the lower edge of the capsule cap by using gelatin sealing liquid;
(5) and (3) curing: and cooling and solidifying the sealed capsule for 10 hours until the sealing liquid is completely dried, thus obtaining the capsule.
Example 2:
| prescription composition | Unit dose (%) |
| Gemadecan | 0.091 |
| Polyoxyl stearate 40(s-40) | 93.409 |
| Poloxamer 188 | 5.5 |
| Ascorbic acid sodium salt | 1.0 |
The preparation process comprises the following steps:
(1) pre- formation: putting stearic acid polyoxyl 40(S-40) and poloxamer 188 into a liquid preparation tank, heating to 70 ℃, and completely melting;
(2) preparing liquid: adding sodium ascorbate into a liquid preparation tank, setting the temperature at 70 deg.C, starting a high-speed homogenizing head, stirring, adding Gemadecan raw material (D90 is less than or equal to 10 μm), maintaining the temperature, and continuously homogenizing at high speed to stir uniformly;
(3) and (3) filling capsules: the filling amount was set to 200mg for filling, and the capsule weight difference was controlled to within. + -. 5%.
(4) And (3) sealing the capsule: coating and sealing the lower edge of the capsule cap by using gelatin sealing liquid;
(5) and (3) curing: and cooling and solidifying the sealed capsule for 24 hours until the sealing liquid is completely dried, thus obtaining the capsule.
Example 3:
| prescription composition | Unit dose (%) |
| Gemadecan | 0.091 |
| Glyceryl monostearate | 98.909 |
| Vitamin E | 0.8 |
| Sodium bisulfite | 0.2 |
The preparation process comprises the following steps:
(1) pre- formation: putting the glyceryl monostearate into a liquid preparation tank, heating to 60 ℃, and completely melting;
(2) preparing liquid: putting vitamin E and sodium bisulfite into a liquid preparation tank, setting the temperature at 60 ℃, starting a high-speed homogenizing head to stir uniformly, putting the gemmacetan raw material (D90 is less than or equal to 80 mu m), keeping the temperature, and continuously homogenizing at high speed to stir uniformly;
(3) and (3) filling capsules: the filling amount was set to 150mg for filling, and the capsule weight difference was controlled to within. + -. 5%.
(4) And (3) sealing the capsule: coating and sealing the lower edge of the capsule cap by using gelatin sealing liquid;
(5) and (3) curing: and cooling and solidifying the sealed capsule for 30 hours until the sealing liquid is completely dried, thus obtaining the capsule.
Example 4:
| prescription composition | Unit dose (%) |
| Gemadecan | 0.091 |
| Poloxamer 188 | 97.359 |
| Dibutylhydroxytoluene (BHT) | 0.05 |
| Meglumine | 2.50 |
The preparation process comprises the following steps:
(1) pre- formation: putting poloxamer 188 into a liquid preparation tank, heating to 55 ℃, and completely melting;
(2) preparing liquid: adding dibutyl hydroxy toluene (BHT) and meglumine into a solution preparation tank, setting the temperature at 65 deg.C, starting a high-speed homogenizing head, stirring, adding Gemadecan raw material (D90 is less than or equal to 40 μm), maintaining the temperature, and continuously homogenizing at high speed to stir uniformly;
(3) and (3) filling capsules: the filling amount was set to 100mg for filling, and the capsule weight difference was controlled within. + -. 5%.
(4) And (3) sealing the capsule: coating and sealing the lower edge of the capsule cap by using gelatin sealing liquid;
(5) and (3) curing: and cooling and solidifying the sealed capsule for 16 hours until the sealing liquid is completely dried, thus obtaining the capsule.
Example 5:
| prescription composition | Unit dose (%) |
| Gemadecan | 0.091 |
| Hydrogenated castor oil | 94.909 |
| Dibutylhydroxytoluene (BHT) | 0.10 |
| Vitamin E | 4.90 |
The preparation process comprises the following steps:
(1) pre- formation: adding hydrogenated castor oil into a liquid preparation tank, heating to 65 ℃, and completely melting;
(2) preparing liquid: adding dibutyl hydroxy toluene (BHT) and vitamin E into a liquid preparation tank, setting the temperature to 55 ℃, starting a high-speed homogenizing head, uniformly stirring, adding a gemmacetan raw material (D90 is less than or equal to 50 mu m), keeping the temperature, and continuously homogenizing at high speed to uniformly stir;
(3) and (3) filling capsules: the filling amount was set to 300mg for filling, and the capsule weight difference was controlled to within. + -. 5%.
(4) And (3) sealing the capsule: coating and sealing the lower edge of the capsule cap by using gelatin sealing liquid;
(5) and (3) curing: and cooling and solidifying the sealed capsule for 18 hours until the sealing liquid is completely dried, thus obtaining the capsule.
Example 6
Prescription composition for unit dose products
| Prescription composition | Unit dose (%) |
| Gemadecan | 0.091％ |
| Lauroyl polyoxyethylene (32) glyceride | 99.109％ |
| Meglumine | 0.5％ |
| Vitamin E | 0.3％ |
The preparation process comprises the following steps:
(1) pre- formation: putting lauroyl polyoxyethylene (32) glyceride into a liquid preparation tank, heating to 60 ℃, and completely melting;
(2) preparing liquid: putting meglumine and vitamin E into a liquid preparation tank, setting the temperature at 70 ℃, starting a high-speed homogenizing head to stir uniformly, putting the gemmacetan raw material (D90 is less than or equal to 60 mu m), keeping the temperature, and continuously homogenizing at high speed to stir uniformly;
(3) and (3) filling capsules: the filling amount was set to 150mg for filling, and the capsule weight difference was controlled to within. + -. 5%.
(4) And (3) sealing the capsule: coating and sealing the lower edge of the capsule cap by using gelatin sealing liquid;
(5) and (3) curing: and cooling and solidifying the sealed capsule for 20 hours until the sealing liquid is completely dried, thus obtaining the capsule.
Effect example 1
Investigation of content uniformity of hot melt
In order to examine the content uniformity in the mixing process of the raw materials and the auxiliary materials, 3 samples, 9 samples in total, are taken from the same plane at different positions of the upper layer, the middle layer and the lower layer of the suspension in the liquid preparation tank of the embodiment 1-6 respectively at random, and the appearance character and the content are checked and detected.
TABLE 1 content uniformity investigation results
The results show that: the raw materials and auxiliary materials of the product are kept at a high speed of 50-70 ℃ for homogeneous stirring, the samples are respectively taken at different positions of an upper layer, a middle layer and a lower layer of the suspension liquid in a container, the appearance character and the content are checked, and the results show that: the appearance and the content of the samples at different positions are basically consistent, the RSD of the content is less than or equal to 2 percent, and no obvious difference exists. The uniformity of the mixing of the liquid medicine in the preparation process of the product is shown, so that the quality consistency of the preparation in the production process is ensured, and the requirement of commercial production is met.
Claims (4)
1. A process for preparing a gemmacetan capsule comprising the steps of:
(1) heating 93.409-99.109% of carrier to 50-70 ℃, and completely melting to obtain hot-melt liquid; wherein the carrier is one or more of polyethylene glycol fatty acid glyceride G44/14, polyethylene glycol fatty acid glyceride G50/13, polyethylene glycol fatty acid glyceride G46/07, poloxamer 188, lauroyl polyoxyethylene 32 glyceride, glyceryl monostearate, polyoxyl stearate 40, hydrogenated castor oil, beeswax, PEG 4000 or PEG 6000;
(2) firstly, 0.8 to 6.5 percent of antioxidant is added into hot melt, the mixture is stirred uniformly, and then the gimatecan is added into the hot melt and stirred uniformly, wherein the percentage is the mass percentage of each component in the raw materials; wherein the antioxidant is one or more of meglumine, tocopherol, vitamin C, vitamin E, fumaric acid, citric acid, tartaric acid, sodium ascorbate, tert-butyl hydroxy anisole, dibutyl hydroxy toluene, sodium metabisulfite, sodium thiosulfate, sodium bisulfite, disodium edetate or sodium laurate, and the D90 of the added gemmacetan is less than or equal to 80 mu m;
(3) filling the hot melt liquid into the capsule, and smearing and sealing the capsule by using the gelatin sealing liquid;
(4) cooling and solidifying the sealed capsule to obtain the product.
2. The process for preparing gemmacetan capsules according to claim 1, wherein the temperature of stirring in step (2) is 50-70 ℃.
3. The process for preparing gemmacetan capsules according to claim 1, wherein the weight of the filled capsules in step (3) is 100mg to 300mg per capsule.
4. The method for preparing a gimatecan capsule according to claim 1, wherein the time for cooling and solidifying the capsule in the step (4) is 10 to 30 hours.
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| CN201711434625.9A CN108066311B (en) | 2017-12-26 | 2017-12-26 | Gemasecan capsule and preparation method thereof |
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| CN108066311B true CN108066311B (en) | 2020-09-08 |
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| ITRM20050418A1 (en) * | 2005-08-04 | 2007-02-05 | Sigma Tau Ind Farmaceuti | IMMEDIATE RELEASE THERAPEUTIC SYSTEMS FOR THE IMPROVED ORAL ABSORPTION OF 7 - [(E) -T-BUTYLOSSIMINOMETHYL] CAMPTOTECIN. |
| CN101991557B (en) * | 2009-08-10 | 2013-09-18 | 杭州赛利药物研究所有限公司 | Liquid vancomycin hydrochloride capsule and preparation method thereof |
| WO2013166366A1 (en) * | 2012-05-04 | 2013-11-07 | Cornell University | Cul4b as predictive biomarker for cancer treatment |
| CN110946836A (en) * | 2014-01-17 | 2020-04-03 | 昂科拉制药有限公司 | Solid oral dosage form of irinotecan for the treatment of cancer |
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