WO2008144996A1 - Composition pharmaceutique liquide stable à base de cucurbitacine - Google Patents
Composition pharmaceutique liquide stable à base de cucurbitacine Download PDFInfo
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- WO2008144996A1 WO2008144996A1 PCT/CN2008/000010 CN2008000010W WO2008144996A1 WO 2008144996 A1 WO2008144996 A1 WO 2008144996A1 CN 2008000010 W CN2008000010 W CN 2008000010W WO 2008144996 A1 WO2008144996 A1 WO 2008144996A1
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- cucurbitacin
- liquid composition
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention belongs to the field of medical technology and relates to a known cucurbitacins-stabilized medicinal liquid composition.
- Cucurbitacins belong to the class of tetracyclic triterpenoids in which the 19-methyl group appears at the C-9 position, mainly distributed in the cucurbitaceae plant, in the cruciferae, Scrophulariaceae, Begonia, Du Yingke, and the number It has also been found in higher plants such as wood and some large fungi.
- Qiu Minghua a researcher at the Kunming Institute of Botany, Chinese Academy of Sciences, led the scientific and technological personnel to study 229 almost all cucurbitacin compounds based on a series of new cucurbitacin found, and proposed a new structural classification model, which re-created the former five types of structural types.
- cucurbitacin BE which is a Chinese herbal melon (alias: bitter clove) extract, mainly containing cucurbitacin B, E and other ingredients.
- the cucurbitin B content in the existing extract is 60%.
- its quality standards are included in China's ministerial standards.
- Cucurbitacin tablets for the treatment of chronic hepatitis (cucurbitacin tablets, Pharmacy Bulletin, 1986, 21 (6): 357), clinically, in 13 hospitals in Shanghai, Beijing, Chongqing, etc., the effective rate was 75.2%, significant The efficiency is 44.6%.
- cucurbitacin tablets can comprehensively improve the common symptoms and main signs of chronic hepatitis, and have obvious effects of S-GPT, turbidity (TTT, ⁇ ) and hypobilirubinemia. It causes S-GPT rebound, and it also has obvious corrective effects on protein inversion and hyperglobulinemia. It can also improve the non-specific cellular immunity of patients with chronic hepatitis without obvious side effects.
- cucurbitacin tablets can also be used to treat primary liver cancer. According to clinical observations in six hospitals in Shanghai, Beijing and Guangxi, 169 cases were counted, with an effective rate of 69% and a marked efficiency of 39%.
- MCT medium-chain triglyceride
- An object of the present invention is to provide a stable cucurbitacin pharmaceutical liquid composition in which a solvent can dissolve cucurbitacin well and at the same time enhance the stability of cucurbitacin.
- a solvent can dissolve cucurbitacin well and at the same time enhance the stability of cucurbitacin.
- the anti-tumor effect of the medicine can be improved; the individual difference can be reduced; and the soft capsule and the liquid type hard capsule can be further prepared into the mouth or the external use; the emulsifier and the like can be added, and the conventional method can be used.
- the molecular state cucurbitacin-stabilized liquid prepared by dissolving cucurbitacin in a complex solvent is dispersed to form an emulsion, which can be injected, orally or externally.
- Cucurbitacin tablets can also be used to treat primary liver cancer and nasopharyngeal cancer.
- a stable cucurbitacin pharmaceutical liquid composition characterized in that the composition comprises the following components: cucurbitacin, liquid fat and vitamin E, wherein the weight ratio of cucurbitacin to liquid fat is: 1: 10 CT1: 5000; Vitamin E is the weight of liquid fat: 1% to 50%.
- the liquid fat described in the above scheme refers to a fat which is liquid at normal temperature, and is selected from the group consisting of: medium chain triglyceride (MCT), long chain triglyceride (LCT), structural oil, soybean oil, peanut oil, olive oil. Or coconut oil, or a mixture of two or more of them;
- MCT medium chain triglyceride
- LCT long chain triglyceride
- structural oil soybean oil, peanut oil, olive oil. Or coconut oil, or a mixture of two or more of them;
- composition of the two liquid fats is: the weight ratio of the two liquid fats is 1: 0 ⁇ 1 : 10;
- the present application recommends: a liquid fat using a medium chain triglyceride, or a mixture of medium chain triglycerides and soybean oil; or a structural oil; or a mixture of medium chain triglycerides and structural oil;
- This application recommends: When vitamin E is 1% to 9% by weight of liquid fat, the vitamin E is a tocopherol with high antioxidant capacity.
- the cucurbitacin described above is a kind of tetracyclic triterpene compound extracted from Cucurbitaceae, Cruciferae, Scrophulariaceae, Begonia, Du Yingke, Tetradaceae and some large fungi; more specifically, gourd It is a cucurbitacin extracted from the stalk of Cucurnnismelo L. (Cudinnismelo L.).
- Cucurbitacin is preferably cucurbitacin BE (received in the 19th volume of the Chinese herbal medicine preparations of the Ministry of Health of the People's Republic of China).
- the main component of cucurbitacin BE is cucurbitacin B.
- the content of cucurbitacin B is more than 60%, which may include cucurbits.
- cucurbitacin may also be a high-purity monomer such as cucurbitacin B having a purity greater than 99% and cucurbitacin E or isolisine B having a purity greater than 95% by HPLC area normalization.
- the medium chain triglyceride is a compound or mixture of triglycerides of 8 to 12 linear carbon atoms, more preferably 8 to 10 linear carbon atoms, such as Miglyol 812, Miglyol 810, Miglyol 818, Miglyol 829 (Caprylic/Capric/Triglyceride) or Miglyol 840 (Propylene Glycol Dicaprylate/Dicaprale, propylene glycol diester of C8 ⁇ C10 saturated vegetable fatty acid) may also be used.
- the MCT recommended for this application is caprylic/capric glyceride, Miglyol 812, Miglyol 810 (see the Medium Chain triglycerides of the European Pharmacopoeia).
- the vitamin E is a tocopherol, a tocotrienol, a tocopherol or a derivative of a tocotrienol (e.g., an ester), or a mixture thereof.
- tocopherol acetate or tocopherol or a mixture thereof is preferred, and a more preferable solution is to use toluene or tocopherol or a mixture thereof.
- the stabilized cucurbitacin pharmaceutical liquid composition is used for the preparation of an injection, oral or topical emulsion, directly emulsified by the formulation, or a conventional pharmaceutical excipient.
- the preparation involved is a soft capsule or a liquid type hard capsule.
- the liquid fat such as MCT in the present invention can dissolve cucurbitacin well.
- the anti-tumor effect of the drug can be improved; the individual difference can be reduced; the addition of vitamin B in the prescription can greatly improve the stability of the cucurbitacin Qualitative.
- MCT and vitamin E into a composite solvent, and use this complex solvent to dissolve cucurbitacin to obtain a stable liquid composition of molecular cucurbitacin. This group can be further prepared into soft capsules and liquid hard capsules.
- the prepared preparation may be used orally or externally; an emulsifier or the like may be added, and the molecular cucurbitacin-stabilized liquid prepared by dissolving cucurbitacin in a complex solvent may be dispersed to form an emulsion, which may be injected orally orally. external use. It is used to treat chronic hepatitis, improve non-specific cellular immunity in patients with chronic hepatitis, and promote white blood cells, inhibit liver fibrosis, prevent liver fatty degeneration and the formation and development of cirrhosis. It can also be used to treat primary liver cancer and nasopharyngeal cancer.
- the dosage form of the stable liquid formulation is 0.1 mg / granule ⁇ lmg / granule, and the human dose is 0.3 mg ⁇ 3 mg / day, divided into 1 time administration.
- Example 1 is a 0-time HPLC chart showing that cucurbitacin is not thermally destroyed in Example 3.
- Example 2 is a sample solution of vitamin E cucurbitacin in Example 3, which was destroyed at 80 ° C for 3 days, wherein the drug solution was basic: each gram of MCT contained linguin;
- Example 3 is a sample solution of cucurbitacin added with 5% tocopheryl acetate in Example 3 at 80 ° C for 3 days, wherein the drug solution is basically composed of: 1 mg of cucurbitacin per gram of MCT;
- Fig. 4 is a sample solution of cucurbitacin added with 5% tocopherol in Example 3 at 80 ° C for 3 days, wherein the drug solution is basically composed of: 1 mg of cucurbitacin per gram of MCT.
- raw materials tocopherol acetate (purchased in BSF company, the second part of the Chinese Pharmacopoeia 2005 edition), tocopherol (purchased in BSF); cucurbitacin BE (purchased in Tianjin Pharmaceutical Research Institute Pharmaceutical Co., Ltd.); MCT (purchased from Shanghai Dongshang Industrial Co., Ltd. or Tieling North Asia Medicinal Oil Co., Ltd.), soybean oil (purchased from Tieling North Asia Pharmaceutical Oil Co., Ltd.).
- Reagents Methanol and acetonitrile are chromatographically pure, and other reagents such as phosphoric acid are analytically pure.
- the solubility of cucurbitacin BE (cucurbitacin B content greater than 60%, commercially available) in soybean oil or MCT.
- the solubility of cucurbitacin BE in soybean oil and MCT was determined by solubility measurement.
- MCT medium chain triglyceride
- MCT has twice the solubility of cucurbitacin BE in soybean oil.
- Cucurbitacin BE (commercially available, after refining, cucurbitacin B content is controlled at 62% to 65%, other components are mainly cucurbitacin E, isoliquirin ⁇ dihydrocucurin B) soybean oil or MCT oil solution inhibition effect.
- cucurbitacin B contains double bonds, it is prone to oxidative damage.
- Antioxidants should be added to the prescription to investigate the effect of adding 5% tocopheryl acetate or 5% tocopherol antioxidant to MCT.
- vitamin E tocopherol acetate
- the basic formula of the sample solution is 1 mg of cucurbitacin per gram of MCT.
- the drug decreased by about 41°/. 35%, 28%, 16%, 12%, 6% and 2%, that is, when the vitamin E content is more than 5%, the antioxidant effect is more obvious, and the drug content is basically unchanged when 30% or more.
- vitamin E as an antioxidant, and the amount should not be too large, so it is recommended to choose 5% ⁇ 10% concentration in the future.
- the concentration of vitamin E is calculated according to (vitamin E I MCT) X 100%.
- MCT and vitamin E are mixed evenly, and a prescribed amount of cucurbitacin is added, and 80 ⁇ is heated and dissolved to obtain a clear and transparent solution.
- the solution can continue to prepare soft capsules or liquid type hard capsules according to a conventional method, 151 mg per capsule, equivalent Each grain contains 1 mg of cucurbitacin.
- Emulsification can be carried out by adding an appropriate emulsifier to prepare an emulsion (10% MCT or 20% MCT emulsion) for injection, oral or topical administration.
- the solution can be prepared according to a conventional method of soft capsules or liquid type hard capsules, each 425mg, equivalent to each containing cucurbitacin 0.6mg.
- Emulsification can be carried out by adding an appropriate emulsifier to prepare an emulsion (5% MCT or 10% MCT emulsion) for injection, oral administration or external administration.
- MCT and vitamin E are mixed evenly, and the prescribed amount of cucurbitacin is added, and 70 ⁇ is heated and dissolved to obtain a clear and transparent solution.
- the solution can be prepared according to a conventional method, soft capsules or liquid type hard capsules, each of which is 20 (kg, equivalent to each cucurbitin containing 0.3 mg.
- Emulsification by adding an appropriate emulsifier can be prepared as an emulsion (5% MCT) Or 10% MCT concentration emulsion), for injection, oral or topical administration.
- MCT and vitamin E are mixed evenly, and the prescribed amount of cucurbitacin is added, and 70 ⁇ is heated and dissolved to obtain a clear and transparent solution.
- 6nig ⁇ The solution can be prepared according to the conventional method of soft capsules or liquid type hard capsules, each containing 360nig, equivalent to each containing cucurbitacin 0. 6nig. Emulsify by adding an appropriate emulsifier to prepare an emulsion (5% MCT or
- the solution can be prepared according to the conventional method of soft capsules or liquid type hard capsules, each 333mg, each containing cucurbitacin 0.3mg.
- Emulsification can be carried out by adding an appropriate emulsifier to prepare an emulsion (10% MCT or 20% MCT emulsion) for injection or oral administration.
- MCT and vitamin E are mixed evenly, and a prescribed amount of cucurbitacin is added, and 60 ⁇ is heated and dissolved to obtain a clear and transparent solution.
- the solution can continue to prepare soft capsules or liquid type hard capsules according to a conventional method, each containing 330 mg , which is equivalent to each containing cucurbitacin 0.
- lmgo is emulsified by adding an appropriate emulsifier to prepare an emulsion (30% MCT concentration emulsion) ), injection, oral administration.
- MCT and vitamin E are mixed evenly, and the prescribed amount of cucurbitacin is added.
- the 5CTC is heated and dissolved to obtain a clear and transparent solution.
- Lmg ⁇ The solution can be prepared in accordance with a conventional method of soft capsules or liquid type hard capsules, each 520mg, equivalent to each containing cucurbitacin 0. lmg.
- Emulsification can be carried out by adding an appropriate emulsifier to prepare an emulsion (5% MCT or 10% MCT emulsion) for injection or oral administration.
- the solution can be prepared according to a conventional method of soft capsules or liquid type hard capsules, each containing 220mg, equivalent to each containing cucurbitacin 0.2 mg.
- Emulsify by adding an appropriate emulsifier to prepare an emulsion (10 blue CT or
- Vitamin E 100g MCT and vitamin E are mixed evenly, and a prescribed amount of cucurbitacin E is added, and 60 ⁇ is heated and dissolved to obtain a clear and transparent solution. 5mg ⁇
- the solution can be prepared according to a conventional method of soft capsules or liquid type hard capsules, each 330mg, which corresponds to each containing cucurbitacin E0. 3mg.
- Emulsification can be carried out by adding an appropriate emulsifier to prepare an emulsion (10% MCT ⁇ 20% MCT emulsion) for injection, oral administration or external administration.
- the emulsion is prepared according to a conventional method for preparing an emulsion, and the concentration of the drug is 0.1 mg/ml ; and the prepared emulsion can be injected, orally or externally.
- the emulsion is prepared according to a conventional method for preparing an emulsion at a drug concentration of 1 mg/ml ; and the prepared emulsion can be administered by injection, orally or externally.
- the emulsion is prepared according to a conventional method for preparing an emulsion, and the concentration of the drug is 0.5 mg/ml; the prepared emulsion can be injected, orally or externally.
- the poloxamer is a polyoxyethylene polyoxypropylene ether block copolymer sold under the trade name Pluronic. This product is supplied by the German company BSF.
- the cells of the liver cancer 2 tumor cells were resuscitated in vitro, and the cells were collected in the exponential growth phase of the cells, centrifuged at 100 o/min, washed twice with PBS, centrifuged to remove the supernatant, diluted with sterile physiological saline, and adjusted to 2 ⁇ 10 7 /ml. Healthy mice were selected, each of which was intraperitoneally injected with 0.2 ml of the above cell suspension. The ascites growth of the inoculated mice was observed. After about one week, the abdomen of the inoculated mice was obviously enlarged and bulged, and ascites was taken, and the ascites was milky white.
- the number of tumor-producing cells was IX 10 7 /ml, and 0.2 ml was inoculated subcutaneously, and a mouse liver cancer H 22 right subcutaneous inoculation model was established.
- mice that successfully modeled were randomly divided into groups of 10 (20 in the control group) and numbered within the group.
- the model control group (administered equal volume of CMC-Na solution); cucurbitacin commercially available tablet group (study fine, suspended in CMC-Na, intragastrically, dose according to total cucurbitacin, 0.2mg-kg- I ; MCT group (administration dose according to total cucurbitacin, 0.2mg-kg- 1 ).
- the administration was started on the second day after the modeling, and was administered continuously for 10 days once a day.
- Tumor inhibition rate (1 mean tumor weight of the drug-administered group / mean tumor weight of the control group) X 100% All data were averaged using the standard deviation to represent soil SD), and the results are shown in Table 2. Table 2. Mouse transplanted liver cancer H22 tumor suppressor results (SSD) Number of animals Weight (g) Tumor weight (g) Group Tumor inhibition rate (SSD).
- the MCT group is the drug solution of Example 9. From the test results, the difference in tumor weight of the tablet group is large (SD is 0.38, 0.43, 0.53, respectively). The rates were lower (37.1%, 31.2%, 30.5%, respectively); while the MCT group had a smaller difference in tumor weight (SD, 0.25, 0.31, 0.28, respectively), and the tumor inhibition rate was higher (41.0%, 38.7%, respectively). 43.3%), indicating that after the cucurbitacin is dissolved by MCT, the absorption of the drug is improved, the individual difference is reduced, and the curative effect is improved.
- Example 21 was substantially the same as Example 13, except that the tocopherol was 9% (450 g) of MCT.
- Example 22 substantially the same as Example 5, but wherein the MCT is changed to a mixture of MCT and soybean oil, the weight ratio of MCT to soybean oil is 1:10;
- the vitamin E is ⁇ -type tocopherol acetate (tocopherol);
- Vitamin E is 1% by weight of the mixture of medium chain triglyceride and soybean oil
- the cucurbitacin is obtained from the cucurbit of the Cucurbitaceae plant Cucumismelo L., which is obtained by extracting the fruit stalk, the pedicle and the cucurbit.
- Example 23 substantially the same as Example 5, but the MCT is changed to a mixture of MCT and soybean oil, the weight ratio of MCT to soybean oil is 1:9;
- the vitamin E is ⁇ -type tocotrienol (tocotrienol);
- Vitamin E is 3% by weight of the mixture of medium chain triglyceride and soybean oil
- the cucurbitacin is cucurbitacin BE, and the content of cucurbitacin B in the cucurbitacin BE is greater than 60%.
- Example 24 substantially the same as Example 5, but wherein the MCT is changed to a mixture of MCT and soybean oil, the weight ratio of MCT to soybean oil is 1:8;
- the vitamin E is an ester derivative of tocopherol
- Vitamin E is 5% by weight of the mixture of MCT and soybean oil
- the cucurbitacin also contains cucurbitacin, isoquerucin, and dihydrocucurin.
- Example 25 was substantially the same as Example 5 except that the MCT was changed to a mixture of MCT and soybean oil, and the weight ratio of MCT to soybean oil was 1:7.
- the vitamin E is an ester derivative of tocotrienol which is 80 parts by weight.
- Example 26 substantially the same as Example 5, but wherein the MCT is changed to a mixture of MCT and soybean oil, the weight ratio of MCT to soybean oil is 1:6;
- the vitamin E is a mixture of tocopherol acetate and tocotrienol.
- Example 27 was substantially the same as Example 5 except that the MCT was changed to a mixture of MCT and soybean oil, and the weight ratio of MCT to soybean oil was 1:5.
- Example 28 was substantially the same as Example 5 except that the MCT was changed to a mixture of MCT and soybean oil, and the weight ratio of MCT to soybean oil was 1:4.
- Example 29 was substantially the same as Example 5 except that the MCT was changed to a mixture of MCT and soybean oil, and the weight ratio of MCT to soybean oil was 1:3.
- Example 30 was substantially the same as Example 5 except that the MCT was changed to a mixture of MCT and soybean oil, and the weight ratio of MCT to soybean oil was 1:2.
- Example 31 was substantially the same as Example 5 except that the MCT was changed to a mixture of MCT and soybean oil, and the weight ratio of MCT to soybean oil was 1:1.
- Example 32 was basically the same as Example 5, but the MCT therein was changed to Miglyol 829.
- Example 33 is basically the same as Embodiment 5, but the MCT therein is changed to Miglyol 840.
- Example 34 which is basically the same as Example 5, but in which the vitamin E is changed to tocopherol acetate and tocopherol 1:
- Example 35 was substantially the same as Example 5 except that the weight ratio (MCT) of cucurbitacin/medium chain triglyceride was 1:800; and vitamin E was 100 parts by weight.
- MCT weight ratio of cucurbitacin/medium chain triglyceride
- Example 36 was substantially the same as Example 5 except that the weight ratio (MCT) of cucurbitacin/medium chain triglyceride was 1:1200 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
- Example 37 was substantially the same as Example 5 except that the liquid fat was a long chain triglyceride (LCT).
- Example 38 is basically the same as Example 5, but the liquid fat therein is a structural oil.
- Example 39 is basically the same as Example 5, but the liquid fat therein is soybean oil.
- Example 40 was substantially the same as Example 5 except that the liquid fat therein was peanut oil.
- Example 41 was substantially the same as Example 5 except that the liquid fat therein was olive oil.
- Example 42 Basically the same as Example 5, but the liquid fat therein was coconut oil.
- Example 43 Basically the same as Example 5, but the liquid fat therein was a mixture of a structural oil and a medium chain triglyceride 1-1.
- Example 44 is substantially the same as Example 5 except that the liquid fat is a mixture of soybean oil, structural oil and medium chain triglyceride 1: 1:1.
- Example 45 which is substantially the same as Example 5, but wherein the liquid fat is a mixture of a structural oil, a medium chain triglyceride and a long chain triglyceride (LCT) 1;
- the liquid fat is a mixture of a structural oil, a medium chain triglyceride and a long chain triglyceride (LCT) 1;
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Abstract
L'invention concerne une composition pharmaceutique liquide stable à base de cucurbitacine comprenant de la cucurbitacine, de la graisse liquide et de la vitamine E, le rapport de poids de la cucurbitacine au liquide est de 1:100~1:5000 et la vitamine E représente 1%~50% du poids de la graisse liquide. Cette graisse liquide est liquide à température normale et est sélectionnée dans le groupe comprenant des triglycérides à chaînes moyennes (TCM), des triglycérides à chaînes longues (TCL), une huile structurale, une huile de soja, une huile d'arachide ou une huile d'olive, ou un mélange de plusieurs huiles. La graisse liquide, telle que les triglycérides à chaînes moyennes, peut dissoudre facilement la cucurbitacine, augmenter l'effet anticancéreux et réduire la différence individuelle. La vitamine E peut améliorer la stabilité de la cucurbitacine. La composition moléculaire liquide stable à base de cucurbitacine peut être préparée sous forme de capsule molle et sous forme de gélule dure de type liquide pouvant être administrée par voie orale ou externe. La composition peut également être préparée sous forme d'émulsion pouvant être administrée par injection, par voie orale ou par voie externe, après adjonction d'un émulsifiant à la composition moléculaire liquide stable à base de cucurbitacine.
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CN2007100115132A CN101062040B (zh) | 2007-05-31 | 2007-05-31 | 稳定型葫芦素液体组方及其制剂 |
CN200710011513.2 | 2007-05-31 |
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CN101062040B (zh) * | 2007-05-31 | 2011-11-16 | 沈阳药科大学 | 稳定型葫芦素液体组方及其制剂 |
EP2394636B1 (fr) * | 2010-05-28 | 2014-03-19 | Novagali Pharma S.A. | Procédé de traitement de conditions de la rétine en utilisant une tamponnade intraoculaire |
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CN1644202A (zh) * | 2004-07-22 | 2005-07-27 | 沈阳药科大学 | 葫芦素液体型组方及其制剂 |
CN1698620A (zh) * | 2005-06-03 | 2005-11-23 | 沈阳药科大学 | 一种可过滤除菌的葫芦素乳剂及制备方法 |
CN101062040A (zh) * | 2007-05-31 | 2007-10-31 | 沈阳药科大学 | 稳定型葫芦素液体组方及其制剂 |
CN101134768A (zh) * | 2007-10-22 | 2008-03-05 | 沈阳药科大学 | 一种葫芦素原料的精制方法及其制剂 |
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CN100377712C (zh) * | 2002-11-28 | 2008-04-02 | 沈阳药科大学 | 葫芦素脂质体组方及其制剂 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1644202A (zh) * | 2004-07-22 | 2005-07-27 | 沈阳药科大学 | 葫芦素液体型组方及其制剂 |
CN1698620A (zh) * | 2005-06-03 | 2005-11-23 | 沈阳药科大学 | 一种可过滤除菌的葫芦素乳剂及制备方法 |
CN101062040A (zh) * | 2007-05-31 | 2007-10-31 | 沈阳药科大学 | 稳定型葫芦素液体组方及其制剂 |
CN101134768A (zh) * | 2007-10-22 | 2008-03-05 | 沈阳药科大学 | 一种葫芦素原料的精制方法及其制剂 |
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