CN100588397C - Armillarisin A solution preparation and its preparing method - Google Patents
Armillarisin A solution preparation and its preparing method Download PDFInfo
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- CN100588397C CN100588397C CN200410020563A CN200410020563A CN100588397C CN 100588397 C CN100588397 C CN 100588397C CN 200410020563 A CN200410020563 A CN 200410020563A CN 200410020563 A CN200410020563 A CN 200410020563A CN 100588397 C CN100588397 C CN 100588397C
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- armillarisin
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- polyethylene glycol
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Abstract
The invention discloses an armillarisin preparation and its manufacturing method, it has characters of quick stripping, scattering and absorption, the individual difference of effect is small and hasadvantage to disease treatment. It produces solution armillarisin with compound solution of polyethylene glycol and other solutions, and it can be produced into liquid soft capsule, liquid hard capsule and drop preparation. The molecular weight of polyethylene glycol is 200-4000 of polyethylene glycol. The other solutions are propylene glycol, glycerine, alcohol and water. Takes the polyethylene glycol, armillarisin with prescription content and heats then to 45-75deg.C, adds in glycerine, water and stabilizer after being dissolved, then cools them to room temperature, the pH value is regulated to 3-9, filters, acquires the liquid, then the acquired liquid can be sued to produce soft capsule and hard capsule.
Description
Technical field:
The present invention relates to medical technical field, exactly it is armillarisin A solution type preparation and preparation method thereof.
Background technology:
Armillarisin A solution can promptly be encircled in the Pseudomonas armillariella tabescens by Armillaria mella tabescens (Scop.ex Fr.) Sing. and extract, but also synthetic, and its character is yellow or light yellow needle-like or crystalline powder, and the effect that promotes bile secretion is arranged, and the 0ddis sphincter is had tangible spasmolysis.In addition, may still have to promote immunologic function and strengthen cytophagous phagocytosis, but also transaminase lowering activity still can be decomposed aspergillus flavus toxin.Be applicable to acute cholecystitis, acute episode of chronic cholecystitis, chronic gastritis and viral hepatitis etc.
Armillarisin A is to separate on the folk remedy basis, and the choleretic of final synthetic, abroad seldom to its research, and it is domestic also few to its research, people's such as Sun Fenzhi result of study shows, the terminal sphincteral tensity of the loose ductus choledochus of energy can make hepatic secretion bile amount obviously increase simultaneously after anesthetized dog intravenous injection this product.After anesthesia rat duodenal administration or intramuscular injection this product, all can promote hepatic secretion bile.Can also cause after anesthetized dog intravenous injection this product that duodenum is loose, blood pressure reduces, decreased heart rate, act on all slight and of short duration.The acute LD of mice by intraperitoneal injection and oral this product
50Be respectively 980mg/kg and＞5000mg/kg.With 25～125 times of human maximum dose level every day respectively intramuscular injection in rat and Canis familiaris L., once a day, continuous three months, the result did not see obvious toxic and side effects (Sun Fenzhi, Deng. the pharmacology and the toxicity research of new choleretic armillarisin A: Acta Pharmaceutica Sinica 1981,16 (6): 401-406).Because armillarisin A soluble,very slightly in ethanol or methanol, almost insoluble in water, made injection need add multiple organic solvent, comprise polyethylene glycol 6000, ethanol, also added Tween 80 (Guo Jianlan simultaneously, Deng. the research pharmacy circular of Stability of Armillarisin A Injection: 1981,16 (11): 8-11).Though, in this prescription, having adopted Polyethylene Glycol, the molecular weight of Polyethylene Glycol only is 6000, the dosage form of being developed is an injection, does not see and adopts Polyethylene Glycol in the oral agents.
Armillarisin A is almost insoluble in water, and existing oral formulations clinical efficacy is often not good, for dissolubility in the water that improves armillarisin A, has literary composition to make polyvinylpyrrolidone (PVP) coprecipitate.Adopt the made coprecipitate of optimal proportion (1: 5) of document, in its water dissolubility only be 249.97ug/ml (Guo Jianlan, etc. the dissolubility pharmacy of improving armillarisin A with coprecipitation method circulates a notice of 1986,21 (5): 261,263); Simultaneously, there is " wearing out " problem in coprecipitate, and long term storage stability is poor.Zhu Jiabi etc. have developed instant (Zhu Jiabi, the development of armillarisin A dissolving tablet and choleretic effect research Acta Pharmaceutica Sinica 1992 thereof, 27 (3): 231～235), made instant of author is by starch, dextrin, an amount of homemade new adjuvant is formed, the stripping quantity of made dissolving tablet in the dissolution medium of being made up of 13.5ml dilute hydrochloric acid and 30% ethanol water (cumulative volume is 650ml) improves greatly than former tablet, but the time of its external stripping 63.2% is 8.5 minutes, we once made cyclodextrin clathrate with armillarisin A, shorten the external dissolution time of armillarisin A greatly, and applied for patent (application number: 02144851.5).In existing literature, do not see and adopt the solvent of Polyethylene Glycol kind solvent as oral formulations, we find that through a large amount of tests Polyethylene Glycol kind solvent and combination solvent thereof can dissolve armillarisin A makes solution, and can utilize this solution to make multiple oral formulations.Because in solution, medicine is to exist in the molecular state mode, and the stripping of medicine, dispersion, absorption are faster, and the curative effect individual variation is littler.Oral formulations is suitable for long-term prescription most.
Summary of the invention:
The objective of the invention is to be achieved by the following scheme, it is characterized in that: select Polyethylene Glycol (PEG200, PEG300, PEG400, PEG600) as solvent, or be aided with other solvents, stabilizing agent, pH regulator agent, preparation armillarisin A solution, Polyethylene Glycol with other solvent burden ratio is: Polyethylene Glycol, propylene glycol, glycerol, ethanol, water etc. mix by a certain percentage.The weight ratio of Polyethylene Glycol and propylene glycol, glycerol, ethanol, water is 1: 0～1: 0～1: 0～1: 0～1, and its optimum range is 1: 0.05～0.5: 0.05～0.5: 0～0.2: 0.1～0.5; The weight ratio of Polyethylene Glycol kind solvent and medicine is 100: 0.2～100: 10, and its optimum range is 100: 0.5～100: 3, and the solution available water of gained is diluted arbitrarily, can be made into dosage forms such as solution-type soft capsule, solution-type hard capsule and drop.The Polyethylene Glycol kind solvent is that molecular weight is 200～4000 Polyethylene Glycol.Described other solvents are propylene glycol, glycerol, ethanol, water.Can add stabilizing agent, pH regulator agent in the prepared armillarisin A solution.Said stabilizing agent comprises one or more mixture in sodium sulfite, sodium sulfite, tocopherol, the tocopheryl acetate etc.; The pH regulator agent is one or more mixture in citric acid, tartaric acid, hydrochloric acid, phosphoric acid, sodium hydroxide, carbonic acid (hydrogen) sodium etc., and the pH scope is: 3～9.Said double solvents is: Polyethylene Glycol, propylene glycol, glycerol, ethanol, water etc.Can add an amount of sweeting agent, essence in the said drop.
Advantage of the present invention is: because in solution, medicine is to exist in the molecular state mode, and the stripping of medicine, dispersion, absorption are faster, and the curative effect individual variation is littler, is beneficial to treatment of diseases.Oral formulations is suitable for long-term prescription most.
The specific embodiment:
Below in conjunction with embodiment the present invention is further illustrated, but not only be confined to listed embodiment.
Embodiment 1: the preparation of armillarisin A solution
Prescription:
Armillarisin A 0.5g
Macrogol 200 (PEG200) 100g
Hydrochloric acid is an amount of
Essence is an amount of
Preparation technology:
Take by weighing the Macrogol 200 and the armillarisin A of recipe quantity, place beaker, heat 50～60 ℃, stirring and dissolving after, add hydrochloric acid, transfer pH to about 3, be cooled to room temperature, add essence, filter, solution.Gained solution can be prepared into drop etc.
Embodiment 2: the preparation of armillarisin A solution
Prescription:
Armillarisin A 2g
PEG400 (PEG400) 100g
Glycerol 10g
Citric acid is an amount of
Water 2g
Preparation technology:
After taking by weighing 65～75 ℃ of PEG400, the armillarisin A heating, stirring and dissolving of recipe quantity, add glycerol, water, it is even to be mixed, and is cooled to room temperature, and citric acid transfers pH about 5, filter, solution.Gained solution can be prepared into soft capsule, hard capsule etc.
Embodiment 3: the preparation of armillarisin A solution
Prescription:
Armillarisin A 5g
PEG400 (PEG400) 100g
Glycerol 15g
Sodium hydroxide is an amount of
Protein sugar is an amount of
Essence is an amount of
Sodium sulfite is an amount of
Water 80g
Preparation technology:
Take by weighing PEG400, glycerol and the armillarisin A of recipe quantity, place beaker, heat 60 ℃, stirring and dissolving after, add entry, sodium sulfite, it is even to be mixed, and is cooled to room temperature, transfers pH to 9 with sodium hydroxide, filter, solution.Gained solution can prepare drop etc.
Embodiment 4: the preparation of armillarisin A solution
Prescription:
Armillarisin A 5g
Macrogol 600 (PEG600) 20g
Macrogol 200 (PEG200) 100g
Propylene glycol 15g
Ethanol 5g
Sodium sulfite 0.1g
Hydrochloric acid is an amount of
Water 5g
Preparation technology:
Take by weighing Macrogol 600, Macrogol 200, propylene glycol, ethanol and the armillarisin A of recipe quantity, place beaker, heat 50 ℃, stirring and dissolving after, add entry, it is even to be mixed, and is cooled to room temperature, transfers pH to about 6 with hydrochloric acid, solution.Gained solution can be prepared into soft capsule, hard capsule.
Embodiment 5: the preparation of armillarisin A solution
Prescription:
Armillarisin A 1g
PEG400 (PEG400) 90g
Polyethylene Glycol 800 (PEG800) 10g
Glycerol 5g
Phosphoric acid is an amount of
Sodium hydroxide is an amount of
Water 1g
Preparation technology:
Take by weighing PEG400, Polyethylene Glycol 800, glycerol and the armillarisin A of recipe quantity, place beaker, heat 70 ℃, stirring and dissolving after, add entry, it is even to be mixed, and is cooled to room temperature, transfer pH to about 7 with phosphoric acid and sodium hydroxide, solution, make soft capsule, hard capsule.
Embodiment 6: the preparation of armillarisin A solution
Prescription:
Armillarisin A 1g
Macrogol 200 (PEG200) 99g
Macrogol 4000 (PEG4000) 1g
Propylene glycol 2g
Ethanol 0.5g
Tocopherol 0.1g
Water 2g
Preparation technology:
Take by weighing Macrogol 200, Macrogol 4000, propylene glycol, ethanol, tocopherol and the armillarisin A of recipe quantity, place beaker, add 60～70 ℃, stirring and dissolving after, add entry, it is even to be mixed, and is cooled to room temperature, solution.Gained solution can be prepared into soft capsule, hard capsule.
Embodiment 7: the preparation of armillarisin A solution
Prescription:
Armillarisin A 5g
PEG400 (PEG400) 35g
Macrogol 600 (PEG600) 15g
Glycerol 50g
Sodium hydroxide is an amount of
Protein sugar is an amount of
Essence is an amount of
Antiseptic is an amount of
Sodium sulfite 0.1g
Water 50g
Preparation technology:
Take by weighing PEG400, Macrogol 600, glycerol, the dissolving of water mixing of recipe quantity, add armillarisin A, transfer pH to about 8 with sodium hydroxide, after the stirring and dissolving, add sodium sulfite, protein sugar, essence, it is even to be mixed, and is cooled to room temperature, solution.Gained solution can be prepared into drop.
Embodiment 8: the preparation of armillarisin A solution
Prescription:
Armillarisin A 1g
PEG400 (PEG400) 99g
Cetomacrogol 1000 (PEG1000) 1g
Propylene glycol 2g
Hydrochloric acid is an amount of
Water 2g
Preparation technology:
Take by weighing PEG400, Polyethylene Glycol 100, propylene glycol and the armillarisin A of recipe quantity, place beaker, heat 60 ℃, stirring and dissolving after, add entry, it is even to be mixed, and transfers pH to about 4～6 with hydrochloric acid, is cooled to room temperature, solution.Gained solution can be prepared into soft capsule, hard capsule.
Embodiment 9: the drug effect of armillarisin A solution
One, armillarisin A is in the intravital function of gallbladder promoting experimental result of rat
Animal: the Wister rat, male.
Equipment: rat fixing head, biliary drainage pipe, bulk pruning cutter, operating scissors, flat tweezer, ophthalmology tweezer, eye scissors, mosquito forceps, syringe.
Reagent: armillarisin A; Armillarisin A solution (embodiment 2, self-control).
The medicine preparation: armillarisin A is made water suspension with 1% sodium carboxymethyl cellulose; Armillarisin A solution available water is diluted arbitrarily.
Method:
18 of male rats are divided into 3 groups at random after weighing, fasting be can't help water 12 hours before the experiment.During experiment every group with after the pentobarbital sodium 40mg/kg anesthesia, face upward the position and be fixed on the fixing head, cut about 2cm along the abdomen median line, open the abdominal cavity, find stomachus pyloricus, the upset duodenum, in the descendant duodenum mesentery, find the bile duct of white flexible, wear two rhizoid lines under it, the ligation pars papillaris is made v-notch to the liver direction, insert plastic tube, promptly as seen have pistac bile to flow out, ligation fixed plastics pipe is collected bile with test tube.After waiting after the operation to stablize 30 minutes, collect 30 minutes bile earlier, respectively organize rat then and give medicine by the dosage of 30mg/kg by duodenum respectively, capacity normal saline such as negative control group injection.
Collected bile once every 10 minutes after the administration, totally 3 times, the record bile flow, changing percentage rate with bile before and after the administration is statistical indicator.
The result:
The results are shown in following table,
Armillarisin A and solution thereof to the excretory influence of rat bile (x ± s, n=6)
*P＜0.05,
*P＜0.01 armillarisin A and solution and normal saline group are relatively;
△P＜0.05 solution group and armillarisin A group are relatively.(list of references 1. Qi Chens. the herbal pharmacology research methodology. Beijing: People's Health Publisher, 1993; 2. Li Yi Kui, Wang Qinmao (chief editor). the herbal pharmacology experimental methodology. Shanghai: Science and Technology of Shanghai publishing house, 1991)
By above data as can be known, armillarisin A made solution after, not only have " rapid-action ", " curative effect height " characteristics, and " individual variation is little ", be beneficial to treatment of diseases.
Claims (3)
1, a kind of armillarisin A preparation, it is characterized in that, by adopting the Polyethylene Glycol kind solvent and preparing the solution-type armillarisin A with the double solvents of other solvent combination, the solution-type soft capsule of making thus again, solution-type hard capsule or drop, the weight ratio of described Polyethylene Glycol kind solvent and medicine is 100: 0.5-100: 3; Said double solvents is: Polyethylene Glycol, propylene glycol, glycerol, ethanol, water, and its weight ratio is 1: 0.05-0.5: 0.05-0.5: 0-0.2: 0.1-0.5; Described Polyethylene Glycol kind solvent is selected from Macrogol 200, Liquid Macrogol, PEG400.
2, armillarisin A preparation according to claim 1 is characterized in that: add stabilizing agent, pH mediator agent in the prepared armillarisin A solution.
3, armillarisin A preparation according to claim 2, it is characterized in that: described stabilizing agent is selected from one or more in sodium sulfite, sodium sulfite, tocopherol, the tocopheryl acetate; The pH regulator agent is selected from one or more in citric acid, tartaric acid, hydrochloric acid, phosphoric acid, sodium hydroxide, sodium carbonate or the sodium bicarbonate; The pH scope is: 3-9.
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| CN200410020563A CN100588397C (en) | 2004-05-19 | 2004-05-19 | Armillarisin A solution preparation and its preparing method |
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| CN200410020563A CN100588397C (en) | 2004-05-19 | 2004-05-19 | Armillarisin A solution preparation and its preparing method |
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| CN100588397C true CN100588397C (en) | 2010-02-10 |
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| CN1895292B (en) * | 2006-06-28 | 2011-09-07 | 四川隆盛药业有限责任公司 | Leukothrix capsule medicine, its discrimination and quality standard inspection |
| CN100420683C (en) * | 2006-09-21 | 2008-09-24 | 王绍杰 | Armiharisin succinic mono ester with cholagogic effect, and its salt and medicinal composition |
| CN104414971A (en) * | 2013-09-10 | 2015-03-18 | 成都力思特制药股份有限公司 | Armillarisin A injection and preparation method thereof |
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Non-Patent Citations (2)
| Title |
|---|
| 亮菌甲素注射液的制备与探讨. 谭主川等.医院药学杂志，第2卷第2期. 1982 |
| 亮菌甲素注射液的制备与探讨. 谭主川等.医院药学杂志，第2卷第2期. 1982 * |
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