WO2010069138A1 - 一种谷维素组合物及其制备方法 - Google Patents

一种谷维素组合物及其制备方法 Download PDF

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Publication number
WO2010069138A1
WO2010069138A1 PCT/CN2009/001466 CN2009001466W WO2010069138A1 WO 2010069138 A1 WO2010069138 A1 WO 2010069138A1 CN 2009001466 W CN2009001466 W CN 2009001466W WO 2010069138 A1 WO2010069138 A1 WO 2010069138A1
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Prior art keywords
acid
oryzanol
pharmaceutical composition
salt
phospholipid
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PCT/CN2009/001466
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English (en)
French (fr)
Inventor
郝守祝
焦玉焕
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北京世纪博康医药科技有限公司
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Publication of WO2010069138A1 publication Critical patent/WO2010069138A1/zh

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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
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention discloses a oryzanol composition containing oryzanol, phospholipid, bile acid and/or a salt thereof, belonging to the field of medical technology
  • Oryzanol is a natural mixture of ferulic acid esters and ferulic acid ferulic acid esters, which are mainly composed of white wood and light yellow crystal powder, odorless and specific flavor. Oryzanol is mainly found in rice bran oil and its oil feet. In rice bran oil, the content of ferulic acid ferulic acid ester is about 70 ⁇ 80%. Long-term studies have found that oryzanol has a variety of physiological functions, including: lowering blood lipids, resisting cholesterol absorption, lowering serum cholesterol, preventing lipid oxidation, and preventing cardiovascular disease. In addition, oryzanol can alleviate the various physical disorders and autonomic dysfunctions that women enter after menopause and improve the dysfunction of the bottom of the ventricle.
  • Oryzanol is hardly soluble in water and easily oxidized, making it difficult to make a stable preparation.
  • the lower solubility and oxidative properties not only result in low absorption in the actual application of oryzanol, but also in production.
  • Chinese patent CN123428 discloses a vegetable oil-soluble preparation of oryzanol, which improves bioavailability and has a clinical effect superior to that of a general tablet.
  • the oil-soluble preparation must be intramuscularly injected during clinical application, the patient has a strong pain and is prone to muscle agglomeration. At the same time, the oil-soluble preparation is slow to take, and it takes about one month for continuous intramuscular injection.
  • Chinese Patent Application 2007100156403 In order to solve the problem of easy precipitation and instability caused by the use of vegetable oil preparations, ethyl oleate is used instead of vegetable oil to prepare an oil-soluble preparation of oryzanol, thereby achieving a stable and less prone to precipitation.
  • the invention still does not substantially solve the drawbacks that the muscle injection caused by the oil-soluble preparation is easy to cause pain, muscle agglomeration and poor compliance.
  • 2004100945568 discloses a technical solution for preparing a oryzanol raw material in combination with cholesterol and a phospholipid to prepare a liposome, and the preparation of the technical solution of the present invention overcomes the problem of poor oral efficacy and low bioavailability of oryzanol.
  • the preparation of liposomes is a costly process, the quality of the production process is not easy to control, and it is impossible to obtain a stable and reliable oryzanol liposome.
  • Patent CN100386082C discloses an injection preparation of oryzanol which obtains an injection preparation by simultaneously combining oryzanol with a surfactant and a co-solvent in combination with a second surfactant.
  • the injection obtained by the solution is an injection emulsion, and must include an oil phase, and the prepared emulsion has a relatively difficult particle size control and relatively poor stability.
  • a milk homogenizer or the like is required, and the operation is complicated and high in cost.
  • injection means a preparation which can be used for intravenous infusion or bolus injection, including but not limited to injection, infusion, lyophilized powder, and the like.
  • the "lyophilized preparation” means any specific substance obtained by freeze-drying, that is, lyophilization of an aqueous solution, and the aqueous solution may contain a nonaqueous solvent.
  • pharmaceutical composition means any composition sufficient to impart usefulness and stability to a pharmaceutical product.
  • therapeutically effective amount refers to an amount administered to some extent to alleviate one or more symptoms of the condition being treated.
  • amount of oryzanol in the pharmaceutical composition which exerts a therapeutic effect against the corresponding condition when the composition of the present invention is applied.
  • pharmaceutically acceptable means that the ingredients used in the pharmaceutical composition do not cause unacceptable loss of pharmacological activity or unacceptable adverse side effects.
  • the present invention provides a oryzanol pharmaceutical composition which is stable in nature, high in water solubility, and suitable for industrial production. In the meantime, the present invention provides a process for the preparation of the composition.
  • the composition of the present invention does not require the addition of an oily component and does not form an emulsion, and effectively solves the problem that the particle size of the emulsion is difficult to control, unstable, high in cost, complicated in operation, and avoids side effects caused by the use of vegetable oil or the like.
  • the final product of the composition of the present invention does not contain an oil phase component and is highly safe to use.
  • the prepared composition can be kept clear for more than 8 hours at room temperature.
  • the composition does not need to be diluted with an organic solvent before use, and can be directly used by adding water for injection or glucose injection, and physiological saline, which simplifies the operation.
  • the lyophilized formulation disclosed herein minimizes or avoids the use of Tween and prevents potential hemolysis problems.
  • the pharmaceutical composition of the present invention not only effectively improves the solubility thereof, but also has a high affinity for the phospholipid group and the cell membrane, and can effectively prolong the action time and improve the bioavailability.
  • the composition of the present invention is stable for a long period of time, is convenient for storage and transportation, can prevent oxidative hydrolysis at the time of injection, and improves bioavailability and therapeutic index.
  • the preparation method of the composition of the invention has simple process and can be industrially produced by using conventional process equipment.
  • the inventors have long found that the addition of a certain amount of phospholipids and bile acids and/or their salts to oryzanol can significantly increase their solubility in water to form a clear, stable composition solution.
  • the use of phospholipids and bile acids is much better than using them alone, which can greatly reduce side effects and save costs.
  • the composition is a clarified colloidal solution, which has no oil phase component and does not form an emulsion, and has a particle diameter of 20 nm or less, which is very effective in solving the problem that the emulsion particle size is difficult to control, unstable, high in cost, and complicated in operation.
  • the present invention provides a oryzanol pharmaceutical composition which is a micelle solution comprising a therapeutically effective amount of oryzanol, a phospholipid, a bile acid and/or a salt thereof.
  • the mass ratio of oryzanol, bile acid and/or its salt and phospholipid is 1: 1-100: 1-500; preferably, the mass ratio of oryzanol, bile acid and/or its salt and phospholipid is 1: 1-50: 1 -100; Most preferably, the ratio of oryzanol, bile acid and/or its salt to phospholipid is 1: 5-40: 5-80
  • the present invention provides a lyophilized powder injection comprising a therapeutically effective amount of oryzanol, a phospholipid, a bile acid and/or a salt thereof. It is obtained by further freeze-drying from the oryzanol micelle solution of the present invention.
  • the mass ratio of oryzanol, bile acid and/or its salt and phospholipid is 1: 1-100: 1-500; preferably, the mass ratio of oryzanol, bile acid and/or its salt and phospholipid is 1: 1-50: 1 Most preferably, the mass ratio of oryzanol, bile acid and/or its salt to phospholipid is 1: 5-40: 5-80.
  • composition of the present invention may further comprise a polyol which may be ethylene glycol, polyethylene glycol, propylene glycol, glycerol or any mixture thereof.
  • a polyol When a polyol is added to the composition, the mass ratio of oryzanol, bile acid and/or its salt, phospholipid, polyol is 1: 1-100: 1-500: 1-50; preferably, oryzanol, bile acid and/or The mass ratio of the salt, the phospholipid and the polyol is 1: 1-50: 1-100: 1-30; most preferably, the mass ratio of oryzanol, bile acid and/or its salt, phospholipid and polyol is 1: 5-40 : 5-80: 2-15.
  • the phospholipid used in the present invention is selected from the group consisting of soybean phospholipid, egg yolk phospholipid, soybean sphingomyelin, egg sphingomyelin, hydrogenated soybean phospholipid, hydrogenated egg yolk phospholipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol , dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, distearylphosphatidylcholine, dipalmitophosphatidylglyceride, dipalmitophosphatidylserine, dimyristoylphosphatidylcholine, dimyristoylphosphatidyl Glycerin, two meats: t decyl succinylethanolamine, dilinoleoyl phosphatidylcholine, dilinoleic acid
  • soybean phospholipids are preferred, egg yolk phospholipids, soybean sphingomyelin, egg sphingomyelin, hydrogenated soybean phospholipids, hydrogenated egg yolk phospholipids, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, most preferably soybean phospholipids, Egg yolk phospholipid, phosphatidylcholine, phosphatidylethanolamine.
  • the addition of bile acids and/or their salts can significantly increase the stability of the compositions of the invention.
  • the bile acid used in the present invention is selected from the group consisting of free bile acids, bound bile acids or mixtures thereof, which are products of bile acids after salt formation.
  • the bile acid is selected from the group consisting of free bile acids, bile acids, or a mixture of the two, and the free bile acids include cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and pig deoxycholate.
  • Acid or the like preferably cholic acid, deoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid; combined bile acid is the carboxaldehyde in the above free bile acid with glycine (H 2 NCH 2 C00H ) or taurine ( H 2 NCH 2 CH 2 S0 3 H) or an amino group-containing compound in which the amino group forms an amide bond, preferably glycocholic acid, glycodeoxycholic acid, glycine chenodeoxycholic acid, glycine Ursodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid; bile acid salt after the above-mentioned free bile acid or combined with bile acid salt
  • the products include, but are not limited to, potassium salts, sodium salts, calcium salts, magnesium salts, zinc salts, selenium salts, iron salts and the like,
  • the addition of the polyol of the composition of the present invention can significantly reduce the particle size of the composition and improve the dissolution rate.
  • the polyol may be propylene glycol, glycerin, ethylene glycol, polyethylene glycol, and/or any mixture thereof.
  • the polyethylene glycol has an average molecular weight of 200 to 10,000, preferably a molecular weight of 200 to 1,000, more preferably polyethylene glycol-400 or polyethylene glycol-200.
  • compositions of the present invention may also optionally contain other excipients including, but not limited to, one of an isotonic modifier, a stabilizer, an antioxidant, a pH adjuster, a preservative, an excipient, and/or more than one
  • excipients including, but not limited to, one of an isotonic modifier, a stabilizer, an antioxidant, a pH adjuster, a preservative, an excipient, and/or more than one
  • excipients including, but not limited to, one of an isotonic modifier, a stabilizer, an antioxidant, a pH adjuster, a preservative, an excipient, and/or more than one
  • the mixture thereby improving the stability of the drug, is beneficial to the control of the quality of the drug.
  • some substances have various functions.
  • sodium sulfite can be either a stabilizer or an antioxidant, so the amount of excipient can be controlled by adding a multi-functional component.
  • the isotonicity adjusting agents include, but are not limited to, 0.9% sodium chloride solution, 5% dextrose solution, preferably 5% dextrose solution.
  • the stabilizers include, but are not limited to, sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, sodium thiosulfate, thiourea, vitamins (;, tert-butyl p-hydroxyanisole, dibutyl phenol, propyl gallate, fertility Phenol, methionine, cysteine hydrochloride, acetylcysteine, N-acetyl-DL-methionine, ascorbyl palmitate, ethylenediaminetetraacetic acid, disodium edetate
  • the antioxidants include, but are not limited to, tocopherol, vitamin E, vitamin C, anhydrous sodium sulfite, sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate, t-butyl p-hydroxyanisole, preferably sodium sulfite: sodium metabisulfite, Sodium bisulfite, vitamin E, most preferably anhydrous sodium sulfite.
  • the pH adjusting agent includes, but not limited to, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, metaphosphoric acid, polymetaphosphoric acid, carbonic acid, sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, sodium hydrogencarbonate. , potassium bicarbonate, ammonium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, ethanolamine, diethanolamine, triethanolamine, 1,2-hexanediamine, sodium carbonate, potassium sodium tartrate, potassium metaphosphate, potassium polypotassium phosphate, One or more of sodium metaphosphate, preferably hydrochloric acid, sodium hydroxide, sodium acetate or any mixture thereof.
  • the preservatives include, but are not limited to, one or more of phenol, cresol, tri-tert-butanol, benzyl alcohol, and paraben, preferably cresol, benzyl alcohol, paraben, and most preferably paraben.
  • the excipient includes, but not limited to, one or more of mannitol, lactose, glucose, sorbitol, sodium chloride, hydrolyzed gelatin, dextran, sucrose, glycine, polyvinylpyrrolidone, etc., preferably Mannitol, lactose, glucose, sorbitol, glycine or any mixture thereof, more preferably mannitol, glycine or any mixture thereof, most preferably mannitol.
  • a solubilizing agent may be added for further improving the solubility of oryzanol.
  • the solubilizing agent is selected from the group consisting of Tween, polyethylene glycol dodecahydroxy hydroxy stearate, hydroxypropyl ⁇ cyclodextrin, ⁇ -cyclodextrin, methyl- ⁇ cyclodextrin, amino acid, polypropylmethyl One of cellulose, povidone, and/or a mixture of more than one.
  • the Tween is selected from the group consisting of Tween-20, Tween-40, Tween-60, Tween-80, preferably Tween-80.
  • the amino acid is selected from the group consisting of lysine, arginine, valine, preferably lysine.
  • the micelle solution obtained by the invention can be directly injected as an injection solution, or further freeze-dried to prepare a lyophilized powder injection, and the prepared lyophilized powder injection is reconstituted by adding water for injection, glucose solution or sodium chloride solution. After that, to clarify the status.
  • the concentration of oryzanol is 1 mg to 100 mg ml
  • the concentration of the phospholipid is 1 mg to 1000 mg/ml
  • the concentration of bile acid and/or its salt is 1 mg to 500 mg/ Ml.
  • the concentration of oryzanol is from 1 mg to 60 mg/ml
  • the concentration of phospholipid is from 1 mg to 400 mg/ml
  • the concentration of bile acid and/or its salt is from 1 mg to 200 mg ml.
  • the pharmaceutical composition of the present invention has a pH of not more than 10, preferably a pH of 6-9.
  • the pharmaceutical composition of the present invention can be produced by a production method comprising the steps of mixing or stirring oryzanol, a phospholipid, a bile salt, and further comprising the step of preparing the above mixture into an injection.
  • the specific process is as follows
  • step 3 Dissolve the organic phase of step 1 in the aqueous phase of step 2 and mix well.
  • the organic solvent covers a pharmaceutically acceptable organic solvent which can dissolve oryzanol, phospholipid, bile acid and/or a salt thereof, including but not limited to ethanol, ethyl acetate, dichloromethane, trichloro One of methane, acetone, and/or a mixture of more than one.
  • Oryzanol, phospholipids, bile acids and/or salts thereof may be added to the organic solvent in any order or simultaneously.
  • a polyol, a solubilizer, a stabilizer, an antioxidant, etc. may be added at any substep of this step as needed.
  • oryzanol may be dissolved in ethyl acetate, and after stirring, a mixture of phospholipid, bile acid and/or a salt thereof may be added. Further, the polyol may be first added to an organic solvent, and then oryzanol, a phospholipid, a bile acid, and/or a salt thereof, and a solubilizing agent are dissolved in an organic solvent, and the mixture is stirred and stirred to obtain an organic phase of the pharmaceutical composition of the present invention. In this step, in order to increase the dissolution rate, the solution should be heated and stirred at 50 to 100 ° C.
  • the amount of the organic solvent used in the step 1 is not particularly limited, and may be not less than the minimum amount of the dissolved oryzanol, phospholipid, bile acid, and/or its salt.
  • an aqueous solution containing an adjuvant is prepared in accordance with a conventional or known method.
  • Various excipients may be added in any order or simultaneously.
  • an isotonic regulator may be added to water, then an antioxidant, a stabilizer, and agitation may be added.
  • the organic solvent in the organic solution of 1 is volatilized according to a conventional method, and then dissolved in the aqueous phase obtained in the step 2, stirred and mixed, and then dispensed.
  • the organic phase obtained after the distillation of 1 is dissolved in water, and stirred at a high speed of 30 ° C to 80 ° C for 0.5 to 1 hour to form an orange-yellow solution, adjusted to pH 6 to 9 by adding a pH adjuster, and dispensed.
  • the adjustment of the pH is not limited to the last, and the composition of the present invention can be obtained by adjusting to a certain range in advance in the step 1 or 2.
  • the preparation method of the composition of the invention further comprises adding the activated carbon filter for injection to the solution after completing step 3 Membrane fine filtration, freeze drying steps.
  • Oryzanol, phosphatidylcholine, and ursodeoxycholic acid were dissolved in 2 ml of ethyl acetate, and heated to 60 ° C to stir until fully dissolved. Ethyl acetate was evaporated to dryness by evaporation under reduced pressure to give an organic phase.
  • the injection water in which mannitol has been dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C to obtain the injection of the present invention.
  • the pH was adjusted to 7.0 with sodium hydroxide solution, and 0. 05% of the injection was stirred for 30 minutes with activated carbon. After decarburization filtration, the 0.222 ⁇ m microfiltration membrane was finely filtered and dispensed into a vial.
  • Oryzanol, taurocholic acid, soybean phospholipid, and phosphatidylcholine are dissolved in 5 ml of ethanol, and heated to 80 ° C to be stirred until fully dissolved. Ethanol was evaporated to dryness by evaporation under reduced pressure to give an organic phase. Add water for injection to the whole amount, and then add the lactose at 60 ° C and mix well to obtain the injection of the present invention. The pH was adjusted to 7.0 with a sodium hydroxide solution, and the mixture was stirred for 30 minutes with activated carbon for 30 minutes. After decarburization filtration, the 0.22 ⁇ m microporous membrane was finely filtered and dispensed into a vial.
  • the oryzanol, glycocholic acid, and hydrogenated egg yolk phospholipid are dissolved in 8 ml of ethanol, heated to 75 Torr, stirred, and heated to be fully dissolved. Ethanol was evaporated to dryness by evaporation under reduced pressure to give an organic phase.
  • the injection water in which glucose is dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed at 70 ° C to obtain the injection of the present invention.
  • the pH was adjusted to 8.5 with sodium hydroxide solution, and 0. 05% was stirred for 30 minutes with activated carbon for injection. After decarburization filtration, the 0.22 U m microporous membrane was finely filtered and then dispensed into a vial. .
  • Oryzanol, sodium glycocholate, and hydrogenated egg yolk phospholipid are dissolved in 15 ml of ethanol, heated to 75 ° C with stirring, and heated and mixed until fully dissolved.
  • the ethanol was distilled by a method of evaporation under reduced pressure to obtain an organic phase.
  • the injection water which has dissolved mannitol is added to the whole amount, and the mixture is thoroughly stirred and mixed at 70 ° C to obtain the injection of the present invention.
  • the pH was adjusted to 6.5 with sodium oxyhydroxide solution, and the mixture was stirred for 30 minutes with activated carbon for 30 minutes. After decarburization filtration, the 0.222 ⁇ m microfiltration membrane was finely filtered and then dispensed into a vial.
  • Oryzanol, glycodeoxycholic acid, phosphatidylethanolamine, and phosphatidylserine were dissolved in 6 ml of ethyl acetate, and the mixture was heated to 80 ° C for stirring, and then heated by adding vitamin C to dissolve sufficiently. Ethyl acetate was evaporated by evaporation under reduced pressure to give an organic phase.
  • the injection water which has dissolved sodium sulfite, polyethylene glycol-400, and mannitol is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C to obtain the injection of the present invention. 05% 05% injection with activated carbon for 30 minutes, decarburization filtration, 0. 22um microporous membrane for fine filtration, dispensing into a vial.
  • Oryzanol, deoxycholic acid, sodium tauro-deoxycholate, soybean phospholipid, and glycerin are dissolved in 5 ml of acetone, and heated to 80 Torr to be fully dissolved.
  • the acetone was evaporated to dryness by evaporation under reduced pressure to give a solid solid.
  • the injection water to which the methyl cyclodextrin, propylene glycol, and lactose have been dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C to obtain the injection liquid of the present invention.
  • the pH was adjusted to 7.5 with sodium hydroxide solution, and the mixture was stirred for 30 minutes with activated carbon for 30 minutes. After decarburization filtration, the 0.222 ⁇ m microporous membrane was finely filtered and dispensed into a vial.
  • Oryzanol, phosphatidylcholine, glycerol, sodium taurocholate, phosphatidylethanolamine, glycine were dissolved in 10 ml of dichloromethane, and heated to 80 Torr to be fully dissolved.
  • Dichloromethane was evaporated to dryness by evaporation under reduced pressure to give an organic phase.
  • the injection water which has dissolved vitamin E, lysine and propylene glycol is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C to obtain the injection of the present invention. 0. 05% of the injection was stirred with activated carbon for 30 minutes. After decarburization filtration, the 0.222 ⁇ m microporous membrane was finely packed into a vial.
  • Oryzanol, phosphatidylcholine, taurocholyl 3, and propylene glycol were dissolved in 5 ml of ethyl acetate, and heated to 75 ° C to be stirred until fully dissolved. Ethyl acetate was evaporated to dryness by evaporation under reduced pressure to give an organic phase.
  • the water for injection having dissolved mannitol and sodium hydrogen sulfite is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C, and then the pH is adjusted to 9 with dilute hydrochloric acid to obtain the injection of the present invention. 05% 05% injection with activated carbon for 30 minutes, decarburization filtration, 0. 22um microporous membrane for fine filtration, dispensing into a vial.
  • Oryzanol, phosphatidylcholine, glycerol, and taurocholic acid are dissolved in 3 ml of ethanol, and heated to 70 ° C to be stirred until fully dissolved. Ethanol was evaporated to dryness by evaporation under reduced pressure to give an organic phase.
  • the injection water which has dissolved glucose, sodium chloride and vitamin E is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C to obtain the injection of the present invention. After adding 0. 05% for injection, the activated carbon was stirred for 30 minutes, and after decarburization filtration, the 0.222 ura microporous membrane was finely filtered and dispensed into a vial.
  • Oryzanol and phosphatidylcholine are dissolved in ethyl acetate, and heated to 60 ° C to be stirred until fully dissolved.
  • Ethyl acetate was evaporated to dryness by evaporation under reduced pressure to give a solid solid, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water, water
  • Oryzanol and deoxycholic acid were dissolved in a 5 mol/L sodium hydroxide solution by heating, and vitamin C was added thereto to stir and dissolve.
  • the phospholipid was dissolved in ethanol and dissolved, and water for injection was added to the whole amount. After adding 0.1% of the injection, the activated carbon was stirred for 30 minutes, decarburized and filtered, and then finely filtered with a 0.54 ⁇ m microfiltration membrane, bottling, and steaming at 100 ° C for 30 minutes. Comparative experiment example 5
  • Soybean oil and oryzanol were placed in a container, the container was placed in an oil bath, heated to 100 ° C, stirred until the drug dissolved, and the temperature was lowered to 80 ° C. Soybean phospholipids, vitamins are then added and stirred until the phospholipids dissolve to form a homogeneous oil phase.
  • 80 ml of water for injection was placed in another container, and glycerin was added thereto under stirring at 80 Torr to form an aqueous phase.
  • the oil phase was added to the aqueous phase with stirring, stirring was continued for 40 minutes to form colostrum, and pH was adjusted to 8 with sodium hydroxide.
  • Add water for injection to 100 ml and homogenize the colostrum with a high pressure homogenizer or ultrasonic probe. The resulting emulsion was not clarified, and a significant precipitate was observed after standing for about 1 hour.
  • the prepared solution and the equal amount of turbidity standard solution were placed in a paired turbidity glass tube, respectively, after 5 minutes of preparation of the turbidity standard solution, Vertically placed under the umbrella shed lamp in the dark room, the illuminance is 1000LX. When viewed from the horizontal direction, the prepared solution is clarified and not deeper than the No. 1 turbidity standard solution.
  • the solutions of Examples 1 to 12 were freeze-dried as follows.
  • Pre-freezing The temperature of the product drops to a 45'C, and the sublimation drying can be carried out after 3 hours of heat preservation;
  • Sublimation drying temperature is controlled below 12'C;
  • Re-drying The maximum temperature in the re-drying phase is controlled at 35'C, and the weight loss on drying should meet the requirements; After the drying is finished, the rubber plug is pressed in the box, and the aluminum cover is released from the box. After the finished product is inspected, the package is obtained.
  • the injection solution prepared by the present invention has a very small change in the content in the accelerated stability test, and fully demonstrates the stability of the preparation of the composition of the present invention.
  • the composition of the present invention has a particle size much smaller than that of the prior art and is more easily absorbed by the patient.
  • the above data demonstrates that the addition of a polyol to the composition of the present invention provides a significant improvement in the particle size of the compositions of the present invention.
  • Example 1 of the present invention and the injection prepared in Comparative Examples 3 and 4 were examined for particle size, appearance, and clarification stabilization time at room temperature, and the results are shown in the following table.
  • Particle size 1, appearance 1, time 1 represents the micelle particle size, appearance, clarification stabilization time of the injection of the present invention
  • particle size 2, appearance 2, time 2, particle size 3, appearance 3, time 3 represents comparative experimental example 3
  • the preparation of the injection preparation prepared by the particle size, appearance, and clarification stabilization time is shown in the following table.
  • the oryzanol injection prepared by the prior art is closer to the suspension, and cannot be stably placed for a long period of time, and is very easy to precipitate, which is greatly limited in industrial production applications.
  • the prior art requires the use of a high concentration of components such as sodium hydroxide, which causes damage to the drug and bile acid, and does not guarantee the quality of the drug.
  • the injection solution disclosed by the present invention is clear, has a small particle size, is stable in nature, and does not damage the composition of the composition during production.
  • the lyophilized product prepared according to the method of Example 1 was subjected to vascular irritation.
  • the method was to take 20 healthy rabbits with no loss of ear and ear, and randomly divided into two groups according to body weight, namely, the oryzanol injection group and the sodium chloride injection control group. Rabbits were dosed according to the clinical adult dose, and were injected slowly from the left ear vein of rabbits. The control group was given an equal volume of sodium chloride injection for 5 consecutive days. The results of the test showed that compared with the sodium chloride injection group, the injection of oryzanol was given by intravenous bolus injection. After the administration and 24 hours after the last administration, no red blood vessels and surrounding tissues were observed by naked eyes, and rabbit ears were observed by tissue biopsy.
  • the vein structure is clear, individual blood vessels are dilated, the wall thickness is uniform, the inner wall is smooth, and there is no inflammatory exudate around the tube. It indicated that the oryzanol injection under the experimental conditions had no obvious stimulating effect on the rabbit ear vein.

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Description

一种谷维素组合物及其制备方法
技术领域
本发明公开了一种谷维素组合物， 含有谷维素、 磷脂、 胆汁酸和 /或其盐， 属于医药技术 领域
背景技术
谷维素是以环木菠萝醇类为主体的阿魏酸酯和甾醇类的阿魏酸酯所组成的一种天然混合 物， 外观为白色至淡黄色晶体粉末、 无味、 有特异香味。 谷维素主要存在于米糠油及其油脚 中。 在米糠油谷维素中， 环木菠萝醇类阿魏酸酯含量约为 70〜80%。 长期研究发现谷维素具 有多种生理功能， 主要包括： 降低血脂、 抵抗胆固醇的吸收、 降低血清胆固醇、 防止脂质氧 化和预防心血管疾病。 除此之外， 谷维素还可以缓和女性进入更年期之后的各种身体障碍状 态和自律神经失调症， 改善间脑视床底部功能失调。
谷维素难溶于水、 易氧化， 导致很难做成一种稳定的制剂。 较低的溶解度和易氧化的特 点不仅导致谷维素实际应用中吸收率低， 在生产中质量也难以控制。 为了解决这些问题， 研 究人员进行了一定的摸索。 中国专利 CN123428公开了一种谷维素的植物油溶制剂， 提高了 生物利用度， 临床效果优于一般片剂。 但是由于油溶制剂临床应用时必须肌肉注射， 病人痛 苦感比较强， 且易导致肌肉结块。 同时油溶制剂起效缓慢， 需要大约一个月的时间进行持续 的肌肉注射。 中国专利申请 2007100156403为了解决釆用植物油制剂带来的易沉淀、 不稳定 问题， 采用油酸乙酯代替植物油做成谷维素的油溶制剂， 从而达到稳定、 不易产生沉淀的效 果。但是该发明依旧没有从本质上解决油溶制剂带来的肌肉注射易导致病人痛苦、肌肉结块、 依从性差的弊端。 中国专利申请 2004100945568公开了谷维素原料与胆固醇、 磷脂结合制备 为脂质体的技术方案， 应用该发明技术方案的制剂克服谷维素口服效果差、 生物利用率低的 问题。 但是制备脂质体是一个成本很高的工艺流程， 生产过程质量不易控制， 无法获得质量 稳定可靠的谷维素脂质体。 专利 CN100386082C公开了谷维素的一种注射制剂， 该发明通过 将谷维素与表面活性剂、 助溶剂同时结合第二表面活性剂的方法， 获得了一种注射制剂。 但 是该方案获得的注射剂为注射乳剂， 必须包括油相， 而且制备的乳液粒径比较难控制、 稳定 性相对不佳， 在制备时需乳均机等设备， 操作较为复杂、 成本高。
在现有的技术方案中， 油溶制剂由于植物油不可能除去， 实际上是一种半固体制剂， 室 温下稳定性比较差。 实际上， 所有应用植物油助溶的解决方案都存在着稳定性较差的问题。
尽管对谷维素制剂的研究取得了一些进展， 但是综合上述内容， 本领域依旧需要一种成 本合理、 药物稳定、 吸收良好的技术方案， 我们申请的专利成功解决了这些问题。 发明内容
本发明中， "注射剂"是指可用于静脉输注或推注的制剂，其包括但不限于注射液、输液、 冻干粉针等。
本发明中， "冻干制剂"是指任何经过冻干， 即水溶液的冷冻干燥得到的具体物质， 水溶 液中可以含有非水溶剂。
本发明中， "药物组合物"是指任何足以使其有作为药物产品实用性和稳定性的组合物形 太、
本发明中， "有效治疗量"或 "治疗有效量"是指在某种程度上减轻被治疗病症的一种或 多种症状的被给药的量。 即将本发明组合物应用的时候针对所对应病症， 起到了治疗效果的 药物组合物中的谷维素的量。
本发明中， "药学上可接受的"是指用于药物组合物的成分不导致不可接受的药理活性丧 失或者不可接受的不良副作用。
本发明提供了一种性质稳定、 水溶性高、 适合工业化生产的谷维素药物组合物。 同吋， 本发明提供了该组合物的制备方法。
本发明组合物中不需要加入油性成分， 也不形成乳剂， 有效地解决了乳剂粒径难以控制、 不稳定、 成本高、 操作复杂的问题， 也避免了使用植物油等带来的副作用。 本发明组合物最 终产物不含有油相成分， 用药安全性高。 所制备的组合物， 在室温条件下能保持澄清 8小时 以上， 组合物在使用前不需要采用有机溶媒稀释， 直接加入注射用水或葡萄糖注射液、 生理 盐水即可使用， 简化了操作。 同时本发明公开的冻干制剂最大限度地减少了或者避免了吐温 的使用， 防止了潜在的溶血问题。 相对于现有的解决方案， 本发明辅料用量减少， 降低了药 物的副作用， 解决了病人药物顺应性差的问题。 本发明药物组合物不仅有效改善其溶解性， 且磷脂基团与细胞膜存在高度亲和性， 可以有效延长药效作用时间， 提高生物利用度。 本发 明组合物长期稳定， 便于贮藏运输， 能防止在注射液时的氧化水解， 提高了生物利用度和治 疗指数。 本发明组合物制备方法工艺简单， 采用常规的工艺设备即可工业生产。
发明人长期研究发现， 在谷维素中加入一定量的磷脂以及胆汁酸和 /或其盐可以显著提高 其在水中的溶解度， 形成澄清、 性质稳定的组合物溶液。 将磷脂类物质、 胆汁酸类物质混合 使用， 其效果远远好于单独使用， 可大大减少副作用、 并且节约成本。 该组合物为澄清胶体 溶液， 其中没有油相成分， 也不形成乳剂， 粒径在 20nm以下,非常有效地解决了乳剂粒径难 以控制、 不稳定、 成本高、 操作复杂的问题。 在进一步的研究中， 发明人发现在上述方案中 加入多元醇可以显著减小其在水溶液中的粒径， 增加溶解速度， 更易于应用吸收。 基于上述 发现， 发明人做出了本发明组合物。 本发明提供了一种谷维素药物组合物， 是一种胶束溶液， 包括治疗有效量的谷维素、 磷 脂、 胆汁酸和 /或其盐。 其中， 谷维素、 胆汁酸和 /或其盐、 磷脂质量比是 1 : 1-100： 1-500； 优选的， 谷维素、 胆汁酸和 /或其盐、 磷脂质量比是 1 : 1-50： 1-100； 最优选， 谷维素、 胆汁 酸和 /或其盐、 磷脂质量比是 1 : 5-40： 5-80
另一方面， 本发明还提供了一种冻干粉针剂， 包括治疗有效量的谷维素、 磷脂、 胆汁酸 和 /或其盐。 其是由本发明的谷维素胶束溶液中进一步冷冻干燥制得的。 其中， 谷维素、 胆汁 酸和 /或其盐、 磷脂质量比是 1 : 1-100： 1-500； 优选的， 谷维素、 胆汁酸和 /或其盐、 磷脂质 量比是 1 : 1-50： 1-100； 最优选， 谷维素、 胆汁酸和 /或其盐、 磷脂质量比是 1 : 5-40： 5-80。
进一步的， 本发明组合物还可包含有多元醇， 所述多元醇可以是乙二醇、 聚乙二醇、 丙 二醇、丙三醇或其任意混合物。 当组合物中加入多元醇时， 谷维素、胆汁酸和 /或其盐、磷脂、 多元醇质量比是 1 : 1-100： 1-500： 1-50； 优选的， 谷维素、 胆汁酸和 /或其盐、 磷脂、 多元醇 质量比是 1 : 1-50： 1-100： 1-30； 最优选的， 谷维素、 胆汁酸和 /或其盐、 磷脂、 多元醇质量 比是 1： 5-40： 5-80： 2-15。
本发明所用的磷脂选自大豆磷脂、 蛋黄磷脂、 大豆鞘磷脂、 蛋黄鞘磷脂、 氢化大豆磷脂、 氢化蛋黄磷脂、 磷脂酰胆碱、 磷脂酰乙醇胺、 磷脂酰丝氨酸、 磷脂酰甘油、 磷脂酰肌醇、 二 棕榈磷脂酰胆碱、 二棕榈磷脂酰乙醇胺、 二硬脂磷脂酰胆碱、 二棕榈磷脂酰甘油脂、 二棕榈 磷脂酰丝氨酸、二肉豆蔻酰磷脂酰胆碱、二肉豆蔻酰磷脂酰甘油、二肉: t蔻酰磯脂酰乙醇胺、 二亚油酰磷脂酰胆碱、 二亚油酸甘油脂磷脂酰胆碱、 二亚油酸甘油脂磷脂酰乙醇胺、 二亚油 酸甘油脂磷脂酰甘油的一种和 /或一种以上的混合物。优选大豆磷脂、蛋黄磷脂、大豆鞘磷脂、 蛋黄鞘磷脂、 氢化大豆磷脂、 氢化蛋黄磷脂、 磷脂酰胆碱、 磷脂酰乙醇胺、 磷脂酰丝氨酸、 磷脂酰甘油、 磷脂酰肌醇， 最优选大豆磷脂、 蛋黄磷脂、 磷脂酰胆碱、 磷脂酰乙醇胺。
胆汁酸和 /或其盐加入后可以显著增加本发明组合物的稳定性。本发明所用的胆汁酸选自 游离胆汁酸、 结合胆汁酸或其混合物， 所述的胆汁酸盐是胆汁酸成盐后的产物。 其中， 胆汁 酸选自游离胆汁酸、 结合胆汁酸或二者的混合物， 游离胆汁酸包括胆酸、石胆酸、 去氧胆酸、 鹅去氧胆酸、 熊去氧胆酸、 猪去氧胆酸等， 优选为胆酸、 去氧胆酸、 鹅去氧胆酸、 猪去氧胆 酸； 结合胆汁酸为上述游离胆汁酸中的羧醛与甘氨酸（H2NCH2C00H )或牛磺酸（H2NCH2CH2S03H) 或其他含有氨基的化合物中的氨基形成酰胺键后的产物， 优选为甘氨胆酸、 甘氨去氧胆酸、 甘氨鹅去氧胆酸、 甘氨熊去氧胆酸、 牛磺胆酸、 牛磺去氧胆酸、 牛磺鹅去氧胆酸、 牛磺熊去 氧胆酸； 胆汁酸盐为上述游离胆汁酸或结合胆汁酸成盐后的产物， 包括但不限于钾盐、钠盐、 钙盐、 镁盐、 锌盐、 硒盐、 铁盐等， 优选为钠盐和钾盐。
本发明组合物加入多元醇可以显著进一步减小组合物胶束粒径， 改善溶解速度。 在谷维 素、 磷脂、 胆汁酸和 /或其盐基础上加入多元醇可以使组合物溶解至完全澄清状态， 并且所得 溶液组合物粒径更小。 在本发明中， 多元醇可以是丙二醇、 丙三醇、 乙二醇、 聚乙二醇和 / 或其任意的混合物。 所述的聚乙二醇， 平均分子量为 200〜10000， 优选分子量为 200-1000， 更优选聚乙二醇 -400、 聚乙二醇 -200。
本发明组合物还可任选地含有其它辅料， 包括但不限于等张调节剂、 稳定剂、 抗氧剂、 PH调节剂、 防腐剂、 赋形剂中的一种和 /或一种以上的混合物， 从而提高药物的稳定性， 有 利于药品质量的控制。 在实际应用中， 有些物质功能是多样的， 比如亚硫酸钠既可以是稳定 剂， 又可以是抗氧化剂， 因此可以通过加入具有多种功能的成分来控制辅料用量。
所述的等张调节剂包括但不限于 0.9%氯化钠溶液、 5%葡萄糖溶液，优选 5%葡萄糖溶液。 所述的稳定剂包括但不限于亚硫酸钠、 亚硫酸氢钠、 焦亚硫酸钠、 硫代硫酸钠、 硫脲、 维生素（；、 叔丁基对羟基茴香醚、 二丁基苯酚、 没食子酸丙酯、 生育酚、 甲硫氨酸、 盐酸半 胱氨酸、 乙酰半胱氨酸、 N-乙酰 -DL-甲硫氨酸、 抗坏血酸棕榈酸酯、 乙二胺四乙酸、 乙二胺 四乙酸二钠中的一种或几种， 优选亚硫酸氢钠、 维生素 C、 没食子酸丙酯、 抗坏血酸棕榈酸 酯， 最优选维生素 C。
所述的抗氧剂包括但不限于生育酚、 维生素 E、 维生素 C、 无水亚硫酸钠、 焦亚硫酸钠、 亚硫酸氢钠、硫代硫酸钠、 叔丁基对羟基茴香醚， 优选亚硫酸钠：焦亚硫酸钠、 亚硫酸氢钠， 维生素 E,最优选无水亚硫酸钠。
所述的 PH调节剂包括但不限于盐酸、 枸櫞酸、 酒石酸、 磷酸、 偏磷酸、 聚偏磷酸、 碳 酸、 氢氧化钠、 氢氧化钾、 枸橼酸钠、 枸橼酸钾、 碳酸氢钠、 碳酸氢钾、 碳酸胺、 磷酸氢二 钠、 磷酸氢二钾、 乙醇胺、 二乙醇胺、 三乙醇胺、 1, 2-己二胺、 碳酸钠、 酒石酸钠钾、 偏磷 酸钾、 聚偏磷酸钾、 偏磷酸钠中的一种或几种， 优选盐酸、 氢氧化钠、 醋酸钠或其任意混合 物。
所述的防腐剂包括但不限于苯酚、 甲酚、 三叔丁醇、 苯甲醇、 尼泊金中的一种或几种， 优选甲酚、 苯甲醇、 尼泊金， 最优选尼泊金。
所述的赋形剂包括但不限于.甘露醇、 乳糖、 葡萄糖、 山梨醇、 氯化钠、 水解明胶、 右旋 糖酐、 蔗糖、 甘氨酸、 聚乙烯吡咯垸酮等中的一种或几种， 优选为甘露醇、 乳糖、 葡萄糖、 山梨醇、 甘氨酸或其任意混合物， 更优选甘露醇、 甘氨酸或其任意混合物， 最优选甘露醇。
在本发明中， 可以加入增溶剂用于进一步改善谷维素的溶解度。 所述增溶剂选自吐温、 聚乙二醇十二位羟基硬脂酸酯、 羟丙基 β环糊精、 Υ -环糊精、 甲基 - β环糊精、 氨基酸、 聚 丙基甲基纤维素、聚维酮中的一种和 /或一种以上的混合物。所述吐温选自吐温 -20， 吐温 -40， 吐温 -60, 吐温 -80， 优选为吐温 -80。 所述氨基酸选自赖氨酸、 精氨酸、 颉氨酸， 优选赖氨酸。 本发明所获得的胶束溶液可作为注射液直接注射给药，或者进一步冷冻干燥制成冻干粉针剂， 所制成的冻干粉针剂在加入注射用水、 葡萄糖溶液或氯化钠溶液复溶后， 为澄清状态。
在所述注射液中或冻干粉针冷冻干燥前的溶液中， 谷维素的浓度为 lmg〜100mg ml， 磷 脂的浓度为 lmg〜1000mg/ml, 胆汁酸和 /或其盐浓度为 lmg〜500mg/ml。 优选的， 谷维素的 浓度为 lmg〜60mg/ml, 磷脂的浓度为 lmg〜400mg/ml， 胆汁酸和 /或其盐浓度为 lmg〜 200mg ml o
本发明的药物组合物的 pH不大于 10, 优选 pH为 6-9。
本发明药物组合物可以通过如下制备方法来制备， 包括将谷维素、 磷脂、 胆盐混合、 搅 拌的步骤， 进一步包括将以上混合物制备成注射液的步骤。 具体过程如下
①将谷维素、 胆汁酸和 /或其盐、 胆盐溶解于有机溶剂中， 搅拌， 形成澄清溶液， 采用 减压蒸馏的方法除去该溶液中的有机溶剂， 从而得到本发明组合物的有机相；
②将本发明药物组合物的辅料等溶解于水中， 从而得到水相；
③将步骤①的有机相溶解于步骤②的水相中充分搅拌混匀。
在步骤①中， 所述的有机溶剂涵盖可以溶解谷维素、 磷脂、 胆汁酸和 /或其盐的药学上可 接受的有机溶剂， 包括但不限于乙醇、 乙酸乙酯、 二氯甲垸、 三氯甲烷、 丙酮中的一种和 / 或一种以上的混合物。 谷维素、 磷脂、 胆汁酸和 /或其盐可以以任意先后顺序或者同时加入到 有机溶剂中。 可以根据需要， 在本步骤的任何分步骤加入多元醇、 增溶剂、 稳定剂、 抗氧化 剂等。 例如， 可以将谷维素溶解于乙酸乙酯中， 搅勾后加入磷脂、 胆汁酸和 /或其盐混合物。 还可以是将多元醇先加入有机溶剂中， 然后分别加入谷维素、 磷脂、 胆汁酸和 /或其盐、 增溶 剂溶解于有机溶剂中， 混匀搅拌得到本发明药物组合物有机相。 在本步骤中， 为了提高溶解 速度， 溶液应处于 50〜100'C加热搅拌状态。 步骤①所用有机溶剂的量并不受到特别限制， 以不低于溶解谷维素、 磷脂、 胆汁酸和 /或其盐最小的量即可。
在所述步骤②中， 按照常规或者已知的方法制备含有辅料的水溶液。 各种辅料可以任意 顺序或者同时加入， 例如可以将等张调节剂加入水中， 然后加入抗氧化剂、 稳定剂， 搅拌混 匀。
在所述步骤③中， 按照常规方法将①的有机溶液中有机溶剂挥发以后溶解于步骤②所得 水相中， 搅拌混匀， 然后分装。 例如， 将①蒸馏后所得有机相溶解于水中， 在 30°C〜80°C条 件下高速搅拌 0. 5〜1小时， 形成橙黄色溶液， 加入 pH调节剂调节至 pH6〜9， 分装。
在上述步骤中，调节 pH并不局限于最后进行，在步骤①或者②中预先调节到一定范围同 样可以获得本发明组合物。
本发明组合物的制备方法， 进一步的包括在完成步骤③后在溶液中加入注射用活性碳滤 膜精滤、 冷冻干燥的步骤。
具体实施方式
下面将通过实施例来说明实现本发明的技术方案， 这些实施方式并不用来限制本发明。 本领域技术人员根据现有知识对本发明进行等同替换或相应的逻辑改进，属于本发明的范围。 在下述实施例中， 加入甘露醇等赋形剂是满足制备成冻干剂型的需要。 如果在实际应用中， 直接使用组合物胶体溶液可以不加入赋形剂。
实施例 1
谷维素 10mg
磷脂酰胆碱 50mg
熊去氧胆酸 50mg
甘露醇 50mg
注射用水 至 10ml
将谷维素、 磷脂酰胆碱、 熊去氧胆酸溶解于 2ml乙酸乙酯中， 加热至 60°C搅拌， 至充 分溶解。 采用减压蒸发的方法蒸干乙酸乙酯， 得到有机相。 加入已经溶解了甘露醇的注射用 水至全量， 60°C下充分搅拌混匀， 即可得本发明注射液。 用氢氧化钠溶液调节 PH到 7. 0， 加 入 0. 05%注射用活性碳搅拌三十分钟， 脱碳过滤后， 0. 22um微孔滤膜进行精滤， 分装至西林 瓶。
实施例 2
谷维素 2mg
大豆磷脂 800mg
磷脂酰胆碱 200mg
牛磺胆酸 200mg
乳糖 80mg
注射用水 至 10ml
将谷维素、 牛磺胆酸、 大豆磷脂、 磷脂酰胆碱溶解于 5ml 乙醇中， 加热至 80'C搅拌， 至 充分溶解。 采用减压蒸发的方法蒸干乙醇， 得到有机相。 加注射用水至全量， 然后加入乳糖 60°C下充分搅拌混匀， 即可得本发明注射液。 用氢氧化钠溶液调节 PH到 7. 0， 加入 0. 05%注 射用活性碳搅拌三十分钟， 脱碳过滤后， 0. 22um微孔滤膜进行精滤， 分装至西林瓶。
实施例 3
谷维素 10mg
大豆鞘磷脂 60mg 甘氨去氧胆酸钠 lOOmg
丙二醇 10mg
甘氨酸 20mg
注射用水 至 10ml
将谷维素、 大豆鞘磷脂、 甘氨去氧胆酸钠、 丙二醇溶解于 7ml二氯甲烷中， 加热至 80 °C搅拌， 至充分溶解。 采用减压蒸发的方法蒸干二氯甲垸，.得到有机相。 加入已经溶解了甘 氨酸的注射用水至全量， 65Ό下充分搅拌混匀， 即可得本发明注射液。 用氢氧化钠溶液调节 ?4到7. 5, 加入 0. 05%注射用活性碳搅拌三十分钟， 脱碳过滤后， 0. 22um微孔滤膜进行精滤， 分装至西林瓶。 ；
实施例 4
谷维素 20mg
甘氨胆酸 200mg
氢化蛋黄磷脂 600mg
葡萄糖 lOOmg
注射用水 至 10ml
将谷维素、 甘氨胆酸、 氢化蛋黄磷脂溶解于 8ml乙醇中， 加热至 75Ό搅拌， 加热混匀， 至充分溶解。 采用减压蒸发的方法蒸干乙醇， 得到有机相。 加溶解了葡萄糖的注射用水至全 量， 70°C下充分搅拌混匀， 即可得本发明注射液。用氢氧化钠溶液调节 PH到 8. 5，加入 0. 05% 注射用活性碳搅拌三十分钟， 脱碳过滤后， 0. 22Um微孔滤膜进行精滤， 然后分装至西林瓶。 实施例 5
谷维素 20mg
甘氨胆酸钠 lOOOmg
氢化蛋黄磷脂 5000mg
甘露醇 200mg
注射用水 至 20ml
将谷维素、 甘氨胆酸钠、 氢化蛋黄磷脂溶解于 15ml 乙醇中， 加热至 75'C搅拌， 加热混 匀， 至充分溶解。 采用减压蒸发的方法蒸千乙醇， 得到有机相。 加入已经溶解了甘露醇的注 射用水至全量， 70'C下充分搅拌混匀，即可得本发明注射液。用氧氧化钠溶液调节 PH到 6. 5， 加入 0. 05%注射用活性碳搅拌三十分钟， 脱碳过滤后， 0. 22um微孔滤膜进行精滤， 然后分装 至西林瓶。
实施例 6 谷维素 40mg
甘氨去氧胆酸 300mg
磷脂酰乙醇胺 lOOmg
磷脂酰丝氨酸 200mg
聚乙二醇- 400 lOOmg
维生素 C 2mg
亚硫酸钠 3mg
甘露醇 lOOmg
注射用水 至 lOml
将谷维素、 甘氨去氧胆酸、 磷脂酰乙醇胺、 磷脂酰丝氨酸溶解于 6ml乙酸乙酯中， 加热 至 80°C搅拌，然后加入维生素 C加热混匀，至充分溶解。采用减压蒸发的方法蒸千乙酸乙酯， 得到有机相。 加入已经溶解了亚硫酸钠、 聚乙二醇 -400、 甘露醇的注射用水至全量， 60°C下 充分搅拌混匀， 即可得本发明注射液。 加入 0. 05%注射用活性碳搅拌三十分钟， 脱碳过滤后， 0. 22um微孔滤膜进行精滤， 分装至西林瓶。
实施例 7
谷维素 18mg
脱氧胆酸 20mg
牛磺鹅去氧胆酸钠 50mg
大豆磷脂 200mg
丙二醇 5mg
丙三醇 20mg
甲基 - β环糊精 20
乳糖 90mg
注射甩水 至 10ml
将谷维素、 脱氧胆酸、 牛磺鹅去氧胆酸钠、 大豆磷脂、 丙三醇溶解于 5ml丙酮中， 加热 至 80Ό搅拌， 至充分溶解。 采用减压蒸发的方法蒸干丙酮， 得到胶状的固体。 加入已经溶解 了甲基 环糊精、 丙二醇、乳糖的注射用水至全量， 60°C下充分搅拌混匀， 即可得本发明注 射液。用氢氧化钠溶液调节 PH至 7. 5， 加入 0. 05%注射用活性碳搅拌三十分钟， 脱碳过滤后， 0. 22um微孔滤膜进行精滤， 分装至西林瓶。
实施例 8
谷维素 lOOmg 大豆磷脂 lOOOmg
甘氨去氧胆酸 200mg
丙三醇 HOmg
吐温 -80 3mg
赖氨酸 15mg
甘氨酸 200mg
注射用水 至 20ml
将谷维素、 大豆磷脂、 甘氨去氧胆酸、 吐温 -80、 丙三醇溶解于 20ml乙酸乙酯中， 加热 至 70°C搅拌， 至充分溶解。 采用减压蒸发的方法蒸干乙酸乙酯， 得到有机相。 加入已经溶解 了赖氨酸、甘氨酸的注射用水至全量， 60°C下充分搅拌混匀，即可得本发明注射液。加入 0. 05% 注射用活性碳搅拌三十分钟， 脱碳过滤后， 0. 22um微孔滤膜进行精滤， 分装至西林瓶。 实施例 9
谷维素 6mg
磷脂酰胆碱 50mg
磷脂酰乙醇胺 50mg
丙三醇 50mg
丙二醇 30mg
牛磺胆酸钠 80mg
赖氨酸 15mg
维生素 E 2mg
甘氨酸 30mg
注射用水 至 10ml
将谷维素、磷脂酰胆碱、 丙三醇、 牛磺胆酸钠、磷脂酰乙醇胺、 甘氨酸溶解于 10ml二氯 甲垸中， 加热至 80Ό搅拌， 至充分溶解。 采用减压蒸发的方法蒸干二氯甲垸， 得到有机相。 加入已经溶解了维生素 E、 赖氨酸、 丙二醇的注射用水至全量， 60'C下充分搅拌混匀， 即可 得本发明注射液。 加入 0. 05%注射用活性碳搅拌三十分钟， 脱碳过滤后， 0. 22um微孔滤膜进 行精滤装至西林瓶。
实施例 10
谷维素 2mg
磷脂酰胆碱 20mg
牛磺胆酸 40mg 丙二醇 25mg
亚硫酸氢钠 50mg
甘露醇 10mg
注射用水 至 10ml
将谷维素、 磷脂酰胆碱、 牛磺胆 ¾、 丙二醇溶解于 5ml乙酸乙酯中， 加热至 75'C搅拌， 至充分溶解。 采用减压蒸发的方法蒸干乙酸乙酯， 得到有机相。 加入已经溶解了甘露醇、 亚 硫酸氢钠的注射用水至全量， 60°C下充分搅拌混匀，然后采用稀盐酸调节 PH为 9即可得本发 明注射液。加入 0. 05%注射用活性碳搅拌三十分钟， 脱碳过滤后， 0. 22um微孔滤膜进行精滤， 分装至西林瓶。
实施例 11
谷维素 15mg
磷脂酰胆碱 45mg
牛磺胆酸 60mg
丙三醇 10mg
葡萄糖 50mg
氯化钠 90mg
维生素 E lmg
注射用水 至 10ml
将谷维素、 磷脂酰胆碱、 丙三醇、 牛磺胆酸溶解于 3ml乙醇中， 加热至 70°C搅拌， 至充 分溶解。 采用减压蒸发的方法蒸干乙醇， 得到有机相。 加入已经溶解了葡萄糖、 氯化钠、 维 生素 E的注射用水至全量， 60°C下充分搅拌混匀， 即可得本发明注射液。 加入 0. 05%注射用 活性碳搅拌三十分钟， 脱碳过滤后， 0. 22ura微孔滤膜进行精滤， 分装至西林瓶。
实施例 12
谷维素 30mg
大豆磷脂酰胆碱 150mg
甘氨胆酸钾盐 140mg
丙三醇 lOmg
丙二醇 30mg
维生素 E 2mg
蔗糖 lOOmg
注射用水 至 10ml 将谷维素、大豆磷脂酰胆碱溶解于 10ml二氯甲垸中， 60°C下充分搅拌下加入溶解了甘氨 胆酸钾盐、 丙二醇、 丙三醇、 维生素 E的注射用水。 采用减压蒸干的方法除去溶液中的二氯 甲垸， 加溶解了蔗糖的注射水至全量 然后加入 0. 05%注射用活性碳搅拌三十分钟， 脱碳过 滤后， 0. 22Um微孔滤膜进行精滤， 分装至西林瓶。
对比实施例 1
谷维素 20mg
磷脂酰胆碱 lOOmg
注射用水 至 10ml
将谷维素、 磷脂酰胆碱溶解于乙酸乙酯中， 加热至 60'C搅拌， 至充分溶解。 采用减压蒸 发的方法蒸干乙酸乙酯， 得到胶状的固体， 加入注射用水至全量， 60 下充分搅拌混匀， 结 果形成颗粒度很大的乳状物， 不澄清。
对比实施例 2
谷维素 20mg
脱氧胆酸钠 150mg
注射用水 至 10ml
将谷维素、 脱氧胆酸钠溶解于乙醇中， 加热至 70'C搅拌， 至充分溶解。 采用减压蒸发的 方法蒸干乙醇， 得到胶状的固体， 加入注射用水至全量， 60'C下充分搅拌混匀， 结果形成颗 粒度很大的乳状物， 不澄清。
对比实施例 3
谷维素 5mg
胆酸 150mg
磷脂 ― 20mg
维生素 E 5mg
注射用水 至 10ml
将复合物和胆酸加热溶于 5mol/L氢氧化钠溶液中， 用 lmol/L盐酸调 PH值至 7. 0， 加入 憐脂、 维生素 E搅拌溶解， 加注射用水至全量。形成有很多大颗粒的混悬液， 并且在 10分钟 内药品成份迅速析出 。 对比实验例 4
谷维素 250mg
脱氧胆酸 2500mg 磷脂 300mg
维生素 C 5mg
乙醇 0. 25ml
注射用水 至 ΙΟπιΙ
将谷维素和脱氧胆酸加热溶解于 5mol/L氢氧化钠溶液中，加入维生素 C搅拌溶解。将磷 脂用乙醇加入后溶解， 加注射用水至全量。 加入 0. 1%注射用活性炭搅拌三十分钟，脱碳过滤 后用 0. 45um微孔滤膜精滤， 装瓶， 100摄氏度流通蒸汽 30分钟灭菌。 对比实验例 5
谷维素 4. 5rag
大豆油 30mg
大豆磷脂 llmg
维生素 E 0. lrag
甘油 2. 5mg
注射用水 至 10ml
将大豆油、 谷维素加入容器中， 将此容器置于油浴中， 加热至 100°C , 搅拌至药物溶解， 降温至 80°C。然后加入大豆磷脂、维生素， 搅拌至磷脂溶解形成均匀油相。将注射用水 80ml 置于另一容器中， 加入甘油于 80Ό下搅拌溶解形成水相。 将油相在搅拌下加入水相中， 继续 搅拌 40分钟形成初乳， 用氢氧化钠调节 PH至 8。 加注射用水至 100ml，将初乳用高压匀质机 或超声探头匀化。 所得乳液不澄清， 放置约 1小时后可见明显沉淀析出。
由上述对比实施例可以看出， 现有技术中的方案并没有很好的解决谷维素的溶解和应用 问题。
实施例 1〜12制的溶液澄清度判断方法
依据 《中国药典 2005年版（二部）》 附录 IX B方法， 将制备的溶液与等量的浊度标准液 分别置于配对的比浊用玻璃管中， 在浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯 下， 照度为 1000LX, 从水平方向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 将实施例 1〜： 12制的溶液按照下述方法进行冷冻干燥
预冻： 制品温度下降至一 45'C， 保温 3小时后即可以进行升华干燥；
升华干燥： 升华干燥温度控制在一 12'C以下；
再干燥： 再干燥阶段最高温度控制在 35'C， 干燥失重应符合规定； 干燥结束后， 箱内压胶塞， 出箱锁铝盖， 成品检验合格后包装即得。
冷冻干燥后， 取实施例 1-12产品， 加入注射用水或 5%葡萄糖溶液复溶。 依据 《中国药 典 2005年版（二部）》附录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比 浊用玻璃管中，在浊度标准液制备 5†钟后，在暗室内垂直同置于伞棚灯下，照度为 lOOOLx, 从水平方向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 13稳定性和粒径考察
3¾实施例 1、 7制备的注射冻干粉针在于 25 ±2°C,相对湿度 60 ± 10%的条件下放置半年， 观察其含量、 粒径情况， 标记为含量 1、 含量 2、 粒径 1、 粒径 2， 以对比实验例 5为对照， 观察其含量、 粒径， 记为含量 3、 粒径 3。 记录为下列表格。
室温留样观察结果
Figure imgf000014_0001
由上述结果可知， 本发明制备的注射溶液在加速稳定性试验中含量变化非常小， 充 分说明了本发明组合物制备注射液的稳定性。 本发明组合物粒径远远小于现有技术制备的产 品， 更易于患者吸收。 同时上述数据证实在本发明组合物基础上加入多元醇对本发明组合物 粒径有明显的改善。 实施例 14
取本发明实施例 1制备的注射液与对比实验例 3和 4制备的注射液在室温下进行了粒径、 外观、 澄清稳定时间检测， 所得结果如下表。 粒径 1、 外观 1、 时间 1代表本发明注射液的胶 束粒径、 外观、 澄清稳定时间， 粒径 2、 外观 2、 时间 2， 粒径 3、 外观 3、 时间 3代表对比 实验例 3和 4制备的注射液注射液的粒径、 外观、 澄清稳定时间。
表 2 对比实验观察
Figure imgf000014_0002
粒径 1 ( nm) <20 <20 〈20 <20 〈20 粒径 2 (nm) 1100 1140 1027 1180 1124 粒径 3 ( nm) 1307 1332 1316 1374 1295 外观 1 澄清 澄清 澄清 澄清 麵
i
外观 2 混浊 混浊 混浊 混浊 混浊 外观 3 明显颗粒状 明显颗粒状 明显颗粒状 明显颗粒状 明显颗粒状 时间 1 8小时无析出 8小时无析出 8小时无析出 8小时无析出 8小时无析出 时间 2 37min 明显沉 35min明显沉 30min明显沉 32min 明显沉 34min 明显沉 淀 淀 淀 淀 淀 时间 3 15min药品析 17min药品析 15min药品析 20min药品析 18min药品析 出 出 出 出 出
由上述数据可见， 现有技术制备的谷维素注射液更接近于混悬液， 并且不能长期稳定放 置， 非常容易析出， 其在工业生产应用上受到巨大限制。 从其制备方法看， 现有技术需要使 用高浓度的氢氧化钠等成分， 这会导致对药品和胆酸的破坏， 无法保证药品的品质。 与之对 比， 本发明所公幵的注射液溶液澄清、 粒径小、 性质稳定， 并且在生产中不会对组合物成分 进行破坏。
实施例 15刺激性考察
将按照实施例 1方法制得的冻干产物进行动物血管的刺激性。 方法是取健康、 耳缘无损 伤家兔 20只， 按体重随机分为两组， 即注射用谷维素试验组和氯化钠注射液对照组。 以临床 成人拟用剂量为依据设计家兔给药剂量， 从家兔左侧耳缘静脉缓慢推注给药， 对照组给予等 容积氯化钠注射液， 连续给予 5天。 试验结果表明， 与氯化钠注射液组相比， 静脉推注给予 注射用谷维素，给药期间及末次给药 24小时后， 肉眼观察未见血管及周围组织红肿， 组织切 片检査可见兔耳静脉结构清晰， 个别血管扩张明显， 管壁厚薄均匀， 内壁平滑， 管周无炎性 渗出物。 表明实验条件下注射用谷维素对家兔耳缘静脉无明显刺激作用。

Claims

权 利 要 求 书 一种谷维素胶束溶液， 包含治疗有效量的谷维素、 胆汁酸和 /或其盐、 磷脂。
一种冻干粉针剂， 包含治疗有效量的谷维素、 胆汁酸和 /或其盐、 磷脂。
根据权利要求 1或 2的谷维素药物组合物， 谷维素、 胆汁酸和 /或其盐、 磷脂质量比是 1 : 1-100： 1-500。
根据权利要求 3的谷维素药物组合物，谷维素、胆汁酸和 /或其盐、磷脂质量比是 1： 1-50: 1-100。
根据权利要求 4的谷维素药物组合物，谷维素、胆汁酸和 /或其盐、磷脂质量比是 1 : 5-40： 5-80
根据权利要求 1或 2的谷维素药物组合物， 其中在所述注射液中或冻干粉针冷冻干燥前 的溶液中， 所述谷维素的浓度为 lmg〜100mg/ml。
根据权利要求 1或 2的谷维素药物组合物， 其中在所述注射液中或冻干粉针冷冻干燥前 的溶液中， 所述磷脂的浓度为 lmg〜1000mg/ml。
根据权利要求 1或 2的谷维素药物组合物， 其中在所述注射液中或冻干粉针冷冻干燥前 的溶液中， 所述胆汁酸和 /或其盐的浓度为 lmg〜500mg/ml。
根据权利要求 1或 2的谷维素药物组合物， 所述磷脂选自大豆磷脂、 蛋黄磷脂、 大豆鞘 磷脂、 蛋黄鞘磷脂、 氢化大豆磷脂、 氢化蛋黄磷脂、 磷脂酰胆碱、 磷脂酰乙醇胺、 磷脂 酰丝氨酸、 磷脂酰甘油、 磷脂酰肌醇、 二棕榈磷脂酰胆碱、 二棕榈磷脂酰乙醇胺、 二硬 脂磷脂酰胆碱、 二棕榈磷脂酰甘油脂、 二棕榈磷脂酰丝氨酸、 二肉豆蔻酰磷脂酰胆碱、 二肉豆蔻酰磷脂酰甘油、 二肉豆蔻酰磷脂酰乙醇胺、 二亚油酰磷脂酰胆碱、 二亚油酸甘 油脂磷脂酰胆碱、 二亚油酸甘油脂磷脂酰乙醇胺、 二亚油酸甘油脂磷脂酰甘油的一种和 / 或其任意混合物。
根据权利要求 1或 2的谷维素药物组合物， 所述胆汁酸选自游离胆汁酸、 结合胆汁酸或 二者的混合物； 所述胆汁酸盐是胆汁酸成盐后的产物。
根据权利要求 10的谷维素药物组合物， 其中的游离胆汁酸为胆酸、 石胆酸、 去氧胆酸、 鹅去氧胆酸、 熊去氧胆酸、 猪去氧胆酸或其混合物； 结合胆汁酸为上述游离胆汁酸中的 羧醛与甘氨酸或牛磺酸或其他含有氨基的化合物中的氨基形成酰胺键后的产物或其混合 物。
根据权利要求 11的谷维素药物组合物， 其中的游离胆汁酸为胆酸、 去氧胆酸、 鹅去氧胆 酸、 熊去氧胆酸、 猪去氧胆酸或其混合物： 其中的结合胆汁酸为甘氨胆酸、 甘氨去氧胆 酸、 甘氨鹅去氧胆酸、 甘氨熊去氧胆酸、 甘氨猪去氧胆酸、 牛磺胆酸、 牛磺去氧胆酸、 牛磺鹅去氧胆酸、 牛磺熊去氧胆酸、 牛磺猪去氧胆酸或其混合物。 根据权利要求 10的谷维素药物组合物， 其中的胆汁酸盐为胆汁酸的钾盐、 钠盐、 钙盐、 镁盐、 锌盐、 硒盐、 铁盐或其混合物。
根据权利要求 1或 2的谷维素药物组合物， 还包含有多元醇。
根据权利要求 14的谷维素药物组合物， 所述多元醇为乙二醇、 聚乙二醇、 丙二醇、 丙三 醇或其任意混合物。
根据权利要求 15 的谷维素药物组合物， 所述多元醇为聚乙二醇时聚乙二醇分子量为 200-10000。
根据权利要求 1或 2的谷维素药物组合物， 还包含增溶剂， 所述增溶剂选自吐温、 聚乙 二醇十二位羟基硬脂酸酯、 羟丙基 3环糊精、 Y -环糊精、 甲基 - β环糊精、 氨基酸、 聚 丙基甲基纤维素、 聚维酮中的一种和 /或一种以上的混合物。
根据权利要求 17的药物组合物， 所需增溶剂的量为权利要求 1所述的磷脂、 胆汁酸和 / 或其盐质量之和的 0〜2倍。
根据权利要求 1或 2的药物组合物， 还包含药学上可以接受的辅料， 所述的辅料包括等 张调节剂、 稳定剂、抗氧剂、 ΡΗ调节剂、 防腐剂、赋形剂中的一种和 /或一种以上的混合 物。
权利要求 1或 2所述的药物组合物的制备方法，包括将谷维素与磷脂、胆汁酸和 /或其盐、 多元醇溶解于有机溶剂的步骤。
根据权利要求 20的制备方法， 有机溶剂选自乙醇、 乙酸乙酯、 二氯甲烷、 三氯甲烷、 丙 酮中的一种和 /或一种以上的混合物。
根据权利要求 20的制备方法， 其中还包括加入活性炭、 过滤、 除菌的步骤。
根据权利要求 20的制备方法， 包括以下步骤：
①将谷维素、 磷脂、 胆汁酸和 /或其盐混合、 搅拌， 形成澄清溶液， 减压蒸馏， 从而 得到本发明组合物的有机相；
② 以注射用水或蒸馏水作为水相， 如还有其它的药学辅料， 也加入到水相中；
③将步骤①的有机相溶解于步骤②的水相中充分搅拌混匀。
根据权利要求 23的制备方法， 还包括将步骤③的组合物冷冻干燥的步骤。
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