CN101480403A - Medicinal composition and preparation method thereof - Google Patents

Medicinal composition and preparation method thereof Download PDF

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Publication number
CN101480403A
CN101480403A CNA2008102401330A CN200810240133A CN101480403A CN 101480403 A CN101480403 A CN 101480403A CN A2008102401330 A CNA2008102401330 A CN A2008102401330A CN 200810240133 A CN200810240133 A CN 200810240133A CN 101480403 A CN101480403 A CN 101480403A
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acid
salt
bile acid
phospholipid
complex
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CN101480403B (en
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郝守祝
焦玉焕
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Nanjing Century Bokang Pharmaceutical Technology Co ltd
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Beijing Century Biocom Pharmaceutical Technology Co Ltd
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Priority to PCT/CN2009/001467 priority patent/WO2010069139A1/en
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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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • 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

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a pharmaceutical composition of cycloartenyl ferulate and 24-methylene cycloartenyl ferulate compound, which comprises the cycloartenyl ferulate and 24-methylene cycloartenyl ferulate compound, phospholipid, bile acid and/or salt thereof. The pharmaceutical composition disclosed by the invention effectively improves the water solubility and stability of the cycloartenyl ferulate and 24-methylene cycloartenyl ferulate compound, and the particle size and stability of the provided pharmaceutical composition are superior to those of the existing products. Furthermore, the invention provides three product forms of injection, freeze-dried powder injection and kit of the pharmaceutical composition and a preparation method thereof.

Description

A kind of Pharmaceutical composition and preparation method thereof
Technical field
The present invention relates to a kind of Pharmaceutical composition, specifically the invention discloses pharmaceutical composition of a kind of injection and preparation method thereof, belong to field of medicaments.
Background technology
Oryzanol is a kind of natural mixture of being formed based on the ferulic acid ester of the ferulic acid ester of ring jackfruit alcohols and sterols, outward appearance for white to the light yellow crystal powder, tasteless, special fragrance arranged.Oryzanol mainly is present in Testa oryzae oil and the oil foot thereof, and in the Testa oryzae oil oryzanol, ring jackfruit alcohols ferulic acid ester content is about 70～80%.Through studying for a long period of time, research worker finds that oryzanol has different physiological roles.Mainly comprise: the absorption of blood fat reducing, cholesterol reducing, reduce serum cholesterol, prevent lipid oxidation and angiocardiopathy preventing.In addition, oryzanol can also relax various health failure conditions and the vegetative dystonie of women after entering into the climacteric period, and improves diencephalon and looks a bed bottom functional disorder.
The problem that exists in oryzanol is used is that oryzanol is insoluble in water, easily oxidation, and this causes being difficult to that oryzanol is made a kind of stable formulation.Contain a lot of active component in the oryzanol, when isolating single component by technological means, it is more severe that dissolubility and stability problem become.Absorbance was low when the characteristics of extremely low dissolubility and easily oxidation not only caused practical application, also caused difficult quality control aborning simultaneously.In order to address these problems, this area research worker has been carried out certain groping.Chinese patent CN123428 discloses a kind of vegetable oil solubility preparation of oryzanol, has improved bioavailability, and clinical effectiveness is better than general tablet.But because must intramuscular injection during oily solubility preparation clinical practice, patient's pain sensation is more intense, and easily causes the muscle caking.Oily solubility preparation onset simultaneously is slow, the intramuscular injection that need continue about one month time.Chinese patent application 2007100156403 adopts ethyl oleate to replace vegetable oil to make the oily solubility preparation of oryzanol in order to solve easy precipitation, the instability problem that adopts the vegetable oil preparation to bring, thereby reaches stable, the difficult sedimentary effect that produces.But this invention is still not from solving the drawback that intramuscular injection that oily solubility preparation brings easily causes patient's misery, muscle caking, compliance difference in essence.Chinese patent application 2004100945568 discloses the technical scheme that oryzanol raw material and cholesterol, phospholipids incorporate are prepared as liposome, and the preparation of using this invention technical scheme overcomes the problem that the oryzanol oral result is poor, bioavailability is low.But the preparation liposome is a technological process that cost is very high, and the production process quality is wayward, can't obtain the reliable oryzanol liposome of steady quality.Patent CN100386082C discloses a kind of ejection preparation of oryzanol, and this invention has obtained a kind of ejection preparation by oryzanol and surfactant, cosolvent being combined the method for second surface activating agent simultaneously.But the injection that this scheme obtains is an injectable emulsion, must comprise oil phase, and the difficult control of emulsion particle diameter, the stability of preparation are not good relatively, needs equipment such as the equal machine of breast in the preparation, and operation is comparatively complicated, cost is high.
Therefore, need still in the prior art that a kind of preparation technology is simple, easy to use, therapeutic effect is good, side effect circlet jackfruit alcohols ferulic acid ester injection.
Summary of the invention
Among the present invention, " injection " is meant the preparation that can be used for venoclysis or inject, and includes but not limited to injection, transfusion, freeze-dried powder etc.
Among the present invention, " lyophilized formulations " is meant any through lyophilizing, i.e. the concrete material that the lyophilization of aqueous solution obtains can contain nonaqueous solvent in the aqueous solution.
Among the present invention, " pharmaceutical composition " is meant and anyly is enough to make it that compositions form as drug products practicality and stability is arranged.
Among the present invention, " effectively therapeutic dose " or " treatment effective dose " be meant alleviate to a certain extent by sanatory one or more symptoms by the amount of administration.At corresponding disease, played the amount of the complex in the pharmaceutical composition of therapeutic effect when being about to the present composition and using.
Among the present invention, " pharmaceutically acceptable " is meant that the composition that is used for pharmaceutical composition does not cause unacceptable pharmacologically active forfeiture or unacceptable side effect.
In inventor's early-stage Study, by the oryzanol ingredient is effectively separated, the content that has obtained cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester is not less than 90% complex, and to this complex application patent (Chinese patent application 200810097493.x), this patent application is incorporated herein in full, as a reference.The applicant studies its practical application subsequently, confirms that it all has a wide range of applications at aspects such as treatment autonomic nerve disorder, climacteric syndrome, primary dysmenorrhea, premenstrual tension syndrome, periodic psychosis, vascular headache, injury of head syndrome, gastrointestinal nervous disorder disease, hyperlipemias.The active component that is adopted among the present invention is cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester compositions, and wherein the content sum of these two kinds of materials accounts for more than 90%, by weight percentage of total composition.In this application, claim that above compositions is cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex.Cycloartenyl ferulate of the present invention and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex can be prepared by the disclosed method of Chinese patent application 200810097493.x, also can adopt disclosed other method of prior art to be prepared.In this complex formulation process of research, the inventor is surprised to find that, adds a certain amount of phospholipid and bile acid and/or its salt and can improve the dissolubility of this complex in water significantly in preparation, forms the solution of clarification, stable in properties.Phospholipid substance and bile acid are mixed use, can significantly increase the dissolubility of cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex in water, its effect is better than the two independent use far away, can significantly reduce side effect and save cost.Said composition does not wherein have oil-phase component for clarification colloid solution, does not form Emulsion yet, particle diameter below 20nm, near true solution, solved effectively the Emulsion particle diameter be difficult to control, unstable, cost is high, the problem of complicated operation.Prepared compositions can keep clarifying more than 8 hours at ambient temperature.Resulting composition does not need to adopt organic solvent dilution before use, directly adds water for injection or glucose injection, normal saline can use, and has simplified operation.Lyophilized formulations disclosed by the invention has reduced or has avoided the use of tween to greatest extent simultaneously, has prevented potential haemolysis problem.With respect to existing solution, supplementary product consumption of the present invention obviously reduces, and has reduced side effects of pharmaceutical drugs.
One aspect of the present invention provides a kind of pharmaceutical composition, comprises cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex, phospholipid and bile acid and/or its salt.Wherein, cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex, bile acid and/or its salt, phospholipid mass ratio can be 1:1-100:1-500; Preferably, complex, bile acid and/or its salt, phospholipid mass ratio can be 1:1-50:1-100; Preferred, complex, bile acid and/or its salt, phospholipid mass ratio can be 1:5-40:5-80.Said composition can be a solid state, can also be liquid.Liquid wherein can also be the micellar solution form.
On the other hand, the present invention also provides a kind of lyophilized injectable powder, it contains cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex, bile acid and/or its salt and the phospholipid for the treatment of effective dose, wherein, cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester quality percentage composition are not less than 90% in described cycloartenyl ferulate and the 24-methylene basic ring jackfruit alcohol ferulic acid ester complex.Wherein, cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex, bile acid and/or its salt, phospholipid mass ratio can be 1:1-100:1-500; Preferably, complex, bile acid and/or its salt, phospholipid mass ratio can be 1:1-50:1-100; Preferred, complex, bile acid and/or its salt, phospholipid mass ratio can be 1:5-40:5-80.
The present invention also provides a kind of test kit, comprise two kinds of unit formulations, wherein comprise cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex, bile acid and/or its salt and the phospholipid for the treatment of effective dose in first kind of unit formulation; Second kind of unit formulation is solvent.Cycloartenyl ferulate in first unit formulation and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex, bile acid and/or its salt, phospholipid mass ratio can be 1:1-100:1-500; Preferably, complex, bile acid and/or its salt, phospholipid mass ratio can be 1:1-50:1-100; Preferred, complex, bile acid and/or its salt, phospholipid mass ratio can be 1:5-40:5-80.Solvent in second kind of preparation is aqueous solution or non-aqueous solution, and preferred aqueous solutions for example is a water for injection, contain the aqueous solution of alcohol, or contains the conventional aqueous solution with adjuvant of injection.Wherein said injection routine is selected from etc. with adjuvant opens a kind of in regulator, stabilizing agent, antioxidant, PH regulator, antiseptic, excipient, the solubilizing agent and/or more than one mixture.Can also comprise the description how guidance is used in the test kit.
The present invention also provides the using method of above preparation box further, comprises first kind of preparation and second kind of blended step of preparation.
The used phospholipid of the present invention can be selected from soybean phospholipid, egg yolk lecithin, the Semen sojae atricolor sphingomyelins, the egg yolk sphingomyelins, hydrogenated soya phosphatide, the hydrogenation egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, two Petiolus Trachycarpi phosphatidylcholines, two Petiolus Trachycarpi PHOSPHATIDYL ETHANOLAMINE, the distearyl phosphatidylcholine, two Petiolus Trachycarpi phosphatidyl glycerol fat, two Petiolus Trachycarpi Phosphatidylserine, dimyristoyl phosphatidyl choline, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two myristoyl PHOSPHATIDYL ETHANOLAMINE, dilinoleoylphosphatidylcholine, dilinoleic acid glyceride phosphatidylcholine, dilinoleic acid glyceride PHOSPHATIDYL ETHANOLAMINE, dilinoleic acid glyceride phosphatidyl glycerol a kind of and/or more than one mixture.Preferred soybean phospholipid, egg yolk lecithin, Semen sojae atricolor sphingomyelins, egg yolk sphingomyelins, hydrogenated soya phosphatide, hydrogenation egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, most preferably soybean phospholipid, egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE.
After adding, bile acid and/or its salt can significantly increase the stability of the present composition.The used bile acid of the present invention is selected from free bile acid, conjugated bile acid or its mixture, and described bile salt is the product behind the bile acid salify.Wherein, bile acid comprises free bile acid, conjugated bile acid or the mixture of the two, free bile acid comprises cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodesoxycholic acid, Hyodeoxycholic Acid etc., is preferably cholic acid, deoxycholic acid, chenodeoxycholic acid, Hyodeoxycholic Acid; Conjugated bile acid is carboxylic aldehyde and the glycine (H in the above-mentioned free bile acid 2NCH 2COOH) or taurine (H 2NCH 2CH 2SO 3H) or other contain product after amino in the amino chemical compound forms amido link, be preferably glycocholic acid, sweet ammonia deoxycholic acid, sweet ammonia chenodeoxycholic acid, sweet ammonia ursodesoxycholic acid, taurocholic acid, taurodeoxycholic acid, Taurochenodeoxycholic Acid, tauroursodeoxycholic acid; Bile salt includes but not limited to potassium salt, sodium salt, calcium salt, magnesium salt, zinc salt, selenium salt, iron salt etc., is preferably sodium salt and potassium salt.
Simultaneously, preparation in compositions of the present invention, freeze-dried powder, the test kit also can randomly contain other adjuvant, include but not limited to cosolvent, etc. open a kind of in regulator, stabilizing agent, antioxidant, PH regulator, antiseptic, the excipient and/or more than one mixture, can improve stability of drug, help the control of drug quality.On following supplementary product consumption, can regulate according to practical application.
Described cosolvent includes but not limited to tween, Polyethylene Glycol, propylene glycol, glycine, preferred glycine.
Described grade is opened regulator and is included but not limited to 0.9% sodium chloride solution, 5% glucose solution, preferred 5% glucose solution.
Described stabilizing agent comprises but is not limited to sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, thiourea, vitamin C, butylated hydroxyarisol, dibutyl phenol, propyl gallate, tocopherol, methionine, cysteine hydrochloride, acetylcysteine, N-acetyl-DL-methionine, ascorbyl palmitate, ethylenediaminetetraacetic acid, the mixture of one or more in the disodiumedetate, preferred sodium sulfite, vitamin C, propyl gallate, a kind of or its any mixture in the ascorbyl palmitate, preferred vitamin C.
Described antioxidant comprises but is not limited to anhydrous sodium sulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, butylated hydroxyarisol, preferred anhydrous sodium sulfite, sodium pyrosulfite, sodium sulfite, most preferably anhydrous sodium sulfite.
Described PH regulator includes but not limited to hydrochloric acid, citric acid, tartaric acid, phosphoric acid, Metaphosphoric acid, poly-Metaphosphoric acid, carbonic acid, sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate, amine carbonate, sodium hydrogen phosphate, dipotassium hydrogen phosphate, ethanolamine, diethanolamine, triethanolamine, 1,2-is one or more in diamidogen, sodium carbonate, potassium sodium tartrate, potassium metaphosphate, Kurrol's salt, the Polymeric sodium metaphosphate., preferred sodium hydroxide, sodium bicarbonate, hydrochloric acid, phosphoric acid, most preferably sodium hydroxide, sodium bicarbonate.
Described antiseptic includes but not limited to one or more in phenol, cresol, three tert-butyl alcohols, benzyl alcohol, the nipalgin, preferred cresol, benzyl alcohol, nipalgin, most preferably nipalgin.
Described excipient includes but not limited to one or more in mannitol, lactose, glucose, sorbitol, sodium chloride, gelatin hydrolysate, dextran, sucrose, glycine, the polyvinylpyrrolidone etc., preferred mannitol, lactose, glycine, glucose, sorbitol or its any mixture, more preferably mannitol, glycine or its mixture, most preferably mannitol.
Preferably, can also add the dissolubility that solubilizing agent is used for further improving cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex in the preparation in the present composition, freeze-dried powder, the test kit.Described solubilizing agent is selected from a kind of and/or its any mixture in Polyethylene Glycol, ethylene glycol, propylene glycol, tween, glycerol, 12 hydroxy stearic acid esters of Polyethylene Glycol, hydroxypropyl beta cyclodextrin, the polyvidone.Described tween is selected from tween 20, Tween-40, and Tween-60, tween 80 is preferably tween 80.Described Polyethylene Glycol, preferred mean molecule quantity are 200～10000 Polyethylene Glycol, more preferably Polyethylene Glycol-200, Polyethylene Glycol-400, Polyethylene Glycol-800.The amount of used solubilizing agent be phospholipid and bile acid and/or its salt quality and 0～2 times, in mass.
Product of the present invention can be solution form, freeze-dried powder form or the combination product form be made up of second unit formulation of first unit formulation and liquid condition.When product was the solution form, it was clarifying micellar solution, can be used as the injection direct injection; When it was freeze-dried powder, lyophilized injectable powder was clear state, then administration after adding water for injection, glucose solution, sodium chloride solution redissolution; When its combination product form of forming by second unit formulation of first unit formulation and liquid condition, two kinds of preparations are mixed, jolting evenly back is used.
In the solution in described injection, before the freeze-dried powder lyophilization or in the combination product in two kinds of mixed solution of preparation, the concentration of complex is 1mg～100mg/ml, the concentration of phospholipid is 1mg～1000mg/ml, and bile acid and/or its salinity are 1mg～500mg/ml.
The pH of pharmaceutical composition of the present invention is not more than 10, and preferred pH is 6-9.
At last, the invention provides the preparation method of above product, comprise the step that cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex, phospholipid and bile acid and/or its salt are mixed, stir.Specifically comprise the steps:
1. complex, phospholipid, bile acid and/or its salt are dissolved in the organic solvent, stir, form settled solution, distilling under reduced pressure, thus obtain the organic facies of the present composition;
2. pharmaceutical composition of the present invention is used adjuvant is dissolved in the water, thereby obtains water.
3. A. injection: step organic facies 1. is dissolved in the abundant stirring and evenly mixing of step aqueous phase 2..
B. freeze-dried powder: according to conventional method 1. resulting organic facies be dissolved in 2. gained aqueous phase of step, stirring and evenly mixing, packing then.For example, the organic phase solution that 1. distills the back gained is dissolved in the water, high-speed stirred is 0.5～1 hour under 30 ℃～80 ℃ conditions, forms settled solution, adds the pH regulator agent and is adjusted to pH6～9, packing.In solution, add injection activated carbon filter membrane fine straining, lyophilization, obtain freeze-dried powder of the present invention.
C. test kit: with step 1. the gained organic facies carry out fine straining with the 0.22um microporous filter membrane, divide to be filled to cillin bottle, be first unit formulation; With step 2. the gained aqueous phase solution add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divide to be filled to cillin bottle, be second unit formulation, test kit of the present invention.When clinical use, second unit formulation is added in first unit formulation, can use behind the jolting mixing.
Step 1. in, described organic solvent general reference can be dissolved the pharmaceutically acceptable organic solvent of complex, phospholipid, bile acid and/or its salt, includes but not limited to a kind of in ethanol, ethyl acetate, chloroform, the propylene glycol and/or more than one mixture.Complex, phospholipid, bile acid and/or its salt can or join in the organic solvent simultaneously with any sequencing.Can be as required, at any other pharmaceutic adjuvants that add step by step of this step.For example, cosolvent, stabilizing agent, antioxidant etc.For example, complex can be dissolved in the ethanol, stir evenly the back and add phospholipid, bile acid and/or its salt mixture.Complex, phospholipid, bile acid and/or its salt, cosolvent can also be dissolved in respectively in the organic solvent, join in the container mixing and stir and obtain pharmaceutical composition organic facies of the present invention.In this step, in order to improve dissolution velocity, solution should be in 50～100 ℃ of heated and stirred states.
Described step 2. in, contain the water of adjuvant according to conventional or known method preparation.Various adjuvants can add or add simultaneously with random order.For example can add antioxidant, stabilizing agent then, stirring and evenly mixing with waiting regulator to add in the entry.
Described step 3. in, the preparation method of injection can will be in the organic solution 1. be dissolved in 2. gained aqueous phase of step, stirring and evenly mixing, packing then after the organic solvent volatilization according to conventional method.For example, will 1. distill back gained organic facies and be dissolved in the water, high-speed stirred is 0.1～1 hour under 30 ℃～80 ℃ conditions, forms colloid solution, adds the PH regulator and is adjusted to PH6～9, packing.
The specific embodiment
To illustrate by embodiment below and realize that technical scheme of the present invention, these embodiments are not used for limiting the present invention.Those skilled in the art according to existing knowledge the present invention are equal to replacement or corresponding logic is improved, and belong to scope of the present invention.
The preparation of embodiment 1 cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex
1. get commercially available oryzanol raw material (purity is 70%) 1kg,, filter, leave standstill, will separate out crystallization and filter drying with ethyl acetate and the dehydrated alcohol mixed solution backflow dissolving that 5 times of amount ratios are 20:1.Exsiccant crystallization (purity is about 84%) is redissolved with the ethyl acetate backflow of 8 times of amounts, filter, leave standstill, drying is filtered in the crystallization of separating out.Above re-crystallization step repeats 3-5 time.
2. the mother solution that leaches behind the recrystallization in the step 1 is merged that to be recycled to volume be behind 2 times of contained solute, to leave standstill, with crystallization filtration, the drying of separating out.
3. with the ethyl acetate backflow dissolving of the crystallization in the step 2 (purity is about 85-87%), filter, leave standstill, crystallization filtration, the drying of separating out with 8 times of amounts.Repeat above re-crystallization step 3-5 time.
4. the mother solution that leaches behind the recrystallization in the step 3 is merged that to be recycled to volume be behind 2 times of contained solute, to leave standstill, with crystallization filtration, the drying of separating out.
5. the crystallization (purity is about 85-87%) of gained in the step 4 is done recrystallization and handled, method is with step 3.
6. with step 1, the crystallized mixed of gained obtains cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex in 3,5.
By the high performance liquid chromatogram detection method, the percentage composition sum that confirms cycloartenyl ferulate, 24-methylene basic ring jackfruit alcohol ferulic acid ester brings up to 93% by original 70%.Cycloartenyl ferulate is 1.16:1 with the content ratio of 24-methylene basic ring jackfruit alcohol ferulic acid ester in the complex.
Complex described in following examples 2-23, the comparative example 1-4 all is meant prepared cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex according to embodiment 1.In the following embodiments, adding excipient such as mannitol is to satisfy the needs that are prepared into freeze-dried formulation.If in actual applications, directly use compositions colloid solution can not add excipient.
Embodiment 2
Complex 10mg
Soybean phospholipid 50mg
Hyodeoxycholic acid 50mg
Mannitol 80mg
Water for injection is to 10ml
Complex, soybean phospholipid, hyodeoxycholic acid are dissolved in the 3ml ethyl acetate, are heated to 80 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved mannitol water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down, get final product present composition injection.Regulate PH to 7.3 with sodium hydroxide solution, add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 3
Complex 40mg
Soybean phospholipid 200mg
Chenodeoxy cholic acid 300mg
Glycine 100mg
Water for injection is to 10ml
Complex, chenodeoxy cholic acid, soybean phospholipid are dissolved in the 5ml propylene glycol, are heated to 80 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved glycine water for injection to full dose, 70 ℃ of abundant stirring and evenly mixings down, get final product present composition injection.Regulate PH to 9.0 with sodium hydroxide solution, add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 4
Complex 1mg
Semen sojae atricolor sphingomyelins 500mg
Lithocholic acid 100mg
Glucose 200mg
Water for injection is to 10ml
Complex, Semen sojae atricolor sphingomyelins, lithocholic acid are dissolved in the 10ml ethyl acetate, are heated to 60 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved glucose water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down, get final product present composition injection.Regulate PH to 6.6 with sodium hydroxide solution, add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 5
Complex 10mg
Glycocholic acid 100mg
Hydrogenation egg yolk lecithin 400mg
Glycine 200mg
Mannitol 200mg
Water for injection is to 10ml
Complex, glycocholic acid, hydrogenation egg yolk lecithin are dissolved in the 2m1 ethyl acetate, are heated to 60 ℃ of stirrings, the heating mixing is to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved mannitol and glycine water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down, get final product present composition injection.Regulate PH to 6.0 with sodium hydroxide solution, add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.45um microporous filter membrane carries out fine straining, and was canned, divided then to be filled to cillin bottle.
Embodiment 6
Complex 50mg
Sweet ammonia deoxycholic acid 100mg
PHOSPHATIDYL ETHANOLAMINE 60mg
Thioglycerol 2mg
Sodium sulfite 1mg
Sorbitol 80mg
Water for injection is to 10m1
Complex, sweet ammonia deoxycholic acid, PHOSPHATIDYL ETHANOLAMINE are dissolved in the 8ml ethyl acetate, are heated to 80 ℃ of stirrings, add thioglycerol heating mixing then, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved sodium sulfite and sorbitol water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down, get final product present composition injection.Add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 7
Complex 50mg
Deoxycholic acid 250mg
Soybean phospholipid 400mg
Polyethylene Glycol-800 10mg
Hydroxypropyl beta cyclodextrin 20mg
Lactose 150mg
Water for injection is to 10ml
Complex, deoxycholic acid, soybean phospholipid, Polyethylene Glycol-800 are dissolved in the 5ml ethanol, are heated to 60 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved hydroxypropyl beta cyclodextrin and lactose water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down, get final product injection of the present invention.Regulate PH to 7.5 with sodium hydroxide solution, add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 8
Complex 1mg
Phosphatidyl glycerol 20mg
Sweet ammonia sodium deoxycholate 10mg
Tween 80 3mg
Mannitol 20mg
Water for injection is to 10ml
Complex, phosphatidyl glycerol, sweet ammonia sodium deoxycholate, tween 80 are dissolved in the 2ml ethyl acetate, are heated to 60 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved mannitol water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down, get final product injection of the present invention.Add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 9
Complex 10mg
Phosphatidylcholine 100mg
Taurocholic acid 80mg
Vitamin E 15mg
Glucose 100mg
Water for injection is to 10ml
Complex, phosphatidylcholine, taurocholic acid are dissolved in the 4ml ethyl acetate, are heated to 75 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved vitamin E and glucose water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down, get final product injection of the present invention.Add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 10
Complex 20mg
Phosphatidylcholine 200mg
Glycocholic acid 300mg
Mannitol 100mg
Water for injection is to 10ml
Complex, phosphatidylcholine, glycocholic acid are dissolved in the 5ml ethyl acetate, are heated to 75 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In organic facies, add dissolved mannitol water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down adopt sodium hydroxide solution to regulate PH to 8 then, get final product injection of the present invention.Add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 11
Complex 15mg
Phosphatidylcholine 180mg
Deoxycholic acid 200mg
Vitamin E 15mg
Glycine 100mg
Glucose 100mg
Water for injection is to 10ml
Complex, phosphatidylcholine, taurocholic acid, vitamin E are dissolved in the 5ml ethanol, are heated to 70 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.Add dissolved glycine and glucose water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down adopt sodium hydroxide solution to regulate PH to 7 then, get final product injection of the present invention.Add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 12
Complex 15mg
Phosphatidylcholine 180mg
Glycocholic acid is received 200mg
Glycine 100mg
Mannitol 120mg
Propylene glycol 10mg
Water for injection is to 10ml
Complex, phosphatidylcholine, NaGC, propylene glycol are dissolved in the 3ml ethanol, are heated to 70 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved sweet acid acid and mannitol water for injection to full dose, 60 ℃ are descended abundant stirring and evenly mixings, get final product injection of the present invention.Add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 13
Complex 15mg
Egg yolk lecithin 180mg
Taurocholic acid potassium 150mg
Glycerol 15mg
Sorbitol 100mg
Glucose 50mg
Water for injection is to 10ml
Complex, egg yolk lecithin, taurocholic acid are dissolved in the 3ml ethyl acetate, are heated to 70 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved glycerol, Pyrusussuriensis alcohol and glucose water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down, adopt then sodium bicarbonate solution regulate PH to 8 get final product injection of the present invention.Add 0.05% injection activated carbon and stirred 20 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 14
Complex 10mg
Phosphatidylcholine 180mg
Taurocholic acid 200mg
Propylene glycol 10mg
Glycerol 10mg
Glycerol 10mg
Water for injection is to 10m1
Complex, phosphatidylcholine, taurocholic acid, glycerol are dissolved in the 2.5ml ethanol, are heated to 70 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved propylene glycol and lactose water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down, get final product injection of the present invention.Add 0.05% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 15
Complex 10mg
S-PC 180mg
NaTDC 200mg
Propylene glycol 10mg
Glycerol 10mg
Mannitol 120mg
Water for injection is to 10ml
Complex, S-PC, sodium taurocholate are dissolved in the 2.5ml ethanol, are heated to 70 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In above organic facies, add dissolved propylene glycol, glycerol and mannitol water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down, get final product injection of the present invention.Add 0.05% injection activated carbon and stirred 25 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle.
Embodiment 16
First unit formulation
Complex 10mg
Phosphatidylcholine 100mg
Taurocholic acid 80mg
Second unit formulation
Vitamin C 15mg
Water for injection 10ml
Complex, phosphatidylcholine, taurocholic acid are dissolved in the 5ml acetone, and 60 ℃ are stirred down fully the method that adopts evaporated under reduced pressure down and remove acetone in the solution, carry out fine straining with the 0.22um microporous filter membrane, and branch is filled to cillin bottle, and label is A;
Vitamin C is dissolved in the 10ml water, adds 0.05% injection activated carbon then and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle, and label is B.
When clinical use, the solution in the B bottle is joined in the A bottle, shake well uses after making it be mixed into settled solution.
Embodiment 17
First unit formulation
Complex 20mg
Phosphatidylcholine 200mg
Glycocholic acid 300mg
Second unit formulation
Glycine 10mg
Water for injection 10ml
Complex, phosphatidylcholine, glycocholic acid are dissolved in the 15ml ethanol, and 60 ℃ are stirred down fully the method that adopts evaporated under reduced pressure down and remove ethanol in the solution, carry out fine straining with the 0.22um microporous filter membrane, and branch is filled to cillin bottle, and label is A;
Glycine is dissolved in the 10ml water, adds 0.05% injection activated carbon then and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle, and label is B.
When clinical use, the solution in the B bottle is joined in the A bottle, shake well uses after making it be mixed into settled solution.
Embodiment 18
First unit formulation
Complex 15mg
Phosphatidylcholine 150mg
Deoxycholic acid 200mg
Vitamin E 10mg
Second unit formulation
Glycine 100mg
Water for injection 10ml
Complex, phosphatidylcholine, deoxycholic acid, vitamin E are dissolved in the 15ml ethanol, and 60 ℃ are stirred down fully the method that adopts evaporated under reduced pressure down and remove ethanol in the solution, carry out fine straining with the 0.22um microporous filter membrane, and branch is filled to cillin bottle, and label is A;
Glycine is dissolved in the 10ml water, adds 0.05% injection activated carbon then and stirred 30 minutes.Add sodium hydroxide solution and regulate pH to 8.0.After decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle, and label is B.
When clinical use, the solution in the B bottle is joined in the A bottle, shake well uses after making it be mixed into settled solution.
Embodiment 19
First unit formulation
Complex 15mg
Phosphatidylcholine 180mg
Glycocholic acid is received 200mg
Propylene glycol 10mg
Second unit formulation
Glycerol 20mg
Glycine 100mg
Water for injection 10ml
Complex, phosphatidylcholine, NaGC and propylene glycol are dissolved in the 10ml chloroform, the method of employing evaporated under reduced pressure is removed the chloroform in the solution under fully stirring under 60 ℃, carry out fine straining with the 0.22um microporous filter membrane, divide to be filled to cillin bottle, label is A;
Glycerol, glycine are dissolved in the 10ml water, add 0.05% injection activated carbon then and stirred 30 minutes.Add sodium bicarbonate solution and regulate pH to 8.After decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle, and label is B.
When clinical use, the solution in the B bottle is joined in the A bottle, shake well uses after making it be mixed into settled solution.
Embodiment 20
First unit formulation
Complex 15mg
Egg yolk lecithin 180mg
Taurocholic acid potassium 150mg
Second unit formulation
Glycerol 15mg
Water for injection 10ml
Complex, egg yolk lecithin, taurocholic acid potassium are dissolved in the 10ml dichloromethane, and 60 ℃ are stirred down fully the method that adopts evaporated under reduced pressure down and remove dichloromethane in the solution, carry out fine straining with the 0.22um microporous filter membrane, and branch is filled to cillin bottle, and label is A;
Glycerol is dissolved in the 10ml water, adds 0.05% injection activated carbon then and stirred 30 minutes.Add sodium bicarbonate solution and regulate pH to 9.After decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle, and label is B.
When clinical use, the solution in the B bottle is joined in the A bottle, shake well uses after making it be mixed into settled solution.
Embodiment 21
First unit formulation
Complex 10mg
Phosphatidylcholine 180mg
Cholyltaurine 200mg
Glycerol 10mg
Second unit formulation
Propylene glycol 10mg
Lactose 10mg
Water for injection 10ml
Complex, phosphatidylcholine, cholyltaurine and glycerol are dissolved in the 10ml ethanol, and 60 ℃ are stirred down fully the method that adopts evaporated under reduced pressure down and remove ethanol in the solution, carry out fine straining with the 0.22um microporous filter membrane, and branch is filled to cillin bottle, and label is A;
Propylene glycol, lactose are dissolved in the 10ml water, add 0.05% injection activated carbon then and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle, and label is B.
When clinical use, the solution in the B bottle is joined in the A bottle, shake well uses after making it be mixed into settled solution.
Embodiment 22
First unit formulation
Complex 10mg
S-PC 180mg
NaTDC 200mg
Glycerol 10mg
Second unit formulation
Propylene glycol 10mg
Vitamin C 2mg
Water for injection 10ml
Complex, S-PC, NaTDC, glycerol are dissolved in the 10ml acetone, and 60 ℃ are stirred down fully the method that adopts evaporated under reduced pressure down and remove acetone in the solution, carry out fine straining with the 0.22um microporous filter membrane, and branch is filled to cillin bottle, and label is A;
Propylene glycol, vitamin C are dissolved in the 10ml water, add 0.05% injection activated carbon then and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle, and label is B.
When clinical use, the solution in the B bottle is joined in the A bottle, shake well uses after making it be mixed into settled solution.
Embodiment 23
First unit formulation
Complex 10mg
Soybean phospholipid 80mg
Glycocholic acid 60mg
Glycerol 15mg
Second unit formulation
Lysine 5mg
Vitamin E 2mg
Water for injection 10ml
Complex, soybean phospholipid, glycocholic acid, glycerol are dissolved in the 10ml chloroform, and 60 ℃ are stirred down fully the method that adopts evaporated under reduced pressure down and remove chloroform in the solution, carry out fine straining with the 0.22um microporous filter membrane, and branch is filled to cillin bottle, and label is A;
Lysine, vitamin E are dissolved in the 10ml water, add 0.05% injection activated carbon then and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divided to be filled to cillin bottle, and label is B.
When clinical use, the solution in the B bottle is joined in the A bottle, shake well uses after making it be mixed into settled solution.The clarity of solution determination methods of embodiment 2～23 systems
Solution during the clinical use of the solution of the foregoing description preparation or embodiment preparation, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.
The solution of embodiment 2～15 systems is carried out lyophilization according to following method
Pre-freeze: products temperature drops to-45 ℃, is incubated and promptly can carries out sublimation drying after 3 hours;
Sublimation drying: the sublimation drying temperature is controlled at below-12 ℃;
Dry again: the drying stage maximum temperature is controlled at 35 ℃ again, and loss on drying should be up to specification;
Behind dry the end, the intrinsic pressure plug of case, outlet lock aluminium lid, the qualified back of product inspection packing is promptly.
The comparative example 1
Complex 20mg
Phosphatidylcholine 260mg
Water for injection is to 10ml
Complex, phosphatidylcholine are dissolved in the ethanol, are heated to 70 ℃ of stirrings, to fully dissolving.Adopt the method distillation ethanol of reduction vaporization, obtain gelationus solid, add water for injection to full dose, 60 ℃ of following abundant stirring and evenly mixings, the result forms the very big milk of granularity, does not clarify.
The comparative example 2
Complex 20mg
Taurocholic acid 100mg
Water for injection is to 10m1
Complex, taurocholic acid are dissolved in the ethanol, are heated to 70 ℃ of stirrings, to fully dissolving.Adopt the method distillation ethanol of reduction vaporization, obtain gelationus solid, add water for injection to full dose, 60 ℃ of following abundant stirring and evenly mixings, the result forms the very big milk of granularity, does not clarify.
The comparative example 3
Complex 5mg
Cholic acid 150mg
Phosphatidase 12 0mg
Vitamin E 5mg
Water for injection is to 10ml
Complex and cholic acid heating are dissolved in the 5mol/L sodium hydroxide solution, transfer pH value to 7.0, add phospholipid, vitamin E stirring and dissolving, add to the full amount of water for injection with 1mol/L hydrochloric acid.Be formed with a lot of oarse-grained suspensions, and the medicine composition is separated out rapidly at short notice.
Contrast experiment's example 4
Complex 4.5mg
Soybean oil 30mg
Soybean phospholipid 11mg
Vitamin E 0.1mg
Glycerol 2.5mg
Water for injection is to 10ml
Soybean oil, complex are added in the container, this container is placed oil bath, be heated to 100 ℃, be stirred to medicine dissolution, be cooled to 80 ℃.Add soybean phospholipid, vitamin then, be stirred to the phospholipid dissolving and form even oil phase.Water for injection 80ml is placed another container, add glycerol and form water in 80 ℃ of following stirring and dissolving.Oil phase is under agitation added aqueous phase, continue to stir 40 minutes formation colostrums, regulate PH to 8 with sodium hydroxide.Add the injection water to 100ml, with colostrum high pressure homogenization machine or ultrasonic probe homogenize.
Embodiment 24
Get the injection freeze-dried powder of embodiment 10 preparations and preserve half a year in the cool, observe its physicochemical property and change, be recorded as following form
Table 1 room temperature reserved sample observing result
Time (moon) 0 1 2 4 6
Outward appearance Off-white color Off-white color Off-white color Off-white color Off-white color
Content 100 99.93 99.92 99.81 99.87
PH 8.30 8.27 8.33 8.31 8.25
By above-mentioned data as seen, present composition steady quality.
Solution appearance after redissolving from it is judged, the clarification of resulting composition solution is placed and do not seen that medicine separated out in two days, and visualization does not have opalescence.According to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical with placing under the umbrella canopy lamp in the darkroom, illumination is 1000Lx, observe, compare from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.
Embodiment 25 particle diameters detect
With contrast experiment's example 3 and 4 and the injection of the embodiment of the invention 2 preparation carried out the particle diameter detection, gained result such as following table.Particle diameter 1 is represented the injection of the embodiment of the invention 2, and particle diameter 2 is that compositions, the particle diameter 3 of contrast experiment's example 4 is the compositions of contrast experiment's example 3.
Table 2 particle diameter observed result
Sample number 1 2 3 4 5
Particle diameter 1 (nm) <20 <20 <20 <20 <20
Particle diameter 2 (nm) 525.3 527.0 525.9 525.1 526.4
Particle diameter 3 (nm) 1047 1039 1040 1045 1035
By The above results as can be known, injection solution particle diameter of the present invention is significantly less than the compositions of contrast experiment's example 3 and 4 preparations.Injection particle diameter of the present invention belongs to micellar solution simultaneously, approaches true solution on particle diameter, and stability is better than the Emulsion and the injection of prior art for preparing.
Embodiment 26
To redissolve the irritation test of laggard action thing blood vessel according to the lyophilized products that embodiment 10 methods make.Method is to get 40 of health, ear edge not damaged rabbit, is divided into two groups at random by body weight, i.e. injection complex test group and sodium chloride injection matched group.Intend with dosage with clinical adult and serve as according to design rabbit dosage, slowly inject administration that matched group gives the isometric(al) sodium chloride injection, gives 5 days continuously from rabbit left side auricular vein.Result of the test shows, compare with the sodium chloride injection group, intravenous injection gives the injection complex, reach the last administration during the administration after 24 hours, blood vessel and surrounding tissue redness are not seen in perusal, the visible rabbit ear vein clear in structure of tissue slice inspection, indivedual vasodilation are obvious, the tube wall thickness is even, and inwall is level and smooth, the Guan Zhouwu inflammatory exudate.Show that the injection complex does not have the obvious stimulation effect to the rabbit auricular vein under the experiment condition.

Claims (61)

1. pharmaceutical composition, comprise the cycloartenyl ferulate for the treatment of effective dose and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex, bile acid and/or its salt, phospholipid, wherein, cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester quality percentage composition are not less than 90% in described cycloartenyl ferulate and the 24-methylene basic ring jackfruit alcohol ferulic acid ester complex.
2. according to the pharmaceutical composition of claim 1, wherein complex, bile acid and/or its salt, phospholipid mass ratio are 1:1-100:1-500.
3. according to the pharmaceutical composition of claim 2, wherein complex, bile acid and/or its salt, phospholipid mass ratio are 1:1-50:1-100.
4. according to the pharmaceutical composition of claim 3, complex, bile acid and/or its salt, phospholipid mass ratio are 1:5-40:5-80.
5. according to the pharmaceutical composition of each claim in the claim 1～4, its preparation method may further comprise the steps: complex, phospholipid, bile acid and/or its salt are mixed, stir, are dissolved in the organic solvent, the volatilization organic solvent.
6. according to the pharmaceutical composition of each claim in the claim 1～4, at solution state, the concentration of described complex is 1mg～100mg/ml.
7. according to the pharmaceutical composition of each claim in the claim 1～4, at solution state, the concentration of described phospholipid is 1mg～1000mg/ml.
8. according to the pharmaceutical composition of each claim in the claim 1～4, at solution state, the concentration of described bile acid and/or its salt is 1mg～500mg/ml.
9. according to the pharmaceutical composition of each claim in the claim 1～4, described phospholipid is selected from soybean phospholipid, egg yolk lecithin, the Semen sojae atricolor sphingomyelins, the egg yolk sphingomyelins, hydrogenated soya phosphatide, the hydrogenation egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, two Petiolus Trachycarpi phosphatidylcholines, two Petiolus Trachycarpi PHOSPHATIDYL ETHANOLAMINE, the distearyl phosphatidylcholine, two Petiolus Trachycarpi phosphatidyl glycerol fat, two Petiolus Trachycarpi Phosphatidylserine, dimyristoyl phosphatidyl choline, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two myristoyl PHOSPHATIDYL ETHANOLAMINE, dilinoleoylphosphatidylcholine, dilinoleic acid glyceride phosphatidylcholine, dilinoleic acid glyceride PHOSPHATIDYL ETHANOLAMINE, dilinoleic acid glyceride phosphatidyl glycerol a kind of and/or more than one mixture.
10. according to the pharmaceutical composition of each claim in the claim 1～4, described bile acid is selected from free bile acid, conjugated bile acid or the mixture of the two; Described bile salt is the product behind the bile acid salify.
11. according to the pharmaceutical composition of claim 10, free bile acid wherein is cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodesoxycholic acid, Hyodeoxycholic Acid or its mixture; Conjugated bile acid is that carboxylic aldehyde in the above-mentioned free bile acid and glycine or taurine or other contain product or its mixture after amino in the amino chemical compound forms amido link.
12. according to the pharmaceutical composition of claim 11, free bile acid wherein is cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodesoxycholic acid, Hyodeoxycholic Acid or its mixture; Conjugated bile acid wherein is glycocholic acid, sweet ammonia deoxycholic acid, sweet ammonia chenodeoxycholic acid, sweet ammonia ursodesoxycholic acid, sweet ammonia Hyodeoxycholic Acid, taurocholic acid, taurodeoxycholic acid, Taurochenodeoxycholic Acid, tauroursodeoxycholic acid, cattle sulphur Hyodeoxycholic Acid or its mixture.
13. according to the pharmaceutical composition of claim 10, bile salt wherein is potassium salt, sodium salt, calcium salt, magnesium salt, zinc salt, selenium salt, iron salt or its mixture of bile acid.
14. pharmaceutical composition according to claim 1, also comprise solubilizing agent, described solubilizing agent is selected from a kind of in tween, 12 hydroxy stearic acid esters of Polyethylene Glycol, Polyethylene Glycol, glycerol, propylene glycol, ethylene glycol, hydroxypropyl beta cyclodextrin, the polyvidone and/or more than one mixture.
15. according to the pharmaceutical composition of claim 14, the amount of required solubilizing agent is phospholipid and bile acid and/or its salt quality sum 0～2 times.
16. according to the pharmaceutical composition of claim 1, also comprise pharmaceutically acceptable adjuvant, described adjuvant comprises etc. opens a kind of in regulator, stabilizing agent, antioxidant, PH regulator, antiseptic, the excipient and/or more than one mixture.
17. lyophilized injectable powder, it contains cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex, bile acid and/or its salt and the phospholipid for the treatment of effective dose, wherein, cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester quality percentage composition are not less than 90% in described cycloartenyl ferulate and the 24-methylene basic ring jackfruit alcohol ferulic acid ester complex.
18. according to the lyophilized injectable powder of claim 17, wherein complex, bile acid and/or its salt, phospholipid mass ratio are 1:1-100:1-500.
19. according to the lyophilized injectable powder of claim 18, wherein complex, bile acid and/or its salt, phospholipid mass ratio are 1:1-50:1-100.
20. according to the lyophilized injectable powder of claim 19, complex, bile acid and/or its salt, phospholipid mass ratio are 1:5-40:5-80.
21. according to the pharmaceutical composition of each claim in the claim 17～20, its preparation method may further comprise the steps: complex, phospholipid, bile acid and/or its salt are mixed, stir, are dissolved in the organic solvent, the volatilization organic solvent.
22. according to the lyophilized injectable powder of each claim in the claim 17～20, in the solution before the described freeze-dried powder lyophilization, the concentration of complex is 1mg～100mg/ml.
23. according to the pharmaceutical composition of each claim in the claim 17～20, in the solution before the described freeze-dried powder lyophilization, the concentration of phospholipid is 1mg～1000mg/ml.
24. according to the lyophilized injectable powder of each claim in the claim 17～20, in the solution before the described freeze-dried powder lyophilization, the concentration of bile acid and/or its salt is 1mg～500mg/ml.
25. according to the lyophilized injectable powder of each claim in the claim 17～20, described phospholipid is selected from soybean phospholipid, egg yolk lecithin, the Semen sojae atricolor sphingomyelins, the egg yolk sphingomyelins, hydrogenated soya phosphatide, the hydrogenation egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, two Petiolus Trachycarpi phosphatidylcholines, two Petiolus Trachycarpi PHOSPHATIDYL ETHANOLAMINE, the distearyl phosphatidylcholine, two Petiolus Trachycarpi phosphatidyl glycerol fat, two Petiolus Trachycarpi Phosphatidylserine, dimyristoyl phosphatidyl choline, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two myristoyl PHOSPHATIDYL ETHANOLAMINE, dilinoleoylphosphatidylcholine, dilinoleic acid glyceride phosphatidylcholine, dilinoleic acid glyceride PHOSPHATIDYL ETHANOLAMINE, dilinoleic acid glyceride phosphatidyl glycerol a kind of and/or more than one mixture.
26. according to the lyophilized injectable powder of each claim in the claim 17～20, described bile acid is selected from free bile acid, conjugated bile acid or the mixture of the two; Described bile salt is the product behind the bile acid salify.
27. according to the lyophilized injectable powder of claim 26, free bile acid wherein is cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodesoxycholic acid, Hyodeoxycholic Acid or its mixture; Conjugated bile acid is that carboxylic aldehyde in the above-mentioned free bile acid and glycine or taurine or other contain product or its mixture after amino in the amino chemical compound forms amido link.
28. according to the lyophilized injectable powder of claim 27, free bile acid wherein is cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodesoxycholic acid, Hyodeoxycholic Acid or its mixture; Conjugated bile acid wherein is glycocholic acid, sweet ammonia deoxycholic acid, sweet ammonia chenodeoxycholic acid, sweet ammonia ursodesoxycholic acid, sweet ammonia Hyodeoxycholic Acid, taurocholic acid, taurodeoxycholic acid, Taurochenodeoxycholic Acid, tauroursodeoxycholic acid, cattle sulphur Hyodeoxycholic Acid or its mixture.
29. according to the lyophilized injectable powder of claim 26, bile salt wherein is potassium salt, sodium salt, calcium salt, magnesium salt, zinc salt, selenium salt, iron salt or its mixture of bile acid.
30. lyophilized injectable powder according to claim 17, also comprise solubilizing agent, described solubilizing agent is selected from a kind of in tween, 12 hydroxy stearic acid esters of Polyethylene Glycol, Polyethylene Glycol, glycerol, propylene glycol, ethylene glycol, hydroxypropyl beta cyclodextrin, the polyvidone and/or more than one mixture.
31. according to the lyophilized injectable powder of claim 30, the amount of required solubilizing agent is phospholipid and bile acid and/or its salt quality sum 0～2 times.
32. according to the lyophilized injectable powder of claim 17, also comprise pharmaceutically acceptable adjuvant, described adjuvant comprises etc. opens a kind of in regulator, stabilizing agent, antioxidant, PH regulator, antiseptic, the excipient and/or more than one mixture.
33. a test kit comprises two kinds of unit formulations, wherein comprises cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex, bile acid and/or its salt and the phospholipid for the treatment of effective dose in first kind of unit formulation; Second kind of unit formulation is solvent.
34. according to the test kit of claim 33, complex, bile acid and/or its salt, phospholipid mass ratio are 1:1-100:1-500 in first kind of preparation.
35. according to the test kit of claim 34, complex, bile acid and/or its salt, phospholipid mass ratio are 1:1-50:1-100 in first kind of preparation.
36. according to the test kit of claim 35, complex, bile acid and/or its salt, phospholipid mass ratio are 1:5-40:5-80 in first kind of preparation.
37. according to the test kit of claim 33, the preparation method of its first kind of preparation may further comprise the steps: component is wherein mixed, stirred, is dissolved in the organic solvent, the volatilization organic solvent.
38. according to the test kit of claim 33, the solvent in second kind of preparation is an aqueous solution.
39. according to the test kit of claim 38, the solvent in second kind of preparation is a water.
40. according to the test kit of claim 38, the solvent in second kind of preparation is to contain the conventional aqueous solution with adjuvant of injection.
41. according to the test kit of claim 40, described injection routine is selected from etc. with adjuvant opens a kind of in regulator, stabilizing agent, antioxidant, PH regulator, antiseptic, excipient, the solubilizing agent and/or more than one mixture.
42. according to the test kit of each claim in the claim 33～41, behind two kinds of preparation mix homogeneously in the test kit, the concentration of described complex is 1mg～100mg/ml.
43. according to the test kit of each claim in the claim 33～41, behind two kinds of preparation mix homogeneously in the test kit, the concentration of described phospholipid is 1mg～1000mg/ml.
44. according to the test kit of each claim in the claim 33～41, behind two kinds of preparation mix homogeneously in the test kit, the concentration of described bile acid and/or its salt is 1mg～500mg/ml.
45. according to the test kit of claim 33, described phospholipid is selected from soybean phospholipid, egg yolk lecithin, the Semen sojae atricolor sphingomyelins, the egg yolk sphingomyelins, hydrogenated soya phosphatide, the hydrogenation egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, two Petiolus Trachycarpi phosphatidylcholines, two Petiolus Trachycarpi PHOSPHATIDYL ETHANOLAMINE, the distearyl phosphatidylcholine, two Petiolus Trachycarpi phosphatidyl glycerol fat, two Petiolus Trachycarpi Phosphatidylserine, dimyristoyl phosphatidyl choline, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two myristoyl PHOSPHATIDYL ETHANOLAMINE, dilinoleoylphosphatidylcholine, dilinoleic acid glyceride phosphatidylcholine, dilinoleic acid glyceride PHOSPHATIDYL ETHANOLAMINE, dilinoleic acid glyceride phosphatidyl glycerol a kind of and/or more than one mixture.
46. according to the test kit of claim 33, described bile acid is selected from free bile acid, conjugated bile acid or the mixture of the two; Described bile salt is the product behind the bile acid salify.
47. according to the test kit of claim 46, free bile acid wherein is cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodesoxycholic acid, Hyodeoxycholic Acid or its mixture; Conjugated bile acid is that carboxylic aldehyde in the above-mentioned free bile acid and glycine or taurine or other contain product or its mixture after amino in the amino chemical compound forms amido link.
48. according to the test kit of claim 47, free bile acid wherein is cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodesoxycholic acid, Hyodeoxycholic Acid or its mixture; Conjugated bile acid wherein is glycocholic acid, sweet ammonia deoxycholic acid, sweet ammonia chenodeoxycholic acid, sweet ammonia ursodesoxycholic acid, sweet ammonia Hyodeoxycholic Acid, taurocholic acid, taurodeoxycholic acid, Taurochenodeoxycholic Acid, tauroursodeoxycholic acid, cattle sulphur Hyodeoxycholic Acid or its mixture.
49. according to the test kit of claim 46, bile salt wherein is potassium salt, sodium salt, calcium salt, magnesium salt, zinc salt, selenium salt, iron salt or its mixture of bile acid.
50. test kit according to claim 33, also comprise solubilizing agent in described first kind of preparation, described solubilizing agent is selected from a kind of in tween, 12 hydroxy stearic acid esters of Polyethylene Glycol, Polyethylene Glycol, glycerol, propylene glycol, ethylene glycol, hydroxypropyl beta cyclodextrin, the polyvidone and/or more than one mixture.
51. according to the test kit of claim 50, the amount of required solubilizing agent is phospholipid and bile acid and/or its salt quality sum 0～2 times.
52., wherein also comprise the description how guidance is used according to the test kit of claim 33.
53. the described preparation of drug combination method of claim 1～16 comprises the step that cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex and phospholipid, bile acid and/or its salt is dissolved in organic solvent, distilling under reduced pressure.
54. according to the described preparation of drug combination method of claim 53, organic solvent is selected from a kind of in ethanol, ethyl acetate, dichloromethane, chloroform, the propylene glycol and/or more than one mixture.
55. the preparation method of the described freeze-dried powder of claim 17～32 comprises the step that cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex and phospholipid, bile acid and/or its salt is dissolved in organic solvent, distilling under reduced pressure.
56. according to the preparation method of the described freeze-dried powder of claim 55, organic solvent is selected from a kind of in ethanol, ethyl acetate, dichloromethane, chloroform, the propylene glycol and/or more than one mixture.
57. the preparation method according to claim 55 or 56 described freeze-dried powders may further comprise the steps: 1. complex, phospholipid, bile acid and/or its salt are mixed, stir, distilling under reduced pressure obtains organic facies; 2. with water for injection or distilled water as water, as also having other pharmacy adjuvant, also join aqueous phase; 3. step organic facies 1. is dissolved in the abundant stirring and evenly mixing of step aqueous phase 2..
58., wherein also comprise with 3. products obtained therefrom adding active carbon, filtration, degerming of step, cryodesiccated step according to the described freeze-dried powder preparation method of claim 57.
59. the preparation method of the described test kit of claim 33～52 comprises the step that cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester complex and phospholipid, bile acid and/or its salt is dissolved in organic solvent, distilling under reduced pressure.
60. according to the described preparation method of claim 59, organic solvent is selected from a kind of in ethanol, ethyl acetate, dichloromethane, chloroform, the propylene glycol and/or more than one mixture.
61. the using method of the described test kit of claim 33～52 comprises first kind of preparation and second kind of blended step of preparation.
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WO2010069139A1 (en) * 2008-12-17 2010-06-24 北京世纪博康医药科技有限公司 Pharmaceutical composition and preparation method thereof
WO2010069140A1 (en) * 2008-12-17 2010-06-24 北京世纪博康医药科技有限公司 Medicinal product of oryzanol and preparation method thereof
CN102058516B (en) * 2009-11-18 2012-07-04 北京世纪博康医药科技有限公司 Solid dispersion and preparation thereof
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WO2010069139A1 (en) * 2008-12-17 2010-06-24 北京世纪博康医药科技有限公司 Pharmaceutical composition and preparation method thereof
WO2010069140A1 (en) * 2008-12-17 2010-06-24 北京世纪博康医药科技有限公司 Medicinal product of oryzanol and preparation method thereof
CN102058516B (en) * 2009-11-18 2012-07-04 北京世纪博康医药科技有限公司 Solid dispersion and preparation thereof
CN115215918A (en) * 2022-08-16 2022-10-21 北京云鹏鹏程医药科技有限公司 Oryzanol monohydrate crystal form and preparation method thereof

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