CN101480406A - 24-methylene cycloartenyl ferulate composition and method for preparing the same - Google Patents
24-methylene cycloartenyl ferulate composition and method for preparing the same Download PDFInfo
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- CN101480406A CN101480406A CN 200810240136 CN200810240136A CN101480406A CN 101480406 A CN101480406 A CN 101480406A CN 200810240136 CN200810240136 CN 200810240136 CN 200810240136 A CN200810240136 A CN 200810240136A CN 101480406 A CN101480406 A CN 101480406A
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Abstract
The invention discloses a pharmaceutical composition of 24-methylene cycloartenyl oryzanolum, which comprises the 24-methylene cycloartenyl oryzanolum, phospholipid, bile acid and/or salt of bile acid. The pharmaceutical composition effectively improves the water solubility and the stability of the 24-methylene cycloartenyl oryzanolum and has better grain diameter and stability than the prior product, and further, the invention provides three product forms including injectio, freeze-dried powder and kits of the pharmaceutical composition, and preparation methods thereof.
Description
Technical field
The present invention relates to a kind of 24-methylene basic ring jackfruit alcohol ferulic acid ester Pharmaceutical composition, specifically the invention discloses 24-methylene basic ring jackfruit alcohol ferulic acid ester 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.
Research thinks that the main active in the oryzanol is cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester.Existing document discloses the method for extracting 24-methylene basic ring jackfruit alcohol ferulic acid ester from Testa oryzae oil or oryzanol.CN200810113430.9, JP63104948A all disclose the technical scheme that obtains 24-methylene basic ring jackfruit alcohol ferulic acid ester from the oryzanol raw material; Also can utilize organic chemistry Synthetic 2 4-methylene basic ring jackfruit alcohol ferulic acid ester, Metabolism ofr-oryzanol in rabbit (YAKUGAKU ZASSHI (Japanese pharmaceutical journal), 1980.100 (10) .1011-1018) discloses a kind of technical scheme of Synthetic 2 4-methylene basic ring jackfruit alcohol ferulic acid ester.The problem that exists during oryzanol is used is that oryzanol is insoluble in water, easily oxidation, and this causes oryzanol to be difficult to make a kind of stable formulation.When isolating single 24-methylene basic ring jackfruit alcohol ferulic acid ester by technological means, it is more severe that dissolubility and stability problem become.Extremely low dissolubility and easy oxidation not only cause absorbance low, difficult quality control in producing simultaneously.Provide some to solve the technical scheme of oryzanol solubility in the existing technology, for example CN123428, CN2007100156403, CN2004100945568 etc. disclose the technical scheme that improves the oryzanol dissolubility, but these schemes exist the defective of self on the one hand, during such as oily solubility preparation clinical practice patient's pain sensation more intense, easily cause muscle caking, onset slow; The liposome cost is very high, the production process quality is wayward etc.These schemes do not have the open solubility that how to solve 24-methylene basic ring jackfruit alcohol ferulic acid ester yet on the other hand.
Therefore, still need the 24-methylene basic ring jackfruit alcohol ferulic acid ester preparation scheme that a kind of preparation technology is simple, easy to use, therapeutic effect is good, side effect is little in the prior art.
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 pure ferulic acid ester of 24-methylene basic ring jackfruit 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.
Among the present invention, 24-methylene basic ring jackfruit alcohol ferulic acid ester does not limit the source, can extract from Testa oryzae oil or oryzanol raw material by the whole bag of tricks, can be to adopt chemical method synthetic yet.
In research 24-methylene basic ring jackfruit alcohol ferulic acid ester preparation process, the inventor is surprised to find that, in preparation, add a certain amount of phospholipid and cholate and can improve the dissolubility of 24-methylene basic ring jackfruit alcohol ferulic acid ester in water significantly, form the compositions of clarification, stable in properties.And, can significantly increase the dissolubility of 24-methylene basic ring jackfruit alcohol ferulic acid ester in water with phospholipid substance and cholate class material mixing use, its effect is better than the two independent use.Do not need to add oil-phase component in the said composition, do not form Emulsion yet, 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, and compositions do 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 24-methylene basic ring jackfruit alcohol ferulic acid ester, phospholipid and bile acid and/or its salt.Wherein, 24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt, phospholipid mass ratio can be 1:1-100:1-500; Preferably, 24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt, phospholipid mass ratio can be 1:1-50:1-100; Preferred, 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 the micellar solution form.
On the other hand, the present invention also provides a kind of lyophilized injectable powder, and it contains 24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt and the phospholipid for the treatment of effective dose.Wherein, 24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt, phospholipid mass ratio can be 1:1-100:1-500; Preferably, 24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt, phospholipid mass ratio can be 1:1-50:1-100; Preferred, 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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, comprises two kinds of unit formulations, wherein comprises 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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.24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt in first unit formulation, phospholipid mass ratio can be 1:1-100:1-500; Preferably, 24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt, phospholipid mass ratio can be 1:1-50:1-100; Preferred, 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 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 24-methylene basic ring jackfruit alcohol ferulic acid ester 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 24-methylene basic ring jackfruit alcohol ferulic acid ester 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 24-methylene basic ring jackfruit alcohol ferulic acid ester, phospholipid and bile acid and/or its salt are mixed, stir.Specifically comprise the steps:
1. 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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.24-methylene basic ring jackfruit alcohol ferulic acid ester, 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, 24-methylene basic ring jackfruit alcohol ferulic acid ester can be dissolved in the ethanol, stir evenly the back and add phospholipid, bile acid and/or its salt mixture.24-methylene basic ring jackfruit alcohol ferulic acid ester, 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.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 1
24-methylene basic ring jackfruit alcohol ferulic acid ester 10mg
Soybean phospholipid 50mg
Sweet ammonia ursodesoxycholic acid 50mg
Glycine 50mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, soybean phospholipid, sweet ammonia ursodesoxycholic acid are dissolved in the 5ml ethyl acetate, are heated to 80 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In organic facies, add dissolved glycine water for injection to full dose, 60 ℃ of following abundant stirring and evenly mixings, get final product injection of the present invention.Regulate PH to 7.2 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 2
24-methylene basic ring jackfruit alcohol ferulic acid ester 10mg
Soybean phospholipid 1000mg
Phosphatidylcholine 100mg
Chenodeoxy cholic acid 400mg
Mannitol 100mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, chenodeoxy cholic acid, soybean phospholipid, phosphatidylcholine, mannitol are dissolved in the 8ml propylene glycol, are heated to 80 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In organic facies, add to the full amount of water for injection, 70 ℃ of following abundant stirring and evenly mixings, get final product injection of the present invention.Regulate PH to 7.0 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 3
24-methylene basic ring jackfruit alcohol ferulic acid ester 20mg
Semen sojae atricolor sphingomyelins 100mg
Taurodeoxycholic acid 200mg
Glucose 100mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, Semen sojae atricolor sphingomyelins, taurodeoxycholic acid are dissolved in the 10ml glycerol, are heated to 80 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In organic facies, add dissolved glucose water for injection to full dose, 60 ℃ of following abundant stirring and evenly mixings, get final product injection of the present invention.Regulate PH to 6.5 with sodium bicarbonate 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
24-methylene basic ring jackfruit alcohol ferulic acid ester 2mg
Glycocholic acid 100mg
Hydrogenation egg yolk lecithin 500mg
Ethylene glycol 10mg
Lactose 20mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, glycocholic acid, hydrogenation egg yolk lecithin are dissolved in the 10ml ethanol, are heated to 70 ℃ of stirrings, add ethylene glycol while stirring, the heating mixing is to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In organic facies, add dissolved lactose water for injection to full dose, 80 ℃ of following abundant stirring and evenly mixings, get final product injection of the present invention.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 5
24-methylene basic ring jackfruit alcohol ferulic acid ester 5mg
Sweet ammonia deoxycholic acid 300mg
PHOSPHATIDYL ETHANOLAMINE 400mg
Thioglycerol 20mg
Sodium sulfite 10mg
Glycerol 15mg
Mannitol 50mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, sweet ammonia deoxycholic acid, PHOSPHATIDYL ETHANOLAMINE are dissolved in the 15ml 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 organic facies, add dissolved sodium sulfite, glycerol, mannitol water for injection to full dose, 60 ℃ of following 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 6
24-methylene basic ring jackfruit alcohol ferulic acid ester 50mg
Deoxycholic acid 500mg
Soybean phospholipid 400mg
Polyethylene Glycol 800 20mg
Methyl-beta cyclodextrin 20mg
Sucrose 150mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, deoxycholic acid, soybean phospholipid, Polyethylene Glycol 800 are dissolved in the 5ml chloroform, are heated to 80 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In organic facies, add dissolved methyl-beta cyclodextrin and sucrose 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 7
24-methylene basic ring jackfruit alcohol ferulic acid ester 40mg
Phosphatidyl glycerol 500mg
Sweet ammonia sodium deoxycholate 1000mg
Tween 80 30mg
Lysine 10mg
Glycine 100mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, phosphatidyl glycerol, sweet ammonia sodium deoxycholate, tween 80 are dissolved in the 5ml ethyl acetate, are heated to 70 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In organic facies, add dissolved lysine and glycine 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 8
24-methylene basic ring jackfruit alcohol ferulic acid ester 5mg
Phosphatidylcholine 100mg
Taurocholic acid 80mg
Lysine 10mg
Glucose 15mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, phosphatidylcholine, taurocholic acid are dissolved in the 10ml acetone, are heated to 75 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In organic facies, add dissolved glucose, lysine water for injection to full dose, 60 ℃ of following 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 and is filled to cillin bottle.
Embodiment 9
24-methylene basic ring jackfruit alcohol ferulic acid ester 20mg
Phosphatidylcholine 200mg
Taurocholic acid 140mg
Sodium sulfite 50mg
Mannitol 50mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, phosphatidylcholine, taurocholic acid are dissolved in the 3ml 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, sodium sulfite water for injection to full dose, 60 ℃ of abundant stirring and evenly mixings down, to adopt sodium bicarbonate to regulate PH to PH then be 6, 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
24-methylene basic ring jackfruit alcohol ferulic acid ester 20mg
Phosphatidylcholine 100mg
Taurocholic acid 200mg
Glucose 100mg
Sodium chloride 90mg
Vitamin E 15mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, phosphatidylcholine, taurocholic acid are dissolved in the 10ml ethanol, are heated to 70 ℃ of stirrings, to fully dissolving.Adopt the method distillation of reduction vaporization, obtain organic facies.In organic facies, add dissolved glucose, sodium chloride, vitamin E water for injection to full dose, 60 ℃ of following 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 11
First unit formulation
24-methylene basic ring jackfruit 10mg
The alcohol ferulic acid ester
Soybean phospholipid 50mg
Sweet ammonia ursodesoxycholic acid 50mg
Second unit formulation
Glycine 50mg
Water for injection 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, soybean phospholipid, sweet ammonia ursodesoxycholic acid are dissolved in the 5ml ethyl acetate, the method of employing distilling under reduced pressure is removed the ethyl acetate 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;
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 12
First unit formulation
24-methylene basic ring jackfruit 10mg
The alcohol ferulic acid ester
Soybean phospholipid 1000mg
Chenodeoxy cholic acid 400mg
Second unit formulation
Glycine 10mg
Water for injection 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, chenodeoxy cholic acid, soybean phospholipid are dissolved in the 15ml ethanol, the method of employing distilling under reduced pressure is removed the ethanol 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;
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 13
First unit formulation
24-methylene basic ring jackfruit 15mg
The alcohol ferulic acid ester
Hydrogenation egg yolk lecithin 150mg
Glycocholic acid 200mg
Second unit formulation
Ethylene glycol 100mg
Lactose 20mg
Water for injection 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, glycocholic acid, hydrogenation egg yolk lecithin are dissolved in the 10ml ethanol, the method of employing distilling under reduced pressure is removed the ethanol in the solution under fully stirring under 70 ℃, carry out fine straining with the 0.22um microporous filter membrane, divide to be filled to cillin bottle, label is A;
Ethylene glycol, lactose are dissolved in the 10ml water, add 0.05% injection activated carbon then and stirred 30 minutes.Add sodium hydroxide solution and regulate pH to 7.8.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 14
First unit formulation
24-methylene basic ring jackfruit 5mg
The alcohol ferulic acid ester
Phosphatidylcholine 300mg
Sweet ammonia sodium deoxycholate 400mg
Propylene glycol 10mg
Second unit formulation
Glycerol 20mg
Glycine 100mg
Sodium sulfite 15mg
Water for injection 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, phosphatidylcholine, sweet ammonia sodium deoxycholate and propylene glycol are dissolved in the 15ml ethyl acetate, the method of employing distilling under reduced pressure is removed the ethyl acetate in the solution under fully stirring under 80 ℃, carry out fine straining with the 0.22um microporous filter membrane, divide to be filled to cillin bottle, label is A;
Glycerol, glycine, sodium sulfite 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 15
First unit formulation
24-methylene basic ring jackfruit 15mg
The alcohol ferulic acid ester
Egg yolk lecithin 180mg
Tauroursodeoxycholic acid potassium 150mg
Second unit formulation
Glycerol 15mg
Polyethylene Glycol 800 7mg
Water for injection 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, egg yolk lecithin, tauroursodeoxycholic acid potassium are dissolved in the 10ml dichloromethane, the method of employing distilling under reduced pressure is removed the dichloromethane in the solution under fully stirring under 80 ℃, carry out fine straining with the 0.22um microporous filter membrane, divide to be filled to cillin bottle, label is A;
Glycerol, Polyethylene Glycol 800 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 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 16
First unit formulation
24-methylene basic ring jackfruit 10mg
The alcohol ferulic acid ester
Phosphatidylcholine 180mg
Cholyltaurine 200mg
Glycerol 10mg
Second unit formulation
Lysine 10mg
Lactose 10mg
Water for injection 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, phosphatidylcholine, cholyltaurine and glycerol are dissolved in the 10ml ethanol, the method of employing distilling under reduced pressure is removed the ethanol in the solution under fully stirring under 70 ℃, carry out fine straining with the 0.22um microporous filter membrane, divide to be filled to cillin bottle, label is A;
Lysine, 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 17
First unit formulation
24-methylene basic ring jackfruit 40mg
The alcohol ferulic acid ester
Phosphatidyl glycerol 480mg
NaTDC 200mg
Glycerol 10mg
Second unit formulation
Propylene glycol 10mg
Vitamin C 2mg
Water for injection 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, S-PC, NaTDC, glycerol are dissolved in the 10ml acetone, the method of employing distilling under reduced pressure is removed the acetone 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;
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.The clarity of solution determination methods of embodiment 1-17 system
Solution during the clinical use of the solution of the foregoing description preparation or product, 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 1～10 system 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
24-methylene basic ring jackfruit alcohol ferulic acid ester 20mg
Soybean phospholipid 250mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, soybean phospholipid are dissolved in the ethyl acetate, are heated to 60 ℃ of stirrings, to fully dissolving.Adopt the method evaporate to dryness ethyl acetate of reduction vaporization, obtain jelly, 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.
Comparative examples 2
24-methylene basic ring jackfruit alcohol ferulic acid ester 20mg
NaGC 100mg
Water for injection is to 10ml
24-methylene basic ring jackfruit alcohol ferulic acid ester, NaGC are dissolved in the ethanol, are heated to 70 ℃ of stirrings, to fully dissolving.Adopt the method evaporate to dryness ethanol of reduction vaporization, obtain jelly, 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.
Contrast experiment's example 3
24-methylene basic ring jackfruit alcohol ferulic acid ester 4.5mg
Soybean oil 30mg
Soybean phospholipid 10mg
Vitamin E 0.1mg
Glycerol 2.5mg
Water for injection is to 10ml
Soybean oil, 24-methylene basic ring jackfruit alcohol ferulic acid ester 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 18
Get the injection freeze-dried powder of embodiment 1 preparation 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 | 99.91 | 98.90 | 99.80 | 98.85 |
| PH | 8.30 | 8.25 | 8.30 | 8.30 | 8.27 |
By above-mentioned data as seen, present composition stable in properties can keep its effectiveness for a long time.
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 19 particle diameters detect
Contrast experiment's example 3 and the injection that the embodiment of the invention 2 prepares have been 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 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) | 1018.2 | 1027.0 | 1035.1 | 1015.8 | 1026.0 |
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 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 20
To carry out the irritation test of animal blood vessels according to the lyophilized products redissolution solution that embodiment 1 method makes.Method is to get 24 of health, ear edge not damaged rabbit, is divided into two groups at random by body weight, i.e. injection 24-methylene basic ring jackfruit alcohol ferulic acid ester 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 injection 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 injection 24-methylene basic ring jackfruit alcohol ferulic acid ester does not have the obvious stimulation effect to the rabbit auricular vein under the experiment condition.
Claims (61)
1. a 24-methylene basic ring jackfruit alcohol ferulic acid ester pharmaceutical composition comprises 24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt, the phospholipid for the treatment of effective dose.
2. according to the pharmaceutical composition of claim 1, wherein 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt, phospholipid mass ratio are 1:1-50:1-100.
4. according to the pharmaceutical composition of claim 3,24-methylene basic ring jackfruit alcohol ferulic acid ester, 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: 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 24-methylene basic ring jackfruit alcohol ferulic acid ester 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, 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. a lyophilized injectable powder, it contains 24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt and the phospholipid for the treatment of effective dose.
18. according to the lyophilized injectable powder of claim 17, wherein 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt, phospholipid mass ratio are 1:1-50:1-100.
20. according to the lyophilized injectable powder of claim 19,24-methylene basic ring jackfruit alcohol ferulic acid ester, bile acid and/or its salt, phospholipid mass ratio are 1:5-40:5-80.
21. pharmaceutical composition according to each claim in the claim 17～20, its preparation method may further comprise the steps: 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 24-methylene basic ring jackfruit alcohol ferulic acid ester 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 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 33,24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 34,24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 35,24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 24-methylene basic ring jackfruit alcohol ferulic acid ester 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 24-methylene basic ring jackfruit alcohol ferulic acid ester and phospholipid, bile acid and/or its salt is dissolved in organic solvent, distilling under reduced pressure.
4. 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 24-methylene basic ring jackfruit alcohol ferulic acid ester 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. 24-methylene basic ring jackfruit alcohol ferulic acid ester, 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 adding active carbon, filtration, degerming, 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 24-methylene basic ring jackfruit alcohol ferulic acid ester 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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