CN102133211B - Asarone medical composition as well as preparation method and preparation thereof - Google Patents
Asarone medical composition as well as preparation method and preparation thereof Download PDFInfo
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- CN102133211B CN102133211B CN2011100092724A CN201110009272A CN102133211B CN 102133211 B CN102133211 B CN 102133211B CN 2011100092724 A CN2011100092724 A CN 2011100092724A CN 201110009272 A CN201110009272 A CN 201110009272A CN 102133211 B CN102133211 B CN 102133211B
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- Prior art keywords
- asarone
- water
- acid
- pharmaceutical composition
- injection
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an asarone medical composition. The composition comprises asarone, phospholipid, bile acid, amino acid and a strongly alkaline substance. Furthermore, the invention discloses a preparation method of the medical composition solution and injection preparation prepared from the medical composition. The experiments conducted by the applicant prove that the problem that the asarone has less possibility of being dissolved in water is solved by adopting the medical composition, and the obtained medical composition has good stability and is suitable for industrial production.
Description
Technical field
The invention discloses a kind of asarone pharmaceutical composition; Comprise asarone, phospholipid, bile acid, aminoacid, strong alkaline substance; Further the invention discloses said preparation of drug combination method and, belong to pharmaceutical field based on the ejection preparation of this pharmaceutical composition.
Background technology
Asarone has another name called alpha-ararin or α-asaricin, extracts the volatile oil from Rhizoma Acori Graminei, also can be synthetic by the chemical industry method.Extensive studies is found effects such as asarone has cough-relieving, eliminates the phlegm, relievings asthma, calmness, spasmolytic, convulsion, also can suppress Diplococcus pneumoniae, staphylococcus aureus and colibacillary growth, is a kind of application ingredient very widely.
The dissolubility of asarone in water is very low; Difference according to temperature; Its dissolubility is between 0.1-1mg/ml; In common organic solvent such as ethanol, methanol dissolubility also only can reach 1.87,1.76mg/ml, this shows and adopt water-soluble or be dissolved in the asarone solution that common organic solvent can not obtain higher concentration.The pharmaceutical usage for preparing the good asarone solution of a kind of dissolubility or other forms of asarin composite form and asarone is closely related, and lower dissolubility will cause its prepared medicine that goes out need strengthen consumption could onset, and safety does not guarantee.
In order to make asarone soluble in water, multiple asarin composite form has been arranged by broad research, main research direction is that asarone is prepared into liquid preparation such as liquid forms such as emulsion, microemulsion.
One Chinese patent application 200510073418.6 discloses a kind of injection solution of asarone, and prepared injection comprises compositions such as asarone, tween, sodium sulfite, calcium disodium edetate, thereby improves the dissolubility of asarone.For the injection that makes its preparation has good dissolution, this scheme has been used a large amount of tweens, and the asarone that dissolves a unit quantity need use the tween of 15 times of amounts at most.Because Asarone injection is in order to be applied to clinical treatment with solution, and tween has significant side effects as pharmaceutic adjuvant, so the disclosed injection clinical safety of this patent is not good.
One Chinese patent application 200510130064.4 discloses a kind of asarone pharmaceutical injection Emulsion.Emulsion is a kind of suspension by water, oil, emulsifying agent preparation, contains components such as injection vegetable oil, emulsifying agent, isoosmotic adjusting agent.Because all contain different classes of injection plant wet goods macromole oils and fats in the Emulsion, its particle diameter is bigger, and is limited to the improvement of asarone dissolubility; And Emulsion is a kind of suspension, and long-term shelf-stability is bad, has medicine to separate out easily.
One Chinese patent application 200610092307.7 discloses a kind of submicron emulsion preparation equally, is active component with the asarone, adopts excipient substances such as oil phase, water, emulsifying agent, co-emulsifier as carrier.As stated, owing to used plant wet goods oil component, prepared microemulsion particle diameter to be not less than 100nm (according to its description).The excipient substance kind of this microemulsion use is a lot of in addition, and quality is restive in actual production, and the stability of its pharmaceutical preparation long-term storage can be affected.
In order to overcome the defective of such scheme, the solubilising scheme based on micellar system becomes the research focus in recent years, is that the different micelle carrier system of starting point structure is by broad research with phospholipid or Polyethylene Glycol-12-hydroxy stearic acid ester especially.For example one Chinese patent application 200810184788 discloses a kind of to be the solubilizing systems of drug-loading system with protein-phospholipid, can to access the dispersion of particle mean size less than 1000nm.Thereby yet being more suitable in organic solvent or macromole oil substances, dissolving the solubilizing effect that reaches suitable at this solubilizing systems described in its technical scheme as this application on the one hand, the solubilizing effect in water or aqueous solution is not good with stability, drug loading.Even if also can only reach the level that is not less than 90nm according to its test its particle diameter in oils and fats, dispersion effect is unsatisfactory; On the other hand, as a kind of solubilizing systems widely, those skilled in the art do not know to expect whether it is applicable to that asarone perhaps is used for the solubilizing effect of asarone.One Chinese patent application 200710012875 discloses a kind of solubilizing systems that is the basis with HS15 (Polyethylene Glycol-12-hydroxy stearic acid ester); Use with HS15 and the collocation of other kinds of surface activating agents; Especially can use with the phospholipid collocation; Although this scheme can reach solubilizing effect and dispersion preferably, yet its resulting solution drug loading is too low, needs to use a large amount of HS15, phospholipid etc. just can reach its effect; This scheme has been used the kinds of surface activating agent, and dispersion is very complicated, and those skilled in the art can't expect that its different auxiliary materials to the mechanism of action of different pharmaceutical composition, can't expect more whether it can be used for asarone or effect; And this technical scheme finally exists in a large amount of ethanol, can't avoid alcoholic acid side effect.One Chinese patent application 200910164296 is a principal agent with the asarone, and HS15 is the injection of solubilizing agent, thereby has tentatively improved the solubility property of asarone.For select using HS15 as for the solubilising adjuvant, all there is following problems in this type scheme: on the one hand at home at present HS15 also be not legal available adjuvant, no commercial production possibility of its application; On the other hand people estimate HS15 as the lower adjuvant of toxicity be since for a long time research worker attempt replacing the solubilising adjuvant of polyoxyethylene castor oil as taxane (paclitaxel, docetaxel) with HS15; Its toxicity and side effect are lower than polyoxyethylene castor oil; And do not mean that HS15 is applied in other drug intoxication property and also is lower than other solubilising adjuvant; In fact HS15 belongs to the bigger adjuvant of a kind of toxicity in excipient substance; The Chinese Academy of Medical Sciences for example; The article that Zhang Jia etc. delivered in " Chinese Journal of New Drugs " 2008.17 phases " four kinds of solubilizing agents such as Tween-80 and poloxamer 188 are to chmice acute toxicity " is studied the toxicity of Tween-80 (Tween 80), poloxamer 188, HP-, HS15; And through experiment confirm with the acute toxicity size opinion, HS15＞Tween-80＞HP-＞poloxamer 188.Though that is to say with HS15 to replace tween to improve its dissolubility, also increased its toxic and side effects simultaneously as the solubilizing agent of asarone.Opinion therefrom, HS15 is not a kind of ideal asarone solubilizing agent.One Chinese patent application 2009100599248 discloses a kind of injection of asarone, is a kind of micellar solution, has tentatively solved the bigger problem of common Aarin preparation particle diameter.But still there is following problem in this scheme: (1) raw material availability and drug loading are low.This scheme adopts the method for centrifugal acquisition asarone micelle thin film to obtain injection; In centrifugal process, can form tangible asarone loss (2) method for preparing more complicated, need in the preparation that the using ultrasound wavelength-division is loose, centrifugation method can't be applied to large-scale industrial production.
In sum, there are problems in the disclosed Aarin preparation of prior art in that to improve stripping still unsatisfactory.
Summary of the invention
In Aarin preparation research, the pleasantly surprised discovery of applicant is used for asarone and can significantly improves its dissolubility at aqueous solution, stability to wherein adding nonacid aminoacid and strong alkaline substance (sodium hydroxide, potassium hydroxide or the mixture of the two) in the aminoacid on traditional phospholipid, cholic acid basis.Adopt this scheme need not use the bigger solubilising adjuvants of toxicity such as traditional tween, HS15, avoided its side effect; And this scheme method for preparing is simple, need not use centrifugal, ultrasonic etc. can't be applied to the big technology of producing of industry, has reduced production cost, is suitable for industrial mass production; Adopt the resulting solution particle diameter of this scheme less than 50nm, mean diameter is not higher than 25nm, is starkly lower than the product that prior art can provide; The solution that this scheme provided adopts normal saline, glucose etc. to be diluted to desired concn when clinical practice as required and gets final product, the convenient use.
Based on above-mentioned discovery; The invention discloses a kind of asarone pharmaceutical composition; Be a kind of solution; Comprise asarone, phospholipid, bile acid, aminoacid, strong alkaline substance, wherein said aminoacid is selected from one or more the mixture in glycine, alanine, leucine, isoleucine, valine, phenylalanine, methionine, tryptophan, serine, glutamine, threonine, cysteine, agedoite, tyrosine, lysine, arginine, the histidine; Described strong alkaline substance is sodium hydroxide, potassium hydroxide or the mixture of the two; Further, the invention discloses the method for preparing of described asarone pharmaceutical composition solution and the application on preparation.
Pharmaceutical composition of the present invention, the mass ratio of asarone wherein, phospholipid, bile acid, aminoacid, strong alkaline substance can be 1: 1-100: 1-150: 1-200: 0.3-30; Preferably, the mass ratio of asarone, phospholipid, bile acid, aminoacid, strong alkaline substance can be 1: 2-50: 2-60: 1-80: 0.5-10.
The aminoacid that the present invention is used; Be the nonacid aminoacid in the aminoacid; Be selected from one or more the mixture in glycine, alanine, leucine, isoleucine, valine, phenylalanine, methionine, tryptophan, serine, glutamine, threonine, cysteine, agedoite, tyrosine, lysine, arginine, the histidine, preferably the mixture of one or more in glycine, alanine, valine, leucine, the isoleucine.
The used strong alkaline substance of the present invention is sodium hydroxide, potassium hydroxide or the mixture of the two; Purpose is to make the aqueous phase solution of pharmaceutical composition of the present invention keep alkalescence; If those skilled in the art adopt other that alkalogenic material of aqueous solution also is fine, it is the wide material sources of considering the two that the present invention uses sodium hydroxide, potassium hydroxide, and preparation is simple; Usually in pharmacy, use, can be applicable to large-scale production.
The used phospholipid of the present invention is selected from one or more mixture of 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, two Petiolus Trachycarpi phosphatidylcholines, two Petiolus Trachycarpi PHOSPHATIDYL ETHANOLAMINEs, distearyl phosphatidylcholine, two Petiolus Trachycarpi phosphatidyl glycerol fat, two Petiolus Trachycarpi Phosphatidylserine, dimyristoyl phosphatidyl choline, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two myristoyl PHOSPHATIDYL ETHANOLAMINEs, dilinoleoylphosphatidylcholine, dilinoleic acid glyceride phosphatidylcholine, dilinoleic acid glyceride PHOSPHATIDYL ETHANOLAMINE, dilinoleic acid glyceride phosphatidyl glycerol; The mixture of one or more in 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, the phosphatidylinositols, most preferably soybean phospholipid, egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE.
The used bile acid of the present invention is selected from free bile acid, conjugated bile acid or its mixture; Free cholic 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 that carboxyl and glycine (H2NCH2COOH) or taurine (H2NCH2CH2SO3H) or other in the above-mentioned free bile acid contain the product after amino in the amino chemical compound forms amido link, is preferably glycocholic acid, sweet ammonia deoxycholic acid, sweet ammonia chenodeoxycholic acid, sweet ammonia ursodesoxycholic acid, taurocholic acid, taurodeoxycholic acid, Taurochenodeoxycholic Acid, tauroursodeoxycholic acid;
On the basis of further investigation pharmaceutical composition SOLUTION PROPERTIES of the present invention, the applicant further finds through in the present composition, adding the dissolubility that water miscible polyhydric alcohol can improve the present composition.The used polyhydric alcohol of the present invention is one type of water-soluble polyol, and especially micromolecular water-soluble polyol includes but not limited to propylene glycol, glycerin, ethylene glycol, Polyethylene Glycol, preferred propylene glycol.Described Polyethylene Glycol can be pharmaceutically available at present any water miscible Polyethylene Glycol, includes but not limited to PEG200, PEG400, PEG600, PEG800 etc., preferred PEG400.
When adding water-soluble polyol, the amount of adding can be regulated according to the needs of actual preparation, and its common quality doubly serves as preferred with the 0.1-1000 of asarone consumption.
On the basis of the above, in conjunction with the needs of preparation, can also add common pharmaceutic adjuvant in the pharmaceutical composition solution of the present invention and open regulator, stabilizing agent, antioxidant, lyophilization excipient etc. as waiting.
Described grade is opened regulator and is included but not limited to 0.9% sodium chloride solution, 5% glucose solution, preferably adopts 0.9% sodium chloride solution.
Described stabilizing agent comprises but is not limited to one or more the mixture in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, butylated hydroxyarisol, dibutyl phenol, propyl gallate, tocopherol, methionine, cysteine hydrochloride, acetylcysteine, N-acetyl-DL-methionine, ascorbyl palmitate, ethylenediaminetetraacetic acid, the disodiumedetate; A kind of or its mixture, most preferably sodium sulfite in preferred sodium sulfite, propyl gallate, the ascorbyl palmitate.
Described antioxidant comprises but is not limited to anhydrous sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, butylated hydroxyarisol; Preferred anhydrous sodium sulfite, sodium pyrosulfite, sodium sulfite, most preferably anhydrous sodium sulfite.
Described excipient can be selected from but be not limited to is in mannitol, lactose, glucose, sorbitol, sodium chloride, gelatin hydrolysate, dextran, sucrose, glycine, the polyvinylpyrrolidone etc. one or more; Be preferably mannitol or glucose, most preferably mannitol.
Pharmaceutical composition solution of the present invention can be prepared as Asarone injection through the formulation method of routine, includes but not limited to injection, freeze-dried powder, concentrated solution, in conjunction with needs, especially Asarone injection liquid clinical and application.
Pharmaceutical composition of the present invention can be prepared as Asarone injection liquid through technologies such as simple filtering degerming, and prepared injection has the excellent specific property of pharmaceutical composition solution, the convenient use.
To those skilled in the art, be that freeze-dried powder is a kind of common preparation process with formulations prepared from solutions.Using excipient through in pharmaceutical composition solution of the present invention, adding lyophilizing, can be freeze-dried powder like one or more the mixture in sucrose, glucose, lactose, mannitol, the sorbitol etc. with preparation of pharmaceutical compositions of the present invention under suitable lyophilisation condition.
On this basis, consider the needs of a large amount of storages and transportation, the invention also discloses a kind of commercial packing, be based on that pharmaceutical composition of the present invention obtains.Described commercial packing comprises two separate units, and first module contains asarone, phospholipid and bile acid; Unit second is the aqueous phase solvent that contains aminoacid and strong alkaline substance; Aminoacid wherein is one or more the mixture in glycine, alanine, leucine, isoleucine, valine, phenylalanine, methionine, tryptophan, serine, glutamine, threonine, cysteine, agedoite, tyrosine, lysine, arginine, the histidine, and strong alkaline substance is sodium hydroxide, potassium hydroxide or the mixture of the two.When clinical practice,, be dissolved in glucose or the normal saline according to clinical needs and use two separate unit mix homogeneously in the commercial packing.
The invention provides asarone preparation of drug combination method; Comprise asarone, phospholipid, bile acid joined in the organic solvent and dissolve; Remove the step of organic solvent, further comprise adding the step that the water that contains aminoacid, strong alkaline substance is prepared into pharmaceutical composition micellar solution.
In one embodiment of the invention, a kind of method for preparing of Asarone injection liquid is provided, has comprised the steps:
1. asarone, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution.Remove organic solvent, as organic facies;
2. with the mixing that is added to the water of aminoacid, strong alkaline substance and/or other adjuvant, dissolving is as water;
3. with above-mentioned organic facies and water mix homogeneously, process Asarone injection liquid according to the conventional method for preparing of injection.
In another embodiment of the present invention, a kind of method for preparing of asarone freeze-dried powder is provided, has comprised the steps:
1. asarone, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution, remove organic solvent, as organic facies;
2. with mixing that is added to the water such as freeze-dried excipient, aminoacid and strong alkaline substances, dissolving is as water;
3. with the organic facies and the water mix homogeneously of above-mentioned steps, process freeze-dried powder according to the method for preparing of conventional lyophilized formulations.
In another embodiment of the present invention, a kind of method for preparing of asarone commercial packing is provided, has comprised the steps:
1. asarone, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution, remove organic solvent, add water-soluble polyol as organic facies;
2. aminoacid, strong alkaline substance and/or other adjuvants commonly used are dissolved in the water, obtain water;
3. above-mentioned organic facies and water are processed organic facies concentrated solution for injection and water injection according to the method for preparing of conventional injection respectively, and packing is formed commercial packing.
In another embodiment of the present invention, the method for preparing of another kind of asarone commercial packing is provided, has comprised the steps:
1. asarone, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution, as organic facies;
2. aminoacid, strong alkaline substance and/or other adjuvants commonly used are dissolved in the water, obtain water;
3. above-mentioned organic facies and water are processed organic facies concentrated solution for injection and water injection according to the method for preparing of conventional injection respectively, and packing is formed commercial packing.
In above-mentioned method for preparing, described organic solvent general reference can be dissolved the organic solvent of asarone, phospholipid, bile acid, includes but not limited to one or more the mixture in ethanol, ethyl acetate, ether, the acetone.Asarone, phospholipid, bile acid can join in the organic solvent with random order, in this step, also can add other adjuvants.
In above-mentioned method for preparing; The order that water adds adjuvant is not restricted. and can be when the preparation water according to the needs of preparation to wherein adding proper supplementary material; To those skilled in the art, it is conspicuous selecting proper supplementary material to conditions such as different specifications, different dosage forms.
Asarone can be widely used in treating diseases such as respiratory tract infection, tracheitis and bronchitis, asthma, acute and chronic cholecystitis, cholelithiasis, epilepsy; Therefore obvious, the application provides the purposes of asarone pharmaceutical composition solution of the present invention in the asarone medicine of the above-mentioned disease of preparation treatment.
Applicant's experiment confirm; With respect to solubilizing systems of the prior art; Common micelle types such as phospholipid-bile acid mixed micelle, albumen-phospholipid micellar system, HS15-phospholipid micellar system for example; Pharmaceutical composition of the present invention joins the solution that forms in phospholipid, the bile acid through employing with the aminoacid strong alkaline substance and has significant synergism; Solubilization to asarone is more obvious, and stability also significantly strengthens, and the gained injection can reach better drug loading and drug level (the highest drug loading about 7%, the concentration of 5mg/ml of only can providing of prior art; And the highest 10% the drug loading that can provide of technical scheme of the present invention, the concentration of 12.5mg/ml).
The specific embodiment:
To explain through embodiment below and realize technical scheme of the present invention, these embodiments do not constitute further qualification to the present invention.Those skilled in the art are equal to replacement or corresponding improvement according to existing knowledge to the present invention, belong to scope of the present invention.In the following example; The applicant provides the method that pharmaceutical composition formulations prepared from solutions of the present invention is become ejection preparation (injection, freeze-dried powder, commercial packing); An instance of only using as pharmaceutical composition of the present invention does not limit pharmaceutical composition solution of the present invention and only is used for this purposes.
Embodiment 1
Asarone, soybean phospholipid, chenodeoxy cholic acid are dissolved in the 1L ethyl acetate, are stirred to mix homogeneously, to fully dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.With alanine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Organic facies is joined the aqueous phase mix homogeneously promptly get pharmaceutical composition solution of the present invention.
(1) asarone, soybean phospholipid, chenodeoxy cholic acid are dissolved in the 1L ethyl acetate, are stirred to mix homogeneously to fully dissolving, the reclaim under reduced pressure ethyl acetate obtains organic facies.With alanine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Organic facies is joined the aqueous phase mix homogeneously obtain micellar solution, add 0.3% injection activated carbon to above-mentioned micellar solution and stirred 30 minutes, after decarburization is filtered; 0.22um microporous filter membrane carries out fine straining; Branch is filled to cillin bottle or peace is cutd open bottle, promptly gets Asarone injection liquid of the present invention, and gained injection concentration is 10mg/ml; Drug loading is 10%, and particle diameter is 24nm.
(2) asarone, soybean phospholipid, chenodeoxy cholic acid are dissolved in the 1L ethyl acetate, are stirred to mix homogeneously to fully dissolving, the reclaim under reduced pressure ethyl acetate obtains organic facies.With alanine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Organic facies is joined the aqueous phase mix homogeneously obtain micellar solution, add mannitol to above-mentioned micellar solution, add 0.3% injection activated carbon and stirred 30 minutes, decarburization after the 0.22um microporous filter membrane carries out fine straining, is adopted following freeze-dry process after filtering:
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 promptly gets.
(3) asarone, soybean phospholipid, chenodeoxy cholic acid are dissolved in the 600ml dehydrated alcohol, are stirred to mix homogeneously to fully dissolving, as organic facies.With alanine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Add 0.3% injection activated carbon to organic facies and aqueous phase respectively 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 or peace is cutd open bottle, and packing promptly gets asarone commercial packing of the present invention respectively.
Embodiment 2
Asarone, phosphatidylcholine, sweet ammonia deoxycholic acid, propylene glycol are dissolved in the 5L ethanol, are heated to 50 ℃ of stirrings, to fully dissolving.Decompression recycling ethanol obtains organic facies; Join in the water for injection mix homogeneously to glycine, potassium hydroxide as water.Promptly get pharmaceutical composition solution of the present invention to organic facies and water mix homogeneously.
(1) aforementioned pharmaceutical compositions solution is added 0.3% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining; Branch is filled to cillin bottle or peace is cutd open bottle; Promptly get Asarone injection liquid of the present invention, gained injection concentration is 5mg/ml, and particle diameter is 15nm.
(2) aforementioned pharmaceutical compositions solution is added lactose, add 0.3% injection activated carbon and stirred 30 minutes, decarburization after the 0.22um microporous filter membrane carries out fine straining, is adopted following freeze-dry process after filtering:
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 promptly gets.
(3) asarone, phosphatidylcholine, sweet ammonia deoxycholic acid are dissolved in the 5L ethanol, are heated to 50 ℃ of stirrings, to fully dissolving.Decompression recycling ethanol adds mixed with propylene glycol then and evenly obtains organic facies; Join in the water for injection mix homogeneously to the glycine potassium hydroxide as water.Add 0.3% injection activated carbon to organic facies and aqueous phase respectively 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 or peace is cutd open bottle, and packing promptly gets asarone commercial packing of the present invention respectively.
Embodiment 3
Asarone, phosphatidylcholine, sweet ammonia deoxycholic acid are dissolved in the 5L ethanol, are heated to 50 ℃ of stirrings, to fully dissolving.Decompression recycling ethanol obtains organic facies; Join in the water for injection mix homogeneously to valine, potassium hydroxide as water.Promptly get pharmaceutical composition solution of the present invention to organic facies and water mix homogeneously.
(1) aforementioned pharmaceutical compositions solution is added 0.3% injection activated carbon and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, and branch is filled to cillin bottle or peace is cutd open bottle, promptly gets Asarone injection liquid of the present invention.Gained injection concentration is 5mg/ml, and particle diameter is 22nm.
(2) aforementioned pharmaceutical compositions solution is added lactose, add 0.3% injection activated carbon and stirred 30 minutes, decarburization after the 0.22um microporous filter membrane carries out fine straining, is adopted following freeze-dry process after filtering:
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 promptly gets.
(3) asarone, phosphatidylcholine, sweet ammonia deoxycholic acid are dissolved in the 1L ethanol, are heated to 50 ℃ of stirrings, to fully dissolving, as organic facies; Join in the water for injection mix homogeneously to valine, potassium hydroxide as water.Add 0.3% injection activated carbon to organic facies and aqueous phase respectively 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 or peace is cutd open bottle, and packing promptly gets asarone commercial packing of the present invention respectively.
Embodiment 4
Asarone, egg yolk sphingomyelins, deoxycholic acid are dissolved in the 10L acetone, are stirred to abundant dissolving.Reclaim under reduced pressure acetone obtains organic facies.Join in the water for injection mix homogeneously to serine, sodium hydroxide as water.Organic facies is added 60 ℃ of following abundant stirring and evenly mixings of aqueous phase, promptly get pharmaceutical composition solution of the present invention.
According to the method for preparing of embodiment 1, can be prepared into injection, freeze-dried powder, commercial packing, gained injection concentration is 10mg/ml, particle diameter is 24nm.
Embodiment 5
Asarone, Semen sojae atricolor sphingomyelins, sweet ammonia deoxycholic acid are dissolved in the 10L ethanol, are stirred to abundant dissolving.Decompression recycling ethanol obtains organic facies.Leucine, threonine, sodium hydroxide are joined in the water for injection mix homogeneously as water.Join the abundant stirring and evenly mixing of aqueous phase to organic facies, promptly get pharmaceutical composition solution of the present invention.
According to the method for embodiment 1, can prepare injection, freeze-dried powder, commercial packing, gained injection concentration is 12.5mg/ml, particle diameter is 23nm.
Embodiment 6
Asarone, sweet ammonia Hyodeoxycholic Acid, Semen sojae atricolor sphingomyelins, PEG400 are dissolved in the 10L ethyl acetate, are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.Join in the water for injection mix homogeneously to glycine, potassium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 2 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 8mg/ml, and particle diameter is 15nm.
Embodiment 7
Asarone, phosphatidylinositols, taurodeoxycholic acid, propylene glycol are dissolved in the 7L ethyl acetate, are heated to 40 ℃ and are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.With sodium hydroxide, potassium hydroxide,, isoleucine joins the water for injection mix homogeneously as water.Add organic facies to aqueous phase and be mixed to abundant dissolving, promptly get pharmaceutical composition solution of the present invention.
Method according to embodiment 2 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 6mg/ml, and drug loading is 9.5%, and particle diameter is 14nm.
Embodiment 8
Asarone, Semen sojae atricolor sphingomyelins, sweet ammonia deoxycholic acid are dissolved in the 5L ethanol, are stirred to abundant dissolving.Decompression recycling ethanol obtains organic facies.Lysine, potassium hydroxide are joined abundant the dissolving as water in the water for injection, promptly get pharmaceutical composition solution of the present invention to wherein adding the organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 5mg/ml, and particle diameter is 23nm.
Embodiment 9
Asarone, Semen sojae atricolor sphingomyelins, sweet ammonia deoxycholic acid, propylene glycol are dissolved in the 5L ethanol, are stirred to abundant dissolving.Decompression recycling ethanol obtains organic facies.Glycine, potassium hydroxide are joined abundant the dissolving as water in the water for injection, promptly get pharmaceutical composition solution of the present invention to wherein adding the organic facies mix homogeneously.
Method according to embodiment 2 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 3.3mg/ml, and drug loading is 9.1%, and particle diameter is 14nm.
Embodiment 10
Asarone, sweet ammonia Hyodeoxycholic Acid, lithocholic acid, Semen sojae atricolor sphingomyelins, hydrogenation egg yolk lecithin, PEG400 are dissolved in the 5L ethyl acetate, are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.Join in the water for injection mix homogeneously to arginine, methionine, potassium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 2 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 4mg/ml, and drug loading is 9.2%, and particle diameter is 16nm.
Embodiment 11
Asarone, lithocholic acid, two Petiolus Trachycarpi PHOSPHATIDYL ETHANOLAMINEs, PEG400 are dissolved in the 5L ethyl acetate, are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.Join in the water for injection mix homogeneously to phenylalanine, cysteine, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 2 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 9.1%, and particle diameter is 13nm.
Embodiment 12
Asarone, sweet ammonia Hyodeoxycholic Acid, Semen sojae atricolor sphingomyelins, Macrogol 200 are dissolved in the 10L ethyl acetate, are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.Join in the water for injection mix homogeneously to agedoite, glutamine, potassium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 2 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 8mg/ml, and drug loading is 8.8%, and particle diameter is 15nm.
Embodiment 13
Asarone, phosphatidylcholine, sweet ammonia deoxycholic acid are dissolved in the 5L ethanol, are stirred to abundant dissolving.Decompression recycling ethanol obtains organic facies.Glycine, potassium hydroxide are joined abundant the dissolving as water in the water for injection, promptly get pharmaceutical composition solution of the present invention to wherein adding the organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 22nm.
Embodiment 14
Asarone, chenodeoxy cholic acid, soybean phospholipid are dissolved in the 10L ethyl acetate, are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.Join in the water for injection mix homogeneously to tyrosine, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 23nm.
Embodiment 15
Asarone, lithocholic acid, soybean phospholipid are dissolved in the 10L ethanol, are stirred to abundant dissolving.Decompression recycling ethanol obtains organic facies.Join in the water for injection mix homogeneously to valine, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 24nm.
Embodiment 16
Asarone, taurocholic acid, distearyl phosphatidylcholine are dissolved in the 10L ethyl acetate, are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.Join in the water for injection mix homogeneously to serine, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 23nm.
Embodiment 17
Asarone, lithocholic acid, soybean phospholipid are dissolved in the 10L acetone, are stirred to abundant dissolving.Reclaim under reduced pressure acetone obtains organic facies.Join in the water for injection mix homogeneously to leucine, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 24nm.
Embodiment 18
Asarone, chenodeoxy cholic acid, soybean phospholipid are dissolved in the 10L ethanol, are stirred to abundant dissolving.Decompression recycling ethanol obtains organic facies.Join in the water for injection mix homogeneously to isoleucine, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 23nm.
Embodiment 19
Asarone, sweet ammonia deoxycholic acid, egg yolk lecithin are dissolved in the 10L ethyl acetate, are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.Join in the water for injection mix homogeneously to phenylalanine, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 24nm.
Embodiment 20
Asarone, taurocholic acid, phosphatidylinositols are dissolved in the 10L ethyl acetate, are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.Join in the water for injection mix homogeneously to methionine, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 24nm.
Embodiment 21
Asarone, tauroursodeoxycholic acid, phosphatidyl glycerol are dissolved in the 10L ethanol, are stirred to abundant dissolving.Decompression recycling ethanol obtains organic facies.Join in the water for injection mix homogeneously to tryptophan, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 24nm.
Embodiment 22
Asarone, glycocholic acid, PHOSPHATIDYL ETHANOLAMINE are dissolved in the 10L ethyl acetate, are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.Join in the water for injection mix homogeneously to glutamine, potassium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 24nm.
Embodiment 23
Asarone, tauroursodeoxycholic acid, phosphatidyl glycerol are dissolved in the 10L ethanol, are stirred to abundant dissolving.Decompression recycling ethanol obtains organic facies.Join in the water for injection mix homogeneously to threonine, potassium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 24nm.
Embodiment 24
Asarone, taurocholic acid, phosphatidylinositols are dissolved in the 10L ethanol, are stirred to abundant dissolving.Decompression recycling ethanol obtains organic facies.Join in the water for injection mix homogeneously to cysteine, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 23nm.
Embodiment 25
Asarone, glycocholic acid, PHOSPHATIDYL ETHANOLAMINE are dissolved in the 10L ethyl acetate, are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.Join in the water for injection mix homogeneously to agedoite, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 2 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 15nm.
Embodiment 26
Asarone, glycocholic acid, PHOSPHATIDYL ETHANOLAMINE are dissolved in the 10L ethyl acetate, are stirred to abundant dissolving.The reclaim under reduced pressure ethyl acetate obtains organic facies.Join in the water for injection mix homogeneously to lysine, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 2 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 14nm.
Embodiment 27
Asarone, lithocholic acid, soybean phospholipid are dissolved in the 10L ethanol, are stirred to abundant dissolving.Decompression recycling ethanol obtains organic facies.Join in the water for injection mix homogeneously to histidine, sodium hydroxide as water.Both got pharmaceutical composition solution of the present invention to water and organic facies mix homogeneously.
Method according to embodiment 1 prepares injection, freeze-dried powder, commercial packing, and gained injection concentration is 10mg/ml, and drug loading is 10%, and particle diameter is 24nm.
The comparative example 1
According to the content of one Chinese patent application 200610092307.7 embodiment 5, the applicant has prepared following Emulsion.
Get oleic acid and injection water, be heated to 40-60 degree centigrade, add purified lecithin and poloxamer, put in the tissue mashing machine, high-speed stirred forms even water, insulation; Other gets asarone and a vitamin E, joins in the Oleum Arachidis hypogaeae semen, is heated to 40-60 degree centigrade, forms oil phase.Under stirring condition, water is slowly added in the oil phase, place tissue mashing machine's high speed to stir and form even colostrum, and it is transferred to even matter in the high pressure homogenization machine rapidly, collect whole emulsions, regulate PH to 7.0 with sodium hydroxide solution.
The comparative example 2
According to the content of one Chinese patent application 2009100599248 embodiment 3, the applicant has prepared following micellar solution.
Take by weighing the Ovum Gallus domesticus Flavus lecithin of 50mg, place the 50ml round-bottomed flask, add solution (10mg/ml) dissolving of the chloroform-methanol equal-volume ratio of 8ml hyocholic acid sodium, obtain liquid storage 1.The a-asarone of 10mg is dissolved in the 1ml chloroformic solution, obtains liquid storage 2,1 and 2 mixing and ultra-sonic dispersion are even.Revolve to steam and remove organic solvent; Bath temperature is 45 degree, is threaded to the taste that does not have organic solvent and forms the layer of transparent thin film, and the sodium dihydrogen phosphate of the PH7.4 of reuse 2.5ml-sodium hydrogen phosphate buffer disperses; Obtain containing the micellar dispersion solution of medicament mixed; With the centrifugal 5min of 13000rpm/min, get supernatant and obtain a-asarone mixed micelle injection, reuse 0.22um filtering with microporous membrane.Getting filtrating and obtain a-asarone mixed micelle injection, is 31nm through measuring its particle diameter, and concentration is 3.67mg/ml, drug loading 7.0%.
Technique scheme is only applicable to the laboratory lab scale, when commercial production, will face the difficult problem that can't use.For example its production scale is amplified to more than hundred feather weight; How the solution more than hundred feather weight being carried out ultrasonic dispersing is difficult to realize in the preparation suitability for industrialized production; Simultaneously the solution more than hundred feather weight is revolved steaming and is dispersed into transparent membrane; In the preparation commercial production, also be very difficult to realize, carry out centrifugally in addition to the above solution of feather weight up to a hundred, use during solid-liquid separation in the synthetic field of medicine up to 13000rpm/min; But this kind equipment is seldom seen in the big production of preparation, and in the big production technology of preparation, uses this equipment very inconvenient.
The comparative example 3
According to the technical scheme of one Chinese patent application 200810187488 embodiment 62, the applicant has prepared following injection:
Asarone 0.1g
Polyene phosphatidylcholine 10g
Tert-butyl alcohol 20ml
Human serum albumin 1g
Sucrose 20g
Get asarone, polyene phosphatidylcholine, the tert-butyl alcohol of recipe quantity; Stirring and dissolving; After adding the abundant mixing of 50% sucrose solution 40ml; Add water for injection to 100ml with circulation of 20000psi high pressure homogenization processing after adding 20% human serum albumin's solution 5ml mixing, its particle diameter is measured in the degerming of 0.22um membrane filtration then.Through its particle diameter of test is 188nm, and concentration is 1mg/ml, and drug loading is 1%.
The comparative example 4
According to one Chinese patent application 200710012875 disclosed technical schemes, the applicant has prepared following embodiment:
Take by weighing the asarone of 1g, the Cita of the HS15 of 30g, 7g EPC, 0.5g is as in the beaker, and adding concentration is 95% ethanol 150ml, and dissolving above-mentioned substance mixing obtains settled solution under nitrogen protection, adds ethanol to 200ml, and mixing both gets.According to clinical method for using, after the employing 5% or 10% glucose injection 100ml dilution, get final product the mixed micelle solution of spontaneous formation clear. through measuring its particle diameter is 34nm, and concentration 3.3mg/ml, drug loading are 2.7%.
The comparative example 5
Glycine is joined mix homogeneously in the sodium hydroxide solution, find that to wherein adding the asarone mix homogeneously precipitation and turbidity appears rapidly in solution, can't form stable solution.
Embodiment 1～27 preparation micellar solution clarity determination methods
According to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method; Just embodiment 1-27 preparation injection or with the freeze-dried powder of embodiment 1-27 preparation with 5ml water for injection jolting dissolving afterwards with the turbidity standard of equivalent place respectively paired than turbid with glass tubing; After 5 minutes, vertical with placing under the umbrella canopy lamp in the darkroom, illumination is 1000Lx in the turbidity standard preparation; Observe relatively from horizontal direction, the clarification of the solution of preparation is not deeper than turbidity standard No. 1.
Test one: room temperature stability is observed
Get the micellar solution of embodiment 2,13 preparations and at room temperature preserved six months, detect variations such as its physicochemical property, be recorded as down table
Table 1 embodiment 13 room temperature reserved sample observing results
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Outward appearance | Clarification | Clarification | Clarification | Clarification | Clarification |
| Content | 100 | 99.94 | 99.92 | 99.88 | 99.81 |
Table 2 embodiment 2 room temperature reserved sample observing results
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Outward appearance | Clarification | Clarification | Clarification | Clarification | Clarification |
| Content | 100 | 99.98 | 99.93 | 99.90 | 99.86 |
Visible by above-mentioned data, injection each item of the present invention detects index and in the room temperature storage process, does not almost change steady quality.Simultaneously can find to add the stability that water-soluble polyol can increase micellar solution asarone of the present invention.
In long-term put procedure, the micellar solution clarification, 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, in the turbidity standard preparation after 5 minutes, vertical same 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.
Test two: particle diameter detects and clarity observation
Injection and comparative example 1 Emulsion, the injection of comparative example 2-4 of getting embodiment 13,2 have carried out particle diameter and clarity detection, gained result such as following table 2.
Get injection and comparative example 1 Emulsion, the mixed micelle injection of comparative example 2-4 of embodiment 13,2 respectively and at room temperature placed six months, observe its clarity, result such as following table 3.
Particle diameter 1 is the particle diameter testing result of the embodiment of the invention 13 injection; Particle diameter 2 is implemented the particle diameter testing result of 2 injection for the present invention; Particle diameter 3 is the particle diameter testing result of comparative example's 1 Emulsion; Particle diameter 4 is the particle diameter testing result of compositions comparative example 2 injection, and particle diameter 5 is comparative example's 3 injection particle diameter testing results, and particle diameter 6 is comparative example 4 a particle diameter testing result.
Table 2 particle diameter testing result
| Sample number | 1 | 2 | 3 | 4 | 5 |
| Particle diameter 1 (nm) | 22 | 23 | 23 | 23 | 22 |
| Particle diameter 2 (nm) | 14 | 15 | 15 | 14 | 15 |
| Particle diameter 3 (nm) | 132.5 | 135.0 | 142.9 | 150.1 | 173.0 |
| Particle diameter 4 (nm) | 30 | 30 | 32 | 31 | 30 |
| Particle diameter 5 (nm) | 187 | 188 | 188 | 187 | 189 |
| Particle diameter 6 (nm) | 34 | 35 | 35 | 34 | 34 |
Table 3 clarity observed result
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Embodiment 13 | Clarification | Clarification | Clarification | Clarification | Clarification |
| Embodiment 2 | Clarification | Clarification | Clarification | Clarification | Clarification |
| Contrast 1 | White emulsion | White emulsion | Separate out | Separate out | Deposition |
| Contrast 2 | Clarification | Clarification | Clarification | Basic clarification | Separate out |
| Contrast 3 | White emulsion | White emulsion | White emulsion | Muddy | Muddy |
| Contrast 4 | Clarification | Clarification | Clarification | Muddy | Muddy |
Can find out by The above results; Micellar solution of the present invention and comparative example's 3 micellar solution particle diameter all is starkly lower than other technologies scheme of the prior art; Technical scheme of the present invention is superior to simple phospholipid, cholic acid system under the situation that does not add polyhydric alcohol; Add after the polyhydric alcohol, the present invention program's obvious technical effects is superior to simple phospholipid, cholate micellar system.Comparative example 3 technical scheme is owing to used material such as macromolecular serum albumin, and causing its gained solution is a kind of emulsion, and particle diameter is greater than 100nm, and long-time stability obviously reduce.The injection of comparative example's 4 gained contains ethanol, be unfavorable for injection, and particle diameter is obviously greater than technical scheme of the present invention, and stability also significantly is lower than technical scheme of the present invention.
Can find out that from above result Asarone injection liquid of the present invention through aminoacid and phospholipid cholic acid, strong alkaline substance are brought into play significant synergism, thereby has the technique effect that significantly is superior to the prior art scheme.
Can find out also from above-mentioned data that simultaneously asarone micellar solution can further be disperseed when micellar solution of the present invention adds polyhydric alcohol, particle diameter reduces.
Test three: the concentration of different injection and drug loading are relatively
Shown in the embodiment of the invention, can reach 12.5mg/ml according to preparation needs injection concentration of the present invention, drug loading reaches 10%.
Compare with asarone solubilising scheme of the prior art, pharmaceutical composition injection solution dissolubility of the present invention obviously is superior to the solubility property that prior art can provide, and can make solution reach higher asarone concentration.
Compare with comparative example 2; It only can provide drug loading is the asarone solution of 7.0% 3.67mg/ml; Pharmaceutical composition solution of the present invention because added aminoacid, strong alkaline substance can make micelle in dissolving, more evenly have significant synergism, thereby effectively improved the solubility property of simple employing phospholipid and cholic acid solubilising.The present invention can provide apparently higher than the micellar solution of prior art asarone concentration, thereby more helps in pharmacy, reducing the consumption of excipient substance, reduces the side effect that clinical drug is used.
Compare with comparative example 3,4; Its use be that high polymer adjuvant such as high molecular weight protein, HS15 and phospholipid combination are used; Owing to used the macromole adjuvant to cause stability not good, the particle diameter of gained solution is also bigger, and technical scheme of the present invention significantly is superior to its technical scheme.
Relatively the embodiment of the invention and comparative example's 2 method for preparing can be seen, ejection preparation method for preparing of the present invention adopts common process, and is simple and convenient, is fit to carry out large-scale industrial production in the industry.And comparative example 2 needs to use technical methods such as ultrasonic dispersing, high speed centrifugation, these methods in laboratory, can prepare sample to use, but in big commercial production, is not having practical value, can't control effectively and quantizes production.
Claims (22)
1. an asarone pharmaceutical composition comprises asarone, phospholipid, bile acid, aminoacid, strong alkaline substance; Said aminoacid is one or more in glycine, alanine, leucine, isoleucine, valine, phenylalanine, methionine, tryptophan, serine, glutamine, threonine, cysteine, agedoite, tyrosine, lysine, arginine, the histidine, and strong alkaline substance is sodium hydroxide, potassium hydroxide or the mixture of the two; Wherein the mass ratio of asarone, phospholipid, bile acid, aminoacid, strong alkaline substance is 1:1-100:1-150:1-200:0.3-30.
2. according to the pharmaceutical composition of claim 1, the mass ratio of asarone, phospholipid, bile acid, aminoacid, strong alkaline substance is 1:2-50:2-60:1-80:0.5-10.
3. according to the pharmaceutical composition of claim 1, said aminoacid is one or more in glycine, alanine, valine, leucine, the isoleucine.
4. according to the pharmaceutical composition of claim 1, said phospholipid is selected from soybean phospholipid, egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols or its mixture.
5. according to the pharmaceutical composition of claim 1, said phospholipid is selected from Semen sojae atricolor sphingomyelins, egg yolk sphingomyelins, hydrogenated soya phosphatide, hydrogenation egg yolk lecithin, two Petiolus Trachycarpi phosphatidylcholines, two Petiolus Trachycarpi PHOSPHATIDYL ETHANOLAMINEs, distearyl phosphatidylcholine, two Petiolus Trachycarpi phosphatidyl glycerol fat, two Petiolus Trachycarpi Phosphatidylserine, dimyristoyl phosphatidyl choline, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two myristoyl PHOSPHATIDYL ETHANOLAMINEs, dilinoleoylphosphatidylcholine, dilinoleic acid glyceride phosphatidylcholine, dilinoleic acid glyceride PHOSPHATIDYL ETHANOLAMINE, dilinoleic acid glyceride phosphatidyl glycerol or its mixture.
6. according to the pharmaceutical composition of claim 1; Bile acid is selected from free bile acid, conjugated bile acid or the mixture of the two; Wherein free bile acid is cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodesoxycholic acid, Hyodeoxycholic Acid or its mixture, and conjugated bile acid is product or these mixture of products after carboxyl and the amino in glycine or the taurine in the above-mentioned free bile acid forms amido link.
7. according to the pharmaceutical composition of claim 6, conjugated bile acid wherein is glycocholic acid, sweet ammonia deoxycholic acid, sweet ammonia chenodeoxycholic acid, sweet ammonia ursodesoxycholic acid, sweet ammonia Hyodeoxycholic Acid or its mixture.
8. according to the pharmaceutical composition of claim 1, contain water-soluble polyol.
9. according to Claim 8 pharmaceutical composition, described water-soluble polyol is one or more in propylene glycol, glycerin, ethylene glycol, the Polyethylene Glycol.
10. according to Claim 8 pharmaceutical composition, described water-soluble polyol is a propylene glycol.
11. pharmaceutical composition according to Claim 8, described water-soluble polyol is PEG400.
12. an Asarone injection liquid comprises the described asarone pharmaceutical composition of claim 1.
13. an asarone freeze-dried powder comprises the described asarone pharmaceutical composition of claim 1.
14. a commercial packing comprises two separate units, first module contains asarone, phospholipid and bile acid; Unit second is the aqueous phase solvent that contains aminoacid and strong alkaline substance; Aminoacid wherein is one or more in glycine, alanine, leucine, isoleucine, valine, phenylalanine, methionine, tryptophan, serine, glutamine, threonine, cysteine, agedoite, tyrosine, lysine, arginine, the histidine, and strong alkaline substance is sodium hydroxide, potassium hydroxide or the mixture of the two; Wherein the mass ratio of asarone, phospholipid, bile acid, aminoacid, strong alkaline substance is 1:1-100:1-150:1-200:0.3-30.
15. each described preparation of drug combination method of claim 1-11 comprises asarone, phospholipid, bile acid are joined organic solvent dissolution, removes the step of organic solvent.
16., also comprise adding the step that the water that contains aminoacid, strong alkaline substance is prepared into micellar solution according to the method for preparing of claim 15.
17. the method for preparing of Asarone injection liquid according to claim 12 comprises the steps:
1. asarone, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution, remove organic solvent, as organic facies;
2. aminoacid and strong alkaline substance are added to the water, mix, the dissolving back is as water;
3. with above-mentioned two step gained organic faciess and water mix homogeneously, form Asarone injection liquid.
18. the method for preparing of asarone freeze-dried powder according to claim 13 comprises the steps:
1. asarone, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution, remove organic solvent, as organic facies;
2. aminoacid, strong alkaline substance and freeze-dried excipient are added to the water, mix, dissolving is as water;
3. with the organic facies and the water mix homogeneously of above-mentioned steps, packing, be prepared into freeze-dried powder.
19. the method for preparing of commercial packing according to claim 14 comprises the steps:
1. asarone, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution as organic facies;
2. aminoacid, strong alkaline substance are dissolved in the water, obtain water;
3. above-mentioned organic facies and water are processed organic facies concentrated solution for injection and water injection according to the method for preparing of conventional injection respectively, and packing is formed commercial packing.
20. according to each described method for preparing of claim 17-19, the 1. described organic solvent of step is one or more the mixture in ethanol, ether, ethyl acetate, the acetone.
21., also comprise the step that in the 1. described organic facies of step, adds water-soluble polyol according to each described method for preparing of claim 17-19.
22. the purposes of pharmaceutical composition according to claim 1 in preparation treatment respiratory tract infection, tracheitis and bronchitis, asthma, acute and chronic cholecystitis, cholelithiasis, epilepsy disease medicament.
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| CN101596160A (en) * | 2009-07-08 | 2009-12-09 | 四川大学 | A kind of α-asarone mixed micelles injection and preparation method thereof |
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| CN101596160A (en) * | 2009-07-08 | 2009-12-09 | 四川大学 | A kind of α-asarone mixed micelles injection and preparation method thereof |
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Application publication date: 20110727 Assignee: Shanxi Pude Pharmaceutics Co.,Ltd. Assignor: BEIJING CENTURY BIOCOM PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Contract record no.: 2014430000141 Denomination of invention: Asarone medical composition as well as preparation method and preparation thereof Granted publication date: 20120822 License type: Exclusive License Record date: 20140724 |
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Effective date of registration: 20201130 Address after: Floor 1, building 1, No. 198, Changping Road, Chongchuan District, Nantong City, Jiangsu Province 226000 Patentee after: NANTONG WEIXING MACHINE CO.,LTD. Address before: Room 1203, building D, No. 606, ningliu Road, Changlu street, Jiangbei new district, Nanjing City, Jiangsu Province Patentee before: Nanjing century Bokang Pharmaceutical Technology Co.,Ltd. |
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