CN100562322C - Colon targeting preparation of a kind of 5-aminosalicylic acid and preparation method thereof - Google Patents
Colon targeting preparation of a kind of 5-aminosalicylic acid and preparation method thereof Download PDFInfo
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- CN100562322C CN100562322C CNB2005100901704A CN200510090170A CN100562322C CN 100562322 C CN100562322 C CN 100562322C CN B2005100901704 A CNB2005100901704 A CN B2005100901704A CN 200510090170 A CN200510090170 A CN 200510090170A CN 100562322 C CN100562322 C CN 100562322C
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Abstract
The present invention relates to colon targeting preparation of a kind of 5-aminosalicylic acid-chitosan microball and preparation method thereof.It is with behind the 5-aminosalicylic acid ultra-sonic dispersion with the chitosan solution mix homogeneously after, mix with the oil phase substance that is added with surfactant, after stirring the stable emulsion of formation, add certain density ammonium sulfate solution, stir separating, washing behind the precipitation certain hour, the chitosan microball colon targeting preparation of uniform particle diameter of 5-aminosalicylic acid that promptly obtained embedding behind the vacuum drying.The chitosan microball of the 5-aminosalicylic acid of this method preparation under the pH of gastric juice environment not swelling and under the pH of colon portion environment swelling and can be played the effect of segmented intestine targeted release medicine by the degraded of the bacterioflora of colon portion, be expected to be used for the treatment of colitis as the new formulation of 5-aminosalicylic acid.
Description
Technical field
The invention belongs to the field of pharmaceutical preparations of pharmaceutical engineering, specifically relate to colon targeting preparation of a kind of 5-aminosalicylic acid and preparation method thereof.
Background technology
Ulcerative colitis is a kind of non-specific chronic intestinal tract disease, and this disease can not be cured so far fully.At present, 5-aminosalicylic acid and derivant thereof are the choice drugs of this disease of treatment.The 5-aminosalicylic acid determined curative effect can play therapeutical effect in the colon part.5-aminosalicylic acid has local inhibitory action to the leukotriene B4 in the mucous membrane of colon, interleukin, prostaglandin and platelet activating factor, also can destroy neutrophilic leukocyte and monocytic chemotaxis, remove cytotoxic oxygen-derived free radicals, play the effect of treatment.But because 5-aminosalicylic acid is directly oral rapid in little intestinal absorption, most of medicine can not arrive colon or small intestinal bottom, can not play therapeutical effect, therefore, treatment such as the prodrug of 5-aminosalicylic acid commonly used at present such as sulfasalazine, Mei Lasha piperazine or pack 5-aminosalicylic acid the capsule of microcrystalline Cellulose, gelatin, acrylic resin into to reach the purpose that plays therapeutical effect in colon portion.But shortcomings such as these methods exist, and side effect is big, targeting is strong, drug release is rapid, therapeutic effect difference.Chitosan has biocompatibility, bioadhesive and biodegradability, is in depth studied and uses widely at biomedicine field.Chitosan can be discharged medicine by the bacterioflora degraded at the colon position, is the extraordinary macromolecular material that is used for colon targeting drug administration.The method for preparing the chitosan drug-loading microsphere at present commonly used mainly contains the glutaraldehyde cross-linking method, and methods such as spray drying method, coacervation, but the segmented intestine targeted property of these methods is not strong can not realize segmented intestine targetedly, and it is fast to discharge the speed of medicine, causes local concentration excessive.The present invention adopts a kind of preparation method of new chitosan microball, microsphere is made in the 5-aminosalicylic acid embedding, overcome the defective of existing preparation method, can and can slowly discharge medicine at colon position target administration, treatment time is prolonged, strengthen therapeutic effect.Therefore, the chitosan microball preparation of this 5-aminosalicylic acid is expected in the treatment of colitis, colon cancer important application is arranged.In addition, this method also is suitable for other drug such as anti-inflammatory agent, the colon targeting drug administration of protein, polypeptide drug.
Summary of the invention
The object of the present invention is to provide a kind of chitosan microball preparation of 5-aminosalicylic acid to be used for colon targeting drug administration treatment colitis, colon cancer.
Another object of the present invention provides the preparation method of the chitosan microball of above-mentioned 5-aminosalicylic acid.
The chitosan microball of 5-aminosalicylic acid provided by the invention is made up of 5-aminosalicylic acid and chitosan, and both mass ratioes are 1: 1～40, and 5-aminosalicylic acid is dispersed in the chitosan.
The molecular weight of described chitosan is 20～1,600,000, and deacetylation is 66～98%, can be single chitosan, also the mixture of being made up of the chitosan with different molecular weight and deacetylation.
The invention provides a kind of preparation method of chitosan microball of above-mentioned 5-aminosalicylic acid, comprise following step:
1) with the 5-aminosalicylic acid ultra-sonic dispersion in the chitosan solution of 0.5～5% (w/v) as water, the mass ratio of 5-aminosalicylic acid and chitosan is 1: 1～40;
The molecular weight of described chitosan is 20～1,600,000, and deacetylation is 66～98%, can be single chitosan, also the mixture of being made up of the chitosan with different molecular weight and deacetylation;
The used solvent of described chitosan solution is the mixed solution of formic acid, acetic acid, propanoic acid, hydrochloric acid, lactic acid, citric acid, tartaric acid, glutamic acid or above-mentioned acid and alkali metal salt;
2) oil phase and the surfactant that accounts for its 0.1～4v% were stirred 5～30 minutes together, rotating speed is 500～2000 rev/mins;
Described oil phase is the mixture of liquid paraffin, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, soybean oil, olive oil, Oleum Helianthi or itself and petroleum ether;
Described surfactant is the mixture of span 20, span 40, sorbester p18, sorbester p38, sorbester p17, span 83, sorbester p37, polysorbas20, polysorbate40, polysorbate60, tween 61, Tween 80, sorbimacrogol oleate100, polysorbate85 or its arbitrary proportion;
3) water with step 1) joins step 2) oil phase in, stir to form stable emulsion; Wherein the volume ratio of water and oil phase is 1: 1～20, stirs 30～60 minutes, and rotating speed is 500～2000 rev/mins;
4) adding concentration in the emulsion that step 3) makes is the ammonium sulfate of 1～65% (w/v), and the volume ratio of chitosan solution and ammonium sulfate is 1: 1～20, continues to stir after 0.5～5 hour to stop;
5) step with centrifugal separation 4) dispersion that makes, supernatant liquid is poured out, tell the microsphere of lower floor's ammonium sulfate precipitation, use pure water, petroleum ether, dehydrated alcohol thorough washing successively, promptly get the chitosan microball that is embedded with 5-aminosalicylic acid of the present invention behind the vacuum drying.
The medicine embedding rate of the chitosan microball of 5-aminosalicylic acid provided by the invention is issued to 96.5% more than 90% in optimized conditions.
The present invention uses the carrier of the chitosan microball of emulsifying dispersion/ammonium sulfate precipitation method preparation as medicine, in the excellent biological compatibility that has kept chitosan, biodegradability, bioadhesive, solved and used chemical cross-linking agent and organic solvent in the existing method for preparing microsphere, and the defective that the segmented intestine targeted property of microsphere is bad, drug release is too fast.The chitosan microball of the 5-aminosalicylic acid of this method preparation under the pH of gastric juice environment not swelling and under the pH of colon portion environment swelling and can be played the effect of segmented intestine targeted release medicine by the degraded of the bacterioflora of colon portion, be expected to be used for the treatment of colitis as the new formulation of 5-aminosalicylic acid.
The preparation method of the colon targeting preparation of chitosan microball provided by the invention also can be used for the treatment that other cancer therapy drugs of embedding are used for colon cancer; Also can be used for the colon targeting drug administration that the embedding polypeptide drugs are used for such medicine.
Description of drawings
The sem photograph that the amplification of the 5-aminosalicylic acid-chitosan microball of Fig. 1 preparation is 300 times.
5-aminosalicylic acid-the chitosan microball of Fig. 2 preparation is at 37 ℃, discharges the release profiles that discharges 4h in the medium of 2h, pH=6.8 and discharge 8h in the buffer of pH=7.4 in the medium of pH=1.5.
5-aminosalicylic acid-the chitosan microball of Fig. 3 preparation is at 37 ℃, discharges the release profiles that discharges 4h in the medium of 2h, pH=6.8 and discharge 8h in the buffer solution of the adding lysozyme of pH=74 in the medium of pH=1.5.
5-aminosalicylic acid-the chitosan microball of Fig. 4 preparation is at 37 ℃, discharges the release profiles that discharges 4h in the medium of 2h, pH=6.8 and discharge 12h in the buffer solution of the adding lysozyme of pH=7.4 in the medium of pH=1.5.
5-aminosalicylic acid-the chitosan microball of Fig. 5 preparation is at 37 ℃, discharges the release profiles that discharges 4h in the medium of 2h, pH=6.8 and discharge 16h in the buffer solution of the adding lysozyme of pH=7.4 in the medium of pH=1.5.
The specific embodiment
Embodiment 1
2g chitosan (molecular weight 300,000, deacetylation 93.2%) is dissolved in 100mL 0.2mol/L acetic acid solution makes chitosan solution.The 50mg 5-aminosalicylic acid was added in the 1mL pure water ultra-sonic dispersion 20 seconds.Get the 10mL chitosan solution, be dispensed into the good 5-aminosalicylic acid of ultra-sonic dispersion as water.Getting 50mL liquid paraffin (oil phase) joins in the reactor, add 1mL sorbester p17 and 1mL Tween 80, stir, rotating speed is 600 rev/mins, disperse after 10 minutes, the chitosan solution that is dispersed with 5-aminosalicylic acid (water) that adds above-mentioned preparation continued dispersed with stirring 30 minutes with same rotating speed, formed stable emulsion; Adding concentration in this emulsion is the ammonium sulfate 40mL of 10% (w/v), continues to stir after 1 hour to stop.Supernatant liquid is poured out in centrifugalize, tells the microsphere of lower floor's ammonium sulfate precipitation, and with pure water, petroleum ether, dehydrated alcohol thorough washing precipitation, the room temperature vacuum drying promptly gets the chitosan microball that is embedded with 5-aminosalicylic acid of the present invention successively.
Be embedded with the diameter of the chitosan microball of 5-aminosalicylic acid with the standard screen test pack, average diameter is 153.24 microns, and its form is shown in the sem photograph of Fig. 1.
Get the chitosan microball that 20mg is embedded with 5-aminosalicylic acid, with the hydrochloric acid of 0.25mol/L with its dissolving after, measure the absorption value of 5-aminosalicylic acid at the 302nm place, and calculate the concentration of 5-aminosalicylic acid, calculate the medicine embedding rate of chitosan microball according to following formula according to standard curve:
The medication amount that adds in medicine embedding rate=(content of microsphere Chinese medicine)/preparation
The medicine embedding rate that calculates the chitosan microball of embodiment 1 preparation is 90.23%.
Detection method according to Chinese Pharmacopoeia version colon targeting preparation in 2000 is investigated the segmented intestine targeted property of the chitosan microball preparation of 5-aminosalicylic acid.Get the above-mentioned chitosan microball that is embedded with 5-aminosalicylic acid of 100mg and put into the hydrochloric acid solution of pH=1.5 at 37 ℃, 50 rev/mins of rotating speeds stir 2h down, took out 1mL in per 0.5 hour, measure the absorption value of 5-aminosalicylic acid at the 302nm place and calculate its concentration with ultraviolet spectrophotometry, add dissolution medium simultaneously; Behind the 2h microsphere is taken out in the buffer solution of pH=6.8,37 ℃, 50 rev/mins of rotating speeds stir 4h down, per 0.5 hour taking-up 1mL, measure the absorption value of 5-aminosalicylic acid at the 331nm place and calculate its concentration with ultraviolet spectrophotometry, add dissolution medium simultaneously; Behind the 4h microsphere is taken out in the buffer solution of pH=7.4,37 ℃, 50 rev/mins of rotating speeds stir 8h down, take out 1mL in per 1 hour, measure the absorption value of 5-aminosalicylic acid at the 331nm place and calculate its concentration with ultraviolet spectrophotometry, add dissolution medium simultaneously; Make the release profiles of chitosan microball under the different intestinal pH value conditions of simulation of 5-aminosalicylic acid.See Fig. 2.As can be known, under the situation of the Gl tract pH that does not add lysozyme, medicine can not discharge fully.
Get the above-mentioned chitosan microball that is embedded with 5-aminosalicylic acid of 100mg and put into the hydrochloric acid solution of pH=1.5 at 37 ℃, 50 rev/mins of rotating speeds stir 2h down, took out 1mL in per 0.5 hour, measure the absorption value of 5-aminosalicylic acid at the 302nm place and calculate its concentration with ultraviolet spectrophotometry, add dissolution medium simultaneously; Behind the 2h microsphere is taken out in the buffer solution of pH=6.8,37 ℃, 50 rev/mins of rotating speeds stir 4h down, per 0.5 hour taking-up 1mL, measure the absorption value of 5-aminosalicylic acid at the 331nm place and calculate its concentration with ultraviolet spectrophotometry, add dissolution medium simultaneously; Behind the 4h microsphere taken out in the buffer solution of the adding lysozyme of pH=7.4,37 ℃, 50 rev/mins of rotating speeds stir 8h down, take out 1mL in per 1 hour, with ultraviolet spectrophotometry in the absorption value of 331nm place mensuration 5-aminosalicylic acid and calculate its concentration; Make the release profiles of chitosan microball under the different intestinal pH value conditions of simulation of 5-aminosalicylic acid.See Fig. 3.As can be known, add at Gl tract pH under the situation of lysozyme, medicine can slowly discharge in 8h fully, illustrates that this microball preparation has good segmented intestine targeted property and controlled drug release, can be used in segmented intestine targeted sustained-release administration.
3g chitosan (molecular weight 550,000, deacetylation 86.3%) is dissolved in 100mL 0.25mol/L propanoic acid solution makes chitosan solution.The 30mg 5-aminosalicylic acid was added in the 1mL pure water ultra-sonic dispersion 20 seconds, get the 10mL chitosan solution, be dispensed into the good 5-aminosalicylic acid of ultra-sonic dispersion as water.Getting 80mL Oleum Arachidis hypogaeae semen (oil phase) joins in the reactor, add the 0.5mL span 20, stir, rotating speed is 1000 rev/mins, disperse to add the chitosan solution that is dispersed with 5-aminosalicylic acid (water) of above-mentioned preparation after 10 minutes, continue dispersed with stirring after 30 minutes with same rotating speed, adding concentration is the ammonium sulfate 100mL of 20% (w/v), continues to stir after 1 hour to stop.Centrifugalize with pure water, petroleum ether, dehydrated alcohol thorough washing precipitation, promptly gets the chitosan microball that is embedded with 5-aminosalicylic acid of the present invention successively behind the room temperature vacuum drying.Be embedded with the diameter of the chitosan microball of 5-aminosalicylic acid with standard sieve method test pack, average diameter is 284.3 microns, and the medicine embedding rate is 93.21%.
Detection method according to Chinese Pharmacopoeia version colon targeting preparation in 2000 is investigated the segmented intestine targeted property of the chitosan microball preparation of 5-aminosalicylic acid.Get the above-mentioned chitosan microball that is embedded with 5-aminosalicylic acid of 100mg and put into the hydrochloric acid solution of pH=1.5 at 37 ℃, 50 rev/mins of rotating speeds stir 2h down, took out 1mL in per 0.5 hour, measure the absorption value of 5-aminosalicylic acid at the 302nm place and calculate its concentration with ultraviolet spectrophotometry, add dissolution medium simultaneously; Behind the 2h microsphere is taken out in the buffer solution of pH=6.8,37 ℃, 50 rev/mins of rotating speeds stir 4h down, take out 1mL in per 0.5 hour, measure the absorption value of 5-aminosalicylic acid with ultraviolet spectrophotometry at the 331nm place and calculate its concentration, add dissolution medium simultaneously; Behind the 4h microsphere taken out in the buffer solution of the adding lysozyme of pH=7.4,37 ℃, 50 rev/mins of rotating speeds stir 12h down, take out 1mL, and calculate its concentration with ultraviolet spectrophotometry in the absorption value of A=331nm place mensuration 5-aminosalicylic acid in per 1 hour; Make the release profiles of chitosan microball under the different intestinal pH value conditions of simulation of 5-aminosalicylic acid.See Fig. 4.As can be known, add at Gl tract pH under the situation of lysozyme, medicine can slowly discharge in 12h fully, illustrates that this microball preparation has good segmented intestine targeted property and controlled drug release, can be used in segmented intestine targeted sustained-release administration.
Embodiment 3
4g chitosan (molecular weight 780,000, deacetylation 779%) is dissolved in the 100mL0.25mol/L lactic acid solution makes chitosan solution.The 10mg 5-aminosalicylic acid was added in the 1mL pure water ultra-sonic dispersion 20 seconds, get the 10mL chitosan solution, be dispensed into the good 5-aminosalicylic acid of ultra-sonic dispersion as water.Getting 150mL soybean oil (oil phase) joins in the reactor, add the 1mL sorbester p18, stir, rotating speed is 1500 rev/mins, disperse to add the chitosan solution that is dispersed with 5-aminosalicylic acid (water) of above-mentioned preparation after 10 minutes, continue dispersed with stirring after 30 minutes with same rotating speed, adding concentration is the ammonium sulfate 200mL of 50% (w/v), continues to stir after 1 hour to stop.Centrifugalize with pure water, petroleum ether, dehydrated alcohol thorough washing precipitation, promptly gets the chitosan microball that is embedded with 5-aminosalicylic acid of the present invention successively behind the room temperature vacuum drying.Be embedded with the diameter of the chitosan microball of 5-aminosalicylic acid with standard screen point-score test pack, average diameter is 382.5 microns, and the medicine embedding rate is 94.05%.
Detection method according to Chinese Pharmacopoeia version colon targeting preparation in 2000 is investigated the segmented intestine targeted property of the chitosan microball preparation of 5-aminosalicylic acid.Get the above-mentioned chitosan microball that is embedded with 5-aminosalicylic acid of 100mg and put into the hydrochloric acid solution of pH=1.5 at 37 ℃, 50 rev/mins of rotating speeds stir 2h down, took out 1mL in per 0.5 hour, measure the absorption value of 5-aminosalicylic acid at the 302nm place and calculate its concentration with ultraviolet spectrophotometry, add dissolution medium simultaneously; Behind the 2h microsphere is taken out in the buffer solution of pH=6.8,37 ℃, 50 rev/mins of rotating speeds stir 4h down, per 0.5 hour taking-up 1mL, measure the absorption value of 5-aminosalicylic acid at the 331nm place and calculate its concentration with ultraviolet spectrophotometry, add dissolution medium simultaneously; Behind the 4h microsphere taken out in the buffer solution of the adding lysozyme of pH=7.4,37 ℃, 50 rev/mins of rotating speeds stir 16h down, take out 1mL in per 1 hour, with ultraviolet spectrophotometry in the absorption value of 331nm place mensuration 5-aminosalicylic acid and calculate its concentration; Make the release profiles of chitosan microball under the different intestinal pH value conditions of simulation of 5-aminosalicylic acid.See Fig. 5.As can be known, add at Gl tract pH under the situation of lysozyme, medicine can slowly discharge in 16h fully, illustrates that this microball preparation has good segmented intestine targeted property and controlled drug release, can be used in segmented intestine targeted sustained-release administration.
Claims (4)
1, a kind of colon targeting preparation of 5-aminosalicylic acid-chitosan microball, be made up of 5-aminosalicylic acid and chitosan, both mass ratioes are 1: 1～40, and 5-aminosalicylic acid is dispersed in the chitosan, it prepares by the following method, and this method comprises following step:
1) with behind the 5-aminosalicylic acid ultra-sonic dispersion, mix as water with the chitosan solution of 0.5～5% (w/v), the mass ratio of 5-aminosalicylic acid and chitosan is 1: 1～40;
Wherein, the used solvent of chitosan solution is the mixed solution of formic acid, acetic acid, propanoic acid, hydrochloric acid, citric acid, tartaric acid, glutamic acid or above-mentioned acid and alkali metal salt;
2) oil phase and the surfactant that accounts for its 0.1～4v% were stirred 5～30 minutes together, rotating speed is 500～2000 rev/mins;
Wherein said oil phase is the mixture of liquid paraffin, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, soybean oil, olive oil, Oleum Helianthi or itself and petroleum ether; Described surfactant is the mixture of span 20, span 40, sorbester p18, sorbester p38, sorbester p17, span 83, sorbester p37, polysorbas20, polysorbate40, polysorbate60, tween 61, Tween 80, sorbimacrogol oleate100, polysorbate85 or its arbitrary proportion;
3) water with step 1) joins step 2) oil phase in, stir to form stable emulsion; Wherein the volume ratio of water and oil phase is 1: 1～20, stirs 30～60 minutes, and rotating speed is 500～2000 rev/mins;
4) adding concentration in the emulsion that step 3) makes is the ammonium sulfate of 1～65% (w/v), and the volume ratio of chitosan solution and ammonium sulfate is 1: 1～20, continues to stir after 0.5～5 hour to stop;
5) step with centrifugal separation 4) dispersion that makes, supernatant liquid is poured out, tell the microsphere of lower floor's ammonium sulfate precipitation, washing, drying obtains being embedded with the chitosan microball of 5-aminosalicylic acid.
2, the colon targeting preparation of 5-aminosalicylic acid-chitosan microball as claimed in claim 1 is characterized in that: the molecular weight of described chitosan is 20～1,600,000, and deacetylation is 66～98%.
3, the colon targeting preparation of 5-aminosalicylic acid-chitosan microball as claimed in claim 1 is characterized in that: described chitosan is single chitosan, or the mixture of being made up of the chitosan with different molecular weight and deacetylation.
4, the preparation method of the colon targeting preparation of the described 5-aminosalicylic acid-chitosan microball of a kind of claim 1 comprises following step:
1) with behind the 5-aminosalicylic acid ultra-sonic dispersion, mix as water with the chitosan solution of 0.5～5% (w/v), the mass ratio of 5-aminosalicylic acid and chitosan is 1: 1～40;
Wherein, the used solvent of chitosan solution is the mixed solution of formic acid, acetic acid, propanoic acid, hydrochloric acid, citric acid, tartaric acid, glutamic acid or above-mentioned acid and alkali metal salt;
2) oil phase and the surfactant that accounts for its 0.1～4v% were stirred 5～30 minutes together, rotating speed is 500～2000 rev/mins;
Wherein said oil phase is the mixture of liquid paraffin, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, soybean oil, olive oil, Oleum Helianthi or itself and petroleum ether; Described surfactant is the mixture of span 20, span 40, sorbester p18, sorbester p38, sorbester p17, span 83, sorbester p37, polysorbas20, polysorbate40, polysorbate60, tween 61, Tween 80, sorbimacrogol oleate100, polysorbate85 or its arbitrary proportion;
3) water with step 1) joins step 2) oil phase in, stir to form stable emulsion; Wherein the volume ratio of water and oil phase is 1: 1～20, stirs 30～60 minutes, and rotating speed is 500～2000 rev/mins;
4) adding concentration in the emulsion that step 3) makes is the ammonium sulfate of 1～65% (w/v), and the volume ratio of chitosan solution and ammonium sulfate is 1: 1～20, continues to stir after 0.5～5 hour to stop;
5) step with centrifugal separation 4) dispersion that makes, supernatant liquid is poured out, tell the microsphere of lower floor's ammonium sulfate precipitation, washing, drying obtains being embedded with the chitosan microball of 5-aminosalicylic acid.
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| FR3026012B1 (en) * | 2014-09-23 | 2017-12-01 | Soc D'exploitation De Produits Pour Les Industries Chimiques Seppic | ORAL ADMINISTRATION OF AT LEAST ONE PHARMACEUTICAL AND / OR ANTIGENIC ACTIVE SUBSTANCE |
| CN111195232B (en) * | 2020-01-15 | 2022-03-18 | 浙江工业大学 | double-pH-sensitive mesalazine colon-targeted sustained-release solid dispersion and preparation method thereof |
| CN113854387A (en) * | 2021-08-13 | 2021-12-31 | 安徽省甘滋罗生物科技股份有限公司 | Chocolate with health care function and production process thereof |
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| US5773033A (en) * | 1995-01-23 | 1998-06-30 | The Regents Of The University Of California | Fibrinogen/chitosan hemostatic agents |
| CN1568954A (en) * | 2004-04-26 | 2005-01-26 | 沈阳药科大学 | Mesalazine colon target releasing micro pills and preparation method thereof |
| CN1607033A (en) * | 2003-10-15 | 2005-04-20 | 中国科学院过程工程研究所 | Chitose microsphere and microcapsule with uniform size and its preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5773033A (en) * | 1995-01-23 | 1998-06-30 | The Regents Of The University Of California | Fibrinogen/chitosan hemostatic agents |
| CN1607033A (en) * | 2003-10-15 | 2005-04-20 | 中国科学院过程工程研究所 | Chitose microsphere and microcapsule with uniform size and its preparation method |
| CN1568954A (en) * | 2004-04-26 | 2005-01-26 | 沈阳药科大学 | Mesalazine colon target releasing micro pills and preparation method thereof |
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