CN101502490A - Ketoprofen bioadhesive gel microsphere and preparation method thereof - Google Patents
Ketoprofen bioadhesive gel microsphere and preparation method thereof Download PDFInfo
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- CN101502490A CN101502490A CN 200910010465 CN200910010465A CN101502490A CN 101502490 A CN101502490 A CN 101502490A CN 200910010465 CN200910010465 CN 200910010465 CN 200910010465 A CN200910010465 A CN 200910010465A CN 101502490 A CN101502490 A CN 101502490A
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Abstract
The invention discloses a ketoprofen bio-adhesive gel microsphere preparation and a preparation method thereof. The microsphere comprises ketoprofen and a drug carrier, wherein, the drug carrier thereof is calcium pectinate formed by mixing a polysaccharide solution and a CaCl2 solution with the proportion of polysaccharide to drugs being (1:1) to (1:6); the concentration of the CaCl2 solution is 0.5% to 20%; and the concentration of the polysaccharide solution is 5%. By preparing the gel microsphere on the basis of the dropping preparation method, the prepared microsphere has the advantages of smaller grain diameter, good sphericity, high entrapment rate and higher drug-loading rate, and the microsphere has good sustained-release effect under the bio-adhesive action; the preparation method has the advantages of mild preparation process, easy operation and simple steps; the carrier of the gel microsphere, as a natural high-polymer polysaccharide substance, has high biocompatibility and minimizes the side effect of the drugs, furthermore, the stability thereof is good, therefore, the preparation of the invention is a safe and effective sustained-release preparation for oral administration.
Description
Technical field
The present invention relates to a kind of bioadhesive gel microsphere and preparation method thereof, be specifically related to a kind of ketoprofen bioadhesive gel microsphere and preparation method thereof.
Background technology
Oral biologic adhesion preparation has lot of advantages as the relatively more popular a kind of drug-delivery preparation of research at present: behind (1) oral administration, it can stick to the gastrointestinal mucosal surface, thereby prolongs preparation in the gastrointestinal time of staying, the effect of prolong drug.(2) less or have the medicine at specific absorption position to dissolubility in gastrointestinal tract, increase the absorption of medicine thereby can delay it in the gastrointestinal time of staying, improve bioavailability.(3) oral biologic adhesion preparation and gastrointestinal tract mucous tight the contact not only increase the drug absorption total amount, and can improve the absorption rate of medicine.(4) can be positioned the gastrointestinal disease position, the performance local therapeutic effects.
Arthritic symptom has circadian variation, and patient's ankylosis increases the weight of in the morning, and consequently " deadlock in morning " becomes one of cardinal symptom of rheumatic arthritis.Ketoprofen (Ketoprofen is called for short KP) is the clinical arthritic main medicine that is used for the treatment of.Ketoprofen is the derivant of ibuprofen, and its antiinflammatory action is stronger than ibuprofen, and untoward reaction is little, has very big market potential.Ketoprofen is insoluble in water, and the interior half-life of body is 1.6-1.9h only.Clinical practice needs frequent drug administration, and ketoprofen has digestive tract side effects, takes for a long time to cause digestive tract ulcer, symptom such as hemorrhage.The ketoprofen slow-release preparation is that ketoprofen bioadhesive gel microsphere can reduce the gastrointestinal side effect, realizes long-time time lag.
Summary of the invention
The purpose of this invention is to provide the oral bioadhesive gel microsphere drug-delivery preparation of a kind of ketoprofen, said preparation can reduce ketoprofen to the gastrointestinal side effect, can realize long-time time lag simultaneously.
Another object of the present invention provides the preparation method of the oral bioadhesive gel microsphere of above-mentioned ketoprofen.
The objective of the invention is to realize by following technical solution:
A kind of oral bioadhesive gel microsphere that contains ketoprofen comprises pharmaceutical carrier and medicine ketoprofen, and pharmaceutical carrier is the calcium salt of polysaccharide pectin or sodium alginate, described pharmaceutical carrier packaging medicine.
The envelop rate of described gel micro-ball Chinese medicine ketoprofen is 71%-87%, and drug loading is 50%-82%.
Described medicine-containing gel microsphere is the solid particle of particle diameter in the 0.8mm-2mm scope.
A kind of method for preparing ketoprofen bioadhesive gel microsphere the steps include: the ketoprofen suspendible is dissolved in the polysaccharide solution, and the ultrasonic medicine that makes is dispersed in the solution, and uniform liquid is splashed into CaCl by No. 5 syringe needles
2In the solution, continue to stir crosslinking curing a period of time, collect also water flushing three times, be drying to obtain.
Polysaccharide solution is pectin solution or sodium alginate soln or the mixed solution of the two, and concentration is 5%.Pectin is to be the macromolecular compound of main chain with poly D2 galacturonic acid, and electronegative in neutral medium, the pKa value is about 3.5.Pectin is water-soluble, can not protect medicine effectively, therefore often is made into water-fast calcium pectinate.Calcium pectinate is stable in the lower solution of pH, then swelling can take place in the solution of alkalescence.By the covalent bond effect of mechanical packing interaction, polymer and contact surface group and the comprehensive function of electrostatic charge captivation, Van der Waals force, hydrogen bond and hydrophobic bond formation, polymer and mucosa are closely linked.Sodium alginate is the main component of alginic cell wall and intercellular substance, and is soluble in water, is the very high polyelectrolyte of a kind of charge density, has the favorable biological degradability and the compatibility.The character of sodium alginate is similar to pectin property, is a kind of anionic polyelectrolyte polysaccharide, utilizes crosslinked its carboxyl of bivalent cation can form gel micro-ball.
Ketoprofen is insoluble in water, and the ultrasonic medicine that makes is dispersed in the polysaccharide solution, and the ratio of polysaccharide and medicine is 1:1-1:6.
Employed CaCl
2Solution be aqueous solution or chitosan solution, concentration is 0.5%-20%.CaCl
2Dissolubility in chitosan solution is less, selects concentration at 0.5-2%, and concentration is chosen as 0.5-20% in aqueous solution.Utilize dropping preparation method, the polysaccharide solution that contains the medicine ketoprofen of positively charged is splashed into electronegative CaCl
2In the solution, the crosslinked dissolubility that reduces polysaccharide solution of negative ions forms water-fast calcium pectinate.Pectin and sodium alginate are the anionic high polymers simultaneously, and energy and cation type polymer chitosan form coacervate.
The crosslinking curing time that preparation process is selected is 10min-1h.
Chitosan [the amino 2-deoxidation-callose of (1 → 4) 2-] is to take off the acetyl gained by the chitin alkalization, is the copolymer of N-acetyl-D-glycosamine and D-glycosamine.Chitosan derives from chitin, and the latter is a kind of natural product, is present in crustacean, insecticide and some funguses.The chitin of commercial usefulness mainly comes from crustacean shrimp, Lobster and Carapax Eriocheir sinensis waste material, and annual production can reach millions of tons.Chitin is only second to cellulose at natural reserves, is a kind of very abundant natural resources.The acetyl rate of taking off of chitin renames as chitosan when reaching 40%-98%.Chitosan can form hydrogen bond with mucous layer, and because of the macromolecular chain of chitosan has compliance, can effectively infiltrate into mucous layer, produces charge effect with mucous layer, makes chitosan suction back form gel, and mucosa is produced strongly adherent.Chitosan is a kind of weak base, and is insoluble under neutral and alkali condition.In acid medium, its amino by protonated, becomes the polysaccharide of positively charged in solution, so use the solvent of the acetate buffer solution of 1%-3% as chitosan solution.Chitosan can form gel, useful as drug carrier with dissimilar bivalence and multivalent anions interactions.Selection is as CaCl
2The concentration of the chitosan solution of solvent is 1mg/ml-10mg/ml.
The oral bioadhesive gel microsphere particle diameter of ketoprofen of the present invention's preparation is less, good sphericity, and the envelop rate height, drug loading is bigger, and adhesiveness is good.The release of ketoprofen gel microsphere in external simulated intestinal fluid of the present invention's preparation can reach 4 to 6 hours, has good slow releasing function.Studies show that of rabbit interior medicine dynamics, the oral bioadhesive gel microsphere of ketoprofen of the present invention's preparation does not discharge substantially at gastric, can reduce ketoprofen to the duodenal zest of harmonization of the stomach, can act on more than 12 hours in vivo, and can improve its bioavailability.The support material of gel micro-ball of the present invention is the natural macromolecule amylose chemical compound, has good biocompatibility, and it is minimum that side effects of pharmaceutical drugs reach.
The preparation method gentleness of ketoprofen bioadhesive gel microsphere provided by the invention, easy operating, step is less, and the preparation microsphere have good mechanical strength, biological degradability and stability are a kind of preparations of sustained-release administration safely and effectively.
Description of drawings
Fig. 1 is the microsphere electron microscope photo scanning
Fig. 2 is ketoprofen calcium pectinate gel micro-ball release profiles in simulated intestinal fluid
Fig. 3 is ketoprofen chitosan-pectin gel microsphere release profiles in simulated intestinal fluid
Fig. 4 is ketoprofen chitosan-pectin-sodium alginate gel microsphere release profiles in simulated intestinal fluid
Fig. 5 is ketoprofen gel microsphere average blood drug level-time graph (n=6) in the rabbit body
Fig. 6 for the ketoprofen gel microsphere in the turn up adhesion experiment (n=5-8) of model of the intestinal that exsomatizes
The specific embodiment
Ketoprofen 0.5 gram suspendible is dissolved in 100 milliliter of 5% pectin solution, and the ultrasonic medicine that makes is dispersed in the solution.It is 5% CaCl that uniform liquid is splashed into concentration by No. 5 syringe needles
2In the solution, continue to stir crosslinking curing 30 minutes, collect also water flushing three times, be drying to obtain.
Adopting with reference to the assay method of the drug release rate of two ones of the Pharmacopoeias of the People's Republic of China (version in 2005) changes the slurry method and carries out release experiment, and dissolution medium is the phosphate buffer 900mL of pH6.8, and rotating speed is 100r/min, and temperature is 37 ± 0.5 ℃.Get the gel micro-ball that contains 25mg medicine ketoprofen and place stripping rotor, regularly get filtrate 5mL, and mend medium with volume, filtrate is measured absorbance with ultraviolet spectrophotometry and is calculated drug release rate at 260nm place, be that abscissa accumulative total burst size is a vertical coordinate drafting release profiles with time.See Fig. 2.As can be known, ketoprofen calcium pectinate gel micro-ball can slowly discharge in 5h fully, illustrates that this gel micro-ball preparation has the excellent drug slow-releasing.
Ketoprofen 2.0 gram suspendibles are dissolved in 100 milliliter of 5% pectin solution, and the ultrasonic medicine that makes is dispersed in the solution.It is 0.5% CaCl that uniform liquid is splashed into concentration by No. 5 syringe needles
2Chitosan solution in (concentration of chitosan is 1mg/ml), continue to stir crosslinking curing 30 minutes, collect and water flushing three times, be drying to obtain.
Adopting with reference to the assay method of the drug release rate of two ones of the Pharmacopoeias of the People's Republic of China (version in 2005) changes the slurry method and carries out release experiment, and dissolution medium is the phosphate buffer 900mL of pH6.8, and rotating speed is 100r/min, and temperature is 37 ± 0.5 ℃.Get the gel micro-ball that contains 25mg medicine ketoprofen and place stripping rotor, regularly get filtrate 5mL, and mend medium with volume, filtrate is measured absorbance with ultraviolet spectrophotometry and is calculated drug release rate at 260nm place, be that abscissa accumulative total burst size is a vertical coordinate drafting release profiles with time.See Fig. 3.As can be known, ketoprofen calcium pectinate gel micro-ball can slowly discharge in 5h fully, illustrates that this gel micro-ball preparation has the excellent drug slow-releasing.
Ketoprofen 1.0 gram suspendibles are dissolved in (wherein pectin and sodium alginate ratio are 4:1) in 100 milliliter of 5% pectin and the mixed solution of sodium alginate, and the ultrasonic medicine that makes is dispersed in the solution.It is 2% CaCl that uniform liquid is splashed into concentration by No. 5 syringe needles
2Chitosan solution in (concentration of chitosan is 10mg/ml), continue to stir crosslinking curing 30 minutes, collect and water flushing three times, be drying to obtain.
Adopting with reference to the assay method of the drug release rate of two ones of the Pharmacopoeias of the People's Republic of China (version in 2005) changes the slurry method and carries out release experiment, and dissolution medium is the phosphate buffer 900mL of pH6.8, and rotating speed is 100r/min, and temperature is 37 ± 0.5 ℃.Get the gel micro-ball that contains 25mg medicine ketoprofen and place stripping rotor, regularly get filtrate 5mL, and mend medium with volume, filtrate is measured absorbance with ultraviolet spectrophotometry and is calculated drug release rate at 260nm place, be that abscissa accumulative total burst size is a vertical coordinate drafting release profiles with time.See Fig. 4.As can be known, ketoprofen calcium pectinate gel micro-ball can slowly discharge in 5h fully, illustrates that this gel micro-ball preparation has the excellent drug slow-releasing.
Utilize the turn up bioadhesion performance of The effects ketoprofen gel microsphere of intestinal capsule.24 hours rat of fasting takes off neck puts to death, and takes out the small intestinal part, utilizes the pH6.8 phosphate buffered solution flush away content wherein that contains the 2g/L glucose.The small intestinal of wash clean is cut into 5 to 6 centimetres segment, with the small intestinal capsula interna that overturns out, will wherein injects the pH6.8 phosphate buffered solution that contains the 2g/L glucose of 1.5mL with Glass rod, two ends are pricked dead with fine rule.Every section intestinal capsule is put into the 10mL test tube respectively, add the pH6.8 phosphate buffered solution that 50mg ketoprofen gel microsphere (record number) and 5mL contain the 2g/L glucose again, the test tube mouth is shut.Accumulate under 37 ℃ educate 5 minutes after, test tube is taken out in constant temperature vibration 30 minutes, perusal sticks to the number of the gel micro-ball on intestinal capsule surface.The percentage ratio that accounts for the number that adds gel micro-ball with the number of adherent ketoprofen gel microsphere is called adhesion rate as the index of estimating the bioadhesion performance, sees Fig. 6.As can be known, after the intestinal capsule turns up and tests, have the gel micro-ball more than 30% to stick to enteral film surface, the adhesion rate of sodium alginate gel microsphere is especially more than 80%.Because individual variation is bigger, the adhesion rate experiment has certain error.The ketoprofen gel microsphere of the present invention's preparation has good bioadhesion performance, sticks on the small intestinal by adhesive attraction, has prolonged the action time of medicine, has played the good slow release effect.
Claims (10)
1, a kind of ketoprofen bioadhesive gel microsphere, it is characterized in that: it obtains by the following method: the ketoprofen suspendible is dissolved in the polysaccharide solution, its liquid is splashed into CaCl by syringe needle
2In the solution, continue to stir crosslinking curing and obtain.
2, ketoprofen bioadhesive gel microsphere according to claim 1 is characterized in that: the envelop rate of gel micro-ball parcel ketoprofen is 70%-87%, and drug loading is 50%-82%.
3, ketoprofen bioadhesive gel microsphere according to claim 1 is characterized in that: the particle diameter of described ketoprofen bioadhesive gel microsphere is 0.8mm-2mm.
4, a kind of preparation method for preparing ketoprofen bioadhesive gel microsphere as claimed in claim 1 is characterized in that: the ketoprofen suspendible is dissolved in the polysaccharide solution, and the ultrasonic medicine that makes is dispersed in the solution, and uniform liquid is splashed into CaCl by syringe needle
2In the solution, continue to stir crosslinking curing a period of time, collect also water flushing three times, be drying to obtain.
5, preparation method according to claim 4 is characterized in that: described polysaccharide solution is the mixed solution of pectin solution or sodium alginate soln or pectin and sodium alginate, and its concentration is 5%.
6, preparation method according to claim 4 is characterized in that: the ratio of described polysaccharide and medicine is 1: 1-1: 6.
7, preparation method according to claim 4 is characterized in that: described CaCl
2Solution is aqueous solution or CaCl
2Chitosan solution.
8, preparation method according to claim 4 is characterized in that: described CaCl
2Concentration be 0.5%-20%.
9, preparation method according to claim 3 is characterized in that: the described crosslinking curing time is 10min-1h.
10, preparation method according to claim 7 is characterized in that: the concentration of described chitosan solution is 1mg/ml-10mg/ml.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101972232A (en) * | 2010-11-01 | 2011-02-16 | 山东大学 | Eudragit S100 coated curcumin pectin microsphere and preparation method thereof |
| CN102406595A (en) * | 2011-11-02 | 2012-04-11 | 沈阳药科大学 | Floating bioadhesive porous hydrogel and preparation method thereof |
| CN102553499A (en) * | 2011-12-13 | 2012-07-11 | 江南大学 | Method for preparing microcapsules based on low-ester pectin and calcium ion gelatinization and application of microcapsules |
| CN108066314A (en) * | 2016-11-17 | 2018-05-25 | 中国科学院大连化学物理研究所 | A kind of pectin is the biological microsphere preparation method and application of wall material |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101039959A (en) * | 2004-06-30 | 2007-09-19 | 杜门蒂斯有限公司 | Compositions and methods for treating inflammatory disorders |
| CN1329022C (en) * | 2004-08-31 | 2007-08-01 | 贵州太和制药有限公司 | Hydrophilic biological sticking gel pasting agent and preparation technique thereof |
| CN1709232A (en) * | 2005-06-15 | 2005-12-21 | 沈阳药科大学 | Injection liposome microball containing ketoprofen or ketoprofen ester and its preparing process |
| CN1768859A (en) * | 2005-10-24 | 2006-05-10 | 天津大学 | Method for assembling multi-biological functional factor on micro-particle surface based on aldehyde group |
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2009
- 2009-02-26 CN CN 200910010465 patent/CN101502490B/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101972232A (en) * | 2010-11-01 | 2011-02-16 | 山东大学 | Eudragit S100 coated curcumin pectin microsphere and preparation method thereof |
| CN102406595A (en) * | 2011-11-02 | 2012-04-11 | 沈阳药科大学 | Floating bioadhesive porous hydrogel and preparation method thereof |
| CN102553499A (en) * | 2011-12-13 | 2012-07-11 | 江南大学 | Method for preparing microcapsules based on low-ester pectin and calcium ion gelatinization and application of microcapsules |
| CN108066314A (en) * | 2016-11-17 | 2018-05-25 | 中国科学院大连化学物理研究所 | A kind of pectin is the biological microsphere preparation method and application of wall material |
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