CN1165037A - PH value response medicine controlled release carrier - Google Patents
PH value response medicine controlled release carrier Download PDFInfo
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- CN1165037A CN1165037A CN 97105119 CN97105119A CN1165037A CN 1165037 A CN1165037 A CN 1165037A CN 97105119 CN97105119 CN 97105119 CN 97105119 A CN97105119 A CN 97105119A CN 1165037 A CN1165037 A CN 1165037A
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Abstract
A pH-responsive controlled releasing carrier for medicine is a chitosan-base gel which is prepared from Chitosan, gelatin and pectin through cross-linking by aldehyde cross-linking agents, and features obvious pH dependency, high biocompatibility and abling to biologically degradate. It can be used for detention-type controlled releasing medicines to avoid toxic' by-effect due to excess dosage.
Description
The invention belongs to biomedicine, natural macromolecular material.
Intellectual material is the new material with sensing, processing and execution function.High-molecular gel becomes the important research field of intelligent macromolecule material as soft wet part material in recent years.The research that Massachusetts Institute Technology changes mutually from the volume of gel emphatically, illustrate the relation of the collaborative and gel stimulating responsive of macromole interphase interaction, and design on this basis and prepared thermosensitive hydrogel, the super water absorbent gel and the molecular recognition gel [U.S., Phase Transitions ofPolymer Gels and Hetropolymer inResearch in Materials, Annual Report.Massachusetts Institute of Technology, 1996, P.323], Hokkaido, Japan university is by the structural research of synthetic high polymer gel, attempt to optimize its performance, focus on chemical machinery systematic research [Japan, ゲ Le To ぉ け Ru information と conversion, long Tian Yiren, chemistry と industry, 1995,49, P.1395].External this type of research work is mainly based on the synthetic polymer gel, but is subjected to the puzzlement of environment and resource problem.The single chitosan of employing that in the technology of preparing of existing medicine carrying microballoons, has, but substrate property and stimulating responsive are difficult to adjust to OK range [on June 29th, 1989, on February 14th, 1991, a day spy discloses flat 3-34927 for Japan, A 61 K31/60]; The use that has the synthetic high polymer base material, but exist the bad and shortcoming that is difficult to degrade of biocompatibility [Japan, porous micropartical The contains カ プ セ Le modulation と そ application with ぃ The ア ス ピ リ Application, thin well Wen Xiong etc., macromolecule collection of thesis, 1985,42, P.415]; The employing polypeptide class natural polymer base material that has, but there is not desired stimulating responsive [Italy, Gelatin Microspheres:Influence of Preparation Parametersand Thermal Treatment on Chemico-physical and Biopharmaceutical Properties, ElisabettaEsposito, Rita Cortesi and Claudio Nastruzzi, Biomaterials, 1996,17, P.2009].The pH value of patients with gastric disease gastric juice begins to feel under the weather when lower (less than 4) usually, because individual patients and degree difference when taking present pharmaceutical preparation, can't guarantee dosage just in time.If the actual drug consumption is on the low side, then gastric juice pH is still lower, can not remove misery; If actual dosage is more, the pH value of patient's gastric juice has reached just often, left drug still in action or controlled release preparation still discharging the active drug composition, then gastric acid secretion is subjected to excessive inhibition, cause pH too high, can cause a series of toxic and side effects, have toxic and side effects as medicine itself.In addition, pH too high (greater than 7) can cause noxious bacteria upstream in the intestinal to stomach in the what is more important gastric juice, produces such as phenomenons such as ulcer infection.
The objective of the invention is to adopt natural polymer chitosan, gelatin and pectin is the main medicine controlled release carrier of forming, and makes the biocompatibility of carrier and biological degradability be better than containing the system of synthetic high polymer, and has the pH response.
The present invention is raw material, has synthesized chitosan-based gel by aldehydes cross-linking agent co-crosslinking that when pH changed, the interior hydrogen bond of this network dissociated or associates, and makes it to have tangible pH response with natural polymers such as chitosan, gelatin and pectin.Drug delivery system with this preparing gel is tangible pH dependency, is pH response medicine delivery systme, can be developed into oral antiacid, treatment gastric ulcer gastric retention type controlled release preparation.
Consisting of of material of the present invention:
● chitosan 50～100%
● gelatin 0～50%
● pectin 0～10%
● 1.5～30% of cross-linking agent (as formaldehyde, Biformyl, glutaraldehyde etc.) chitosan weight
● medicine (cimetidine, chlorhexidine acetate) 10-50%
1 part of chitosan is dissolved in forms the solution of 2～10% concentration in 2～10% acid (as formic acid, acetic acid, the hydrochloric acid etc.) aqueous solution and placed 24～48 hours, add gelatin, pectin, medicine, under 40～60 ℃ of conditions, fully mix, drip 0.5～5% aldehydes (as formaldehyde, Biformyl, the glutaraldehyde etc.) aqueous solution of 0.3～30ml after cooling, fully mix back film forming drying under 30～80 ℃ of conditions.Consisting of of microsphere of the present invention:
Composition is identical with the invention described above material composition, is added with in addition
● oil (hydrocarbon mixture such as paraffin oil, turbine wet goods) oil-water ratio is 5～20
● emulsifying agent (as sorbitan oleate, polyoxyethylene ether (20) sorbitan oleate etc.)
1/100～1/50 of water
1 part of chitosan and gelatin (pectin, medicine) be dissolved in form 2～10% solution in 2～10% acid (as formic acid, acetic acid, the hydrochloric acid etc.) aqueous solution and placed 24～48 hours, being heated to 40～60 ℃ fully mixes it, place night deaeration again, add that emulsifying agent and oil drip 10～50% aldehydes (as formaldehyde, Biformyl, the glutaraldehyde etc.) reactant aqueous solution 1～4 hour of 0.03～3ml under 30～60 ℃ of temperature, 400-1200rpm mechanical agitation, fully clean with methanol or ether behind the discharging vacuum filtration and dry under 20～80 ℃ of conditions.
Outstanding advantage of the present invention is can be used for the treatment of gastrointestinal tract disease etc., belongs to intelligent controlled release drug carrier of new generation; Especially the release of medicine responds the focus signal and moves, and controlled by gastric juice pH, and pH began to discharge less than 7 o'clock, and stopped to discharge greater than 7 o'clock, can avoid discharging the toxic and side effects that dose excessively causes; The employing natural macromolecular material is a controlled release carrier, good biocompatibility, and biodegradable.
Accompanying drawing-1 is the result of carrying the chitosan-based microsphere of cimetidine pH response releasing research in different pH buffer mediums of the embodiment of the invention 4 preparations, and transverse axis is expressed as the time, and left side 0-60 is minute (min), and the right 1-72 is hour (hr); The longitudinal axis is for discharging percentage ratio (%).Accompanying drawing-2 is the result of carrying the chitosan-based gel releasing research of chlorhexidine acetate of the embodiment of the invention 5 preparations.Transverse axis is time (min) among the figure, and the longitudinal axis is for discharging percentage ratio (%).
The preparation of embodiment 1 chitosan
(1) shrimp (Eriocheir sinensis) shell after the cleaning soaked 5 hours with 5% hydrochloric acid solution, removed the inorganic salt in shelling.
(2) with 10% sodium hydroxide solution digestion 10 hours, remove the protein in shelling.
(3) soaked 5 hours kept at room temperature overnight down at 60～120 ℃ with 50% sodium hydroxide solution.
(4) extremely neutral with hot water wash, 60 ℃ of oven dry down.
The physical and chemical index of chitosan used herein is as follows:
Outward appearance: faint yellow tablet
Moisture content:＜8%
Ash:＜1.0%
Degree of deacetylation: 63%-92%
Viscosity-average molecular weight: 40～1,600,000
Pb(ppm) ：＜5
As (ppm): the preparation of＜5 embodiment 2 chitosan-based gels
The 1g chitosan is dissolved in 5% acetic acid aqueous solution of 19g and placed 24 hours, add that 1g gelatin and 0.1g pectin fully mix under 50～60 ℃ of conditions, drip after cooling and pour glass plate into behind the 1% glutaraldehyde water solution mix homogeneously of 1ml and make its curtain coating, all volatilize down to liquid 55 ℃ of conditions, obtain chitosan-based gel film.The preparation of embodiment 3 chitosan-based gel micro-balls
1g chitosan and 1g gelatin and 0.1g pectin are dissolved in be heated to about 65 ℃ in 5% acetic acid aqueous solution of 8g and make concentrated solution, place and make its deaeration a night, under 40 ℃ of conditions, stirred earlier 10 minutes after adding 0.4g sorbitan oleate and 200ml paraffin oil with the mixing speed of 400rpm, drip 2ml 25% glutaraldehyde water solution reaction 2 hours, vacuum filtration removes the back reuse methanol cleaning that deoils, bone dry under 60 ℃ of conditions.The preparation of the chitosan-based gel micro-ball of 4 years cimetidine of embodiment
1g chitosan and 1g gelatin and 0.1g pectin are dissolved in be heated to about 65 ℃ in 5% acetic acid aqueous solution of 8g and make concentrated solution, and add that the 0.5g cimetidine fully mixes, place night deaeration, under 30 ℃ of conditions, stirred earlier 20 minutes after adding 0.2g sorbitan oleate and 300ml paraffin oil with the mixing speed of 600rpm, drip 1ml 50% glutaraldehyde water solution reaction 1 hour, the reuse ether was cleaned after vacuum filtration was removed oil removing, at room temperature placed 3 days bone dries.The preparation of 5 years chitosan-based gels of chlorhexidine acetate of embodiment
Be dissolved in the 1g chitosan in the 2%19g acetic acid aqueous solution and placed 24 hours, add that 1g gelatin and 0.1g pectin and 0.2g chlorhexidine acetate fully mix under 50 ℃ of conditions, pour glass plate into behind the 1% glutaraldehyde water solution mix homogeneously of dropping 1ml and make its curtain coating, all volatilize down to liquid 50 ℃ of conditions.The preparation of 6 years chitosan-based gels of cimetidine one chlorhexidine acetate of embodiment
Method has added the 0.5g cimetidine again in addition with embodiment 5.The controlled-release effect of hybrid medicine: o'clock lasting release the in pH＜7, pH＞7 o'clock burst size seldom.
Claims (3)
1. one kind is the controlled release preparation material of raw material with the natural polymer, the invention is characterized in consisting of of controlled release preparation material: chitosan: 50～100%, gelatin: 0～50%, pectin: 0～10%, aldehydes cross-linking agent (aldehydes such as formaldehyde, Biformyl, glutaraldehyde): be 1.5～30% of chitosan, medicine (cimetidine, chlorhexidine acetate) 10～50%; Consisting of of controlled release preparation microsphere: outside above-mentioned controlled release preparation material was formed, add oil (hydrocarbon mixture such as paraffin oil, turbine wet goods) again: oil-water ratio was 5～20; Emulsifying agent (as sorbitan oleate, polrvinyl chloride ether (20) sorbitan oleate etc.): be 1/100～1/50 of water.
2. described controlled release preparation material of claim 1, it is characterized in that the controlled release preparation material by the preparation technology who forms is: 1 part of chitosan is dissolved in 2～10% acid (as formic acid, acetic acid, hydrochloric acid etc.) form the solution of 2～10% concentration in the aqueous solution, placed 24～48 hours, and added gelatin, pectin, medicine, under 40～60 ℃ of conditions, stir with abundant mixing, drip 0.3～30 part 10～50% aldehydes cross-linking agent aqueous solution after cooling, dry under 30～80 ℃ of conditions.
3. described controlled release preparation material of claim 1, the preparation technology who it is characterized in that the controlled release preparation microsphere is: with 1 part of chitosan and gelatin, pectin, medicine is dissolved in 2～10% acid (as formic acid, acetic acid, hydrochloric acid etc.) forming 2～10% solution in the aqueous solution placed 24～48 hours, being heated to 40～60 ℃ fully mixes it, place night deaeration again, add emulsifying agent and oil and under 30～60 ℃ and 400～1200rpm mechanical agitation, dripped 0.03～3 part of 10～50% aldehydes cross-linking agent aqueous solution reaction 1～4 hour, behind the discharging vacuum filtration with formaldehyde or ether thorough washing and under 20～80 ℃ of conditions drying make.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97105119 CN1165037A (en) | 1997-06-04 | 1997-06-04 | PH value response medicine controlled release carrier |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 97105119 CN1165037A (en) | 1997-06-04 | 1997-06-04 | PH value response medicine controlled release carrier |
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| CN1165037A true CN1165037A (en) | 1997-11-19 |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100522246C (en) * | 2005-03-18 | 2009-08-05 | 中国科学院过程工程研究所 | Chitosan pellet/microsac and preparation thereof |
| CN101972232A (en) * | 2010-11-01 | 2011-02-16 | 山东大学 | Eudragit S100 coated curcumin pectin microsphere and preparation method thereof |
| CN101260191B (en) * | 2008-04-01 | 2011-04-20 | 武汉大学 | Temperature sensitive type chitosan/glutin hydrogel and its preparation method and use |
| CN106109400A (en) * | 2016-07-22 | 2016-11-16 | 金陵科技学院 | A kind of oral drugs hydrogel slow-released carrier and preparation method and applications |
| CN106187996A (en) * | 2016-07-07 | 2016-12-07 | 华南师范大学 | A kind of composite aquogel containing rare earth compounding of novel pH response and its preparation method and application |
| CN107183335A (en) * | 2017-07-25 | 2017-09-22 | 宿松县大坂农业开发有限公司 | A kind of preparation method for promoting to digest ox feed |
| CN110452054A (en) * | 2019-09-10 | 2019-11-15 | 山东胜伟盐碱地科技有限公司 | A kind of dedicated MULTILAYER COMPOSITE fertiliser granulates of alkaline land improving and preparation method thereof |
| CN111467320A (en) * | 2020-05-13 | 2020-07-31 | 四川大学 | Microcapsule with pH response and intestinal targeting effects and preparation method thereof |
-
1997
- 1997-06-04 CN CN 97105119 patent/CN1165037A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100522246C (en) * | 2005-03-18 | 2009-08-05 | 中国科学院过程工程研究所 | Chitosan pellet/microsac and preparation thereof |
| CN101260191B (en) * | 2008-04-01 | 2011-04-20 | 武汉大学 | Temperature sensitive type chitosan/glutin hydrogel and its preparation method and use |
| CN101972232A (en) * | 2010-11-01 | 2011-02-16 | 山东大学 | Eudragit S100 coated curcumin pectin microsphere and preparation method thereof |
| CN106187996A (en) * | 2016-07-07 | 2016-12-07 | 华南师范大学 | A kind of composite aquogel containing rare earth compounding of novel pH response and its preparation method and application |
| CN106187996B (en) * | 2016-07-07 | 2018-11-09 | 华南师范大学 | A kind of composite hydrogel and its preparation method and application containing rare earth compounding of novel pH responses |
| CN106109400A (en) * | 2016-07-22 | 2016-11-16 | 金陵科技学院 | A kind of oral drugs hydrogel slow-released carrier and preparation method and applications |
| CN107183335A (en) * | 2017-07-25 | 2017-09-22 | 宿松县大坂农业开发有限公司 | A kind of preparation method for promoting to digest ox feed |
| CN110452054A (en) * | 2019-09-10 | 2019-11-15 | 山东胜伟盐碱地科技有限公司 | A kind of dedicated MULTILAYER COMPOSITE fertiliser granulates of alkaline land improving and preparation method thereof |
| CN111467320A (en) * | 2020-05-13 | 2020-07-31 | 四川大学 | Microcapsule with pH response and intestinal targeting effects and preparation method thereof |
| CN111467320B (en) * | 2020-05-13 | 2021-07-27 | 四川大学 | Microcapsule with pH response and intestinal targeting effects and preparation method thereof |
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