CN101024086A - Composition formed from chitosan and its derivatives and low-molecular heparin and pneparation and preparing method - Google Patents
Composition formed from chitosan and its derivatives and low-molecular heparin and pneparation and preparing method Download PDFInfo
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- CN101024086A CN101024086A CNA2007100105588A CN200710010558A CN101024086A CN 101024086 A CN101024086 A CN 101024086A CN A2007100105588 A CNA2007100105588 A CN A2007100105588A CN 200710010558 A CN200710010558 A CN 200710010558A CN 101024086 A CN101024086 A CN 101024086A
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Abstract
The present invention belongs to the field of medicine technology. In particular, it relates to a compound made up by using chitosan, its derivative and low-molecular heparin, its preparation and preparation method. Said compound can raise stability of low-molecular heparin, and can further raise bioavailability of said medicine preparation. Said compound can be made into various oral preparations, injection, spray, nose drops, aerosol and suppository, etc.
Description
Technical field
The present invention relates to medical technical field, the definite Nano/micron complex that utilizes chitosan and derivant and Low molecular heparin thereof to form of saying so increases the picked-up of cell to Low molecular heparin as carrier, utilize the bioadhesive of chitosan and derivant thereof and of short durationly open intercellular close-connected characteristic and further increase Low molecular heparin and see through biomembranous amount, formation by complex improves the stability of Low molecular heparin, provides the convenience of clinical application by making different preparations.
Background technology
Low molecular heparin (LMWH) is the low molecular weight heparin component that the low-molecular-weight heparin fragment that obtained through degraded by heparin or classified method obtain, the polysaccharide that the residue chain is formed that replaces by D-glycosamine and alduronic acid, the relative molecular mass scope is generally 3000～8000, is mainly used in prevention and treatment thrombotic disease such as deep venous thrombosis, pulmonary infarction etc. clinically.Compare with unfractionated heparin, LMWH and proteic combination rate reduce, and the half-life of medicine prolongs, thereby the drug dose that produces the identical required injection of anticoagulant effect has reduced, the probability of the complication that causes bleeding reduces greatly, and application prospect is extensive clinically, is a kind of extremely promising medicine.
Yet LMWH is still because the construction features of big, the many hydrogen bond of its relative molecular mass and bear electric charge makes it be difficult to see through gastrointestinal mucosa absorbs, at present clinically can only be with vein or muscle injection mode administration, and need frequent drug administration, patient's poor compliance.Also very inconvenience of medication behind the patient discharge.Therefore, the oral formulations or the long-acting injection of research Low molecular heparin have extremely important clinical meaning.We utilize modern preparation technique, the chitosan of employing biodegradable, biocompatibility and derivant thereof and Low molecular heparin are prepared into the Nano/micron complex of Low molecular heparin and make corresponding dosage forms, provide efficient, stable, safe drugs preparation for clinical, benefit the common people.
Summary of the invention:
The purpose of this invention is to provide Nano/micron complex and preparation thereof that a kind of chitosan and derivant thereof and Low molecular heparin form, they have good absorbing, bioavailability height, curative effect height, the little characteristics of side effect.But and provide the preparation method of industrial applications.
The present invention selects the chitosan of N-trimethyl chitosan TMC, sulfhydrylation of chitosan, the Pegylation of chitosan, N-trimethyl chitosan TMC, the Pegylation of different molecular weight as carrier, form the Nano/micron complex with Low molecular heparin, regulate the drug release rate of Low molecular heparin in case of necessity by sodium alginate, sodium carboxymethyl cellulose or the sodium triphosphate that adds different molecular weight.
The Nano/micron complex of the Low molecular heparin described in the present invention, the weight ratio of chitosan and derivant thereof and Low molecular heparin are 0.1-100: any one in 1.
The preparation of the Nano/micron complex that said Low molecular heparin forms among the present invention can be adopted emulsion polymerization method, any one or a few of emulsion-solvent evaporation method, investment, self-assembling technique, freeze-drying, spray drying method, ultrasonic method.
The Nano/micron complex that the made Low molecular heparin of the present invention forms can be prepared into various dosage forms, as oral formulations (comprising tablet, granule, capsule, dry suspension, micropill etc.), injection (comprising freeze-dried powder, aseptic powder injection) also can be made into transdermal absorption formulation, nasal drop, spray, aerosol, suppository etc.
The said oral or ejection preparation of the present invention can be conventional formulation, also can be the release preparation.
In " tablet " of the present invention, comprise common plain sheet, coated tablet, solution sheet, Sublingual tablet, cheek diaphragm, release sheet etc.
In " capsule " of the present invention, except that the Nano/micron complex that contains the formation of Low molecular heparin and chitosan and derivant thereof, appropriate excipients be can contain, hard capsule or soft capsule are prepared into.
" dry suspension " of the present invention mainly contains Nano/micron complex, the appropriate excipients that Low molecular heparin and chitosan and derivant thereof form, and exists with dry powder, uses preceding with using behind the supporting solvent suspendible.
Said among the present invention " freeze-dried powder " mainly contains Nano/micron complex, the suitable proppant/excipient that Low molecular heparin and chitosan and derivant thereof form, waiting one or more to mix as " mannitol ", " lactose ", " sucrose ", " sorbitol ", " dextran " uses, gets by lyophilization.
Said among the present invention " aseptic powder injection " mainly contains Nano/micron complex, the suitable proppant/excipient that Low molecular heparin and chitosan and derivant thereof form, wait one or more to mix as " mannitol ", " lactose ", " sucrose ", " sorbitol ", " dextran " and use, the powder that obtains by lyophilization/spray drying carries out aseptic subpackaged getting.
The invention solves the oral of Low molecular heparin can not absorb, and need the problem of frequent drug administration by injection, and the stability of Low molecular heparin improves greatly.The Nano/micron complex that Low molecular heparin of the present invention and chitosan and derivant thereof form can be used for making various preparations, made preparation can be routine/release preparation, improve curative effect, increased the convenience of medication, reduced side effects of pharmaceutical drugs.
The specific embodiment
Embodiment 1: the preparation of Low molecular heparin and different molecular weight chitosan nano/micron complex: the chitosan that takes by weighing different molecular weight is according to the above ratio made the solution of debita spissitudo, take by weighing Low molecular heparin according to the above ratio and make the solution of debita spissitudo, under stirring condition, join in the above-mentioned chitosan solution, continue to stir 10 minutes, stop to stir, room temperature hatching 30 minutes, promptly.
Embodiment 2: the preparation of Low molecular heparin and different molecular weight N-trimethyl chitosan TMC Nano/micron complex: the N-trimethyl chitosan TMC that takes by weighing different molecular weight is according to the above ratio made the solution of debita spissitudo, take by weighing Low molecular heparin according to the above ratio and make the solution of debita spissitudo, under stirring condition, join in the above-mentioned N-trimethyl chitosan TMC solution, continue to stir 10 minutes, stop to stir, room temperature hatching 30 minutes, promptly.
Embodiment 3: the preparation of the chitosan nano of Low molecular heparin and different molecular weight Pegylation/micron complex: the chitosan that takes by weighing different molecular weight polyethylene glycolization is according to the above ratio made the solution of debita spissitudo, take by weighing Low molecular heparin according to the above ratio and make the solution of debita spissitudo, under stirring condition, join in the chitosan solution of above-mentioned Pegylation, continue to stir 10 minutes, stop to stir, room temperature hatching 30 minutes, promptly.
Embodiment 4: the preparation of the N-trimethyl chitosan TMC Nano/micron complex of Low molecular heparin and different molecular weight Pegylation: the N-trimethyl chitosan TMC that takes by weighing different molecular weight polyethylene glycolization is according to the above ratio made the solution of debita spissitudo, take by weighing Low molecular heparin according to the above ratio and make the solution of debita spissitudo, under stirring condition, join in the N-trimethyl chitosan TMC solution of above-mentioned Pegylation, continue to stir 10 minutes, stop to stir, room temperature hatching 30 minutes, promptly.
Embodiment 5: the preparation of the sulfhydrylation chitosan nano/micron complex of Low molecular heparin and different molecular weight different degree of substitution: the sulfhydrylation chitosan that takes by weighing the different molecular weight different degree of substitution is according to the above ratio made the solution of debita spissitudo, take by weighing Low molecular heparin according to the above ratio and make the solution of debita spissitudo, under stirring condition, join in the sulfhydrylation chitosan solution of above-mentioned different molecular weight different degree of substitution, continue to stir 10 minutes, stop to stir, room temperature hatching 30 minutes, promptly.
Embodiment 6: the preparation of the Low molecular heparin Nano/micron complex of different chitosans and derivant thereof: get certain density chitosan aqueous solution 20ml according to the above ratio and place beaker, magnetic agitation.Other gets the Low molecular heparin aqueous solution that 20ml contains sodium alginate, at the uniform velocity splashes in the chitosan solution, drips off back room temperature hatching 30 minutes, promptly.
Embodiment 7: the preparation of the Low molecular heparin Nano/micron complex of different chitosans and derivant thereof: get certain density chitosan aqueous solution 20ml according to the above ratio and place beaker, magnetic agitation.Other gets the Low molecular heparin aqueous solution that 20ml contains sodium carboxymethyl cellulose, at the uniform velocity splashes in the chitosan solution, drips off back room temperature hatching 30 minutes, promptly.
Embodiment 8: the preparation of the Low molecular heparin Nano/micron complex of different chitosans and derivant thereof: get certain density chitosan aqueous solution 20ml according to the above ratio and place beaker, magnetic agitation.Other gets the Low molecular heparin aqueous solution that 20ml contains sodium triphosphate, at the uniform velocity splashes in the chitosan solution, drips off back room temperature hatching 30 minutes, promptly.
Embodiment 9: the preparation of the Low molecular heparin Nano/micron complex of different chitosans and derivant thereof: get certain density 2ml sodium alginate and Low molecular heparin aqueous solution and be emulsifiable in the vegetable oil that 50mL contains 1% sorbester p17, behind the 10min, add the 3%CaCl that 50ml contains the variable concentrations chitosan
2Aqueous solution.Behind the 30min, centrifugalize, acetone, distillation washing, vacuum drying.
Embodiment 10: get the Nano/micron complex of an amount of Low molecular heparin and chitosan and derivant thereof, with an amount of auxiliary materials and mixing pelletizing press sheet, get various Low molecular heparin sheets.Mixing tabletting after selecting for use different materials to granulate can get the release sheet.
Embodiment 11: get the Nano/micron complex of an amount of Low molecular heparin and chitosan and derivant thereof, with an amount of auxiliary materials and mixing, directly granulate/make micropill after, encapsulated, promptly get capsule.After made micropill carried out coating with different coating materials, mixing, encapsulated, promptly get the release capsule.
Embodiment 12: gets the Nano/micron complex of an amount of Low molecular heparin and chitosan and derivant thereof, granulates with suitable solubility auxiliary materials and mixing, and drying, granule is sub-packed in the drop bottle.Face with getting nasal drop after the supporting solvent dissolving of preceding usefulness.
Embodiment 13: get the Nano/micron complex of an amount of Low molecular heparin and chitosan and derivant thereof, with appropriate excipients mixed pelletization, drying, granule is sub-packed in the bottle.Use with making suspensoid behind the supporting solvent suspendible before using.
Embodiment 14: get an amount of Low molecular heparin for preparing and the Nano/micron complex of chitosan and derivant thereof under aseptic condition, add an amount of lactose and water for injection, gained solution is sub-packed in the cillin bottle, carries out lyophilization, gets freeze-dried powder.Size and its drug release rate of composition control by control Nano/micron complex.
Embodiment 15: get an amount of Low molecular heparin for preparing and the Nano/micron complex of chitosan and derivant thereof under aseptic condition, add an amount of mannitol and water for injection, gained solution is sub-packed in the cillin bottle, carries out lyophilization, gets freeze-dried powder.Size and its drug release rate of composition control by control Nano/micron complex.
Claims (10)
1, the complex of a kind of chitosan and derivant thereof and Low molecular heparin formation, it is characterized in that: the weight ratio of chitosan and derivant thereof and Low molecular heparin is 0.1-100: 1, form the Nano/micron complex.
2, the complex of a kind of chitosan according to claim 1 and derivant thereof and Low molecular heparin formation, it is characterized in that: described Low molecular heparin is the low molecular sodium heparin of mean molecule quantity less than 10000Da, low molecular heparin calcium, Enoxaparin, Fragmin; Described chitosan be N-trimethyl chitosan TMC, the sulfhydrylation of chitosan, the Pegylation of chitosan, N-trimethyl chitosan TMC, the Pegylation of different molecular weight chitosan, other manually modified chitosans a kind of/multiple.
3, the complex of a kind of chitosan according to claim 2 and derivant thereof and Low molecular heparin formation, it is characterized in that: described chitosan is the chitosan of different molecular weight, different deacetylations, the N-trimethyl chitosan TMC of different molecular weight, different methyl and methylene substitution value, the chitosan of different molecular weight, different Polyethylene Glycol substitution values and N-trimethyl chitosan TMC, the chitosan and the N-trimethyl chitosan TMC of different molecular weight, different sulfydryl substitution values.
4, the complex of a kind of chitosan according to claim 1 and derivant thereof and Low molecular heparin formation, it is characterized in that: the chitosan of described Pegylation, the N-trimethyl chitosan TMC of Pegylation are Polyethylene Glycol 550,1000,2000,5000,10000,12000,20000 different molecular weights of modifying, the chitosan and the N-trimethyl chitosan TMC of different Polyethylene Glycol substitution values.
5, the complex of a kind of chitosan according to claim 1 and derivant thereof and Low molecular heparin formation is characterized in that: can be by add the sodium alginate of different molecular weight or the sodium carboxymethyl cellulose of different molecular weight, the release that sodium triphosphate is regulated Low molecular heparin in " Nano/micron complex ".
6, the complex of chitosan according to claim 1 and derivant thereof and Low molecular heparin formation, it is characterized in that: formed Nano/micron complex can be prepared into tablet, granule, capsule, dry suspension, micropill, release preparation with appropriate excipients; Also can be freeze-dried powder, aseptic powder injection; Nasal drop, spray, aerosol, transdermal absorption formulation, suppository.
7, the complex of chitosan according to claim 6 and derivant thereof and Low molecular heparin formation, it is characterized in that: described tablet comprises common plain sheet, coated tablet, solution sheet, Sublingual tablet, cheek diaphragm, release sheet; Capsule comprises hard capsule, soft capsule.
8, the complex of chitosan according to claim 6 and derivant thereof and Low molecular heparin formation, it is characterized in that: described dry suspension mainly contains the Nano/micron complex and the appropriate excipients preparation of Low molecular heparin and chitosan and derivant formation thereof and gets, and uses preceding with using behind the supporting solvent suspendible.
9, the complex of chitosan according to claim 6 and derivant thereof and Low molecular heparin formation, it is characterized in that: described freeze-dried powder mainly contains Nano/micron complex, the suitable proppant/excipient that Low molecular heparin and chitosan and derivant thereof form, and gets by lyophilization; Aseptic powder injection mainly contains Nano/micron complex, the suitable proppant/excipient that Low molecular heparin and chitosan and derivant thereof form, and the powder that obtains by lyophilization/spray drying carries out aseptic subpackaged getting.
10, the preparation method of the complex of a kind of chitosan as claimed in claim 1 and derivant thereof and Low molecular heparin formation, it is characterized in that: the preparation of the complex of described Low molecular heparin can be adopted emulsion polymerization method, any one or a few of emulsion-solvent evaporation method, investment, self-assembling technique, freeze-drying, spray drying method, ultrasonic method;
The chitosan that takes by weighing different molecular weight is according to the above ratio made certain density solution, takes by weighing the solution of Low molecular heparin according to the above ratio, joins under stirring condition in the above-mentioned chitosan solution, continue to stir 10 minutes, stop to stir, room temperature hatching 30 minutes promptly gets complex;
Get certain density chitosan aqueous solution 20ml according to the above ratio and place beaker, magnetic agitation, other gets the Low molecular heparin aqueous solution that 20ml contains sodium alginate, at the uniform velocity splashes in the chitosan solution, drips off back room temperature hatching 30 minutes, promptly gets complex;
Get certain density chitosan aqueous solution 20ml according to the above ratio and place beaker, magnetic agitation.Other gets the Low molecular heparin aqueous solution that 20ml contains sodium triphosphate, at the uniform velocity splashes in the chitosan solution, drips off back room temperature hatching 30 minutes, promptly gets complex;
The preparation of the Low molecular heparin Nano/micron complex of different chitosans and derivant thereof: get certain density 2ml sodium alginate and Low molecular heparin aqueous solution and be emulsifiable in the vegetable oil that 50mL contains 1% sorbester p17, behind the 10min, add the 3%CaCl2 aqueous solution that 50ml contains the variable concentrations chitosan.Behind the 30min, centrifugalize, acetone, distillation washing, vacuum drying;
Get the Nano/micron complex of an amount of Low molecular heparin and chitosan and derivant thereof,, get various Low molecular heparin sheets, select different material granulation back mixing tablettings for use, can get the release sheet with an amount of auxiliary materials and mixing pelletizing press sheet;
Get the Nano/micron complex of an amount of Low molecular heparin and chitosan and derivant thereof, with an amount of auxiliary materials and mixing, directly granulate/make micropill after, encapsulated, promptly get capsule, made micropill is carried out coating with different coating materials after, mixing, encapsulated, promptly get the release capsule;
Get the Nano/micron complex of an amount of Low molecular heparin and chitosan and derivant thereof, granulate with suitable solubility auxiliary materials and mixing, drying, granule is sub-packed in the drop bottle, faces with must nasal drop after the supporting solvent dissolving of preceding usefulness,
Get the Nano/micron complex of an amount of Low molecular heparin and chitosan and derivant thereof, with appropriate excipients mixed pelletization, drying, granule is sub-packed in the bottle, uses with making suspensoid behind the supporting solvent suspendible before using;
Get an amount of Low molecular heparin for preparing and the Nano/micron complex of chitosan and derivant thereof under aseptic condition, add an amount of lactose and water for injection, gained solution is sub-packed in the cillin bottle, carries out lyophilization, gets freeze-dried powder.Size and its drug release rate of composition control by control Nano/micron complex;
Get an amount of Low molecular heparin for preparing and the Nano/micron complex of chitosan and derivant thereof under aseptic condition, add an amount of mannitol and water for injection, gained solution is sub-packed in the cillin bottle, carries out lyophilization, gets freeze-dried powder.Size and its drug release rate of composition control by control Nano/micron complex.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007100105588A CN101024086A (en) | 2007-03-09 | 2007-03-09 | Composition formed from chitosan and its derivatives and low-molecular heparin and pneparation and preparing method |
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| CNA2007100105588A CN101024086A (en) | 2007-03-09 | 2007-03-09 | Composition formed from chitosan and its derivatives and low-molecular heparin and pneparation and preparing method |
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| CN101249063B (en) * | 2008-03-14 | 2010-12-08 | 褚红女 | Calciparine/sodium salt nano oral preparation and preparation technique thereof |
| CN101768263B (en) * | 2008-12-30 | 2012-04-04 | 上海医药工业研究院 | Method for synthesizing hydrosulfo-polyethylene glycol for preparing macrocyclic liposome |
| CN102475686A (en) * | 2010-11-29 | 2012-05-30 | 吴忠仕 | Low molecular heparin iron nanoparticles and preparation method thereof |
| CN102652834A (en) * | 2012-01-13 | 2012-09-05 | 诸敏 | Preparation method and composite of low-molecular heparin nanopolymer |
| CN102671232A (en) * | 2012-05-18 | 2012-09-19 | 成都理工大学 | Tourmaline/chitosan hydrochloride compound spray-type aqueous dressing and preparation method thereof |
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| CN105640879A (en) * | 2016-02-25 | 2016-06-08 | 青岛科技大学 | Heparin nasal drop preparation and preparation method thereof |
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- 2007-03-09 CN CNA2007100105588A patent/CN101024086A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101249063B (en) * | 2008-03-14 | 2010-12-08 | 褚红女 | Calciparine/sodium salt nano oral preparation and preparation technique thereof |
| CN101768263B (en) * | 2008-12-30 | 2012-04-04 | 上海医药工业研究院 | Method for synthesizing hydrosulfo-polyethylene glycol for preparing macrocyclic liposome |
| CN102475686A (en) * | 2010-11-29 | 2012-05-30 | 吴忠仕 | Low molecular heparin iron nanoparticles and preparation method thereof |
| CN102475686B (en) * | 2010-11-29 | 2015-05-06 | 吴忠仕 | Low molecular heparin iron nanoparticles and preparation method thereof |
| CN102652834A (en) * | 2012-01-13 | 2012-09-05 | 诸敏 | Preparation method and composite of low-molecular heparin nanopolymer |
| CN102671232A (en) * | 2012-05-18 | 2012-09-19 | 成都理工大学 | Tourmaline/chitosan hydrochloride compound spray-type aqueous dressing and preparation method thereof |
| CN102671232B (en) * | 2012-05-18 | 2014-08-13 | 成都理工大学 | Tourmaline/chitosan hydrochloride compound spray-type aqueous dressing and preparation method thereof |
| CN104798823A (en) * | 2015-04-30 | 2015-07-29 | 山东大学齐鲁医院 | Bactericide for clinical laboratory |
| CN105640879A (en) * | 2016-02-25 | 2016-06-08 | 青岛科技大学 | Heparin nasal drop preparation and preparation method thereof |
| CN107223784A (en) * | 2017-06-30 | 2017-10-03 | 云南农业大学 | A kind of newborn piglet is adjusted and its application method with iron |
| CN109157529A (en) * | 2018-10-16 | 2019-01-08 | 江西浩然生物医药有限公司 | A kind of preparation method of Enoxaparin Sodium microballoon |
| CN110840829A (en) * | 2019-09-10 | 2020-02-28 | 安徽相王医疗健康股份有限公司 | Dust-washing lung liquid and preparation method thereof |
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