CN103467755B - Medicinal sustained-release hydrogel as well as preparation method and application thereof - Google Patents
Medicinal sustained-release hydrogel as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses medicinal sustained-release hydrogel as well as a preparation method and an application thereof. Monodisperse medicament-containing calcium alginate microspheres are prepared by adopting a high-pressure electrostatic sessile drop method, to realize direct encapsulation of growth factors and keep the activity of medicaments; and the medicament-carrying calcium alginate microspheres are put into the netlike structure of the hydrogel to realize sustained release of the medicaments. The matrix of the hydrogel contains carboxymethyl chitosan and polyvinyl alcohol, the volume ratio of the carboxymethyl chitosan solution to the polyvinyl alcohol solution is n: (6-n), 0<n<=4, and the release rate of the medicaments is controlled through different volume ratios.
Description
Technical field
The invention belongs to technical field of macromolecules and medicament slow release technical field.In particular to a kind of medicament slow release hydrogel and preparation method thereof.
Background technology
Somatomedin has the function promoting wound and ulcer healing; can be used for the treatment of the diseases such as wound, burn, ulcer; but the multiplex aqua of the route of administration of FGF-2 or sprays; cause production cost compared with high, easily by wound proteasome degradation, dressing change frequency is many, the surface of a wound residence time is short, to the effect of surface of a wound unprotect, use the problems such as inconvenient, Clinical practice is very limited.For improving its bioavailability, exploitation has slow releasing function FGF-2 new preparation wide prospect, can improve speed of wound healing and the quality of this kind of patient, and then improves the quality of life of patient.Transdermal therapeutic system is a kind of special case of medicine sustained and controlled release, can produce lasting, constant, controlled Plasma Concentration, improves bioavailability, alleviates the misery of injecting drug use, and medication and drug withdrawal conveniently, can reduce administration number of times and dosage.How to adopt relatively gentle condition parcel somatomedin to keep its long-effect active, realize controllable release, and preparation capable of permeating skin easy detachable, a small amount of skin sepage of Absorbable rod is an important directions of current burn and scald local skin preparation capable of permeating skin research.
Hydrogel is the three-dimensional crosslinked network structure that hydrophilic polymer is formed by chemical bond or physical force, water insoluble but a large amount of water can be absorbed and the swelling solid form that simultaneously keeps, there is the characteristics such as good swelling behavior, mechanical property, biocompatibility, be widely used in medicament slow release and skin wound dressing.
Lalgine is the natural polymer obtained from brown alga, due to it biocompatibility, hypotoxicity, non-immunogenicity and become gel with calcium ion crosslinking and be widely used in drug release and organizational project.But calcium alginate microsphere internal structure exists larger interstitial structure and larger swelling medicine, medicine is dashed forward in early days and releases seriously, long-acting release cannot be realized.
Polyvinyl alcohol is by the polymer of polyvinyl acetate Lipase absobed, adopts freeze-thaw legal system is standby repeatedly polyvinyl alcohol hydrogel not relate to the use of the organic chemical reagents such as linking agent.Hydrogel prepared by this method is at room temperature more stable, and has snappiness.
Cm-chitosan is a kind of water-soluble chitosan derivatives, due to the chemistry of its uniqueness, physics and biological property, especially good biocompatibility, has been widely used in the biomedical applications such as such as wound dressings, artificial bone tissue and skin, antibacterial, anticoagulation reagent.
Chinese Patent Application No. is 201110239757.2 disclose a kind of combining high-voltage electrostatic liquid droplet and the LBL self-assembly legal system method for self-assembly medicine carrying microballoons, this invention with the sodium alginate aqueous solution containing somatomedin for stock liquid, take calcium chloride solution as coagulation bath, microcapsule are prepared in high tension electrostatic field, somatomedin is made to be uniformly distributed in microgel, and then with electrostatic nanometer layer-by-layer at micro-gel surface assembling layer high molecule polyelectrolyte film, obtain self-assembly medicine carrying microballoons, the chitosan that complex polyelectrolyte particle film in this technology is used and dextran solution need to dissolve use in acid condition, therefore, in order to reduce the impact that acidic solution causes protein drug, all need before experiment to regulate the PH dissolving chitosan acidic solution at every turn, simultaneously, under acidic solution condition, this solution may have an impact to the activity of basic protein medicine.And the drug controlled release system that this technology prepares lacks application vector.
Chinese Patent Application No. 200810001455.X discloses a kind of polyvinyl alcohol hydrogel releasing negative ion and preparation thereof, by changing the per-cent of negative ion and then changing the negative ion concentration of product, but the rate of release of negative ion and time are not studied, and in gel, use rare-earth additive may cause certain cytotoxicity, skin is had an impact.This product also cannot reach the object of the skin repair such as burn, scald that the present invention will apply.
Summary of the invention
Not enough for prior art, an object of the present invention is to provide a kind of medicament slow release hydrogel.The present invention, by medicine carrying hydrogel microsphere and hydrogel matrix compound, carrys out the rate of release of regulating medicine by the volume ratio regulating hydrogel matrix to form.High-voltage electrostatic liquid droplet prepares the calcium alginate microsphere of single dispersing drug containing, realizes somatomedin and directly encapsulates, and keeps pharmaceutical activity.Medicine carrying calcium alginate microsphere is inserted in hydrogel reticulated structure, realizes medicine sustained and controlled release and put; And hydrogel compound system has good absorb subsemimodule, give wound wet environment, accelerating wound speed, easy detachable, do not have any material and remain in wound.
Two of object of the present invention is the preparation method of the medicament slow release hydrogel providing one of object.
Three of object of the present invention is the purposes of the medicament slow release hydrogel providing one of object.
Above-mentioned purpose of the present invention is achieved by the following technical programs:
Microballoon of the present invention-gel composite medicine slow-release solid support material obtained by hydrogel matrix load medicine carrying hydrogel microsphere.Described gel matrix is cm-chitosan and polyvinyl alcohol blending hydrogel, and medicine carrying microballoons is calcium alginate microsphere.Cm-chitosan has good antimicrobial property as the derivative of chitosan simultaneously.Prepared hydrogel, when ensureing skin wet, enables the activated somatomedin of release promote the regeneration of skin.
Described hydrogel microsphere adopts described in the preparation of high pressure static electricity encapsulation technique, and hydrogel matrix adopts the preparation of circulating frozen freezing process.Circulating frozen-freezing process easily makes hydrogel shaping, and the hydrogel microsphere of medicine carrying can be made to be distributed to uniformly in hydrogel, forms uniform hydrogel microsphere-hydrogel matrix medicine-carried system.
Described calcium alginate microsphere is prepared as follows: the preparation of medicine carrying calcium alginate microsphere: with CaCl
2the aqueous solution is receptor, drug containing 1 ~ 3% sodium alginate soln formed in high tension electrostatic field fine droplet fall into 0.5 ~ 6% calcium chloride solution solidification 5 ~ 15min, deionization forms calcium alginate microsphere after washing three times.Realize the direct encapsulating of somatomedin, obtain the microballoon of smooth surface, rounding, good uniformity, diameter is 100 ~ 600 μm.
Wherein, the sodium alginate soln Chinese traditional medicine of described drug containing and the mass ratio m:(10-m of sodiun alginate), m is 0 ~ 5, and the medicine of different mass ratio and sodium alginate can prepare the hydrogel microsphere of different carrying drug ratio.Syringe needle internal diameter 200 ~ 800 μm is selected in described high tension electrostatic field, keeps needle point and CaCl
2the liquid level of solution is apart from being 15 ~ 25 cm, and voltage of electric field is 10 ~ 20kV.
Described gel matrix is prepared by circulating frozen freezing process by cm-chitosan and polyvinyl alcohol, by non-covalent interaction, can avoid the use of chemical organic solvent.Freeze-thaw method prepare blended gel load medicine carrying microballoons method, comprise the steps:
(1) by the carboxymethyl chitosan solution obtaining 1 ~ 5wt% soluble in water for cm-chitosan, polyvinyl alcohol is heated at 85 ~ 95 DEG C 1 ~ 2h and be dissolved in the water, obtain 5 ~ 15wt% polyvinyl alcohol;
(2) be n:(6-n by volume by carboxymethyl chitosan solution and polyvinyl alcohol solution at ambient temperature), 0 < n≤4 mixing, and stir;
(3) joined by the calcium alginate microsphere of preparation in the mixing solutions of carboxymethyl chitosan solution and polyvinyl alcohol, be uniformly dispersed by calcium alginate microsphere, freeze-thaw circulation repeatedly 3 ~ 7 forms composite aquogel.
Owing to having amino and carboxyl to make it have PH susceptibility in carboxymethyl chitosan glycan molecule, regulate pH value can change the swelling ratio of hydrogel to acid or alkalescence, thus the medicine changed in hydrogel add up release rate.
Described circulating frozen-freezing process, by the solution of preparation first freezing 8 ~ 23h at-10 ~-80 DEG C, then the 1 ~ 4h that thaws at 4 ~ 25 DEG C, the number of times that circulating frozen thaws is 3 ~ 7 times.Increasing its degree of crystallinity by increasing circulating freezing resistance number of times, reducing freezing temp, reducing thaw point, thus increasing the physical strength of hydrogel; The physical strength adding membership reduction hydrogel of part cm-chitosan simultaneously.The physical strength of wet gel is 1 ~ 5MPa, and the physical strength of xerogel is 10 ~ 50MPa.
Described medicine is protein drug, acid-sensitive medicine, antibiotic medicine, calcium antagonist medicine etc.Alginates has and is easy to encystation, cheaply the advantage such as is easy to get, and because encapsulation process does not relate to organic solvent, chemical reagent, makes it be suitable for bag and carries a protein drug; Encapsulation process is formed in neutral solution, makes it be suitable for bag and carries acid-sensitive medicine; Because most of antibiotic medicine, calcium antagonist medicine are all water miscible, make alginates in saccilar process, easily realize encapsulating.
By above-mentioned preparation method prepare medicament slow release hydrogel there is certain medicament slow release effect and good biocompatibility, can be used as empyrosis dressing.The diameter of described hydrogel microsphere is 100 ~ 600 μm, and the thickness of described hydrogel matrix is 1 ~ 5mm.
Tool of the present invention has the following advantages:
(1) the present invention selects cm-chitosan and polyvinyl alcohol to be hydrogel based material; freeze-thaw method is adopted to prepare blended gel; there is the premium propertiess such as good elasticity, water-absorbing-retaining, air-and water-permeable, prevent adhesion wound, to the surface of a wound, there is provide protection well.
(2) volume ratio of carboxymethyl chitosan solution and polyvinyl alcohol solution in hydrogel matrix is regulated, can the rate of release of regulating medicine.
(3) the microsphere gel complex carrier prepared of the present invention, can realize medicine and directly encapsulate, available protecting medicine biological activity, has medicament slow release performance.
(4) solid support material preparation used in the present invention is simple, and mild condition, preparation cost is low.
(5) hydrogel microsphere in the present invention-hydrogel based plastome can not have an impact to activity that is acid or basic protein medicine.Meanwhile, adopt hydrogel microsphere-hydrogel matrix that drug release is needed through two kinds of gels to reach the effect of medicament slow release, and preparation method is simple, is beneficial to and realizes industrialization, the medicine carrying gel prepared also is applicable to storing.
figure of description
Fig. 1: be BSA Cumulative release profile figure
Fig. 2: be the swelling ratio figure of hydrogel microsphere-hydrogel matrix compound system
Fig. 3: be the gel fraction figure of hydrogel microsphere-hydrogel matrix compound system.
Embodiment
embodiment 1
Experiment material: sodium alginate (when 25 DEG C, the viscosity of 2% aqueous solution is 250cps), Sigma company; Polyvinyl alcohol (alcoholysis degree: 99.8 ~ 100%), Aladdin company; Cm-chitosan (deacetylation: >=90, carboxylation degree: >=80%), Fei Bo bio tech ltd, Guangzhou; Heparin sodium (> 170 units/milligram), lark prestige company; Bovine serum albumin (BSA), Genview company; Basic Fibroblast Growth Factor (bFGF), Ji'nan University's biological medicine base.
High-voltage DC power supply (DW-P503-4ACCD), Tianjin San Chuan company; Microsyringe pump (LSP01-1A), Baoding Lange company; Digital display gas bath constant temperature oscillator (CHA-S), Community of Jin Tan County company limited; Syringe (2.5ml), Zhejiang Jing Huan medical treatment product company; Polystyrene plates (6,24 hole), Nai Si bio tech ltd.
Experiment content: adopt high-voltage electrostatic liquid droplet to prepare calcium alginate microsphere, with the sodium alginate aqueous solution of BSA and 2wt% containing 10mg/ml for stock liquid, 3%(w/v) CaCl
2the aqueous solution is receptor, selects syringe needle internal diameter 200 μm, keeps needle point and CaCl
2the liquid level of solution is apart from being 20 cm, and voltage of electric field is 10kV.Solidification 10min, deionization washes three times.The moisture of microsphere surface is filtered with filter paper, the calcium alginate microsphere taking 100mg joins in two mixed uniformly hydrogel matrixes respectively, 2% cm-chitosan and 10% polyvinyl alcohol solution is contained in hydrogel matrix, its volume ratio is respectively 2:4,3:3 and 4:2, and the vortex several seconds makes it be uniformly dispersed.Hydrogel containing calcium alginate microsphere is placed in-20 DEG C of freezing 20h, then the 4h that thaws at 25 DEG C, the number of times that circulating frozen thaws is 3 times.
Appeal gained composite aquogel is placed in the PBS solution of the PH=7.4 of 10ml, 37 DEG C, vitro drug release is carried out in 40rpm constant temperature oscillator, the specific time gets 1ml supernatant liquor, add the fresh PBS of same volume, BCA test kit test b SA content, calculates drug accumulation release rate, draws BSA Cumulative release profile.
Drug accumulation release rate %=(t time drug release total amount/actual drug loading) %.
Fig. 1 is BSA Cumulative release profile, I represents medicine calcium alginate microsphere, II to represent cm-chitosan and polyvinyl alcohol solution volume ratio be the medicine hydrogel that the medicine hydrogel, III of 2:4 represents that cm-chitosan and polyvinyl alcohol solution volume ratio are 3:3, and IV represents the medicine hydrogel that cm-chitosan and polyvinyl alcohol solution volume ratio are 4:2.
As shown in Figure 1, the medicine in calcium alginate microsphere has obvious prominently to release.After the calcium alginate microsphere of medicine carrying being compound to the blended gel of cm-chitosan and polyvinyl alcohol, in two weeks, medicine has obvious slow releasing function in hydrogel microsphere-hydrogel matrix., can find out, the content reducing the cm-chitosan in hydrogel matrix can improve the accumulative release rate of medicine meanwhile.
Fig. 2,3 is that cm-chitosan is with under polyvinyl alcohol solution different volumes ratio, the swelling ratio of hydrogel microsphere-hydrogel matrix compound system and gel fraction, in figure, 1,2,3,4 represent cm-chitosan (CMCS) with polyvinyl alcohol (PVA) liquor capacity respectively than the hydrogel for 0:6,2:4,3:3,4:2.
From Fig. 2,3 can find out, the content increasing cm-chitosan can reduce the gel fraction of hydrogel, but can increase the swelling ratio of hydrogel simultaneously.Cm-chitosan can meet the rapid hydration swelling of water in hydrogel, has good swelling behavior.Along with the content of cm-chitosan increases, the cross-link intensity of gel reduces, and gel fraction reduces; Meanwhile, gel network aperture increases, and swelling ratio increases.And uncrosslinked part is oozed out from solution, make the corresponding increase of surface-area in composite aquogel, thus the dissolution rate of medicine is slowed down, reduce the rate of release of medicine.And, along with the content of cm-chitosan increases, the release of medicine from Lalgine acid calcium microballoon can be intercepted, cause the reduction of drug accumulation release rate.Find out from release profiles, when the volume ratio of cm-chitosan and polyvinyl alcohol is larger, it is lower that medicine adds up release rate, and therefore, we can by reducing the volume ratio of cm-chitosan and polyvinyl alcohol thus improving the preparation of medicine.When the volume ratio of methyl chitosan and polyvinyl alcohol is 4:2, its drug accumulation release rate is 42%, lower than 50%, and when the volume ratio of cm-chitosan and polyvinyl alcohol is 0:6, be difficult to medicine be detected in release liquid, this may be because polyvinyl alcohol itself has higher degree of crystallinity and makes gel surface very fine and close.So there is good physicals and release performance, the optimum range of the volume ratio X of cm-chitosan and polyvinyl alcohol in gel in order to what ensure gel: (0:6) < X≤(4:2)
embodiment 2
Adopt high-voltage electrostatic liquid droplet to prepare calcium alginate microsphere, with 1.17 μ g/ml containing the sodium alginate aqueous solution of the 1wt% heparin solution of Basic Fibroblast Growth Factor (bFGF) and 2wt% for stock liquid, 3%(w/v) CaCl
2the aqueous solution is receptor, selects syringe needle internal diameter 200 μm, keeps needle point and CaCl
2the liquid level of solution is apart from being 20 cm, and voltage of electric field is 10kV.Solidification 10min, deionization washes three times.The moisture of microsphere surface is filtered with filter paper, the calcium alginate microsphere taking 50mg joins in two mixed uniformly hydrogel matrixes respectively, contain 2% cm-chitosan and 10% polyvinyl alcohol solution in hydrogel matrix, its volume is 2:4, and the vortex several seconds makes it be uniformly dispersed.Hydrogel containing calcium alginate microsphere is placed in-20 DEG C of freezing 20h, then the 4h that thaws at 4 DEG C, the number of times that circulating frozen thaws is 3 times.
Claims (8)
1. a preparation method for medicament slow release hydrogel, is characterized in that, comprises the following steps:
S1. medicine carrying calcium alginate microsphere is prepared;
S2. the preparation of hydrogel matrix: the carboxymethyl chitosan solution of 1 ~ 5% and the polyvinyl alcohol solution of 5 ~ 15% n:(6-n by volume), 0 < n≤4, mixing, stirs;
S3. the preparation of sustained-release hydrogel: the medicine carrying calcium alginate microsphere prepared by S1 adds in hydrogel matrix prepared by S2, and medicine carrying calcium alginate microsphere is uniformly dispersed, and circulating frozen-thaw formation hydrogel through 3 ~ 7 times;
Described medicine carrying calcium alginate microsphere is prepared as follows: drug containing 1 ~ 3% sodium alginate soln formed in high tension electrostatic field fine droplet fall into 0.5 ~ 6% calcium chloride solution solidification 5 ~ 15min formed calcium alginate microsphere.
2. the preparation method of medicament slow release hydrogel according to claim 1, is characterized in that, the sodium alginate soln Chinese traditional medicine of described drug containing and the mass ratio m:(10-m of sodium alginate), m is that 0 ~ 5, m is not equal to 0.
3. the preparation method of medicament slow release hydrogel according to claim 1, is characterized in that, syringe needle internal diameter 200 ~ 800 μm is selected in described high tension electrostatic field, keeps needle point and CaCl
2the liquid level of solution is apart from being 15 ~ 25 cm, and voltage of electric field is 10 ~ 20kV.
4. the preparation method of medicament slow release hydrogel according to claim 1, is characterized in that, the polyvinyl alcohol solution of described 5 ~ 15% is prepared as follows: described polyvinyl alcohol is heated at 85 ~ 95 DEG C 1 ~ 2h and be dissolved in the water.
5. the preparation method of medicament slow release hydrogel according to claim 1, is characterized in that, described circulating frozen-freezing process is by the solution of preparation first freezing 8 ~ 23h at-10 ~-80 DEG C, then the 1 ~ 4h that thaws at 4 ~ 25 DEG C.
6. the preparation method of medicament slow release hydrogel according to claim 1, is characterized in that, described medicine is protein drug, acid-sensitive medicine, antibiotic medicine or calcium antagonist medicine.
7. the medicament slow release hydrogel prepared under the medicament slow release hydrogel preparation method described in claim 1 ~ 6, is characterized in that, the diameter of described hydrogel microsphere is 100 ~ 600 μm, and the thickness of described hydrogel matrix is 1 ~ 5mm.
8. the application in empyrosis dressing prepared by medicament slow release hydrogel according to claim 7.
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