CN103467755A - 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.Be particularly related to a kind of medicament slow release hydrogel and preparation method thereof.
Background technology
Somatomedin has the function that promotes 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 than high, easily by the 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, in clinical use, be very limited.For improving its bioavailability, exploitation has slow releasing function FGF-2 new preparation wide prospect, can improve this class patient's speed of wound healing and quality, and then improves patient's quality of life.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 are convenient, 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 the preparation capable of permeating skin easy detachable, can absorb a small amount of skin sepage, be 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 passes through chemical bond or physical force formation, water insoluble but can absorb a large amount of water and swelling keeps solid form simultaneously, 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 with calcium ion crosslinking, become gel to be widely used in drug release and organizational project.Yet the calcium alginate microsphere internal structure exists larger interstitial structure and larger swelling medicine, make medicine prominent releasing seriously in early days, can't realize long-acting release.
Polyvinyl alcohol is the polymer synthetic by polyvinyl acetate, adopts repeatedly the standby polyvinyl alcohol hydrogel of freeze-thaw legal system 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, chemistry, physics and biological property due to its uniqueness, especially good biocompatibility, be widely used such as in the biomedical applications such as wound dressings, artificial bone tissue and skin, antibiotic, anticoagulation reagent.
Chinese Patent Application No. be 201110239757.2 disclose a kind of combining high-voltage electrostatic liquid droplet and layer by layer self-assembly method prepare the method for self-assembly medicine carrying microballoons, this sodium alginate aqueous solution of inventing to contain somatomedin is stock liquid, take calcium chloride solution as coagulation bath, prepare microcapsule in high tension electrostatic field, somatomedin is uniformly distributed in microgel, and then assemble the layer high molecule polyelectrolyte film with static nanometer layer-by-layer at micro-gel surface, obtain the self-assembly medicine carrying microballoons, the chitosan that complex polyelectrolyte particle film in this technology is used and dextran solution need to dissolve use under acidic conditions, therefore, impact protein drug caused in order to reduce acidic solution, all need to regulate the PH that dissolves the chitosan acidic solution before experiment at every turn, simultaneously, under the acidic solution condition, this solution may exert an influence 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 the per-cent that changes negative ion and then the negative ion concentration that changes product, but rate of release and the time of negative ion are not studied, and in gel, use rare-earth additive may cause certain cytotoxicity, skin is exerted an influence.This product also can't reach the purpose of the skin repair such as burn that the present invention will apply, scald.
Summary of the invention
For the prior art deficiency, one of purpose of the present invention is to provide a kind of medicament slow release hydrogel.The present invention is compound by medicine carrying hydrogel microsphere and hydrogel matrix, and the volume formed by the adjusting hydrogel matrix is the rate of release of regulating medicine recently.The single calcium alginate microsphere disperseed containing medicine of high-voltage electrostatic liquid droplet preparation, realize that somatomedin directly seals, and keeps pharmaceutical activity.The medicine carrying calcium alginate microsphere is inserted in the netted structure of hydrogel, realize that medicine sustained and controlled release puts; And the hydrogel compound system has good water-absorbing-retaining performance, gives the wound wet environment, accelerating wound speed, easy detachable, do not have any material and remain in wound.
Two of purpose of the present invention is to provide the preparation method of the medicament slow release hydrogel of one of purpose.
Three of purpose of the present invention is to provide the purposes of the medicament slow release hydrogel of one of purpose.
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 is resulting 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 is in the situation that guarantee skin wetness, and the activated somatomedin that makes to discharge can promote the regeneration of skin.
It is described that described hydrogel microsphere adopts the high pressure static electricity encapsulation technique to prepare, and hydrogel matrix adopts the preparation of circulating frozen freezing process.Circulating frozen-freezing process easily makes the hydrogel moulding, and can make the hydrogel microsphere of medicine carrying 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, forms fine droplet containing 1 ~ 3% sodium alginate soln of medicine in high tension electrostatic field and falls into 0.5 ~ 6% calcium chloride solution and solidify 5 ~ 15min, and deionization forms calcium alginate microsphere after washing three times.Realize directly sealing of somatomedin, obtain the microballoon of smooth surface, rounding, good uniformity, diameter is 100 ~ 600 μ m.
Wherein, the described sodium alginate soln Chinese traditional medicine containing medicine and the mass ratio m:(10-m of sodiun alginate), m is 0 ~ 5, the medicine of different mass ratio and sodium alginate can prepare the hydrogel microsphere of different carrying drug ratios.Syringe needle internal diameter 200 ~ 800 μ m are selected in described high tension electrostatic field, keep needle point and CaCl
2the liquid level of solution is apart from being 15 ~ 25 cm, and voltage of electric field is 10 ~ 20kV.
Prepared by the circulating frozen freezing process by cm-chitosan and polyvinyl alcohol by described gel matrix, 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 cm-chitosan carboxymethyl chitosan sugar soln that obtains 1 ~ 5wt% soluble in water, polyvinyl alcohol is heated to 1 ~ 2h under 85 ~ 95 ℃ and be dissolved in the water, obtain 5 ~ 15wt% polyvinyl alcohol;
(2) by carboxymethyl chitosan sugar soln and polyvinyl alcohol solution, be n:(6-n by volume at ambient temperature), mix 0<n≤4, and stir;
(3) calcium alginate microsphere of preparation is joined in the mixing solutions of carboxymethyl chitosan sugar soln and polyvinyl alcohol, calcium alginate microsphere is uniformly dispersed, the freeze-thaw circulation repeatedly 3 ~ 7 forms composite aquogel.
Owing to having amino and carboxyl to make it there is PH susceptibility in the carboxymethyl chitosan glycan molecule, regulate pH value and can change the swelling ratio of hydrogel to acid or alkalescence, thus the medicine accumulative total release rate in the change hydrogel.
Described circulating frozen-freezing process, by the freezing 8 ~ 23h under-10 ~-80 ℃ of the solution of preparation elder generation, then the 1 ~ 4h that thaws under 4 ~ 25 ℃, the number of times that circulating frozen thaws is 3 ~ 7 times.Increase its degree of crystallinity by increasing the circulating freezing resistance number of times, reduce freezing temp, reduce thaw point, thereby increase the physical strength of hydrogel; The physical strength that adds membership reduction hydrogel of while part cm-chitosan.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 medicaments, antibiotic medicine, calcium antagonist medicine etc.Alginates has the encystation of being easy to, the cheap advantage such as be 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 forms in neutral solution, makes it be suitable for bag and carries acid sensitive medicaments; Because most of antibiotic medicine, calcium antagonist medicine are all water miscible, make alginates easily realize sealing in saccilar process.
By above-mentioned preparation method, prepared the 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 μ m, and the thickness of described hydrogel matrix is 1 ~ 5mm.
The present invention has following advantage:
(1) to select cm-chitosan and polyvinyl alcohol be hydrogel based material in the present invention; adopt freeze-thaw method to prepare blended gel; there is the premium propertiess such as good elasticity, water-absorbing-retaining, air-and water-permeable, prevent the adhesion wound, the surface of a wound is had to provide protection well.
(2) regulate the volume ratio of carboxymethyl chitosan sugar soln and polyvinyl alcohol solution in hydrogel matrix, rate of release that can regulating medicine.
(3) the microsphere gel complex carrier that prepared by the present invention, can realize that medicine directly seals, and effectively protects the medicine biological activity, has the medicament slow release performance.
(4) solid support material preparation used in the present invention is simple, mild condition, and preparation cost is low.
(5) hydrogel microsphere in the present invention-hydrogel based plastome can not exert an influence to the activity of acidity or basic protein medicine.Simultaneously, adopt hydrogel microsphere-hydrogel matrix to make the drug release need to be through two kinds of gels to reach the effect of medicament slow release, and the preparation method is simple, is beneficial to and realizes industrialization, the medicine carrying gel prepared also be applicable to storing.
figure of description
Fig. 1: be BSA accumulative total releasing curve diagram
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
Experiment material: sodium alginate (viscosity of 2% aqueous solution is 250cps 25 ℃ the time), Sigma company; Polyvinyl alcohol (alcoholysis degree: 99.8 ~ 100%), Aladdin company; Cm-chitosan (deacetylation: >=90, the carboxylation degree: >=80%), the luxuriant and rich with fragrance rich bio tech ltd in 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), capital, Zhejiang ring medical treatment product company; Polystyrene orifice plate (6,24 hole), the bio tech ltd of anti-the think of.
Experiment content: adopt high-voltage electrostatic liquid droplet to prepare calcium alginate microsphere, take containing the BSA of 10mg/ml and the sodium alginate aqueous solution of 2wt% is stock liquid, CaCl 3%(w/v)
2the aqueous solution is receptor, selects syringe needle internal diameter 200 μ m, keeps needle point and CaCl
2the liquid level of solution is apart from being 20 cm, and voltage of electric field is 10kV.Solidify 10min, deionization washing three times.Filter the moisture of microsphere surface with filter paper, the calcium alginate microsphere that takes 100mg joins respectively in two mixed uniformly hydrogel matrixes, 2% cm-chitosan and 10% polyvinyl alcohol solution have been comprised in hydrogel matrix, its volume ratio is respectively 2:4,3:3 and 4:2, and the vortex several seconds is uniformly dispersed it.To be placed in containing the hydrogel of calcium alginate microsphere-20 ℃ freezing 20h, then the 4h that thaws under 25 ℃, the number of times that circulating frozen thaws is 3 times.
Appeal gained composite aquogel is placed in to the PBS solution of the PH=7.4 of 10ml, 37 ℃, carry out vitro drug release in the 40rpm constant temperature oscillator, the specific time is got the 1ml supernatant liquor, the fresh PBS that adds equal volume, BCA test kit test b SA content, calculate the drug accumulation release rate, draws BSA accumulative total release profiles.
Drug accumulation release rate %=(t time drug release total amount/actual drug loading) %.
Fig. 1 is BSA accumulative total release profiles, I represents the medicine calcium alginate microsphere, II represents that medicine hydrogel, III that cm-chitosan and polyvinyl alcohol solution volume ratio are 2:4 represent the medicine hydrogel 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 apparent in view prominent releasing.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 that reduces the cm-chitosan in hydrogel matrix can improve the accumulative total release rate of medicine simultaneously.
Fig. 2, the 3rd, under cm-chitosan compares with the polyvinyl alcohol solution different volumes, swelling ratio and the gel fraction of hydrogel microsphere-hydrogel matrix compound system, in figure, 1,2,3,4 represent respectively the hydrogel that cm-chitosan (CMCS) and polyvinyl alcohol (PVA) liquor capacity ratio are 0:6,2:4,3:3,4:2.
From Fig. 2,3 can find out, the content that increases cm-chitosan can reduce the gel fraction of hydrogel, but can increase the swelling ratio of hydrogel simultaneously.Cm-chitosan can be met the rapid hydration swelling of water in hydrogel, has swelling behavior preferably.Along with the content increase of cm-chitosan, the cross-link intensity of gel reduces, and gel fraction reduces; Simultaneously, the 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, thereby make the dissolution rate of medicine slow down, reduced the rate of release of medicine.And, along with the content increase of cm-chitosan, can intercept the release of medicine from Lalgine acid calcium microballoon, cause the reduction of drug accumulation release rate.From release profiles, find out, when the volume ratio of cm-chitosan and polyvinyl alcohol is larger, medicine accumulative total release rate is lower, and therefore, thereby we can improve by the volume ratio that reduces cm-chitosan and polyvinyl alcohol 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, discharge in liquid and be difficult to detect medicine, this may be because polyvinyl alcohol itself has higher degree of crystallinity and makes gel surface very fine and close.So in order to guarantee physicals and the release performance preferably of having of gel, the optimum range of the volume ratio X of cm-chitosan and polyvinyl alcohol in gel: (0:6)<X≤(4:2)
Adopt high-voltage electrostatic liquid droplet to prepare calcium alginate microsphere, the 1.17 μ g/ml of take are stock liquid containing the 1wt% heparin solution of Basic Fibroblast Growth Factor (bFGF) and the sodium alginate aqueous solution of 2wt%, CaCl 3%(w/v)
2the aqueous solution is receptor, selects syringe needle internal diameter 200 μ m, keeps needle point and CaCl
2the liquid level of solution is apart from being 20 cm, and voltage of electric field is 10kV.Solidify 10min, deionization washing three times.Filter the moisture of microsphere surface with filter paper, the calcium alginate microsphere that takes 50mg joins respectively in two mixed uniformly hydrogel matrixes, comprised 2% cm-chitosan and 10% polyvinyl alcohol solution in hydrogel matrix, its volume is 2:4, and the vortex several seconds is uniformly dispersed it.To be placed in containing the hydrogel of calcium alginate microsphere-20 ℃ freezing 20h, then the 4h that thaws under 4 ℃, the number of times that circulating frozen thaws is 3 times.
Claims (9)
1. the preparation method of a medicament slow release hydrogel, is characterized in that, comprises the following steps:
S1. prepare the medicine carrying calcium alginate microsphere;
S2. the preparation of hydrogel matrix: 1 ~ 5% carboxymethyl chitosan sugar soln and 5 ~ 15% polyvinyl alcohol solution be n:(6-n by volume), 0<n≤4, mix, and stirs;
S3. the preparation of slowly-releasing hydrogel: in the hydrogel matrix that medicine carrying calcium alginate microsphere prepared by S1 adds S2 to prepare, the medicine carrying calcium alginate microsphere is uniformly dispersed, circulating frozen-the formation hydrogel thaws through 3 ~ 7 times.
2. the preparation method of medicament slow release hydrogel according to claim 1, it is characterized in that, described medicine carrying calcium alginate microsphere is prepared as follows: forms fine droplet containing 1 ~ 3% sodium alginate soln of medicine in high tension electrostatic field and fall into 0.5 ~ 6% calcium chloride solution and solidify 5 ~ 15min formation calcium alginate microsphere.
3. the preparation method of medicament slow release hydrogel according to claim 2, is characterized in that, the described sodium alginate soln Chinese traditional medicine containing medicine and the mass ratio m:(10-m of sodium alginate), m is 0 ~ 5.
4. the preparation method of medicament slow release hydrogel according to claim 2, is characterized in that, syringe needle internal diameter 200 ~ 800 μ m are 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.
5. the preparation method of medicament slow release hydrogel according to claim 1, is characterized in that, described 5 ~ 15% polyvinyl alcohol solution is prepared as follows: described polyvinyl alcohol is heated to 1 ~ 2h under 85 ~ 95 ℃ and be dissolved in the water.
6. the preparation method of medicament slow release hydrogel according to claim 1, is characterized in that, described circulating frozen-freezing process is the freezing 8 ~ 23h under-10 ~-80 ℃ of solution elder generation that will prepare, then the 1 ~ 4h that thaws under 4 ~ 25 ℃.
7. the preparation method of medicament slow release hydrogel according to claim 1, is characterized in that, described medicine is protein drug, acid sensitive medicaments, antibiotic medicine or calcium antagonist medicine.
8. the medicament slow release hydrogel prepared under the described medicament slow release hydrogel of claim 1 ~ 7 preparation method is characterized in that the diameter of described hydrogel microsphere is 100 ~ 600 μ m, and the thickness of described hydrogel matrix is 1 ~ 5mm.
9. the application of medicament slow release hydrogel claimed in claim 8 in preparing empyrosis dressing.
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