CN104546691A - Temperature-sensitive in-situ gel preparation composition for anticular injection and preparation method thereof - Google Patents
Temperature-sensitive in-situ gel preparation composition for anticular injection and preparation method thereof Download PDFInfo
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- CN104546691A CN104546691A CN201510046501.8A CN201510046501A CN104546691A CN 104546691 A CN104546691 A CN 104546691A CN 201510046501 A CN201510046501 A CN 201510046501A CN 104546691 A CN104546691 A CN 104546691A
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Abstract
The invention relates to a temperature-sensitive in-situ gel preparation composition for intra-articular injection and a preparation method thereof, and belongs to the field of medicine preparations. The preparation method comprises the following steps: preparing diclofenac sodium-carrying sodium alginate microspheres by combining a microsphere technology with a temperature-sensitive gel technology, and then carrying the medicine-carrying microspheres in a chitosan/beta-sodium glycerophosphate temperature-sensitive in-situ gel system to obtain a diclofenac sodium in-situ gel preparation composition. The composition is in a liquid state at a room temperature, capable of being converted to a semi-solid gel at a body temperature and forming a medicine storeroom at a medication part after being partially injected to enter an articular cavity, and beneficial to slowly releasing the medicine, prolonging the time of staying at the injection part, of the medicine, and enhancing the efficacy. The composition disclosed by the invention can be used for treating arthritis diseases of rheumatism, rheumatoid arthritis, osteoarthritis, synovitis and the like, as well as applicable to both diclofenac sodium and other arthritis treatment medicines of non-steroidal anti-inflammatory medicines, steroid hormone medicines, biological preparations and the like.
Description
Technical field
The present invention relates to a kind of joint cavity injection thermosensitive in-situ gel preparation composition and method of making the same, belong to field of pharmaceutical preparations.
Background technology
Along with the aggravation of China's economic development and aged tendency of population, the sickness rate of the inflammatory joint disease such as rheumatism, rheumatoid arthritis and osteoarthritis is more and more higher, and presents the trend of rejuvenation.Arthritis is a kind of chronic disease, clinical manifestation be joint red, swollen, hot, bitterly, dysfunction and joint deformity, severe patient causes joint disabled, and the state of an illness further develops and can involve internal organs, affect patients ' life quality, to patient body, psychology and bring very large burden economically.
At present, arthritis optimal treatment mode is early diagnosis and intervention, and the irreversible joint injury that it causes, the method for but also not curing, brings physiology and psychological burden to patient.Arthritis treatment medicine mainly contains NSAID (non-steroidal anti-inflammatory drug), antipyretic analgesic, mucus supplement and hormone medicine etc., generally by oral, intramuscular injection and joint cavity injection administration, also has the therapeutic modalities such as transdermal patch.Wherein, joint cavity injection can directly by drug conveying to inflammation part, thus change medicine distribution in vivo, avoid medicine transport in vivo in physiologic barrier, with the drug effect that minimum dosages is maximum, therefore studied widely in arthritis treatment.But for the preparation of joint cavity injection mainly with solution form administration, after administration, medicine rapid permeability enters body circulation, and make medicine retention time in articular cavity short, duration of efficacy is short, needs frequent drug administration.
Situ-gel, also known as at body gel, is at room temperature liquid, after being expelled to agents area, is subject to the impact of other environmental factorss of organism physiology conditioned disjunction, and namely the preparation that phase in version forms semi-solid gel state occurs.According to the preparation principle of situ-gel system, responsive to temperature type, ion-sensitive type and pH responsive type etc. can be divided into.Chitosan (chitosan) is natural alkaline cationic polysaccharide, by chitin deacetylase base gained; its molecular memory at a large amount of amino, its wide material sources, nontoxic; and there is good biocompatibility and biodegradable, be one of conventional thermosensitive hydrogel material.Current most study be chitosan/glycerophosphate (glycerophosphate salt) temperature sensing in situ gel rubber system, the mixed liquor of chitosan and glycerophosphate is liquid condition under room temperature and low temperature state, under the physiological temp of human body, phase in version occurs becomes semi-solid gel.Chitosan thermosensitive hydrogel has nontoxic, good biocompatibility and biodegradable advantage.After this gel systems local injection, drug depot can be formed at agents area, be conducive to slow releasing medicine, the time that prolong drug retains in injection site, strengthen drug effect.Meanwhile, its space structure is tridimensional network, can the particulate delivery system such as load microsphere, liposome, nanoparticle, builds composite drug administration system, to reach enhancing slow release effect, reduces the object of burst effect.
Diclofenac sodium is phenylacetic acid analog derivative, belongs to nonsteroidal antiinflammatory drug, and chemistry diclofenac by name, has antiinflammatory, analgesia and refrigeration function, is mainly used in treatment rheumatism, rheumatoid arthritis, tatanic myelitis and lupus erythematosus etc. clinically.As the choice drug of arthritis treatment, commercially available diclofenac preparation of sodium mostly is oral formulations, also comprises the other administration routes such as percutaneous dosing, rectally, intramuscular injection and intravenous injection.But because patient needs Long-term taking medicine, and diclofenac sodium is at blood in human body in slurry half-life short (t
1/2=1.5h), need frequent drug administration, often cause the side effect of gastrointestinal tract and kidney etc.And the administering modes such as oral, rectally, intramuscular injection, intravenous injection all can not change the distribution of its systemic drug, and prolonged application side effect is large.At present, very active to the exploitation of diclofenac preparation of sodium both at home and abroad, its research mainly concentrates on minimizing untoward reaction, and the aspect such as heighten the effect of a treatment.
Therefore, the present invention utilizes the advantage of joint cavity injection administration, in conjunction with the feature of in-situ gel preparation, diclofenac sodium is loaded in chitosan thermosensitive hydrogel, make a kind of novel for joint cavity injection temperature sensing in situ gel rubber, in order to delay drug release further, diclofenac sodium being loaded into sodium alginate micro ball, preparing the sodium alginate micro ball/chitosan thermo-sensitive gel composition being loaded with diclofenac sodium.Compared with traditional arthritis treatment preparation, this injections in articular cavity in-situ gel preparation compositions has significant advantage: can for a long time with joint tissue close contact, there is good bioadhesive, Drug controlled release, overcome solution type preparation retention time in articular cavity short, need the shortcoming of frequent drug administration, improve the compliance of patient; Under in vitro conditions in runny liquid condition, easy fill, is convenient to suitability for industrialized production.
Summary of the invention
The object of this invention is to provide a kind of easy to use, reliable and stable diclofenac sodium joint cavity injection thermosensitive in-situ gel preparation composition and method of making the same, be intended to overcome the deficiency existing for traditional arthritis treatment.
Concrete technical scheme of the present invention is as follows:
A kind of joint cavity injection thermosensitive in-situ gel preparation compositions, is combined by the sodium alginate micro ball and chitosan thermosensitive hydrogel being loaded with diclofenac sodium.This compound formulation is at room temperature liquid, is expelled to after in body, and in vivo under physiological temp (37 DEG C), phase in version occurs becomes semi-solid gel, as drug depot slow releasing medicine.The present invention can be expected to improve the drug level of diclofenac sodium in articular cavity, improves therapeutic effect, reduces the generation of the untoward reaction such as gastrointestinal tract.
Medicine carrying sodium alginate micro ball of the present invention is prepared from by diclofenac sodium, sodium alginate, poloxamer188, cross-linking agent calcium chloride etc.Each constituent content is as follows by mass volume ratio: sodium alginate concentration is 10.0 ~ 25.0mg/mL, preferably 15.0 ~ 20.0mg/mL; The concentration of poloxamer188 is 0 ~ 25.0mg/mL, and preferably 7.5 ~ 10.0mg/mL calcium chloride concentration is 50.0 ~ 150.0mg/mL, preferably 70.0 ~ 100mg/mL.Described medicine carrying sodium alginate micro ball preparation method is the two emulsifyings/outside cross-linking method of improvement, and the oil phase adopted is liquid paraffin, and emulsifying agent is the mixture of sorbester p17 and Tween 80, preferred sorbester p17: Tween 80 weight ratio is 6: 4 ~ 7: 3; Emulsifying rate is 2800 ~ 6000rpm, preferably 3000 ~ 4000rpm.
Situ-gel substrate of the present invention adopts chitosan/sodium β-glycerophosphate temperature sensitive type in-situ gel.The consumption of chitosan is 10.0 ~ 25.0mg/mL, preferably 15.0 ~ 20.0mg/mL; The consumption of sodium β-glycerophosphate is 5.0 ~ 20.0mg/mL, preferably 10.0 ~ 20.0mg/mL.
Joint cavity injection thermosensitive in-situ gel preparation compositions of the present invention, the amount containing sodium alginate micro ball in every mL chitosan thermosensitive hydrogel is 0 ~ 30.0mg, preferably 10 ~ 20mg.
Joint cavity injection thermosensitive in-situ gel preparation compositions provided by the invention, its preparation method mainly comprises following step:
(1) diclofenac sodium of recipe quantity is dissolved in certain density poloxamer188, adds sodium alginate and stir 1h to dissolving completely, obtain certain density pastille sodium alginate soln;
(2) 1 gained pastille sodium alginate soln is added in certain volume liquid paraffin (containing emulsifying agent), stir through high speed disperser, make Emulsion A;
(3) cross-linking agent calcium chloride solution is added in certain volume liquid paraffin (containing emulsifying agent), stir through high speed disperser, make Emulsion B;
(4) 3 gained Emulsion B are added drop-wise in 2 gained Emulsion A, magnetic agitation certain hour make it cross-linking reaction completely after, sucking filtration is separated microsphere, and lyophilization, obtains medicine carrying sodium alginate micro ball lyophilized powder;
(5) take a certain amount of chitosan, be dissolved in glacial acetic acid solution, be mixed with the glacial acetic acid aqueous solution of the chitosan of certain solubility, 4 DEG C store for future use;
(6) take a certain amount of sodium β-glycerophosphate, deionized water dissolving is configured to certain density sodium β-glycerophosphate solution, and 4 DEG C store for future use;
(7) according to prescription, under the condition that ice-water bath stirs, in chitosan solution, dropwise add sodium β-glycerophosphate solution, continue stirring and make its mix homogeneously, 4 DEG C store for future use;
(8) according to prescription, by 4 gained medicine carrying sodium alginate micro ball lyophilized powders, join in 7 gained chitosans/sodium β-glycerophosphate solution mixed solution, stir and obtain invention formulation.
Joint cavity injection thermosensitive in-situ gel preparation compositions of the present invention, medicine carrying sodium alginate micro ball particle diameter < 50 μm, drug loading is 10 ~ 30%, and chitosan thermosensitive hydrogel gelation temperature is 31 ~ 37 DEG C, gelling time is 2 ~ 10min, and vitro drug release reaches 2 ~ 7d.
The present invention adopts Microspheres Technique and situ-gel technical tie-up to use, adopt the mode of intraarticular injection, control the release of principal agent composition diclofenac sodium, be conducive to the curative effect of medication improving principal agent, reduce the toxic and side effects of principal agent composition, improve the compliance of patient; And easily fill, be convenient to suitability for industrialized production.The present invention is expected to for rheumatism, rheumatoid arthritis, the treatment of the inflammatory joint disease such as osteoarthritis and synovitis, be not only applicable to the NSAID (non-steroidal anti-inflammatory drug) such as diclofenac sodium, be also applicable to hormone medicine, improve state of an illness class medicine and the medicine such as biotic factor, monoclonal antibody.
Accompanying drawing explanation
Accompanying drawing 1: the external gelling test picture of specific embodiment 1 gained joint cavity injection thermosensitive in-situ gel preparation compositions
Accompanying drawing 2: the specific embodiment 1 gained joint cavity injection drug release patterns in vitro of thermosensitive in-situ gel preparation compositions
Accompanying drawing 3: the specific embodiment 2 gained joint cavity injection drug release patterns in vitro of thermosensitive in-situ gel preparation compositions
Detailed description of the invention
Be explained and illustrated in more detail the present invention below in conjunction with example, should be appreciated that given embodiment is illustrative, it forms any restriction to scope of the present invention never in any form.
Specific embodiment 1
Take diclofenac sodium 0.2g to be dissolved in the poloxamer188 solution of 10mg/mL, add sodium alginate 0.2g stir 1h to completely dissolve after, add 30mL containing 2.5% emulsifying agent liquid paraffin in, high speed disperser 4000rpm stirs 3min, makes Emulsion A.5mL25% calcium chloride solution is added to 15mL containing in the liquid paraffin of 2.5% emulsifying agent, high speed disperser 4000rpm stirs 3min, makes Emulsion B.Emulsion B is added drop-wise in Emulsion A, magnetic agitation 30min make it cross-linking reaction completely after, sucking filtration is separated microsphere, and lyophilization, obtains medicine carrying sodium alginate micro ball lyophilized powder.Medicine carrying sodium alginate micro ball particle diameter is 1 ~ 20 μm, and drug loading is about 25%.
Chitosan (0.02g) is dissolved in 1mL glacial acetic acid solution (0.1M), under ice-water bath stirring condition, by sodium β-glycerophosphate (60%, 0.35mL) dropwise join in chitosan solution, continue to stir, add obtained medicine carrying sodium alginate micro ball lyophilized powder 27mg, stir, obtain diclofenac sodium joint cavity injection thermosensitive in-situ gel preparation compositions.Said composition is liquid condition when room temperature, and syringeability is good, and under 37 DEG C of water bath condition, 2.5min can gelling.Accompanying drawing 1 is shown in external gelling test.
Specific embodiment 2
Take diclofenac sodium 0.2g to be dissolved in the poloxamer188 solution of 10mg/mL, add sodium alginate 0.2g stir 1h to completely dissolve after, add 30mL containing 2.5% emulsifying agent liquid paraffin in, high speed disperser 4000rpm stirs 3min, makes Emulsion A.5mL25% calcium chloride solution is added to 15mL containing in the liquid paraffin of 2.5% emulsifying agent, high speed disperser 4000rpm stirs 3min, makes Emulsion B.Emulsion B is added drop-wise in Emulsion A, magnetic agitation 30min make it cross-linking reaction completely after, sucking filtration is separated microsphere, and lyophilization, obtains medicine carrying sodium alginate micro ball lyophilized powder.Medicine carrying sodium alginate micro ball particle diameter is 1 ~ 20 μm, and drug loading is about 25%.
Chitosan (0.02g) is dissolved in 1mL glacial acetic acid solution (0.1M), under ice-water bath stirring condition, by sodium β-glycerophosphate (60%, 0.35mL) dropwise join in chitosan solution, continue to stir, add obtained medicine carrying sodium alginate micro ball lyophilized powder 13.5mg, stir, obtain diclofenac sodium joint cavity injection thermosensitive in-situ gel preparation compositions.Said composition is liquid condition when room temperature, and syringeability is good, and under 37 DEG C of water bath condition, 3.0min can gelling.
Specific embodiment 3
The joint cavity injection thermosensitive in-situ gel preparation compositions of instantiation 1 gained of the present invention is carried out vitro drug release test, and its drug release patterns in vitro result as shown in Figure 2.
Test method: precision measures 1mL instantiation 1 resulting composition, joins in 10mL tool plug test tube, places 1h under 37 ± 1 DEG C of water bath condition, after abundant gelling, add the phosphate buffer of 10mL pH 7.4, be placed in 37 ± 1 DEG C, vibrate in 100rpm shaking table.In fixing sampling time point (0.25,0.5,1,2,4,6,8,12,24,36,48,60,72,96,120h) take out whole release medium, and supplement the fresh dissolution medium of same volume.Through 0.45 μm of membrane filtration, get subsequent filtrate, measure absorbance by ultraviolet spectrophotometry at 275nm wavelength place, calculate cumulative release rate.
Specific embodiment 4
The joint cavity injection thermosensitive in-situ gel preparation compositions of instantiation 2 gained of the present invention is carried out vitro drug release test, and its drug release patterns in vitro result as shown in Figure 3.
Test method: precision measures 1mL instantiation 2 resulting composition, joins in 10mL tool plug test tube, places 1h under 37 ± 1 DEG C of water bath condition, after abundant gelling, add the phosphate buffer of 10mL pH 7.4, be placed in 37 ± 1 DEG C, vibrate in 100rpm shaking table.In fixing sampling time point (0.25,0.5,1,2,4,6,8,12,24,36,48,60,72,96,120h) take out whole release medium, and supplement the fresh dissolution medium of same volume.Through 0.45 μm of membrane filtration, get subsequent filtrate, measure absorbance by ultraviolet spectrophotometry at 275nm wavelength place, calculate cumulative release rate.
Claims (9)
1. a joint cavity injection thermosensitive in-situ gel preparation composition and method of making the same, it is characterized in that said composition is made up of the sodium alginate micro ball and chitosan/sodium β-glycerophosphate temperature sensing in situ gel rubber being loaded with diclofenac sodium, can for joint cavity injection, for the treatment of arthritis drug.
2. joint cavity injection thermosensitive in-situ gel preparation compositions according to claim 1, be liquid when it is characterized in that said composition room temperature, convenient injection, when temperature is elevated to body temperature (37 DEG C) left and right, namely there is phase in version and become semi-solid gel, vitro drug release reaches 2 ~ 7d, and cumulative release percentage rate can reach 70% ~ 80%.
3. joint cavity injection thermosensitive in-situ gel preparation compositions according to claims 1 to 2, it is characterized in that said composition gelation temperature is 31 ~ 37 DEG C, gelling time is 2 ~ 10min.
4. joint cavity injection thermosensitive in-situ gel preparation compositions according to claims 1 to 3, it is characterized in that described sodium alginate micro ball except adopting sodium alginate as micro-sphere material, calcium chloride, as beyond cross-linking agent, also adopts poloxamer188 as the solubilizing agent of micro-sphere material and medicine.
5. joint cavity injection thermosensitive in-situ gel preparation compositions according to claims 1 to 4, is characterized in that the concentration of described poloxamer188 is 0 ~ 25.0mg/mL, preferably 7.5 ~ 10.0mg/mL.
6. joint cavity injection thermosensitive in-situ gel preparation compositions according to claims 1 to 3, it is characterized in that described situ-gel substrate adopts chitosan to be gel rubber material, sodium β-glycerophosphate is the mixture of cross-linking agent, preferred chitosan and sodium β-glycerophosphate.
7. the thermosensitive in-situ gel preparation compositions of the joint cavity injection according to claims 1 to 3 and 6, is characterized in that chitosan solution is the glacial acetic acid aqueous solution of chitosan, aqueous hydrochloric acid solution and lactic acid aqueous solution, the glacial acetic acid aqueous solution of preferred chitosan; The consumption of chitosan is 10.0 ~ 25.0mg/mL, preferably 15.0 ~ 20.0mg/mL.
8. the thermosensitive in-situ gel preparation compositions of the joint cavity injection according to claims 1 to 3 and 6, is characterized in that the consumption of sodium β-glycerophosphate is 5.0 ~ 20.0mg/mL, preferably 10.0 ~ 20.0mg/mL.
9. joint cavity injection thermosensitive in-situ gel preparation compositions according to claims 1 to 8, is characterized in that the amount containing sodium alginate micro ball in every mL chitosan thermosensitive hydrogel is 0 ~ 30.0mg, preferably 10 ~ 20mg.
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| CN105708789A (en) * | 2016-03-16 | 2016-06-29 | 四川大学 | Drug-loaded nanofiber microsphere/hydrogel compound and preparation method and application thereof |
| CN106822874A (en) * | 2017-01-13 | 2017-06-13 | 河北师范大学 | A kind of Exenatide nasal cavity administrated preparation and preparation method thereof |
| CN107349477A (en) * | 2017-06-08 | 2017-11-17 | 西安交通大学 | Surface Texture filling graphene oxide slow release lubricant gel and its production and use |
| CN109498852A (en) * | 2018-12-29 | 2019-03-22 | 广州噢斯荣医药技术有限公司 | Biodegradation material and its application for treating orthopaedic disease |
| CN109550079A (en) * | 2018-12-07 | 2019-04-02 | 中国人民解放军陆军军医大学第附属医院 | A kind of bionical matrix of cartilaginous tissue and preparation method thereof |
| CN109789223A (en) * | 2016-08-25 | 2019-05-21 | 医药研究产品有限公司 | Joint cavity injection composition comprising nucleic acid and chitosan |
| CN110935008A (en) * | 2019-12-10 | 2020-03-31 | 昆明医科大学第一附属医院 | TN14003 temperature-sensitive gel for treating osteoarthritis by articular cavity injection and preparation method thereof |
| CN111346227A (en) * | 2020-03-25 | 2020-06-30 | 天津大学 | Synthetic method of continuous photocatalytic treatment system for RA |
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| CN105708789A (en) * | 2016-03-16 | 2016-06-29 | 四川大学 | Drug-loaded nanofiber microsphere/hydrogel compound and preparation method and application thereof |
| CN105708789B (en) * | 2016-03-16 | 2018-12-21 | 四川大学 | A kind of medicament-carrying nano-fiber microballoon/hydrogel composites and its preparation method and application |
| CN109789223B (en) * | 2016-08-25 | 2023-06-16 | 医药研究有限公司 | Use of composition containing nucleic acid and chitosan as preparation for joint cavity injection |
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| CN109789223A (en) * | 2016-08-25 | 2019-05-21 | 医药研究产品有限公司 | Joint cavity injection composition comprising nucleic acid and chitosan |
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| CN107349477A (en) * | 2017-06-08 | 2017-11-17 | 西安交通大学 | Surface Texture filling graphene oxide slow release lubricant gel and its production and use |
| CN109550079B (en) * | 2018-12-07 | 2021-10-22 | 中国人民解放军陆军军医大学第一附属医院 | Cartilage tissue bionic matrix and preparation method thereof |
| CN109550079A (en) * | 2018-12-07 | 2019-04-02 | 中国人民解放军陆军军医大学第附属医院 | A kind of bionical matrix of cartilaginous tissue and preparation method thereof |
| CN109498852B (en) * | 2018-12-29 | 2022-06-24 | 广州噢斯荣医药技术有限公司 | Biodegradable material for treating orthopedic diseases and application thereof |
| CN109498852A (en) * | 2018-12-29 | 2019-03-22 | 广州噢斯荣医药技术有限公司 | Biodegradation material and its application for treating orthopaedic disease |
| CN110935008A (en) * | 2019-12-10 | 2020-03-31 | 昆明医科大学第一附属医院 | TN14003 temperature-sensitive gel for treating osteoarthritis by articular cavity injection and preparation method thereof |
| CN110935008B (en) * | 2019-12-10 | 2023-09-26 | 昆明医科大学第一附属医院 | TN14003 temperature-sensitive gel for treating osteoarthritis by injecting into joint cavity and preparation method thereof |
| CN111346227A (en) * | 2020-03-25 | 2020-06-30 | 天津大学 | Synthetic method of continuous photocatalytic treatment system for RA |
| CN111374940A (en) * | 2020-04-13 | 2020-07-07 | 宁波赛缪斯生物科技有限公司 | Collagen injection capable of in-situ polymerization and use method thereof |
| CN113197842A (en) * | 2021-04-19 | 2021-08-03 | 石家庄学院 | Cannabidiol injectable hydrogel, preparation method and application thereof |
| CN117643650A (en) * | 2024-01-30 | 2024-03-05 | 哈尔滨悦之美芳华医疗美容门诊有限公司 | Subcutaneous gel filling composite material and preparation method thereof |
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