CN104546691B - A kind of joint cavity injection thermosensitive in-situ gel preparation composition and preparation method thereof - Google Patents
A kind of joint cavity injection thermosensitive in-situ gel preparation composition and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of injections in articular cavity thermosensitive in-situ gel preparation compositions and preparation method thereof, belong to field of pharmaceutical preparations.Present invention combination Microspheres Technique and thermo-sensitive gel technology first prepare the sodium alginate micro ball for being loaded with C14H10Cl2NNaO2, then medicine-containing microsphere are loaded into chitosan/sodium β-glycerophosphate temperature sensing in situ gel rubber system, obtain C14H10Cl2NNaO2 in-situ gel preparation composition.The composition is in liquid condition in room temperature, after locally injecting enters articular cavity, can be changed into semi-solid gel under body temperature, forms drug depot in agents area, is conducive to slow release drug, extend the time that drug is retained in injection site, enhances drug effect.The present invention can be used for rheumatism, rheumatoid arthritis, and the treatment of the inflammatory joint diseases such as osteoarthritis and synovitis is applicable not only to C14H10Cl2NNaO2, be also applied for the arthritis treatments drugs such as other non-steroidal anti-inflammatory drugs, steroid hormone class drug and biological agent.
Description
Technical field
The present invention relates to a kind of joint cavity injection thermosensitive in-situ gel preparation compositions and preparation method thereof, belong to drug
Formulation art.
Background technique
With China's economic development and the aggravation of aging of population, rheumatism, rheumatoid arthritis and osteoarthritis etc. are closed
The disease incidence for saving inflammation disease is higher and higher, and shows the trend of rejuvenation.Arthritis is a kind of chronic disease, clinical manifestation
For the red, swollen, hot of joint, pain, dysfunction and joint deformity, it is disabled that serious person leads to joint, and the state of an illness further develops meeting
Involve internal organ, influence patients ' life quality, to patient body, psychology and economically brings very big burden.
Currently, arthritis optimal treatment mode is early diagnosis and intervenes, and irreversible joint injury caused by it, but also
The method that do not cure brings physiology and psychological burden to patient.Arthritis treatment object mainly has non-steroidal anti-inflammatory
Medicine, analgesic-antipyretic, mucus replenishers and hormone medicine etc., it is general to be administered by oral, intramuscular injection and joint cavity injection,
Also there are the therapeutic modalities such as transdermal patch.Wherein, drug directly can be delivered to inflammation part by joint cavity injection, to change drug
Distribution in vivo, avoid drug transport in vivo in physiologic barrier, with the maximum drug effect of the smallest dosages, therefore closing
It is widely studied in the scorching treatment of section.But the preparation for joint cavity injection is mostly administered with solution form, drug after administration
Body circulation is quickly penetrated into, so that drug retention time in articular cavity is short, duration of efficacy is short, needs frequent drug administration.
Situ-gel is at room temperature liquid, after being injected into agents area, by organism physiology condition also known as in body gel
Or the influence of other environmental factors, that is, the preparation that phase transition forms semi-solid gel state occurs.According to situ-gel system
Preparation principle can be classified as responsive to temperature type, ion-sensitive type and pH responsive type etc..Chitosan (chitosan), is natural
Alkaline kation polysaccharide, obtained by chitin deacetylation, there are a large amount of amino for intramolecular, from a wealth of sources, nontoxic, and have
There are good biocompatibility and biodegradable, is one of common thermo-sensitive gel material.Most study is shell at present
Glycan/glycerophosphate (glycerophosphate salt) temperature sensing in situ gel rubber system, chitosan and glycerophosphate mix
It is liquid condition that liquid, which is closed, under room temperature and low-temperature condition, and under the physiological temp of human body, phase transition, which occurs, becomes semi-solid gel.
Chitosan thermo-sensitive gel has the advantages that nontoxic, good biocompatibility and biodegradable.The gel systems locally injecting
Afterwards, drug depot can be formed in agents area, is conducive to slow release drug, extends the time that drug is retained in injection site,
Enhance drug effect.Meanwhile space structure is tridimensional network, can load the particles such as microballoon, liposome, nanoparticle administration system
System, constructing composite drug administration system to reach enhancing slow release effect reduces the purpose of burst effect.
C14H10Cl2NNaO2 is phenylacetic acid analog derivative, belongs to non-steroid anti-inflammatory drug, the entitled diclofenac of chemistry,
With it is anti-inflammatory, analgesia and refrigeration function, be clinically mainly used for treat rheumatism, rheumatoid arthritis, tatanic myelitis and
Lupus erythematosus etc..As the choice drug of arthritis treatment, commercially available Diclofenac preparation of sodium is mostly oral preparation, further includes percutaneous
The other administration routes such as administration, rectally, intramuscular injection and intravenous injection.However, since patient needs Long-term taking medicine, and double chlorine
The fragrant acid sodium short (t of the plasma half-life in human body1/2=1.5h), frequent drug administration is needed, the secondary of gastrointestinal tract and kidney etc. is often caused to make
With.Moreover, the administration modes such as oral, rectally, intramuscular injection, intravenous injection cannot change the distribution of its systemic drug, it is long
Phase is big using side effect.Currently, very active to the exploitation of Diclofenac preparation of sodium both at home and abroad, its research is concentrated on reductions
Adverse reaction, heighten the effect of a treatment etc..
Therefore, the present invention utilizes the advantage of joint cavity injection administration, in conjunction with the characteristics of in-situ gel preparation, by Diclofenac
Sodium is loaded into chitosan thermo-sensitive gel, be made it is a kind of novel for joint cavity injection temperature sensing in situ gel rubber, in order to further prolong
Slow drug release, is loaded into sodium alginate micro ball for C14H10Cl2NNaO2, be prepared be loaded with the sodium alginate micro ball of C14H10Cl2NNaO2/
Chitosan thermo-sensitive gel composition.Compared with traditional arthritis treatment preparation, the injections in articular cavity in-situ gel preparation
Composition, which has the significant advantage that, to be in close contact for a long time with joint tissue, there is preferable bioadhesive, control medicine
The shortcomings that object release, it is short to overcome solution type preparation retention time in articular cavity, needs frequent drug administration, improves complying with for patient
Property；It is under in vitro conditions in runny liquid condition, it is easily filling, it is convenient for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of easy to use, reliable and stable temperature sensitive originals of C14H10Cl2NNaO2 joint cavity injection
Position gel preparation composition and preparation method thereof, it is intended to overcome the shortcomings of present in traditional arthritis treatment.
The specific technical solution of the present invention is as follows:
A kind of joint cavity injection thermosensitive in-situ gel preparation composition, by the sodium alginate micro ball for being loaded with C14H10Cl2NNaO2
It is composed with chitosan thermo-sensitive gel.The compound formulation is liquid at room temperature, after being injected into vivo, physiological temp in vivo
Under (37 DEG C), phase transition, which occurs, becomes semi-solid gel, as drug depot slow release drug.The present invention can be expected to improve double
Drug concentration of the fragrant sour sodium of chlorine in articular cavity, improves therapeutic effect, reduces the generation of the adverse reactions such as gastrointestinal tract.
Load medicine sodium alginate micro ball of the present invention is by C14H10Cl2NNaO2, sodium alginate, poloxamer188, crosslinking agent
Calcium chloride etc. is prepared.Each component content is as follows by mass volume ratio: sodium alginate concentration is 10.0~25.0mg/mL, excellent
Select 15.0~20.0mg/mL；The concentration of poloxamer188 is 0~25.0mg/mL, and preferably 7.5~10.0mg/mL calcium chloride is dense
Degree is 50.0~150.0mg/mL, preferably 70.0~100mg/mL.The load medicine sodium alginate micro ball preparation method is improvement
Double emulsifications/external cross-linking method, it is used oil mutually be atoleine, emulsifier be sorbester p17 and Tween 80 mixture, it is excellent
Select sorbester p17: Tween 80 weight ratio is 6: 4~7: 3；Emulsifying rate is 2800~6000rpm, preferably 3000~4000rpm.
Situ-gel matrix of the present invention uses chitosan/sodium β-glycerophosphate temperature sensitive type in-situ gel.Chitosan
Dosage be 10.0~25.0mg/mL, preferably 15.0~20.0mg/mL；The dosage of sodium β-glycerophosphate is 5.0~20.0mg/
ML, preferably 10.0~20.0mg/mL.
Joint cavity injection of the present invention thermosensitive in-situ gel preparation composition contains in every mL chitosan thermo-sensitive gel
The amount of sodium alginate micro ball is 0~30.0mg, preferably 10~20mg.
Joint cavity injection provided by the invention thermosensitive in-situ gel preparation composition, preparation method mainly include following
Several steps:
(1) C14H10Cl2NNaO2 of recipe quantity is dissolved in certain density poloxamer188, sodium alginate stirring is added
1h is to being completely dissolved to get certain density drug containing sodium alginate soln；
(2) 1 gained drug containing sodium alginate soln is added in certain volume atoleine (containing emulsifier), through high speed point
Device stirring is dissipated, emulsion A is made；
(3) crosslinking agent calcium chloride solution is added in certain volume atoleine (containing emulsifier), through high speed disperser
Stirring, is made emulsion B；
(4) 3 gained emulsion B are added drop-wise in 2 gained emulsion A, magnetic agitation certain time be allowed to cross-linking reaction it is complete after,
Separation microballoon is filtered, freeze-drying is to get load medicine sodium alginate micro ball freeze-dried powder；
(5) a certain amount of chitosan is weighed, is dissolved in glacial acetic acid solution, the ice vinegar of the chitosan of certain solubility is configured to
Aqueous acid, 4 DEG C store for future use；
(6) a certain amount of sodium β-glycerophosphate is weighed, deionized water dissolving is configured to certain density sodium β-glycerophosphate
Solution, 4 DEG C store for future use；
(7) it is molten that sodium β-glycerophosphate is added dropwise into chitosan solution under conditions of ice-water bath stirring according to prescription
Liquid, continuing stirring is uniformly mixed it, and 4 DEG C store for future use；
(8) according to prescription, 4 gained is carried into medicine sodium alginate micro ball freeze-dried powder, are added to 7 gained chitosans/β-glycerol phosphorus
In acid sodium solution mixed solution, stir evenly up to invention formulation.
Joint cavity injection of the present invention thermosensitive in-situ gel preparation composition carries medicine sodium alginate micro ball partial size < 50
μm, drugloading rate is 10~30%, and chitosan thermo-sensitive gel gelation temperature is 31~37 DEG C, and gelling time is 2~10min, in vitro
Drug release is up to 2~7d.
The present invention is used using Microspheres Technique and situ-gel technical tie-up, by the way of intraarticular injection, control
The release of main ingredient ingredient C14H10Cl2NNaO2 is conducive to the curative effect of medication for improving main ingredient, reduces the toxic side effect of main ingredient ingredient, mention
The compliance of high patient；And it is easily filling, it is convenient for industrialized production.The present invention is expected to be used for rheumatism, rheumatoid arthritis, and bone closes
The treatment of the inflammatory joint diseases such as section inflammation and synovitis, is applicable not only to the non-steroidal anti-inflammatory drugs such as C14H10Cl2NNaO2, is also applied for
Hormone medicine improves the drugs such as state of an illness class drug and biotic factor, monoclonal antibody.
Detailed description of the invention
Attached drawing 1: the external gelling test of specific embodiment 1 gained joint cavity injection thermosensitive in-situ gel preparation composition
Picture
Attached drawing 2: the vitro drug release of 1 gained joint cavity injection thermosensitive in-situ gel preparation composition of specific embodiment
Curve
Attached drawing 3: the vitro drug release of 2 gained joint cavity injection thermosensitive in-situ gel preparation composition of specific embodiment
Curve
Specific embodiment
The present invention is explained and illustrated in more detail below with reference to example, it should be understood that given embodiment is only
Be it is illustrative, not in any way to the scope of the present invention constitute any restrictions.
Specific embodiment 1
It weighs C14H10Cl2NNaO2 0.2g to be dissolved in the poloxamer188 solution of 10mg/mL, sodium alginate 0.2g is added and stirs
1h is mixed to after being completely dissolved, is added in atoleine of the 30mL containing 2.5% emulsifier, high speed disperser 4000rpm stirs 3min,
Emulsion A is made.5mL25% calcium chloride solution is added in atoleine of the 15mL containing 2.5% emulsifier, high speed disperser
4000rpm stirs 3min, and emulsion B is made.Emulsion B is added drop-wise in emulsion A, it is complete that magnetic agitation 30min is allowed to cross-linking reaction
Afterwards, separation microballoon is filtered, freeze-drying is to get load medicine sodium alginate micro ball freeze-dried powder.Carry medicine sodium alginate micro ball partial size be 1~
20 μm, drugloading rate is about 25%.
Chitosan (0.02g) is dissolved in 1mL glacial acetic acid solution (0.1M), under ice-water bath stirring condition, by β-glycerol
Sodium phosphate (60%, 0.35mL) is added dropwise in chitosan solution, continues to stir evenly, and load medicine sodium alginate obtained is added
Microballoon lyophilized powder 27mg stirs evenly to get C14H10Cl2NNaO2 joint cavity injection thermosensitive in-situ gel preparation composition.The group
It is liquid condition that object, which is closed, in room temperature, and syringeability is good, and 2.5min can be gelled under 37 DEG C of water bath conditions.External gelling test is shown in attached
Fig. 1.
Specific embodiment 2
It weighs C14H10Cl2NNaO2 0.2g to be dissolved in the poloxamer188 solution of 10mg/mL, sodium alginate 0.2g is added and stirs
1h is mixed to after being completely dissolved, is added in atoleine of the 30mL containing 2.5% emulsifier, high speed disperser 4000rpm stirs 3min,
Emulsion A is made.5mL25% calcium chloride solution is added in atoleine of the 15mL containing 2.5% emulsifier, high speed disperser
4000rpm stirs 3min, and emulsion B is made.Emulsion B is added drop-wise in emulsion A, it is complete that magnetic agitation 30min is allowed to cross-linking reaction
Afterwards, separation microballoon is filtered, freeze-drying is to get load medicine sodium alginate micro ball freeze-dried powder.Carry medicine sodium alginate micro ball partial size be 1~
20 μm, drugloading rate is about 25%.
Chitosan (0.02g) is dissolved in 1mL glacial acetic acid solution (0.1M), under ice-water bath stirring condition, by β-glycerol
Sodium phosphate (60%, 0.35mL) is added dropwise in chitosan solution, continues to stir evenly, and load medicine sodium alginate obtained is added
Microballoon lyophilized powder 13.5mg stirs evenly to get C14H10Cl2NNaO2 joint cavity injection thermosensitive in-situ gel preparation composition.It should
Composition is liquid condition in room temperature, and syringeability is good, and 3.0min can be gelled under 37 DEG C of water bath conditions.
Specific embodiment 3
The resulting joint cavity injection of specific example 1 of the present invention is subjected to external drug with thermosensitive in-situ gel preparation composition
Release test, drug release patterns in vitro result are as shown in Fig. 2.
Test method: precision measures 1 resulting composition of 1mL specific example, is added in 10mL tool plug test tube, 37 ± 1 DEG C
1h is placed under water bath condition, after being sufficiently gelled, the phosphate buffer of 10mL pH 7.4 is added, is placed in 37 ± 1 DEG C,
It is vibrated in 100rpm shaking table.In fixed sampling time point (0.25,0.5,1,2,4,6,8,12,24,36,48,60,72,96,
Whole dissolution mediums 120h) are taken out, and supplement the fresh dissolution medium of same volume.Through 0.45 μm of membrane filtration, subsequent filtrate is taken,
Absorbance is measured at 275nm wavelength by ultraviolet spectrophotometry, calculates cumulative release rate.
Specific embodiment 4
The resulting joint cavity injection of specific example 2 of the present invention is subjected to external drug with thermosensitive in-situ gel preparation composition
Release test, drug release patterns in vitro result are as shown in Fig. 3.
Test method: precision measures 2 resulting composition of 1mL specific example, is added in 10mL tool plug test tube, 37 ± 1 DEG C
1h is placed under water bath condition, after being sufficiently gelled, the phosphate buffer of 10mL pH 7.4 is added, is placed in 37 ± 1 DEG C,
It is vibrated in 100rpm shaking table.In fixed sampling time point (0.25,0.5,1,2,4,6,8,12,24,36,48,60,72,96,
Whole dissolution mediums 120h) are taken out, and supplement the fresh dissolution medium of same volume.Through 0.45 μm of membrane filtration, subsequent filtrate is taken,
Absorbance is measured at 275nm wavelength by ultraviolet spectrophotometry, calculates cumulative release rate.
Claims (2)
1. a kind of joint cavity injection thermosensitive in-situ gel preparation composition, it is characterised in that: by the sea for being loaded with C14H10Cl2NNaO2
Mosanom microballoon and situ-gel matrix composition, the situ-gel matrix is the mixed liquor of chitosan and sodium β-glycerophosphate；
The sodium alginate micro ball for being loaded with C14H10Cl2NNaO2 and the mass volume ratio of situ-gel matrix are 10-20mg: 1mL；
The dosage of chitosan is 10.0-25.0mg/mL in the situ-gel matrix, and the dosage of sodium β-glycerophosphate is 5.0-
20.0mg/mL；
It is liquid when joint cavity injection thermosensitive in-situ gel preparation composition room temperature, facilitates injection, when temperature is increased to
At 37 DEG C of body temperature, i.e. generation phase transition becomes semi-solid gel, and for vitro drug release up to 2~7d, cumulative release percentage is reachable
70%~80%.
2. the joint cavity injection described in claim 1 preparation method of thermosensitive in-situ gel preparation composition, it is characterised in that:
The following steps are included:
Step 1, C14H10Cl2NNaO2 0.2g is dissolved in the poloxamer188 solution of 10mg/mL, sodium alginate 0.2g is added,
1h is stirred to after being completely dissolved ,-atoleine that 30mL contains 2.5% emulsifier, high speed disperser 4000rpm stirring is added
Emulsion A is made in 3min, 5mL 25wt.% calcium chloride solution is added in atoleine of the 15mL containing 2.5% emulsifier, high speed
Disperser 4000rpm stirs 3min, and emulsion A is made, emulsion B is added drop-wise in emulsion A, and it is anti-that magnetic agitation 30min is allowed to crosslinking
After answering completely, separation microballoon is filtered, is freeze-dried to get the sodium alginate micro ball freeze-dried powder for being loaded with C14H10Cl2NNaO2；
Step 2, chitosan 0.02g is dissolved in 1mL 0.1M glacial acetic acid solution, under ice-water bath stirring condition, by 0.35mL
60wt.% sodium β-glycerophosphate is added drop-wise in chitosan solution, is stirred evenly, and situ-gel matrix is obtained；
Step 3, sodium alginate micro ball freeze-dried powder 27mg or 13.5mg that C14H10Cl2NNaO2 is loaded with obtained by step 1 are added into step 2
In gained situ-gel matrix, stirring, joint cavity injection thermosensitive in-situ gel preparation composition；
The emulsifier is the mixture of sorbester p17 and Tween 80, and sorbester p17 and Tween 80 weight ratio are 6: 4-7: 3.
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| CN105342989A (en) * | 2015-12-14 | 2016-02-24 | 天津医科大学口腔医院 | Aspirin-encapsulated nano-microsphere composite temperature-sensitive gel slow-release inhibitor |
| 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 |
| KR101916193B1 (en) | 2016-08-25 | 2018-11-07 | 주식회사 파마리서치프로덕트 | Injectable composition comprising nucleic acid and chitosan for articular cavity |
| CN106822874B (en) * | 2017-01-13 | 2021-05-04 | 河北师范大学 | Exenatide nasal administration 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 |
| 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 |
| 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 |
| 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 |
| CN113197842B (en) * | 2021-04-19 | 2022-08-19 | 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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| US20090220618A1 (en) * | 2008-02-29 | 2009-09-03 | Erning Xia | Pharmaceutical formulations comprising polyanionic materials and source of hydrogen peroxide |
| CN102018674A (en) * | 2010-12-14 | 2011-04-20 | 同济大学 | Diclofenac sodium hydrogel microballoon with pH sensitivity, preparation method and application thereof |
| CN103479568A (en) * | 2013-10-22 | 2014-01-01 | 中国药科大学 | Novel hydrochloric acid topotecan intratumor injection preparation composition and preparation method thereof |
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