CN101225146B - Chitosan-ketoprofen grafts and preparation method thereof - Google Patents
Chitosan-ketoprofen grafts and preparation method thereof Download PDFInfo
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- CN101225146B CN101225146B CN2008100593571A CN200810059357A CN101225146B CN 101225146 B CN101225146 B CN 101225146B CN 2008100593571 A CN2008100593571 A CN 2008100593571A CN 200810059357 A CN200810059357 A CN 200810059357A CN 101225146 B CN101225146 B CN 101225146B
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Abstract
The invention rglates to chitosan-ketoprofen grafted substance and the preparation method, belonging to pharmacy field, which can be grafted on the framework of degradable macromolecular material chitosan to make polymer medicine. The preparation method adopts the degradable macromolecular material chitosan to structure qualify the ketoprofen and uses the 1- (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride as the catalyst, and then accelerates the chitosan and the ketoprofen to connect by the amido links to compose chitosan-ketoprofen grafted substance. The chitosan-ketoprofen grafted substance can be used in curing the arthritis and prolonging the medicine acting time when adopting the injection medication. The preparation method for the chitosan-ketoprofen grafted substance also has the advantages of simple preparation method, easy operation and good reproduction quality.
Description
Technical field
The present invention relates to pharmacy field, be prepared into a kind of chitosan-ketoprofen grafts of polymeric medicine and preparation method thereof especially for being grafted on the biodegradable polymer chitosan skeleton.
Background technology
NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) is that wide in variety in recent years, quantity is big, determined curative effect, a development class medicine rapidly.Traditional NSAIDs has gi tract in various degree and kidney untoward reaction by suppressing COX-1 simultaneously and COX-2 plays a role.Seeking the COX-2 selective depressant was once becoming focus, but clinical application widely finds, took the cox 2 inhibitor of highly selective such as rofecoxib etc. for a long time, can cause the untoward reaction of aspects such as cardiovascular and cerebrovascular.In recent years, people's sight is transferred to traditional NSAIDs once again, pass through structural modification, methods such as the preparation of polymeric medicine are modified traditional NSAIDs, (document sees reference: Zhao Yimei in preparation as the ester class prodrug of Ibuprofen BP/EP, Xia Dan, Ai Caiping etc. the synthetic and anti-inflammatory activity [J] of ibuprofen derivative. Chinese pharmaceutical chemistry magazine, 2006,15 (6): 360-362. Song Ni, Li Yingxia, Sun Xue etc. synthetic [J] of ibuprofen sugar derivative. Acta Pharmaceutica Sinica, 2004,39 (2): 105-109.), the glucosides prodrug be exactly one of them (document sees reference: Song Ni, Li Yingxia, Sun Xue etc. synthetic [J] of ibuprofen sugar derivative. Acta Pharmaceutica Sinica, 2004,39 (2): 105-109.Jonna B, Andrzej S, Glycosyl.Derivatives of 2-bromosugar of selected non steroidal anti-inflammatorydrugs.Synthesis and QSAR data[J] .Farmaeo, 2001,56:257-262.CN1226300C Ibuprofen BP/EP glycoconjugate and its production and application .), the purpose for preparing these polymeric medicines is mainly the action time of prolong drug, reduces side effect.
Chitosan is natural polycation polysaccharide derivates, contains more active group in the molecule, is suitable for the chemically modified of medicine, is quite paid close attention in the polymeric medicine preparation.Be seen in the modification that mainly contains cancer therapy drug of document, (document sees reference: Youhua SONG as chitosan graft cancer therapy drug mitomycin, HirakuONISHI, and Tsuneji NAGAI.Synethesis and Drug-Release Characteristics ofthe Conjugates of Mitomycin C with N-Succinyl-chitosan andCarboxylmethyl-chitin[J] .Chem.Pharm.Bull, 40 (10): 2882-2885.) and 5 FU 5 fluorouracil etc. (document sees reference: Lu Fengqi, Zhuan Zhaoxia, Cao Jing etc. the synthetic and release property research [J] of chitosan-5 FU 5 fluorouracil prodrug. journal of Shandong university (medicine), 2004,40 (2): 226-228.), very few but this technology is used for the report of NSAID (non-steroidal anti-inflammatory drug) modification.
Ketoprofen belongs to NSAID (non-steroidal anti-inflammatory drug), and its effect is better than Ibuprofen BP/EP, mainly treats ankylosis rachitis, rheumatic arthritis and osteoarthritis, and patient needs long-term medication treatment.Ketoprofen mostly is oral dosage form in the market, needs frequent drug administration.For studying long lasting Ketoprofen, (document sees reference: ZL02160197.6 slightly water-soluble steroidal to have the investigator to attempt adopting the mode that changes formulation, the biodegradation type implant and the preparation method of NSAID (non-steroidal anti-inflammatory drug)), the somebody carries out chemically modified synthesizing ester prodrug to it, as the Ketoprofen methyl esters, ethyl ester, (document sees reference such as isopropyl esters etc.: Wang Yanjiao, what sea ice, Chen Jian etc. Ketoprofen isopropyl ester extracorporeal hydrolysis dynamics research [J]. Chinese Journal of New Drugs, 2006,15 (23): 2039-2042.), but can not well solve the fast problem of Ketoprofen metabolism with small numerator modified.(document sees reference: Xi Miaomiao to improve its physico-chemical property and pharmacokinetic property and adopt macromole such as pectin modification Ketoprofen to be prepared into polymeric medicine both at home and abroad, Zhang San is strange, Gu Yi etc., synthetic and the in-vitro evaluation [J] of pectin Ketoprofen prodrug. The Fourth Military Medical University's journal, 2004,25 (14): 1284-1286.), and this polymeric medicine is mainly used in the oral colon administration.
Summary of the invention
The purpose of this invention is to provide a kind of chitosan-ketoprofen grafts and preparation method thereof.Be prepared into polymeric medicine by Ketoprofen being grafted on the biodegradable polymer chitosan skeleton, this polymeric medicine has biodegradable characteristics, by the injection system administration can prolong drug action time, thereby reach the purpose of retarding action time, reduce the toxicity, side effect of Ketoprofen, and technology is simple to operation, favorable reproducibility, and can treatment of arthritis.
The present invention adopts following technical scheme: the chitosan-ketoprofen grafts that the present invention relates to, be connected with amido linkage with amino in the chitosan by the carboxyl in the Ketoprofen, and the molecular formula of grafts is (C
8H
13NO
5) n (C
6H
11NO
4) m-x (C
22H
23NO
6) x, structural formula is:
Wherein R is
The preparation method of chitosan-ketoprofen grafts of the present invention is for being material with the chitosan, by catalyzer and Ketoprofen at methyl alcohol and N, stirring reaction in the mixed solvent of N-ethyl pyrrolidone, reaction finishes after-filtration, adopt aqueous hydrochloric acid, deionized water, methanol wash gained throw out successively, through vacuum-drying, promptly get chitosan-ketoprofen grafts.
Concrete steps are as follows:
1. with methyl alcohol and N, and N-ethyl pyrrolidone mixed solvent (5: 4, v/v) be reaction solvent.
2. chitosan and Ketoprofen charging capacity are 1 by chitosan glucosamine units and Ketoprofen mol ratio: 3-1: 9 feed intake.
3. by catalyzer 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride catalyzed reaction, temperature of reaction is controlled at 25 ± 10 ℃, and reacting solution pH value is 6.0 ± 0.3, stirring reaction 3h-24h.
4. reaction finishes after-filtration, adopts aqueous hydrochloric acid, deionized water, methanol wash gained throw out successively, and vacuum-drying promptly gets chitosan-ketoprofen grafts faint yellow solid.
The chitosan molecule amount that relates among the present invention is 5000Da-126KDa, and deacetylation is 50%-90%.
Chitosan-ketoprofen grafts of the present invention can be used infrared spectra, UV spectrum, and chemical analysis methods such as nucleus magnetic resonance characterize.Reaction formula is as follows:
The invention has the advantages that with the chitosan-modified Ketoprofen of Biodegradable Polymers, be prepared into biodegradable polymeric medicine, prolonged the action time of medicine, reduced the toxic side effect of Ketoprofen, this method has been avoided the use of some poisonous reagents simultaneously, and technology is simple to operation, favorable reproducibility, and the energy treatment of arthritis, significant to arthritic long-term treatment.
Description of drawings
Chitosan-ketoprofen grafts release in vitro the curve of Fig. 1 for preparing by embodiment 1.
Chitosan-ketoprofen grafts release in vitro the curve of Fig. 2 for preparing by embodiment 2.
Chitosan-ketoprofen grafts release in vitro the curve of Fig. 3 for preparing by embodiment 3.
Embodiment
Below in conjunction with specific embodiment technical scheme of the present invention is further described.
Embodiment 1:
Get low-molecular weight chitoglycan (Mr=5000Da, deacetylation 64.3%) 100mg, add 10ml 0.1mol/L hydrochloric acid and make the chitosan dissolving.Add 10ml methyl alcohol and 8mlN again, the N-ethyl pyrrolidone adds the 0.56g Ketoprofen, vibration makes dissolving, regulates pH to 6.0, and jolting limit, limit adds 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride of 0.1M, keep pH 6.0, at 25 ℃ of stirring reaction 3h.After reaction finished, suction filtration obtained precipitation, uses 3 * 15ml 0.1mol/L hydrochloric acid successively, 3 * 15ml deionized water, 3 * 15ml methanol wash.Vacuum-drying 24h obtains chitosan-Ketoprofen faint yellow solid, and grafts Chinese traditional medicine content is 41.24%, and yield is 72.4%.
This compound is respectively through infrared spectra, UV spectrum, and nucleus magnetic resonance is identified.The infrared spectra of chitosan and grafts is similar, and the two difference is, 1658cm in the grafts spectrum
-1There is the last one absorption peak at the place, illustrates-existence of C=O, and this is that amido linkage of Ketoprofen and chitosan formation causes
1H NMR (500MHz, DMSO-d
6) δ: 7.79～7.96 (m, 8H, ArH), the appearance of fragrant hydrogen has been a chitosan graft circumstantial evidence of Ketoprofen.Sample is through UV scanning, and the maximum absorption wavelength of Ketoprofen is 260nm, and its grafts obtained the maximum absorption occurs at the 261nm place, and blank chitosan does not absorb.Prove that more than the gained compound is chitosan-ketoprofen grafts.
Release in vitro:
Release conditions: release medium is a 50ml 0.5mol/L phosphate buffered saline buffer (pH10.0), and controlled temperature is 37 ℃, rotating speed 50r/min, and certain hour takes out all release liquid in the bottle at interval, and in time replenishes fresh release medium 50ml, continues jolting.The extracorporeal releasing experiment result of study is seen Fig. 1, and the grafts of this molecular weight discharges slowly, 162d cumulative release 19.89mg Ketoprofen/g grafts.
Embodiment 2:
Get chitosan (Mr=46KDa, deacetylation 70.9%) 100mg, add 10ml 0.1mol/L hydrochloric acid and make the chitosan dissolving.Add 10ml methyl alcohol and 8mlN again, the N-ethyl pyrrolidone adds the 0.71g Ketoprofen, vibration makes dissolving, regulates pH to 6.0, and jolting limit, limit adds 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride of 0.1M, keep pH at 6.0,25 ℃ of stirring reaction 3h.After reaction finished, suction filtration obtained precipitation, uses 3 * 15ml 0.1mol/L hydrochloric acid successively, 3 * 15ml deionized water, 3 * 15ml methanol wash.Vacuum-drying 24h obtains chitosan-Ketoprofen faint yellow solid, and grafts Chinese traditional medicine content is 48.05%, and yield is 86.99%.
Release in vitro:
Release conditions: release medium is a 50ml 0.5mol/L phosphate buffered saline buffer (pH10.0), and controlled temperature is 37 ℃, rotating speed 50r/min.Certain hour takes out all release liquid in the bottle at interval, and in time replenishes fresh release medium 50ml, continues jolting.The extracorporeal releasing experiment result of study is seen Fig. 2, and the grafts of this molecular weight discharges slowly, 162d cumulative release 15.16mg Ketoprofen/g grafts.
Embodiment 3:
Get high molecular weight chitosan (Mr=126KDa, deacetylation 89.1%) 100mg, add 10ml0.1mol/L hydrochloric acid and make the chitosan dissolving.Add 10ml methyl alcohol and 8mlN again, N-ethyl pyrrolidone, the Ketoprofen of adding 0.86g, vibration makes dissolving, regulates pH to 6.0, and jolting limit, limit adds 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride of 0.1M, keep pH at 6.0,25 ℃ of following stirring reaction 3h.After reaction finished, suction filtration obtained precipitation, uses 3 * 15ml0.1mol/LHCl successively, 3 * 15ml deionized water, 3 * 15ml methanol wash.Vacuum-drying 24h obtains chitosan-Ketoprofen faint yellow solid, and grafts Chinese traditional medicine content is 47.6%, and yield is 80.78%.
Release in vitro:
Release conditions: release medium is a 50ml 0.5mol/L phosphate buffered saline buffer (pH10.0), and controlled temperature is 37 ℃, rotating speed 50r/min.Certain hour takes out all release liquid in the bottle at interval, and in time replenishes fresh release medium 50ml, continues jolting.The extracorporeal releasing experiment result of study is seen Fig. 3, and the grafts of this molecular weight discharges slowly, 162d cumulative release 13.58mg Ketoprofen/g grafts.
Embodiment 4:
Adopt mice caused by dimethylbenzene xylene ear swelling inflammation method to carry out pharmacodynamic study to having comprised the segmental release liquid of water miscible grafts (embodiment 2), whether checking still has anti-inflammatory action.Only get mouse ICR50, body weight 18～22g, be divided into five groups at random, male and female half and half are respectively negative control, low dosage positive control (40.5 μ g/ml), high dosage positive control (81.4 μ g/ml), low dosage chitosan-ketoprofen grafts release liquid (40.5 μ g/ml) and high dosage chitosan-ketoprofen grafts and discharge liquid (81.4 μ g/ml).As negative control, the Ketoprofen damping fluid adopts abdominal injection as positive control with damping fluid, and volume injected is a 0.3ml/20g mouse body weight.0.5h after the administration injects dimethylbenzene 10 μ l in each mouse right ear, and left ear is not done any processing.Mouse is put to death in the cervical vertebra dislocation behind the 1h, cut ears along the auricle baseline, go out auricle with diameter 8mm punch tool and two ear same area, electronic analytical balance is weighed respectively, represent the swelling degree with the difference of two ear weight, and the calculating inhibiting rate, inhibiting rate (%)=(1 one administration groups, two ear swelling degree/negative control group, two ear swelling degree) * 100%.Data represent with X ± S, and medication group and negative control relatively adopt the Dunnett-t check, adopt 4 parallel lines calibratings to carry out the positive control Ketoprofen simultaneously and chitosan-the ketoprofen grafts potency ratio.Experimental result shows, this release liquid still has certain anti-inflammatory action, the release liquid inhibiting rate of high low dosage chitosan-ketoprofen grafts is respectively 47.67%, 20.28%, using symmetric 4 parallel lines checking methods, is that the relative potency of reference substance calibrating chitosan-ketoprofen grafts release liquid is 85.3% with the Ketoprofen.
Claims (6)
1. the grafts of a chitosan-Ketoprofen is characterized in that the carboxyl in the Ketoprofen is connected with amido linkage with amino in the chitosan, and the molecular formula of grafts is (C
8H
13NO
5) n (C
6H
11NO
4) m-x (C
22H
23NO
6) x, structural formula is:
Wherein R is
The chitosan molecule amount is 5000Da-126KDa, and deacetylation is 50%-90%;
Concrete preparation method is as follows: with the chitosan is material, by catalyzer and Ketoprofen at methyl alcohol and N, stirring reaction in the mixed solvent of N-ethyl pyrrolidone, reaction finishes after-filtration, adopt aqueous hydrochloric acid, deionized water, methanol wash gained throw out successively, vacuum-drying, promptly.
2. chitosan-ketoprofen grafts according to claim 1 is characterized in that the application in the treatment of arthritis medicine.
3. chitosan according to claim 1-ketoprofen grafts preparation method, the volume ratio that it is characterized in that reacting used mixed solvent is methyl alcohol and N, the ratio of N-ethyl pyrrolidone 5: 4.
4. chitosan according to claim 1-ketoprofen grafts preparation method, it is characterized in that by chitosan glycosamine repeating unit and Ketoprofen mol ratio be 1: 3-1: 9 feed intake.
5. chitosan according to claim 1-ketoprofen grafts preparation method is characterized in that catalyst system therefor is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride.
6. chitosan according to claim 1-ketoprofen grafts preparation method, reacting liquid temperature is 25 ± 10 ℃ when it is characterized in that preparing, and the reaction times is 3h-24h, and reacting liquid pH value is 6.0 ± 0.3.
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