CN101104651A - Preparation for modified chitosan metal complexes micro-sphere used for carrying medicament and preparation for the modified chitosan - Google Patents

Preparation for modified chitosan metal complexes micro-sphere used for carrying medicament and preparation for the modified chitosan Download PDF

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CN101104651A
CN101104651A CNA2007100351972A CN200710035197A CN101104651A CN 101104651 A CN101104651 A CN 101104651A CN A2007100351972 A CNA2007100351972 A CN A2007100351972A CN 200710035197 A CN200710035197 A CN 200710035197A CN 101104651 A CN101104651 A CN 101104651A
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chitosan
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modified chitosan
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黄可龙
丁萍
刘素琴
刘艳飞
王蔚玲
李桂银
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Central South University
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Abstract

Disclosed are the preparation of a modified chitosan metal complex microsphere used for drug-loading and the preparation of the modified chitosan. The invention provides a preparation method of a modified chitosan which has good solubility, high biological activity and can reduce the dependence to PH value during drug release, and provides a preparation method of a chitosan derivative based metal complex microsphere for drug-loading. The micorshpere prepared by the invention can be used for drug-loading, and is characterized in improving the drug releasing and simple preparation process.

Description

Be used for the preparation of modified chitosan metal complexes micro-sphere of medicine carrying and the preparation of this modified chitosan
Technical field
The invention belongs to medical technical field, relate to the preparation of the modified chitosan of a class formation novelty, and the preparation of this modified chitosan derivant metal complex medicine carrying microballoons.
Background technology
Chitosan is more and more noticeable in the application of pharmaceutical field in recent years, and the auxiliary material that it can be used as medicine is used for pharmaceutical preparation, as the research as pharmaceutical preparation packings such as controlled release, slowly-releasing, targets; Because chitosan has amino isoreactivity group, these active groups can carry out chemical bonding with multiple medicine, generate polymer drug, the side effect that reduction cancer therapy drug etc. stimulate human body, and the degraded product oligochitosan of chitosan has certain antitumous effect; In addition, chitosan self can also use as medicine and healthcare products, Japanese government once invested 6,000,000,000 yen and entrusts colleges and universities of tens of family and scientific research institution year to carry out the research of chitin/chitosan Products Development surplus lasting 10, obtained a large amount of scientific payoffss, and the part achievement has been realized industrialization, only be that the protective foods of main raw material just has the kind about 20 to go on the market with the chitosan.1994, the sales volume that functional health-care food " is rescued how kind " reached more than 1,000 hundred million yen, it serves to show that its market potential is big.Because special construction and solvability that chitosan possessed, it can bring into play effective function at aspects such as controlled delivery of pharmaceutical agents and release, the solvability of improving medicine and absorptivities.
Medicine carrying has determined the needs that the quality of medicine, the kind of domestic pharmaceutical polymers and quality far can not adapt to formulation development research and produce to a great extent with macromolecular material.The domestic new auxiliary material of having developed has propenoic acid resin series, Vltra tears, cellulose acetate, pregelatinized Starch etc. to be used for tablet or granule, PVAC polyvinylalcohol is mainly used in film, beta-cyclodextrin is mainly used in inclusion compound, polyoxyethylene glycol PEG is used in various external applications, (as the tablet coating material) and the injection for oral administration (as solvent), methylcellulose gum is used for tablet coating (share with cellulose acetate), and natural polysaccharides such as sodium alginate, chitosan are used for the controlled release fertilizer preparation.Wherein chitosan has been listed country's eight or five tackling key problem auxiliary material research projects in.Zhao Ruizhi etc. are retarding agent with the chitosan, the slow release type matrix tablet that has prepared 11 kinds of medicines of different nature such as pseudoephedrine hydrochloride, phloride, Carbamzepine, relatively its result of extraction finds that the slow releasing function of chitosan reduces and strengthens with the enhancing of medicine alkalescence, molecular weight increase, solubleness.When drug molecule amount and solubleness were close, alkaline drug was better than acidic drug slow release effect.Show that chitosan has pH value dependency in drug release process, and chitosan both had been insoluble to common organic solvent, also water insoluble, thus limited its widespread use.So improve the solubility property of chitosan, solve the pH value dependency of chitosan in drug release process, the polymer substance that particularly is made into pH value independence is one of the most noticeable direction in the research of chitosan chemical modification.
Chitosan has demonstrated good biodegradability and biocompatibility as a kind of resourceful natural polycationic compounds, has good medical property and metal ion accumulation ability, has a extensive future in medical science and water treatment field.But tegument glycan molecular weight is very big, and its crystalline structure closely, is insoluble to usual vehicle, and poorly soluble, biological activity is low, has pH value dependency etc. in the drug release process, has limited its range of application.Many unique functions of chitosan just can show during by modification.Therefore select appropriate means that chitosan is carried out modification and just seem particularly important.
Chitosan-based metal complexes has both the character such as coordination of the good physiologically active of chitosan, polymer performance and metal ion; in fields such as medical material, functional materials even pharmaceutical preparations good prospects for application is arranged all; not only be used for environment protection and monitoring; realize the recovery of sewage disposal and heavy metal ion, also can be used for the preparation of many hot topics and new industry such as manual simulation's enzyme, medicine industry, biotechnology and nano material etc.Therefore, very valuable to the research and development of the metal complexes of chitosan and derivative thereof.Chitosan derivatives, the content that improves metal ion and title complex will help to enlarge chitosan-based metal complexes material to the adaptive faculty of different pH systems range of application that the preparation structure properties is good.
For achieving the above object, the present invention is by carrying out modification to chitosan, synthetic α-Tong Wuersuan chitosan (KCTS) and the azanol α-Tong Wuersuan chitosan (HKCTS) that contracts that contracts, and be carrier with the modified chitosan, utilize ionic cross-linking to prepare the sustained-release micro-spheres of carrying medicament.
Summary of the invention
The object of the present invention is to provide a kind of solvability good, the biological activity height can reduce in the drug release process preparation method to the dependent modified chitosan of pH value.
Another object of the present invention is to provide a kind of chitosan derivatives Base Metal title complex medicine carrying microballoons and preparation method.Microballoon by method preparation of the present invention is used for medicine carrying, has the advantages that to improve controlled drug release, and its preparation process is simple.
The objective of the invention is to realize by following manner:
Modified chitosan α-Tong Wuersuan being prepared as of chitosan (KCTS) of contracting: take by weighing chitosan (CTS) dry sample, the abundant swelling of distilled water, add α-Tong Wuersuan, filter, regulating pH with NaOH solution is 4-5, sustained reaction in the 35-38 ℃ of water-bath, add sodium borohydride, regulate pH=6.5-7.0, continue reaction 20-28h with rare HCl solution, pour reaction mixture into 90-97% ethanol termination reaction, KCTS separates out, decompress filter, washing, product changes apparatus,Soxhlet's over to and extracts 6-9h continuously, dry the white powder solid α-Tong Wuersuan chitosan (KCTS) that contracts.
Modified chitosan azanol α-Tong Wuersuan being prepared as of chitosan (HKCTS) of contracting: during 0.5-1.0g KCTS is dissolved in, the pH value of adjusting polymers soln with the 0.1mol/L hydrochloric acid soln is under 4.0-5.0 stirs 0.74-1.48g dicyclohexylcarbodiimide (DCCI) Xu to be added mixture, behind the reaction 2-3h, add the 5.0-10.0g hydroxylamine hydrochloride, under agitation further react 1h; Use the sodium hydroxide adjust pH to 9.0-10.0 again, at room temperature stir more than the 20-28h, termination reaction when the HKCTS precipitation appears in reaction mixture in the mixed liquid of 10-20ml concentrated hydrochloric acid and 250-300ml acetone.Filter, wash, resulting polymers is dried overnight at room temperature.
By the chitosan solubility property after the modification big improvement has been arranged, in addition, the twice-modified product HKCTS solvability of chitosan then more will be significantly better than KCTS and CTS, can be water-soluble fully, can be dissolved in 2%NaOH and 10% ammoniacal liquor simultaneously.The good solubility property of HKCTS is more easy to use, helps further applying of chitosan derivatives.KCTS has the biopolymer of special sequestering action to metal ion, and has the characteristics of biodegradable.Here except introducing carbonyl and-NH 2Outside reacting, also introduced carboxyl simultaneously, improved the ability of chitosan derivatives adsorbing metal ions, and helped utilizing the introduction carboxyl to carry out twice-modified chitosan derivatives.HKCTS is more prone to form stable five-ring inner complex with metal ion owing to introduced-the CONHOH group, can significantly increase the chelate stability and relevant pH independence of synthesized polymer body, has greatly improved the ability of chitosan derivatives adsorbing metal ions.
α-Tong Wuersuan provided by the invention the contract synthetic route of chitosan (HKCTS) of chitosan (KCTS) and azanol α-Tong Wuersuan that contracts is as follows:
Figure A20071003519700051
The preparation method of modified chitosan derivant metal complex medicament slow-release microsphere of the present invention comprises the steps:
(1) take by weighing the abundant swelling 30-50min of NaOH solution that 0.5-1g KCTS or HKCTS add 20-40.0ml 0.1mol/L, add the required medicine of 0.1-0.3g, constant temperature 38-42 ℃ is stirred 1h;
(2) slowly drip ion crosslinking agent ZnSO again 4Or CaCl 2The aqueous solution is regulated corresponding pH value to 6-6.5 or 9-10, stirs 7-10h;
(3) suction filtration, with a small amount of distilled water and absolute ethanol washing, the about 2-3d of seasoning at ambient temperature, promptly obtain modified chitosan derivant metal complex medicament slow-release microsphere.
The beneficial effect that adopts preparation method of the present invention to reach is:
1, Zhi Bei medicine carrying grain diameter is little, drug loading is high, sustained release performance good;
2, the present invention utilizes the good biological intermiscibility that chitosan has, low toxicity and internal metabolism ability, with the modified chitosan is the solvability that carrier can increase medicine, also increases the perviousness on medicine cell membrane surface simultaneously, has improved the body-internal-circulation cycle of medicine and has reduced toxic side effect;
3, the present invention may avoid using deleterious linking agent, tensio-active agent and organic solvent;
4, cost of the present invention is low, and preparation technology is simple, and mild condition is fit to large-scale production.
Description of drawings
Fig. 1 to Fig. 4 is a chitosan derivatives Base Metal title complex medicine carrying microballoons scanning electron photomicrograph.
Fig. 1 KCTS-Zn-T microballoon SEM photo
Fig. 2 KCTS-Ca-T microballoon SEM photo
Fig. 3 HKCTS-Zn-T microballoon SEM photo
Fig. 4 HKCTS-Ca-T microballoon SEM photo
Embodiment
Embodiment 1
Modified chitosan α-Tong Wuersuan being prepared as of chitosan (KCTS) of contracting: take by weighing chitosan (CTS) dry sample, the abundant swelling of distilled water, add α-Tong Wuersuan, filter, regulating pH with NaOH solution is 4-5, sustained reaction in the 35-38 ℃ of water-bath, add sodium borohydride, regulate pH=6.5-7.0, continue reaction 20-28h with rare HCl solution, pour reaction mixture into 90-97% ethanol termination reaction, KCTS separates out, decompress filter, washing, product changes apparatus,Soxhlet's over to and extracts 6-9h continuously, dry the white powder solid α-Tong Wuersuan chitosan (KCTS) that contracts.
Utilize C on the chitosan molecule 2Active free amino group-the NH of position 2Carry out macromolecular reaction with α-Tong Wuersuan, the functional polymer α-Tong Wuersuan that can the synthesize band Schiff base groups chitosan (KCTS) that contracts.The KCTS solubility property of preparation has had certain improvement, and metal ion is had special sequestering action, and has the characteristics of biodegradable.Here except introducing carbonyl and-NH 2Outside reacting, also introduced carboxyl simultaneously, can form more stable inner complex, improved the ability of chitosan derivatives adsorbing metal ions with metal ion, and it is twice-modified to help utilizing the introduction carboxyl that chitosan derivatives is carried out, and has greatly enlarged its range of application.
Embodiment 2
Modified chitosan azanol α-Tong Wuersuan being prepared as of chitosan (HKCTS) of contracting: during 0.5-1.0g KCTS is dissolved in, the pH value of adjusting polymers soln with the 0.1mol/L hydrochloric acid soln is under 4.0-5.0 stirs 0.74-1.48g dicyclohexylcarbodiimide (DCCI) Xu to be added mixture, behind the reaction 2-3h, add the 5.0-10.0g hydroxylamine hydrochloride, under agitation further react 1h; Use the sodium hydroxide adjust pH to 9.0-10.0 again, at room temperature stir more than the 20-28h, termination reaction when the HKCTS precipitation appears in reaction mixture in the mixed liquid of 10-20ml concentrated hydrochloric acid and 250-300ml acetone.Filter, wash, resulting polymers is dried overnight at room temperature.
The solubility property of the HKCTS of preparation is greatly improved, can be water-soluble fully, be dissolved in 2%NaOH and 10% ammoniacal liquor.HKCTS introducing-CONHOH group is more prone to form stable five-ring inner complex with metal ion, can significantly increase the chelate stability and relevant pH independence of synthesized polymer body, has improved the ability of chitosan derivatives adsorbing metal ions greatly.
Embodiment 3
(1), accurately take by weighing the KCTS (preparation) of 1.000g, it is joined in the NaOH solution of 20.00mL0.1mol/L, fully swelling or dissolving 30min stir;
(2), accurately take by weighing the oral theophylline medicine of 1.000g, add in the above-mentioned system, constant temperature stirs 1h for 40 ℃, promptly obtains milky viscous polymers solution;
(3), accurately take by weighing 1.8gZnSO 47H 2O is made into the ZnSO that concentration is 18mg/mL 47H 2O aqueous solution 100.00mL;
(4), milky viscous polymers solution gently is added drop-wise to the ZnCl of 18mg/mL 2Among the aqueous solution 100.00mL, about the pH=6 of regulation system, in water-bath, keep promptly having generated the polymer microballoon of a large amount of whites more than the constant temperature stirring reaction 9h;
(5), carry out decompress filter, leach thing and use distilled water, a small amount of absolute ethanol washing 2-3 time successively, under 35 ℃ temperature, carry out vacuum-drying 8h, promptly get the chitosan sugar derivatives and the Zn of the oral theophylline medicine of load 2+The crosslinked polymer microballoon.
The chitosan derivatives and the Zn of the oral theophylline medicine of load of preparation 2+Crosslinked polymer microballoon mean particle size is 571nm, even particle size distribution, and the medicine carrying particle is regular circular, smooth surface.Drug loading is 155.525mgg -1, maximum release is approximately 46.011% in 8h.Inside and outside dependency experiment shows, with absorption fraction in the body cumulative in vitro release is carried out linear fit, optical density is respectively the dissolution in vitro regression equation in the synthetic KCTS-Zn-T theophylline polymer sustained-release microsphere: Y=-13.66+1.92X, r=0.978, show that absorbing percentage ratio in release in vitro degree percentage ratio and the body has favorable linearity dependency (α=5, P＜0.0001).
Embodiment 4
(1), accurately take by weighing the HKCTS (preparation) of 1.000g, join in the NaOH solution of 20.00mL0.1mol/L after being dissolved in it in 20mL distilled water, fully swelling or dissolving 30min stir;
(2), accurately take by weighing the oral theophylline medicine of 1.000g, add in the above-mentioned system, constant temperature stirs 1h for 40 ℃, promptly obtains milky viscous polymers solution;
(3), accurately take by weighing 1.8gZnSO 47H 2O is made into the ZnSO that concentration is 18mg/mL 47H 2O aqueous solution 100.00mL;
(4), milky viscous polymers solution gently is added drop-wise to the ZnCl of 18mg/mL 2Among the aqueous solution 100.00mL, about the pH=6 of regulation system, in water-bath, keep promptly having generated the polymer microballoon of a large amount of whites more than constant temperature stirring reaction 9 h;
(5), carry out decompress filter, leach thing and use distilled water, a small amount of absolute ethanol washing 2-3 time successively, under 35 ℃ temperature, carry out vacuum-drying 8 h, promptly get the chitosan sugar derivatives and the Zn of the oral theophylline medicine of load 2+The crosslinked polymer microballoon.
The chitosan sugar derivatives and the Zn of the oral theophylline medicine of load of preparation 2+Crosslinked polymer microballoon mean particle size is 324nm, even particle size distribution, and the medicine carrying particle is regular circular, smooth surface.Drug loading is 205.020mgg -1, maximum release is approximately 58.996% in 8h.Inside and outside dependency experiment shows, with absorption fraction in the body cumulative in vitro release is carried out linear fit, optical density is respectively the dissolution in vitro regression equation in the synthetic KCTS-Zn-T theophylline polymer sustained-release microsphere: Y=-16.97+1.84X, r=0.987, show that absorbing percentage ratio in release in vitro degree percentage ratio and the body has favorable linearity dependency (α=5, P＜0.0001).
Embodiment 5
(1), accurately take by weighing the KCTS (preparation) of 1.000g, it is joined in the NaOH solution of 20.00mL0.1mol/L, fully swelling or dissolving 30min stir;
(2), accurately take by weighing the oral theophylline medicine of 1.000g, add in the above-mentioned system, constant temperature stirs 1h for 40 ℃, promptly obtains milky viscous polymers solution;
(3), accurately take by weighing the anhydrous CaCl of 1.000g 2Be made into the CaCl that concentration is 10mg/mL 2Aqueous solution 100.00mL;
(3), milky viscous polymers solution gently is added drop-wise to the CaCl of 10mg/mL 2100.00mL in, about the pH=9-10 of regulation system, in water-bath, keep promptly having generated the polymer microballoon of a large amount of whites more than constant temperature stirring reaction 9 h;
(4), carry out decompress filter, leach thing and use distilled water, a small amount of absolute ethanol washing 2 ~ 3 times successively, under 35 ℃ temperature, carry out vacuum-drying 8h, promptly get the chitosan sugar derivatives and the Ca of the oral theophylline medicine of load 2+The crosslinked polymer microballoon.
The chitosan sugar derivatives and the Ca of the oral theophylline medicine of load of preparation 2+Crosslinked polymer microballoon mean particle size is 534nm, even particle size distribution, and the medicine carrying particle is regular circular, smooth surface.Drug loading is 152.430mgg -1, maximum release is approximately 45.662% in 8h.Inside and outside dependency experiment shows, with absorption fraction in the body cumulative in vitro release is carried out linear fit, optical density is respectively the dissolution in vitro regression equation in the synthetic KCTS-Ca-T theophylline polymer sustained-release microsphere: Y=-26.47+2.54X, r=0.993, show that absorbing percentage ratio in release in vitro degree percentage ratio and the body has favorable linearity dependency (α=5, P＜0.0001)
Embodiment 6
(1), accurately take by weighing the HKCTS (preparation) of 1.000g, it is dissolved in the 20mL distilled water, join then in the NaOH solution of 20.00mL0.1mol/L, fully swelling or dissolving 30min stir;
(2), accurately take by weighing the oral theophylline medicine of 1.000g, add in the above-mentioned system, constant temperature stirs 1h for 40 ℃, promptly obtains milky viscous polymers solution;
(3), accurately take by weighing the anhydrous CaCl of 1.000g 2Be made into the CaCl that concentration is 10mg/mL 2Aqueous solution 100.00mL;
(4), milky viscous polymers solution gently is added drop-wise to the CaCl of 10mg/mL 2100.00mL in, about the pH=9-10 of regulation system, in water-bath, keep promptly having generated the polymer microballoon of a large amount of whites more than the constant temperature stirring reaction 9h;
(5), carry out decompress filter, leach thing and use distilled water, a small amount of absolute ethanol washing 2 ~ 3 times successively, under 35 ℃ temperature, carry out vacuum-drying 8h, promptly get the chitosan sugar derivatives and the Ca of the oral theophylline medicine of load 2+The crosslinked polymer microballoon.
The chitosan sugar derivatives and the Ca of the oral theophylline medicine of load of preparation 2+Crosslinked polymer microballoon mean particle size is 283nm, even particle size distribution, and the medicine carrying particle is regular circular, smooth surface.Drug loading is 201.008mgg -1, maximum release is approximately 56.606% in 8h.Inside and outside dependency experiment shows, with absorption fraction in the body cumulative in vitro release is carried out linear fit, optical density is respectively the dissolution in vitro regression equation in the synthetic HKCTS-Ca-T theophylline polymer sustained-release microsphere: Y=-21.00+2.46X r=0.991, show that absorbing percentage ratio in release in vitro degree percentage ratio and the body has favorable linearity dependency (α=5, P＜0.0001).

Claims (3)

1. modified chitosan α-Tong Wuersuan being prepared as of chitosan of contracting: it takes by weighing the chitosan dry sample, the abundant swelling of distilled water, add α-Tong Wuersuan, filter, regulating pH with NaOH solution is 4-5, sustained reaction in the 35-38 ℃ of water-bath, add sodium borohydride, regulate pH=6.5-7.0, continue reaction 20-28h with rare HCl solution, pour reaction mixture into 90-97% ethanol termination reaction, KCTS separates out, decompress filter, washing, product changes apparatus,Soxhlet's over to and extracts 6-9h continuously, dry the white powder solid α-Tong Wuersuan chitosan that contracts.
2. modified chitosan azanol α-Tong Wuersuan being prepared as of chitosan of contracting: during 0.5-1.0g KCTS is dissolved in, the pH value of adjusting polymers soln with the 0.1mol/L hydrochloric acid soln is under 4.0-5.0 stirs the 0.74-1.48g dicyclohexylcarbodiimide to be added mixture slowly, behind the reaction 2-3h, add the 5.0-10.0g hydroxylamine hydrochloride, under agitation further react 1h; Use the sodium hydroxide adjust pH to 9.0-10.0 again, at room temperature stir more than the 20-28h, termination reaction when the HKCTS precipitation appears in reaction mixture in the mixed liquid of 10-20ml concentrated hydrochloric acid and 250-300ml acetone.Filter, wash, resulting polymers is dried overnight at room temperature.
3. the preparation method of modified chitosan derivant metal complex medicament slow-release microsphere is characterized in that,
(1) take by weighing 0.5-1g α-Tong Wuersuan chitosan or the azanol α-Tong Wuersuan chitosan that contracts that contracts and add the abundant swelling 30-50min of NaOH solution of 20-40.0ml 0.1mol/L, add the required medicine of 0.1-0.3g, constant temperature 38-42 ℃ is stirred 1h;
(2) slowly drip ion crosslinking agent ZnSO again 4Or CaCl 2The aqueous solution is regulated corresponding pH value to 6-6.5 or 9-10, stirs 7-10h;
(3) suction filtration, with a small amount of distilled water and absolute ethanol washing, the about 2-3d of seasoning at ambient temperature, promptly obtain modified chitosan derivant metal complex medicament slow-release microsphere.
CNA2007100351972A 2007-06-22 2007-06-22 Preparation for modified chitosan metal complexes micro-sphere used for carrying medicament and preparation for the modified chitosan Pending CN101104651A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103169957A (en) * 2011-12-22 2013-06-26 国家纳米科学中心 Nano thrombin and preparation method thereof
CN105688222A (en) * 2016-03-14 2016-06-22 广东药学院 Application of chitosan metal complex particles as dosage carrier based on active oxygen responsiveness
CN109235033A (en) * 2018-08-10 2019-01-18 苏州市天翱特种织绣有限公司 A kind of preparation method of antibacterial fabric deodorization finishing agent
CN112370577A (en) * 2020-10-15 2021-02-19 浙江省肿瘤医院 Portable fistula protection drainage mechanism

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103169957A (en) * 2011-12-22 2013-06-26 国家纳米科学中心 Nano thrombin and preparation method thereof
CN105688222A (en) * 2016-03-14 2016-06-22 广东药学院 Application of chitosan metal complex particles as dosage carrier based on active oxygen responsiveness
CN109235033A (en) * 2018-08-10 2019-01-18 苏州市天翱特种织绣有限公司 A kind of preparation method of antibacterial fabric deodorization finishing agent
CN109235033B (en) * 2018-08-10 2021-12-17 苏州市天翱特种织绣有限公司 Preparation method of antibacterial and deodorant finishing agent for fabric
CN112370577A (en) * 2020-10-15 2021-02-19 浙江省肿瘤医院 Portable fistula protection drainage mechanism

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