CN101297973B - Highly bioadhesive and thermosensitive hydrogel, and preparation method and application thereof - Google Patents
Highly bioadhesive and thermosensitive hydrogel, and preparation method and application thereof Download PDFInfo
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- CN101297973B CN101297973B CN2008100478056A CN200810047805A CN101297973B CN 101297973 B CN101297973 B CN 101297973B CN 2008100478056 A CN2008100478056 A CN 2008100478056A CN 200810047805 A CN200810047805 A CN 200810047805A CN 101297973 B CN101297973 B CN 101297973B
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Abstract
The invention relates to a temperature sensitive hydrogel with high bioadhesion, the components of which includes: 10 percent to 40 percent of poloxamer, 0.1 percent to 10 percent of carboxymethyl chitosan and 50 percent to 99.8 percent of water while the percentages are weight percentages. The invention also provides a preparation method of the temperature sensitive hydrogel: the poloxamer is added with water to be evenly stirred, and added with the carboxymethyl chitosan to be evenly stirred to obtain the temperature sensitive hydrogel with high bioadhesion. The temperature sensitive hydrogel can be used as a drug carrier after being defoamed. The preparation method of the invention can be used for the preparation of mucosal drug delivery preparations and injection drug delivery preparations and obtain an intelligent drug slow-release preparation, the hydrogel property of which meets the application requirements in the conditions of pathological mechanism and physiology, thus being convenient for clinical application, being capable of reducing the frequency of the drug delivery and improving the adaptability of patients; enhancing treatment effect and reducing toxic and side effects. Compared with the pure poloxamer hydrogel, the temperature sensitive hydrogel of the invention can obviously enhance the mechanical strength and the mucosa bioadhesion and obviously prolong the detention time in vivo under the condition of ensuring excellent fluidity and favorable hydrogel temperature condition.
Description
Technical field
The present invention relates to a kind of bioadhesive and thermosensitive hydrogel and preparation method and the application in mucosa delivery preparation, injection slow releasing preparation thereof.
Background technology
For a long time, medical circle is expected to find a kind of method always, can be in needs the medicine of requirement be fed into human organ. utilize intelligent gel to know intravital state and the release of controlling medicine more and more causes people's attention from innervation. the drug-supplying system that a class is new---intelligent drug delivery system arises at the historic moment. and intelligent drug delivery system can be made response by certain stimulus signal to external world, character according to stimulus signal, the strong and weak release of adjusting medicine. according to the difference of stimulus signal, intelligent drug delivery system can be divided into physical stimulation response medicine delivery system, chemical stimulation response medicine delivery system and bio signal stimulating responsive drug delivery system, wherein thermal stimulus response medicine delivery system is the most deep system of research at present.Thermosensitive hydrogel is the widest dosage form of this system applies, adopt a class to change and the macromolecular material of generation deformation (swelling or contraction) by response temperature, the conformational energy response temperature of this class high polymer gel macromolecular chain stimulates and changes, at lower critical solution temperature (low critical solution temperature, LCST) sudden contraction and expansion can take place in gel volume down, reach the purpose of convenient use, control drug release.
Poly--N-N-isopropylacrylamide (Poly-N-isopropylacrylamide, PNIPAAm) be exactly wherein typical case representative, its LCST is about 32 ℃, near 37 ℃ of body temperatures, and this temperature can realize by the hydrophilic or hydrophobic components in the telomerized polymer skeleton moving or descending, and therefore has been subjected to people's extensive attention.But PNIP AAm hydrogel generally is that safety is affected with the method preparation of organic crosslinking agent [as N, N ' methylene-bisacrylamide (BIS)] by chemical crosslinking.
Temperature sensitive property chitosan (chitosa)-sodium glycerophosphate (GP) but be a kind of pH value neutral, can keep material liquid, gelation when temperature changes body temperature in room temperature or when being lower than room temperature, be expected to become a kind of medicine, the especially carrier of biomacromolecule preparation and cytoskeleton material of injectable, non-intestinal non-vein by prophesy.But chitosan (chitosa)-sodium glycerophosphate (GP) is actually a kind of plan temperature control hydrogel, promptly also there is gelling to exist at low temperatures, just gelling time is longer, the longlyest reach 3 months, this characteristic be because of can't guaranteeing the stability of medicine in storage process, and had a strong impact on its application prospect as pharmaceutical carrier.
Poloxamer (poloxamer) is a macromolecular material of studying the most deeply preparation temperature responsive type situ-gel at present, the prescription that contains poloxamer can increase the residence time of medicine at site of action, improve bioavailability and drug effect, and have suitable gelation temperature, weak point is that the gelling mechanical strength is low, erodible fast.(chitosan cs) with the poloxamer use in conjunction, has greatly improved gel and has got mechanical strength, and can increase the mucosa permeability, improves viscosity, delays the effect of drug release to have the scholar to adopt chitosan.But chitosan does not dissolve under neutral and alkali condition, and pH value surpasses 6.2 and the hydrogel sample occurs and precipitate, and the body normal physiological pH value, except that the pH of vagina, stomach below 4, all the other are all above pH6.5-8.Therefore, the use in conjunction of poloxamer and chitosan although solved the mechanical strength of gel, can't solve the gel that (removes vagina, stomach) under normal physiological pH condition and separate out problem, has limited its application as drug administration by injection and mucosa delivery.
Carboxymethyl chitosan is the higher derivative of chitosan, is obtained with chloroacetate reaction under alkali condition by chitin.Compare with chitin, its physics, chemical property all are optimized, has 100% water solublity, kept the series of advantages of general chitosan to body-care, also possess the characteristics more favourable such as the not available no astringent taste of general chitosan to health, comprise effects such as antibiotic, antiinflammatory, fabulous medicinal characteristic is arranged.
Summary of the invention
The present invention provides a kind of high bio-adhesive thermosensitive hydrogel and preparation method thereof at the problems referred to above exactly, can be used for the preparation of mucosa delivery preparation and injecting and administering preparations, and obtain a kind of under pathology, physiological condition, gel characteristic meets the intellectual drug slow releasing preparation of application requirements, to make things convenient for clinical practice, reduce administration frequency, improve patient compliance; Strengthen therapeutic effect, reduce toxic and side effects.
Technical scheme provided by the invention is: its composition of highly bioadhesive and thermosensitive hydrogel comprises: 10-40% poloxamer, 0.1-10% carboxymethyl chitosan and 50%-99.8% water, and each component sum is 100%, above percentage ratio is weight percentage.
The pH value of above-mentioned temperature-sensitive hydrogel is 5-12.
The present invention also provides above-mentioned temperature-sensitive hydrogel preparation method: poloxamer is added water stir, add carboxymethyl chitosan, stir, obtain highly bioadhesive and thermosensitive hydrogel.Can be used as pharmaceutical carrier behind this temperature-sensitive hydrogel froth breaking uses.
Medicine is added gel behind the froth breaking, the dispersed with stirring dissolving, pressure sterilizing, sterile filling, sealing promptly get mucosa delivery with preparation and drug administration by injection preparation.
Highly bioadhesive and thermosensitive hydrogel of the present invention can be used for the preparation of mucosa delivery preparation and injecting and administering preparations, and obtain a kind of under pathology, physiological condition, gel characteristic meets the intellectual drug slow releasing preparation of application requirements, made things convenient for clinical practice, can reduce administration frequency, improve patient compliance; Strengthen therapeutic effect, reduce toxic and side effects.By the embodiments of the invention experimental result as seen, 0.5% diammonium glycyrrhizinate temperature-sensitive hydrogel, be administered once in per two days (ordinary preparation once a day), through 7 administrations, can effectively treat inflammatory bowel, and better than existing clinical commonly used drug balsalazide sodium therapeutic effect, show that this pastille thermosensitive hydrogel therapeutic effect is better, see accompanying drawing 3.
The present invention as temperature sensing material, as mucosa adhesion reinforcing agent, prepares high bioadhesive thermosensitive hydrogel with carboxymethyl chitosan with poloxamer.With pure poloxamer gel phase ratio, poloxamer-carboxymethyl chitosan gel is guaranteeing that mechanical strength, mucosa bio-adhesive power obviously strengthen under good flowability and the suitable gelation temperature condition, and holdup time significant prolongation in the body the results are shown in Figure 1, Fig. 2.
Description of drawings
Fig. 1 be the gel strength of poloxamer gel and poloxamer-carboxymethyl chitosan gel and bio-adhesive force rate.Compare * * * P＜0.001 with the poloxamer group;
Fig. 2 compares the interior holdup time of the body of poloxamer gel and poloxamer-carboxymethyl chitosan gel.A:PBS aqueous solution+india ink group; B: poloxamer-carboxymethyl chitosan group+india ink group; C: poloxamer+india ink group;
Fig. 3 is 0.5% diammonium glycyrrhizinate poloxamer-carboxymethyl chitosan gel inflammatory enteropathy therapeutical effect.A: normal group; B: model group; C: model+0.5% diammonium glycyrrhizinate (50mg/kg) aqueous solution group; D: model+0.5% diammonium glycyrrhizinate (50mg/kg) thermosensitive hydrogel group; E: model+5% balsalazide sodium normal saline group positive controls.
The specific embodiment
The present invention is described further by following examples.
Embodiment 1: high bio-adhesive power temperature-sensitive hydrogel, form by the carboxymethyl chitosan of 18wt% poloxamer 407,15wt% poloxamer 188,0.3wt% and the water of surplus.Poloxamer 407 and poloxamer 188 mixed, adds water and stir, add carboxymethyl chitosan, stir, promptly obtain highly bioadhesive and thermosensitive hydrogel.Measure gelation temperature with the magneton paddling process, the gelation temperature of this gel is 35 ℃, gelling time 5min.(pH7.4 value).
Gel strength is measured: sample thief 20g, put in the graduated cylinder of 50ml, put into 37 ℃ of constant temperature water baths again, make the sample gelling, the 100g counterweight is placed on the pressure push-rod, the other end of push rod connects a disk that closely contacts and be drilled with 6 diameter 2mm circular holes with cylinder inner wall, is subjected to the size of the needed time representation gel strength of drops 2cm with disk.The result shows that with poloxamer gel phase ratio, the gel strength of poloxamer-carboxymethyl chitosan gel is 4 times of poloxamer gel.Referring to Fig. 1.
Bioadhesion power is measured: get two sections of fresh rat colons, area is s, one section is connected in balance, and another section is fixing, outside mucosa faces, 37 ℃ of 20min of constant temperature, 0.15 gram gel is spread upon in the colon, two sections colons are fitted tightly, separately lucky at the other end increase counterweight of balance up to two sections tissues, the weight m of record counterweight, bio-adhesive power equals the peeling force f=0.98m/s (dyne/cm of unit are
2), the result shows that with poloxamer gel phase ratio, the bioadhesion power of poloxamer-carboxymethyl chitosan gel increases by 40%.Referring to Fig. 1.
Rat is divided into three groups, after the anesthesia respectively per rectum pour into 0.1% india ink, contain 0.1% india ink the poloxamer gel, contain 0.1% poloxamer-carboxymethyl chitosan gel.Expose colon, respectively at after the coloclysis 0.5,1,3,6,12,16,24h Taking Pictures recording enema is at the retention degree of rectum, the result as seen, basic emptying behind the water formulation 3h, basic emptying behind the poloxamer gel 12h; Poloxamer-carboxymethyl chitosan gel can be detained to 24h, referring to Fig. 2.
Embodiment 2: high bio-adhesive power temperature-sensitive hydrogel, form by the carboxymethyl chitosan of 18wt% poloxamer 407,15wt% poloxamer 188,5wt% and the water of surplus.Poloxamer 407 is added water stir, add carboxymethyl chitosan, stir, promptly obtain highly bioadhesive and thermosensitive hydrogel.Measure gelation temperature with the magneton paddling process, the gelation temperature of this gel is 35 ℃, gelling time 1min.(pH value 9.0)
Embodiment 3: high bio-adhesive power temperature-sensitive hydrogel, form by the carboxymethyl chitosan of 7wt% poloxamer 407,5wt% poloxamer 188,10wt% and the water of surplus.Poloxamer 407 is added water stir, add carboxymethyl chitosan, stir, promptly obtain highly bioadhesive and thermosensitive hydrogel.Measure gelation temperature with the magneton paddling process, the gelation temperature of this gel is 35 ℃, gelling time 30min.(pH value 8.0)
The high bio-adhesive power temperature-sensitive hydrogel that adopts the foregoing description 1 or 2 or 3 is as blank gel, add diammonium glycyrrhizinate, stir, preparation contains the temperature-sensitive hydrogel of 0.5% diammonium glycyrrhizinate, measure gelation temperature with the magneton paddling process, the gelation temperature of this gel is 35.5 ℃, gelling time 5min.
The present invention is model drug with the diammonium glycyrrhizinate, and preparation diammonium glycyrrhizinate poloxamer-carboxymethyl chitosan thermosensitive hydrogel enema is used for the inductive rat colonitis treatment of TNBS, and concrete grammar is as follows:
The SD rat is divided into 5 groups at random, 4 every group.Normal group, model group, 0.5% diammonium glycyrrhizinate poloxamer-carboxymethyl chitosan group, 0.5% diammonium glycyrrhizinate normal saline solution group, 5% balsalazide sodium normal saline solution group.With 150mg/kgTNBS (50% alcoholic solution) coloclysis modeling, after the modeling 1 day, normal group, model group coloclysis give normal saline 1ml/100g, and administration group coloclysis respectively gives respective concentration medicine 1ml/100g, and two days once, totally 14 days, after administration the 15th day, rat was put to death under general anesthesia, gets colon, observe pathological change, carry out the colon scoring.Experimental result sees Table 1, Fig. 3.
By appraisal result as seen, model group presents pathological manifestations such as ulcer, edema, megacolon, 0.5% diammonium glycyrrhizinate poloxamer-carboxymethyl chitosan group can obviously be improved the pathological change of colitis rat colon, effect is good than 5% balsalazide sodium, 0.5% diammonium glycyrrhizinate normal saline solution group, show, diammonium glycyrrhizinate can be used for the treatment of inflammatory bowel, and high bio-adhesive power thermosensitive hydrogel preparation helps improving the curative effect of diammonium glycyrrhizinate treatment inflammatory bowel.
The scoring of table 1. colon
Claims (4)
1. highly bioadhesive and thermosensitive hydrogel comprises: 10-40% poloxamer, 0.1-10% carboxymethyl chitosan and 50%-99.8% water, and each component sum is 100%, above percentage ratio is weight percentage; The gel pH value is 5-12.
2. the preparation method of the described temperature-sensitive hydrogel of claim 1, it is characterized in that: be 100% percentage by weight by 10-40% poloxamer, 0.1-10% carboxymethyl chitosan and 50%-99.8% water and each component sum, poloxamer is added water to stir, add carboxymethyl chitosan, stir, obtain highly bioadhesive and thermosensitive hydrogel.
3. the application of the described temperature-sensitive hydrogel of claim 1 in preparation mucosa delivery preparation or injection slow releasing preparation.
4. application according to claim 3 is characterized in that: behind described temperature-sensitive hydrogel froth breaking, add medicine, dispersed with stirring dissolving, pressure sterilizing, fill, sealing.
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| CN102145191A (en) * | 2011-04-01 | 2011-08-10 | 秦益民 | Hydrogel dressing and preparation method thereof |
| CN102989036B (en) * | 2011-09-10 | 2015-10-21 | 浙江海正药业股份有限公司 | Hydrogel containing heparin-poloxamer complex being applied to angiostomy and preparation method thereof |
| CN102989035B (en) * | 2011-09-10 | 2014-12-17 | 浙江海正药业股份有限公司 | Hydrogel applicable to angiostomy and preparation method thereof |
| CN102949754A (en) * | 2012-05-25 | 2013-03-06 | 江西圣济药业有限公司 | Uterine cavity hemostasis anti-adhersion temperature-sensitive gel and preparation method thereof |
| CN103520091A (en) * | 2013-10-15 | 2014-01-22 | 山东赛克赛斯药业科技有限公司 | Acidic buffer temperature-sensitive gel preparation for vagina as well as preparation method and application thereof |
| CN108126237B (en) * | 2018-01-10 | 2022-03-29 | 中国人民解放军军事科学院军事医学研究院 | Silver sulfadiazine temperature-sensitive gel and preparation method and application thereof |
| CN108478544A (en) * | 2018-05-15 | 2018-09-04 | 杭州易敏生物医药科技有限公司 | A kind of mucous membrane disease treatment system and its application |
| CN108653197B (en) * | 2018-05-15 | 2021-06-04 | 九江高科制药技术有限公司 | Carboxymethyl chitosan quaternary ammonium salt temperature-sensitive gel and preparation method thereof |
| CN109575683B (en) * | 2018-11-26 | 2021-11-16 | 西安理工大学 | Preparation method of hydrogel ink suitable for 3D bioprinting |
| CN109820816B (en) * | 2019-02-18 | 2023-04-28 | 江苏拓弘生物科技有限公司 | Temperature sensitive biogel preparation and application thereof |
| CN112439054B (en) * | 2019-08-28 | 2023-05-16 | 深圳翰宇药业股份有限公司 | Teriparatide sustained-release gel injection and preparation method thereof |
| CN114306211B (en) * | 2021-12-29 | 2023-12-22 | 中国药科大学 | Glycyrrhizic acid supermolecule self-assembled temperature-sensitive interpenetrating network gel and preparation method and application thereof |
| CN116172944A (en) * | 2023-03-01 | 2023-05-30 | 南通大学 | Preparation method and application of temperature/pH response ginsenoside-carrying hydrogel |
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