CN101283966A - Biodegradability hydrogel controlled-release preparation and its preparation method and application - Google Patents
Biodegradability hydrogel controlled-release preparation and its preparation method and application Download PDFInfo
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- CN101283966A CN101283966A CNA2008100385742A CN200810038574A CN101283966A CN 101283966 A CN101283966 A CN 101283966A CN A2008100385742 A CNA2008100385742 A CN A2008100385742A CN 200810038574 A CN200810038574 A CN 200810038574A CN 101283966 A CN101283966 A CN 101283966A
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Abstract
The invention relates to a biodegradable hydrogel controlled release preparation and a preparation and an application thereof, belonging to the technology field of medicines. The preparation method comprises the steps of: synthesizing poly(lactic acid)-polyethylene glycol-poly(lactic acid) (PLA-PEG-PLA) triblock copolymer by inducing L-lactide and D-lactide to respectively conduct ring-expansion polymerization by using zinc powder, zinc lactate or stannous octoate as catalyst and polyethylene glycol (PEG) 2,000-20,000; respectively dissolving poly-L-lactic acid-polyethylene glycol-poly-L-lactic acid and poly-D-lactic acid-polyethylene glycol-poly-D-lactic acid in water to obtain solutions with concentration of 0.05-0.5g/mL, swelling, mixing, and allowing gelatinization under constant temperature to obtain PLA-PEG-PLA triblock copolymer hydrogel for injection by complexing reaction. The hydrogel has good biological compatibility and biodegradability, can be used for embedding water-soluble drugs, and is an ideal drug controlled release carrier.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of Biodegradable hydrogel controlled release preparation and its production and application.
Background technology
In recent years, along with medical science and development of biology, increasing product has been developed in pharmaceuticals industry, biologically active drugs such as polypeptide and protein, and gradually by synthetic, these medicines need sustained release system competence exertion or better play effectiveness.Simultaneously the medicine controlled releasing system need long-term prescription, a large amount of medication, drug toxicity is big or have the application of aspects such as addicted cardiovascular diseases, respiratory system disease, pain relieving, malignant tumor, disease of immune system, contraception that great potential is arranged.Common some digestive system medicine, anti-infective also are suitable for using sustained-release preparation.In addition, in recent years, high amount of drug will lose the patent protection of main drugmaker, find new prescription will prolong the life of a medicine by new drug delivery system.
The use of medicine control release technic means and overcomes the biopharmacy defective: keep stable drug level in the scope of treatment needs, prolong action time, reduce administration number of times, reduce side reaction, and can accomplish to discharge at regular time and quantity at lesions position directed release medicine with according to the pharmacokinetics principle, increase curative effect of medication, satisfy medical treatment and patient's demand better.
The application of medicament slow release system can be divided into two classes.The first kind is larger-size various graft, and they are applicable to the operation drug delivery implant, and its advantage is to discharge medicine long-term effectively, and shortcoming is to implant by surgical operation.Another kind of is injectable slow-releasing system, comprise hydrogel, micropartical, nanoparticle, micelle and water miscible macromolecular drug, can send into (S.M.Liand M.Vert in the body to medicine by subcutaneous, intramuscular or intravenous injection, " Biodegradablepolymers:polyesters ", in Encyclopedia of Controlled Drug Delivery, E.Mathiowitz ed., John Wiley﹠amp; Sons, 1999, pp.71-93).Hydrogel is because there is a large amount of moisture in inside; with the natural tissues characteristic close; thereby has a good biocompatibility; be specially adapted to the control delivery of protein, gene or nucleic acid etc.; because hydrogel can protect these bioactive molecules to exempt to be influenced by the adverse circumstances, the network structure in the hydrogel is also more convenient for the control of drug release simultaneously.With other the medicine controlled releasing system for example the microsphere controlled release compare, hydrogel can reach fully for bioactive macromolecules such as protein and discharge, there is not the situation of condensing and absorbing, also can satisfy simultaneously some special medication demands (S.J.de Jong et al., Journal of controlled release, 2001,71 (3): 261-275).Polylactic acid-polyglycol-polylactic acid triblock copolymer (PLA-PEG-PLA) has good biocompatibility, biological degradability and bioresorbable and special physicochemical property, can prepare medicament slow release system (Pierri, E. such as hydrogel, micropartical, nanoparticle, nano-micelle by distinct methods; Avgoustakis, K., J.Biomed.Mater.Res.2005,75A, 639-647.)
Hydrogel can be divided into chemical water gel and chemical water gel.The chemical water gel is that hydrophilic polymer is by covalently cross-linked formation network, need organic solvent, catalyst, initiator, cross-linking agent etc. in the preparation process, these materials are difficult to remove fully, for some drugs (as pharmaceutical grade protein) negative effect is arranged, human body is had certain hazardness as the medicine controlled releasing goods.Physical hydrogel usually by hydrogen bond, crystal region or hydrophilic hydrophobic interaction form (A.S.Hoffman, Adv.DrugDelivery Rev.2002,54,3.).Contain in the physical hydrogel of polylactic acid in preparation,, but need with an organic solvent in the preparation process, and organic solvent residue has limited being extensive use of of this aquogel system usually by hydrophilic hydrophobic interaction.(Molina?I.，LiS.M.，Martinez?M.B.，Biomaterials，2001，22(4)：363-369)
Summary of the invention
It is simple to an object of the present invention is to provide a kind of operating procedure, can remove the preparation method of Biodegradable hydrogel controlled release preparation of the influence of organic solvent.
Another object of the present invention provides a kind of Biodegradable hydrogel controlled release preparation by this inventive method preparation.
A further object of the invention provides a kind of application of the Biodegradable hydrogel controlled release preparation by the inventive method preparation.
The preparation method of Biodegradable hydrogel controlled release preparation provided by the invention, concrete steps are as follows:
(1) preparation polylactic acid-polyglycol-polylactic acid triblock copolymer
With metal zinc, zinc lactate or stannous octoate is catalyst, and making molecular weight is that two hydroxyl Polyethylene Glycol (PEG) and the lactide of 2000-20000 carries out ring-opening polymerization, preparation polylactic acid-polyglycol-polylactic acid triblock copolymer (PLA-PEG-PLA); Catalyst amount is the 0.02%-0.2% of two hydroxyl Polyethylene Glycol and lactide gross mass, lactide is that 1: 1.5～6 repetitive mol ratios with control polylactic acid and Polyethylene Glycol are 1: 2～12 with two hydroxyl Polyethylene Glycol molar ratios, be reflected under the vacuum condition and carry out, vacuum is 10
-2Pa～10
-5Pa, reaction temperature is 100～160 ℃, the response time is 1～8 day; Lactide is levorotatory lactide or dextrorotation lactide, promptly is raw material with the levorotatory lactide, and synthetic product is Poly-L-lactic acid-Polyethylene Glycol-Poly-L-lactic acid triblock copolymer; With the dextrorotation lactide is raw material, and synthetic product is dextrorotation polylactic acid-polyglycol-dextrorotation polylactic acid triblock copolymer;
(2) preparation hydrogel controlled release preparation
After obtaining polylactic acid-polyglycols-polylactic acid triblock copolymer according to step (1), respectively that the Poly-L-lactic acid-polyglycols-Poly-L-lactic acid and the dextrorotation polylactic acid-polyglycol-dextrorotation polylactic acid of equivalent is water-soluble, be configured to the solution of concentration at 0.05～0.5g/ml, two kinds of copolymers after the abundant swelling are mixed, stir, the centrifugal bubble of removing, the constant temperature gelation can obtain the Biodegradable hydrogel controlled release preparation in 37 ℃ to the 50 ℃ scopes.
The present invention also provides a kind of Biodegradable hydrogel controlled release preparation by the preparation of foregoing invention method.
The present invention also provides the application by the Biodegradable hydrogel controlled release preparation of foregoing invention method preparation, promptly as the controlled release carrier of medicine.Water soluble drug adds when two kinds of copolymers mix simultaneously, stirs, and water soluble drug is dissolved in the large quantity of moisture of absorbed gradually, enters hydrogel network shape inside configuration; After reaching in patient's body by injection or operation implantation, the release of medicine is driven by two aspects: the one, and the gradient difference of hydrogel Chinese medicine concentration and body fluid Chinese medicine concentration; The 2nd, the degraded of polymer.Thereby the hydrogel of the present invention preparation is the excellent drug controlled release carrier, can embedding protein, bioactive molecules such as gene or nucleic acid.
Resulting polylactic acid-polyglycol-the copolymer of poly lactic acid of the present invention is determined its chemical composition by nuclear magnetic resonance, NMR (Nuclear magneticresonance), (size-exclusion chromatography) measures its molecular weight by size exclusion chromatograph, (X-ray diffraction) determines its crystalline state structure by X-ray diffraction, and (Differentialscanning calorimetry) tests its hot property by differential scanning.
The resulting polyalcohol hydrogel of the present invention is by dynamic rheometer (Dynamic Rheometer) test water gel rheology matter.
The advantage of preparation method of the present invention is: by the synthesising biological biodegradable block copolymer, under the situation without any other substance, use temperate condition to prepare the biodegradation hydrogel, got rid of the organic solvent and the temperature factor that influence pharmaceutical properties.This hydrogel can some biologically actives of embedding medicine, reduce the ratio of this type of medicine inactivation greatly, increase the utilization rate of these expensive medication, for new approach has been opened up in the extensive use of hydrogel controlled release goods.The present invention has simplified the preparation method of hydrogel, has reduced preparation process, has reduced operative temperature, has removed the influence of organic solvent, has shortened preparation time.This hydrogel can be injected, the relevant issues of having avoided operation to bring.Simultaneously, change polymer concentration and polymeric molecular weight and form the speed that to regulate drug release, to satisfy the requirement of different control deliveries.
The specific embodiment
Embodiment 1
Adding 22g molecular weight is two hydroxyl Polyethylene Glycol of 6000 in the 100ml reaction bulb, 12g levorotatory lactide (or dextrorotation lactide) and 46mg zinc lactate, tube sealing behind the evacuation, put into reaction chamber, 140 ℃ of reaction taking-ups after 3 days down, dissolve with dichloromethane, the absolute ether precipitation, vacuum drying is to constant weight, the sample that obtains is determined Poly-L-lactic acid and Polyethylene Glycol with the nuclear magnetic resonance method test, the repetitive mol ratio of dextrorotation polylactic acid and Polyethylene Glycol is respectively 1/3.9 and 1/3.9, measure its fusing point with the differential scanning calorimetry and be respectively 54.9 ℃ and 54.8 ℃, glass transition temperature is respectively-52.0 ℃ and-50.2 ℃, and cold crystallization temperature is respectively-32.6 ℃ and-32.6 ℃.Respectively two kinds of each 0.15g of polymer are dissolved in the 1ml deionized water for stirring and evenly make the solution that concentration is 0.15g/ml.Fully after the swelling two kinds of solution mixed in equal amounts are made the mixed solution of concentration 0.15g/ml, remove bubble, constant temperature (37 ℃) made its abundant gelation in 48 hours.
Embodiment 2
Adding 33g molecular weight is two hydroxyl Polyethylene Glycol of 12000 in the 100ml reaction bulb, 12g levorotatory lactide (or dextrorotation lactide) and 12mg zinc lactate, tube sealing behind the evacuation, put into reaction chamber, 100 ℃ of reaction taking-ups after 8 days down, dissolve with dichloromethane, the absolute ether precipitation, vacuum drying is to constant weight, the sample that obtains is determined Poly-L-lactic acid and Polyethylene Glycol with the nuclear magnetic resonance method test, the repetitive mol ratio of dextrorotation polylactic acid and Polyethylene Glycol is respectively 1/8.5 and 1/8.0, measure its fusing point with the differential scanning calorimetry and be respectively 59.2 ℃ and 55.6 ℃, glass transition temperature is respectively-57.9 ℃ and-56.4 ℃, and cold crystallization temperature is respectively-46.6 ℃ and-45.6 ℃.Respectively two kinds of each 0.40g of polymer are dissolved in the 1ml deionized water for stirring and evenly make the solution that concentration is 0.4/ml.Fully after the swelling two kinds of solution mixed in equal amounts are made the mixed solution that concentration is 0.4g/ml, remove bubble, constant temperature (37 ℃) made its abundant gelation in 48 hours.
Embodiment 3
Adding 44g molecular weight is two hydroxyl Polyethylene Glycol of 20000 in the 100ml reaction bulb, 12g levorotatory lactide (or dextrorotation lactide) and 12mg zinc lactate, tube sealing behind the evacuation, put into reaction chamber, 160 ℃ of reaction taking-ups after 1 day down, dissolve with dichloromethane, the absolute ether precipitation, vacuum drying is to constant weight, the sample that obtains is determined Poly-L-lactic acid and Polyethylene Glycol with the nuclear magnetic resonance method test, the repetitive mol ratio of dextrorotation polylactic acid and Polyethylene Glycol is respectively 1/11.0 and 1/10.0, measure its fusing point with the differential scanning calorimetry and be respectively 60.7 ℃ and 59.9 ℃, glass transition temperature is respectively-61.4 ℃ and-62.2 ℃, and cold crystallization temperature is respectively-50.6 ℃ and-50.3 ℃.Respectively each 0.20g of polymer is dissolved in the 1ml deionized water for stirring and evenly makes the solution that concentration is 0.2g/ml.Fully after the swelling two kinds of solution mixed in equal amounts are made the mixed solution that concentration is 0.20g/ml, remove bubble, constant temperature (50 ℃) made its abundant gelation in 48 hours.
Embodiment 4
With example 1,2, two kinds of blended whiles of aqueous solutions of polymers of the formation in 3, add 40mg cancer therapy drug Thymopentin, constant temperature (37 ℃) made its abundant gelation in 48 hours then, behind the gel formation, add phosphate buffered solution (PBS), the immersion water gel, sampling at once, the content of Thymopentin in the solution around the use high performance liquid chromatography test water gel.After 24 hours, sampling and testing once more.As a result, do not contain Thymopentin in first sample, Thymopentin is described fully by the hydrogel embedding, envelop rate 100%.Contain a certain amount of Thymopentin in second sample, illustrate that the Thymopentin that is embedded in the hydrogel has begun slow release.And sustained drug release effect forms and to distinguish to some extent with the different of content along with hydrogel, can be by changing the different of the hydrogel concentration that forms and each constituent content, and the adjustment drug release is to satisfy the different pharmaceutical release request.
Claims (3)
1. the preparation method of a Biodegradable hydrogel controlled release preparation is characterized in that concrete steps are:
(1) preparation polylactic acid-polyglycol-polylactic acid triblock copolymer
With metal zinc, zinc lactate or stannous octoate is catalyst, and making molecular weight is that two hydroxyl Polyethylene Glycol and the lactide of 2000-20000 carries out ring-opening polymerization, preparation polylactic acid-polyglycol-polylactic acid triblock copolymer; Catalyst amount is the 0.02%-0.2% of two hydroxyl Polyethylene Glycol and lactide gross mass, and lactide is 1: 1.5～6 with two hydroxyl Polyethylene Glycol molar ratios, is reflected under the vacuum condition and carries out, and vacuum is 10
-2Pa～10
-5Pa, reaction temperature is 100～160 ℃, the response time is 1～8 day; Lactide is levorotatory lactide or dextrorotation lactide, promptly is raw material with the levorotatory lactide, and synthetic product is Poly-L-lactic acid-Polyethylene Glycol-Poly-L-lactic acid triblock copolymer; With the dextrorotation lactide is raw material, and synthetic product is dextrorotation polylactic acid-polyglycol-dextrorotation polylactic acid triblock copolymer;
(2) preparation hydrogel controlled release preparation
After obtaining polylactic acid-polyglycol-polylactic acid triblock copolymer according to step (1), respectively that the Poly-L-lactic acid-Polyethylene Glycol-Poly-L-lactic acid and the dextrorotation polylactic acid-polyglycol-dextrorotation polylactic acid of equivalent is water-soluble, be configured to the solution of concentration at 0.05～0.5g/ml, two kinds of copolymers after the abundant swelling are mixed, stir, the centrifugal bubble of removing, the constant temperature gelation promptly makes the Biodegradable hydrogel controlled release preparation in 37 ℃ to the 50 ℃ scopes.
2. Biodegradable hydrogel controlled release preparation that preparation method as claimed in claim 1 obtains.
3. a Biodegradable hydrogel controlled release preparation as claimed in claim 2 is as the application of medicine controlled release carrier.
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010488A (en) * | 2010-10-28 | 2011-04-13 | 浙江大学 | Thermo-sensitive and degradable micro hydrogel as well as preparation method and application thereof |
| CN103709386A (en) * | 2012-10-09 | 2014-04-09 | 上海微创医疗器械（集团）有限公司 | Modified polylactic acid degradable stent and preparation method thereof |
| CN104592727A (en) * | 2015-01-19 | 2015-05-06 | 浙江大学 | Biodegradable physical hydrogel capable of being rapidly gelatinized in situ and preparation method of biodegradable physical hydrogel |
| CN110577654A (en) * | 2019-08-31 | 2019-12-17 | 贵州大学 | Preparation method of hectorite-reinforced polylactic acid-polyethylene glycol-polylactic acid triblock copolymer nano-stereocomplex hydrogel |
| CN111825956A (en) * | 2020-07-07 | 2020-10-27 | 江西师范大学 | Preparation method of blend of polylactic acid block copolymer |
| CN111888523A (en) * | 2020-09-08 | 2020-11-06 | 尹振宇 | Preparation method of polylactic acid gel for improving skin |
| CN112354018A (en) * | 2020-11-03 | 2021-02-12 | 南京思元医疗技术有限公司 | Soft tissue filling hydrogel for medical cosmetology and preparation method thereof |
| CN113289062A (en) * | 2021-05-17 | 2021-08-24 | 辽宁省计划生育科学研究院 | Solvent precipitation type in-situ gel injection implant and application |
| CN115427012A (en) * | 2020-08-31 | 2022-12-02 | 株式会社百艺 | Biodegradable polymer dispersion, composition containing same, and skin improvement system |
| CN117986488A (en) * | 2024-04-07 | 2024-05-07 | 中海汇润(天津)能源技术有限公司 | Preparation method of polyethylene glycol-acrylamide-polylactic acid ester emulsion polymer |
| CN118141972A (en) * | 2024-02-27 | 2024-06-07 | 天津大学 | Injectable hemostatic anti-adhesion hydrogel and preparation method and application thereof |
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2008
- 2008-06-05 CN CNA2008100385742A patent/CN101283966A/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010488A (en) * | 2010-10-28 | 2011-04-13 | 浙江大学 | Thermo-sensitive and degradable micro hydrogel as well as preparation method and application thereof |
| CN102010488B (en) * | 2010-10-28 | 2012-02-01 | 浙江大学 | Thermo-sensitive and degradable micro hydrogel as well as preparation method and application thereof |
| CN103709386A (en) * | 2012-10-09 | 2014-04-09 | 上海微创医疗器械（集团）有限公司 | Modified polylactic acid degradable stent and preparation method thereof |
| CN103709386B (en) * | 2012-10-09 | 2016-03-30 | 上海微创医疗器械（集团）有限公司 | Polydactyl acid biodegradable stent and preparation method thereof |
| CN104592727A (en) * | 2015-01-19 | 2015-05-06 | 浙江大学 | Biodegradable physical hydrogel capable of being rapidly gelatinized in situ and preparation method of biodegradable physical hydrogel |
| CN110577654A (en) * | 2019-08-31 | 2019-12-17 | 贵州大学 | Preparation method of hectorite-reinforced polylactic acid-polyethylene glycol-polylactic acid triblock copolymer nano-stereocomplex hydrogel |
| CN111825956A (en) * | 2020-07-07 | 2020-10-27 | 江西师范大学 | Preparation method of blend of polylactic acid block copolymer |
| CN115427012A (en) * | 2020-08-31 | 2022-12-02 | 株式会社百艺 | Biodegradable polymer dispersion, composition containing same, and skin improvement system |
| CN111888523A (en) * | 2020-09-08 | 2020-11-06 | 尹振宇 | Preparation method of polylactic acid gel for improving skin |
| CN112354018A (en) * | 2020-11-03 | 2021-02-12 | 南京思元医疗技术有限公司 | Soft tissue filling hydrogel for medical cosmetology and preparation method thereof |
| CN113289062A (en) * | 2021-05-17 | 2021-08-24 | 辽宁省计划生育科学研究院 | Solvent precipitation type in-situ gel injection implant and application |
| CN118141972A (en) * | 2024-02-27 | 2024-06-07 | 天津大学 | Injectable hemostatic anti-adhesion hydrogel and preparation method and application thereof |
| CN117986488A (en) * | 2024-04-07 | 2024-05-07 | 中海汇润(天津)能源技术有限公司 | Preparation method of polyethylene glycol-acrylamide-polylactic acid ester emulsion polymer |
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