CN102755282A - Temperature sensitive injectable drug-loading controlled release system - Google Patents

Abstract

Translated fromChinese

本发明公开了一种温度敏感性可注射载药控制释放系统，星形聚乙丙交酯-聚乙二醇单甲醚嵌段共聚物和人体模拟液，共聚物含量为15-40wt%。该药物控释系统在室温或室温以下以可自由流动的液态存在，在人体温度下快速转变为不可流动的乳白色物理交联水凝胶。表现为可逆溶胶-凝胶转变行为。所述的载药控制释放系统能够均匀分散所载药物，在室温或室温以下以自由流动的液体形式存在，在体温下以不能自由流动的凝胶形式存在；作为阴道载药控制释放系，采用溶液共混法将避孕药复方雌、孕激素和消炎药载入共聚物水凝胶载体，制备的载药系统作为节育喷剂。在妇女月经完后喷入中，其形成网状凝胶附着于壁，缓慢可控地释放药物，起到节育作用。

The invention discloses a temperature-sensitive injectable drug-carrying controlled release system, a star polylactide-polyethylene glycol monomethyl ether block copolymer and a human body simulation fluid, and the content of the copolymer is 15-40wt%. The drug controlled-release system exists in a free-flowing liquid state at or below room temperature, and rapidly transforms into an immobile milky white physically cross-linked hydrogel at human body temperature. It exhibits a reversible sol-gel transition behavior. The drug-loaded controlled-release system can uniformly disperse the loaded drug, and exists in the form of a free-flowing liquid at or below room temperature, and in the form of a gel that cannot flow freely at body temperature; as a vaginal drug-loaded controlled-release system, it adopts The contraceptive compound estrogen, progesterone and anti-inflammatory drug were loaded into the copolymer hydrogel carrier by the solution blending method, and the prepared drug-loading system was used as a contraceptive spray. After women's menstruation is sprayed, it forms a mesh gel and adheres to the wall, releasing the drug slowly and controllably to play a role in birth control.

Description

Translated fromChinese

一种温度敏感性可注射载药控制释放系统A temperature-sensitive injectable drug-loaded controlled release system

技术领域technical field

本发明属于可生物降解高分子材料及药物控制释放领域，具体涉及一种温度敏感性可注射载药控制释放系统，本发明尤其适用于作为可注射阴道载药控制释放系统。 The invention belongs to the field of biodegradable polymer materials and drug controlled release, in particular to a temperature-sensitive injectable drug-loaded controlled release system, and the invention is especially suitable as an injectable vaginal drug-loaded controlled release system. the

背景技术Background technique

随着生活水平的提高及科学技术的发展，人们对各种短期灵活的节育措施需求在增加，针对阴道的灵活节育措施的研究也更活跃。阴道凝胶作为各种药物的载体在过去几十年中一直是研究热点，其包覆的各种避孕药物及阴道杀菌剂等取得的科研成果推动了女性生理、生殖安全的进步及生物医用材料学科的发展。目前，应用于避孕药包覆释放的阴道凝胶主要有羟乙基纤维素、羟丙基纤维素、甲基纤维素、聚卡波非、海藻酸钠、羧甲基纤维素钠及温度敏感性的聚氧化丙烯-聚氧化乙烯-聚氧化丙烯三元嵌段共聚物等，前几种高分子材料在药物包覆时需要在体外制备好载药的阴道凝胶，然后植入阴道内，进而达到释放的目的，这种植入的方式可能会引起患者的不适感。而聚氧化丙烯-聚氧化乙烯-聚氧化丙烯三元嵌段共聚物在制备方法上不同，其由于具有温敏性，在室温下为自由流动的溶胶，药物在这个状态下加入，在体温（37℃）下立即形成有一定强度的不能自由流动凝胶，利用这种高聚物特殊的溶胶-凝胶转变性能，可以采用注射或喷入方法来完成载药体系的放置，不会引起患者的不适或疼痛感。但是上述的几种不能在体内降解的阴道凝胶在药物释放完成后，会在阴道内堆积，从而堵塞阴道。在较短时间内完全降解性的，同时能满足药物释放治疗要求的温敏性高分子应该是解决这些问题的好办法。 With the improvement of living standards and the development of science and technology, people's demand for various short-term flexible birth control measures is increasing, and the research on vaginal flexible birth control measures is also more active. Vaginal gel, as a carrier of various drugs, has been a research hotspot in the past few decades. The scientific research achievements of various contraceptive drugs and vaginal bactericides coated by it have promoted the progress of female physiology and reproductive safety and biomedical materials. subject development. At present, the vaginal gels used for the coating and release of contraceptives mainly include hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polycarbophil, sodium alginate, sodium carboxymethyl cellulose, and temperature-sensitive gels. Sexual polyoxypropylene-polyoxyethylene-polyoxypropylene ternary block copolymers, etc., the first few polymer materials need to prepare drug-loaded vaginal gel in vitro during drug coating, and then implanted in the vagina, In order to achieve the purpose of release, this implantation method may cause discomfort to the patient. And polyoxypropylene-polyoxyethylene-polyoxypropylene ternary block copolymer is different in preparation method, and it is the sol of free flow at room temperature because of its thermosensitivity, and medicine is added in this state, at body temperature ( 37°C) immediately forms a non-free-flowing gel with a certain strength. Using the special sol-gel transition properties of this polymer, the drug-loading system can be placed by injection or spraying without causing patients discomfort or pain. However, the above-mentioned vaginal gels that cannot be degraded in the body will accumulate in the vagina after the release of the drug, thereby blocking the vagina. Temperature-sensitive polymers that are completely degradable in a short period of time and can meet the requirements of drug release therapy should be a good way to solve these problems. the

近二十年来，可完全生物降解性温敏性高分子作为生物医用材料应用于药物的控制释放、细胞的增殖及组织的再生等方面成为了各国科学家的研究热点，聚酯-聚乙二醇嵌段或接枝共聚物尤为常见。Jeong B.等人合成了一系列以聚酯（PLGA）与聚乙二醇（PEG）为嵌段的温敏性可降解的共聚物，例如，线性三元嵌段共聚物PEG-PLGA-PEG（Jeong B.et al.，Advanced Drug Delivery Reviews.2002,54,37–51）、接枝共聚物PLGA-g-PEG和PEG-g-PLGA(Jeong B.et al.,Chem.Commun.,2001,1516–1517;Jeong B.et al.,J.Phys.Chem.B2003,107,10032-10039.），这类两亲性高聚物一定浓度的水溶液具有温敏性，即在室温下为流动的液相，而在体温下快速转变为不能流动的凝胶，表现为可逆的溶胶-凝胶转变现象，同时具有良好的生物相容性和生物降解性，适合作为注射用制剂的载体材料。在控制药物释放研究中，以亲水性药物Ketoprofen和疏水性药物Spironolactone为释放药物（Jeong B.et al.,J.Controlled Release,2000,63,155-163），发现对疏水性药物有明显的增溶作用，药物早期以扩散释放为主，后期以扩散释放伴随降解稳定释放为主。Zentner等（Zentner GM.et al.,J.Controlled Release,2001,72,203-215）以辛酸亚锡为催化剂通过开环聚合的方式合成了PLGA-PEG-PLGA三元线性温敏性嵌段共聚物并将其开发成为商品ReGel（共聚物浓度为23wt%）。邹鹏等人报道了一种温敏性星形四臂PLGA-mPEG嵌段共聚物的合成方法，该共聚物水凝胶具有溶胶-凝胶转变性能、优良的体内及体外生物降解性能、体内生物相容性（Peng Z.et al.,J.Mater.Chem.,2012,22,6316-6326）。丁建东等在CN 1823726A中公开了一种可降解的温敏性物理水凝胶及其制备方法，通过异辛酸亚锡、氢化钙或锌粉为催化剂，以聚乙二醇为大分子引发剂合成了PLGA-PEG-PLGA三元线性温敏性嵌段共聚物。目前上述温敏性凝胶主要应用于胰岛素、环孢素A、紫杉醇、 睾酮、吲哚美辛、基因等生物活性物质的控制释放及细胞培养等组织工程领域和术后粘连防止。在避孕药物的控制释放领域很少有文献报道，特别是雌、孕激素和吲哚美辛三种复合避孕消炎药的控制释放未见文献报道。 In the past two decades, the application of fully biodegradable temperature-sensitive polymers as biomedical materials in the controlled release of drugs, cell proliferation, and tissue regeneration has become a research hotspot for scientists from all over the world. Polyester-polyethylene glycol Block or graft copolymers are especially common. Jeong B. et al. synthesized a series of temperature-sensitive degradable copolymers with polyester (PLGA) and polyethylene glycol (PEG) as blocks, for example, linear ternary block copolymer PEG-PLGA-PEG (Jeong B.et al., Advanced Drug Delivery Reviews.2002,54,37–51), graft copolymers PLGA-g-PEG and PEG-g-PLGA (Jeong B.et al., Chem.Commun., 2001,1516–1517; Jeong B.et al., J.Phys.Chem.B2003,107,10032-10039.), the aqueous solution of this kind of amphiphilic high polymer has temperature sensitivity, that is, at room temperature It is a mobile liquid phase, but rapidly transforms into an immobile gel at body temperature, showing a reversible sol-gel transition phenomenon, and has good biocompatibility and biodegradability, and is suitable as a carrier for injection preparations Material. In the controlled drug release study, the hydrophilic drug Ketoprofen and the hydrophobic drug Spironolactone were used as the release drug (Jeong B. et al., J. Controlled Release, 2000, 63, 155-163), and it was found that there was a significant increase in the release rate of the hydrophobic drug. In the early stage, the drug is mainly released by diffusion, and in the later stage, the drug is mainly released by diffusion accompanied by degradation and stable release. Zentner et al. (Zentner GM. et al., J. Controlled Release, 2001, 72, 203-215) synthesized PLGA-PEG-PLGA ternary linear temperature-sensitive block copolymers by ring-opening polymerization using stannous octoate as a catalyst And developed it into commercial ReGel (copolymer concentration of 23wt%). Zou Peng et al. reported a synthesis method of a temperature-sensitive star-shaped four-armed PLGA-mPEG block copolymer. The copolymer hydrogel has sol-gel transition properties, excellent in vivo and in vitro biodegradability, and in vivo Biocompatibility (Peng Z. et al., J. Mater. Chem., 2012, 22, 6316-6326). Ding Jiandong et al. disclosed a degradable temperature-sensitive physical hydrogel and its preparation method in CN 1823726A. It was synthesized by using stannous isooctanoate, calcium hydride or zinc powder as a catalyst and polyethylene glycol as a macromolecular initiator. A PLGA-PEG-PLGA ternary linear thermosensitive block copolymer was developed. At present, the above-mentioned thermosensitive gel is mainly used in tissue engineering fields such as insulin, cyclosporin A, paclitaxel, testosterone, indomethacin, genes and other biologically active substances, cell culture, and postoperative adhesion prevention. There are few reports in the field of controlled release of contraceptive drugs, especially the controlled release of three compound contraceptive anti-inflammatory drugs of estrogen, progesterone and indomethacin has not been reported in the literature. the

发明内容Contents of the invention

本发明的目的在于提供一种温度敏感性可注射载药控制释放系统；所述的载药控制释放系统能够均匀分散所载药物，在室温或室温以下以自由流动的液体形式存在，在体温下以不能自由流动的凝胶形式存在。 The object of the present invention is to provide a temperature-sensitive injectable drug-loaded controlled release system; the drug-loaded controlled-release system can uniformly disperse the loaded drug, and exists in the form of a free-flowing liquid at room temperature or below room temperature. Available as a non-free flowing gel. the

本发明提供的一种温度敏感性可注射载药控制释放系统，其特征在于，星形聚乙丙交酯-聚乙二醇单甲醚嵌段共聚物和人体模拟液，所述共聚物的质量百分比含量为15-40%。 A temperature-sensitive injectable drug-loaded controlled release system provided by the present invention is characterized in that, star-shaped polyethylene lactide-polyethylene glycol monomethyl ether block copolymer and human body simulation fluid, the copolymer The mass percentage content is 15-40%. the

作为上述技术方案的一种改进，所述人体模拟液为模拟阴道液，所载药物为炔雌醇、孕二烯酮及吲哚美辛的混合物，所载药物为系统总质量的0.01-8wt%。 As an improvement of the above technical solution, the human body simulation fluid is a simulated vaginal fluid, the drug contained is a mixture of ethinyl estradiol, gestodene and indomethacin, and the drug contained is 0.01-8wt of the total mass of the system %. the

本发明提出的温度敏感性可注射载药控制释放系统与已有的可生物降解温敏性水凝胶相比具有如下特点： Compared with the existing biodegradable temperature-sensitive hydrogel, the temperature-sensitive injectable drug-loaded controlled release system proposed by the present invention has the following characteristics:

载药控制释放系统的重要组成成分星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物在分子结构上表现为几何拓扑结构规整、对称，致使该载药控制释放系统在低温下具有更低的粘度、更高的共聚物浓度及更高的药物包覆量，同时仍然保持较快的降解速度。 The molecular structure of the star polylactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer, an important component of the drug-loaded controlled release system, is geometrically topologically regular and symmetrical, which makes the loading The drug controlled release system has lower viscosity, higher copolymer concentration and higher drug coating amount at low temperature, while still maintaining a faster degradation rate. the

作为阴道载药控制释放系统，同时包覆雌激素（炔雌醇）、孕激素（孕二烯酮）及消炎药（吲哚美辛），既能达到短期避孕（一次喷入阴道）或长期避孕（每月喷入阴道一次）的效果，又能起到消炎的 作用。 As a vaginal drug-loaded controlled release system, it is also coated with estrogen (ethinyl estradiol), progesterone (gestodene) and anti-inflammatory drugs (indomethacin), which can achieve short-term contraception (one-time spray into the vagina) or long-term It has the effect of contraception (sprayed into the vagina once a month), and it can also play an anti-inflammatory effect. the

本发明提出的载药控制释放系统，只有在10-45wt%浓度范围内才表现出溶胶-凝胶转变特性。当浓度过高时，其在室温及室温以下以不能流动的凝胶态形式存在，随着温度的提高只能发生凝胶-溶胶的转变；当浓度过低时，其随着温度的提高只能发生冷溶胶-热溶胶-沉淀的转变，不经过凝胶形态过程，故上述两种情形都不适合药物的包覆，而当共聚物浓度为10-45wt%时，其随着温度的提高能够发生溶胶-凝胶转变特性，具体转变现象为冷溶胶（低温）-凝胶（体温）-热溶胶（较高温度）-沉淀（更高温度），故在这一浓度范围内的高聚物溶液系统可用于药物包覆便于注射操作，更为合适浓度为15-40wt%。 The drug-loaded controlled release system proposed by the present invention exhibits sol-gel transition characteristics only in the concentration range of 10-45wt%. When the concentration is too high, it exists in an immobile gel state at room temperature and below room temperature, and can only undergo gel-sol transition as the temperature increases; when the concentration is too low, it only The transformation of cold sol-hot sol-precipitation can occur without going through the gel form process, so the above two situations are not suitable for drug coating, and when the concentration of the copolymer is 10-45wt%, it increases with the increase of temperature Sol-gel transition characteristics can occur, and the specific transition phenomenon is cold sol (low temperature)-gel (body temperature)-hot sol (higher temperature)-precipitation (higher temperature), so the high polymer in this concentration range The substance solution system can be used for drug coating to facilitate injection operation, and the more suitable concentration is 15-40wt%. the

本发明提出的载药控制释放系统可以通过与雌激素（炔雌醇）、孕激素（孕二烯酮或左炔诺孕酮）及消炎药（吲哚美辛）以混合的方式包覆药物。聚合物的溶剂为模拟阴道液。复合药物的释放速率可通过调整丙交酯与乙交酯的物质的量比例及共聚物的浓度等因素来控制。凝胶的载药量没有严格的限制，除非载药量影响共聚物溶液的溶胶-凝胶转变行为。给药途径可以是阴道载药控制释放系统喷入阴道或者皮下注射。 The drug-loaded controlled release system proposed by the present invention can coat the drug in a mixed manner with estrogen (ethinyl estradiol), progesterone (gestodene or levonorgestrel) and anti-inflammatory drug (indomethacin) . The solvent of the polymer is simulated vaginal fluid. The release rate of the compound drug can be controlled by adjusting the ratio of lactide to glycolide, the concentration of the copolymer and other factors. The drug loading of the gel is not strictly limited unless the drug loading affects the sol-gel transition behavior of the copolymer solution. The route of administration can be spraying into the vagina or subcutaneous injection of the vaginal drug-carrying controlled release system. the

与其它药物控释载体相比，本发明提出的可降解温敏性载药控制释放系统具有如下特点： Compared with other drug controlled release carriers, the degradable thermosensitive drug-loaded controlled release system proposed by the present invention has the following characteristics:

1.载药控制释放系统同时具有智能性、可短时间内完全降解性、可注射性。 1. The drug-loaded controlled release system is intelligent, fully degradable and injectable in a short period of time. the

2.载药控制释放系统中重要组成成分星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物由亲水性嵌段mPEG及疏水性嵌段PLGA组成，具有两亲性，其能在特定溶剂中自组装成纳米级别的 胶束（20-50nm）。 2. An important component in the drug-loaded controlled release system. The star polylactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer is composed of a hydrophilic block mPEG and a hydrophobic block PLGA , with amphiphilicity, which can self-assemble into nanoscale micelles (20-50nm) in specific solvents. the

3.载药控制释放系统中重要组成成分星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物在分子结构上为星形大分子链拓扑结构，规整、对称，致使载药控制释放系统具有更低的粘度、更高的共聚物浓度及更高的药物包覆量，同时仍然保持较快的降解速度。 3. The star polylactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer, an important component of the drug-loaded controlled release system, has a star-shaped macromolecular chain topology in molecular structure, regular , symmetry, resulting in a drug-loaded controlled release system with lower viscosity, higher copolymer concentration and higher drug coating amount, while still maintaining a faster degradation rate. the

4.载药控制释放系统中重要组成成分星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物完全由合成高分子材料构成，各嵌段组成具有很好的生物相容性。 4. The important component of the drug-loaded controlled release system is the star polylactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer, which is completely composed of synthetic polymer materials, and each block has a wide range of properties. Good biocompatibility. the

5.载药控制释放系统不带电荷，其降解行为主要为酯键的水解，产物为小分子乳酸、乙醇酸及聚乙二醇单甲醚，前两者通过三羧酸循环代谢成二氧化碳及水排出，后者经肾脏由尿液排出，对人体安全无毒。 5. The drug-loaded controlled release system has no charge, and its degradation behavior is mainly the hydrolysis of ester bonds. The products are small molecule lactic acid, glycolic acid and polyethylene glycol monomethyl ether. The former two are metabolized into carbon dioxide and The latter is excreted in urine through the kidneys, which is safe and non-toxic to the human body. the

6.通过调整聚乙二醇单甲醚所占的质量分数及分子量大小、丙交酯与乙交酯的物质的量比例及共聚物的浓度等因素来任意调节该载药控制释放系统的溶胶-凝胶转变温度、降解速率及释药速率。 6. Adjust the sol of the drug-loaded controlled release system arbitrarily by adjusting the mass fraction and molecular weight of polyethylene glycol monomethyl ether, the ratio of lactide to glycolide, and the concentration of the copolymer. - Gel transition temperature, degradation rate and drug release rate. the

7.载药控制释放系统对疏水性药物有较明显的增溶作用，提高了药物在共聚物溶液中的溶解性。 7. The drug-loaded controlled release system has a more obvious solubilization effect on hydrophobic drugs and improves the solubility of drugs in copolymer solutions. the

8.作为阴道载药控制释放系，采用溶液共混法将避孕药复方雌、孕激素（炔雌醇，孕二烯酮）和消炎药（吲哚美辛）载入共聚物水凝胶载体，制备的载药系统作为节育喷剂。在妇女月经完后喷入中，其形成网状凝胶附着于壁，缓慢可控地释放药物，既能达到短期避孕（一次喷入阴道）或长期避孕（每月喷入阴道一次）的效果，又能起到消炎的作用。 8. As a vaginal drug-loaded controlled release system, the contraceptive compound estrogen, progesterone (ethinyl estradiol, gestodene) and anti-inflammatory drug (indomethacin) are loaded into the copolymer hydrogel carrier by solution blending method , the prepared drug-loaded system as a birth control spray. After women's menstruation is sprayed, it forms a mesh gel and adheres to the wall, releasing the drug slowly and controllably, which can achieve the effect of short-term contraception (spray into the vagina once) or long-term contraception (spray into the vagina once a month) , and can play an anti-inflammatory role. the

附图说明Description of drawings

图1是载药控制释放系统于不同浓度下随温度升高的流变曲线； Fig. 1 is the rheological curve of the drug-loaded controlled release system as the temperature rises under different concentrations;

图2是高效液相色谱确定的药物测试流动相混合比例曲线； Fig. 2 is the drug test mobile phase mixing ratio curve determined by high performance liquid chromatography;

图3是三种药物的出峰先后顺序曲线； Fig. 3 is the peak sequence curve of three kinds of drugs;

图4是吲哚美辛、孕二烯酮与炔雌醇的累积释放曲线； Fig. 4 is the cumulative release curve of indomethacin, gestodene and ethinyl estradiol;

图5是炔雌醇的Higuchi模型拟合曲线。 Figure 5 is a Higuchi model fitting curve for ethinyl estradiol. the

具体实施方式Detailed ways

本发明的载药控制释放系统包括温度敏感性的星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物、人体模拟液，用于包埋所载的药物。 The drug-loaded controlled release system of the present invention includes a temperature-sensitive star polylactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer and a human body simulation fluid for embedding the loaded drug drug. the

载药控制释放系统的重要组成星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物中的疏水嵌段PLGA的含量为55-85wt%，亲水嵌段mPEG的含量为15-45wt%，更为合适的组成为，疏水嵌段PLGA的含量为60-75wt%，亲水嵌段mPEG的含量为25-40wt%。 An important component of the drug-loaded controlled release system. The content of the hydrophobic block PLGA in the star-shaped polyethylene lactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer is 55-85wt%, and the hydrophilic block The content of segment mPEG is 15-45wt%, and the more suitable composition is that the content of hydrophobic block PLGA is 60-75wt%, and the content of hydrophilic block mPEG is 25-40wt%. the

载药控制释放系统的重要组成星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物的疏水嵌段PLGA中，丙交酯含量为0-100mol%，乙交酯含量为0-100mol%；更为合适的组成为，丙交酯含量为50-90mol%，乙交酯含量为10-50mol%。 An important component of the drug-loaded controlled release system In the hydrophobic block PLGA of the star-shaped polyethylene lactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer, the lactide content is 0-100mol%, The glycolide content is 0-100mol%; a more suitable composition is that the lactide content is 50-90mol%, and the glycolide content is 10-50mol%. the

载药控制释放系统的重要组成星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物的亲水嵌段mPEG的数均分子量为350-1000，更为合适的分子量为350-750。 An important component of the drug-loaded controlled release system. The number average molecular weight of the hydrophilic block mPEG of the star polylactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer is 350-1000, which is more A suitable molecular weight is 350-750. the

本发明提供的载药控制释放系统不仅可以作为载药控制释放系统，也可以作为其它药物的控制释放系统，其15-40wt%的水溶液、模拟液或其它模拟液（PBS缓冲液、模拟体液、模拟宫腔液）在室温或室温以下为自由流动的液态溶胶，而在人体温度下快速转变为不可 自由流动的凝胶。 The drug-loaded controlled release system provided by the present invention can not only be used as a drug-loaded controlled release system, but also can be used as a controlled release system for other drugs. Its 15-40wt% aqueous solution, simulated liquid or other simulated liquid (PBS buffer, simulated body fluid, Simulated intrauterine fluid) is a free-flowing liquid sol at or below room temperature, but rapidly transforms into a non-free-flowing gel at human body temperature. the

当作为阴道载药控制释放系统时，将药物（炔雌醇、孕二烯酮及吲哚美辛）均匀包埋于任何一种阴道载药控制释放系统的模拟阴道液，在室温或室温以下为自由流动的液态溶胶，而在人体温度下快速转变为不可自由流动的载药凝胶。 When used as a vaginal drug-loaded controlled release system, the drugs (ethinyl estradiol, gestodene, and indomethacin) are evenly embedded in any simulated vaginal fluid of a vaginal drug-loaded controlled release system at or below room temperature It is a free-flowing liquid sol, which rapidly transforms into a non-free-flowing drug-loaded gel at body temperature. the

所述载药控制释放系统的重要组成星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物的含量为15-40wt%，所述药物的含量为0.01-8wt%，余量为溶剂。 An important component of the drug-loaded controlled release system is a star polylactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer with a content of 15-40 wt%, and the drug content of 0.01 -8wt%, the balance is solvent. the

所述阴道载药控制释放系统中的药物为复方避孕药雌、孕激素（炔雌醇、孕二烯酮、左炔诺孕酮）及消炎药吲哚美辛。 The drugs in the vaginal drug-loaded controlled release system are compound contraceptives estrogen and progesterone (ethinyl estradiol, gestodene, levonorgestrel) and anti-inflammatory drug indomethacin. the

下面通过实例对载药控制释放系统进行说明。本发明不仅仅局限以下实施例。 The drug-loaded controlled-release system will be described below with an example. The present invention is not limited only to the following examples. the

实施例1 Example 1

星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物，其聚乙丙交酯（PLGA）嵌段中丙交酯摩尔比例为90%，乙交酯摩尔比例为10%，将其完全溶解于2-4℃的模拟阴道液，配制成浓度为30wt%星形共聚物溶液。将2.0mg炔雌醇、4.80mg孕二烯酮及12mg吲哚美辛溶解于1ml浓度为30wt%上述星形共聚物溶液，制备出阴道载药控制释放系统。 Star-shaped polyethylene lactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer, the molar ratio of lactide in the polyglycolide (PLGA) block is 90%, glycolide The molar ratio is 10%, and it is completely dissolved in simulated vaginal fluid at 2-4°C to prepare a star-shaped copolymer solution with a concentration of 30wt%. 2.0 mg ethinyl estradiol, 4.80 mg gestodene and 12 mg indomethacin were dissolved in 1 ml of the star-shaped copolymer solution with a concentration of 30 wt % to prepare a vaginal drug-loaded controlled release system. the

升高温度观察阴道载药控制释放系统的溶胶-凝胶转变行为及采用静态流变仪研究其粘度变化情况。当阴道载药控制释放系统在玻璃瓶倒转时不能流动的状态被定义为凝胶状态。图1是阴道载药控制释放系统于不同浓度下（20,25,30,35及40wt%）随温度升高的流变曲线。粘度急剧增加时对应的温度为溶胶-凝胶转变点。阴道载药控制释放系统的可逆性非常明显，溶胶在受热时形成凝胶，其凝胶在冷却时又回复成可流动的溶胶。 The sol-gel transition behavior of vaginal drug-loaded controlled release system was observed at elevated temperature and the viscosity change was studied by static rheometer. The state in which the vaginal drug-loaded controlled-release system could not flow when the glass bottle was inverted was defined as the gel state. Figure 1 is the rheological curves of the vaginal drug-loaded controlled release system at different concentrations (20, 25, 30, 35 and 40wt%) with increasing temperature. The temperature corresponding to the sharp increase in viscosity is the sol-gel transition point. The reversibility of the vaginal drug-loaded controlled release system is very obvious. The sol forms a gel when heated, and the gel returns to a flowable sol when cooled. the

实施例2 Example 2

星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物，其聚乙丙交酯（PLGA）嵌段中丙交酯摩尔比例为75%，乙交酯摩尔比例为25%，将其完全溶解于2-4℃的模拟阴道液，配制成浓度为30wt%星形共聚物溶液。将2.0mg炔雌醇、4.80mg孕二烯酮及12mg吲哚美辛溶解于1ml浓度为30wt%上述星形共聚物溶液，制备出阴道载药控制释放系统。 Star-shaped polyethylene lactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer, the molar ratio of lactide in the polyglycolide (PLGA) block is 75%, glycolide The molar ratio is 25%, and it is completely dissolved in simulated vaginal fluid at 2-4°C to prepare a star-shaped copolymer solution with a concentration of 30wt%. 2.0 mg ethinyl estradiol, 4.80 mg gestodene and 12 mg indomethacin were dissolved in 1 ml of the star-shaped copolymer solution with a concentration of 30 wt % to prepare a vaginal drug-loaded controlled release system. the

实施例3 Example 3

星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物，其聚乙丙交酯（PLGA）嵌段中丙交酯摩尔比例为50%，乙交酯摩尔比例为50%，将其完全溶解于2-4℃的模拟阴道液，配制成浓度为30wt%星形共聚物溶液。将2.0mg炔雌醇、4.80mg孕二烯酮及12mg吲哚美辛溶解于1ml浓度为30wt%上述星形共聚物溶液，制备出阴道载药控制释放系统。 Star-shaped polyethylene lactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer, the molar ratio of lactide in the polyglycolide (PLGA) block is 50%, glycolide The molar ratio is 50%, and it is completely dissolved in simulated vaginal fluid at 2-4°C to prepare a star-shaped copolymer solution with a concentration of 30wt%. 2.0 mg ethinyl estradiol, 4.80 mg gestodene and 12 mg indomethacin were dissolved in 1 ml of the star-shaped copolymer solution with a concentration of 30 wt % to prepare a vaginal drug-loaded controlled release system. the

实施例4 Example 4

星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物，其聚乙丙交酯（PLGA）嵌段中丙交酯摩尔比例为50%，乙交酯摩尔比例为50%，将其完全溶解于2-4℃的模拟阴道液，配制成浓度为30wt%星形共聚物溶液。将4.0mg炔雌醇、10mg孕二烯酮及25mg吲哚美辛溶解于1ml浓度为30wt%上述星形共聚物溶液，制备出阴道载药控制释放系统。 Star-shaped polyethylene lactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer, the molar ratio of lactide in the polyglycolide (PLGA) block is 50%, glycolide The molar ratio is 50%, and it is completely dissolved in simulated vaginal fluid at 2-4°C to prepare a star-shaped copolymer solution with a concentration of 30wt%. Dissolve 4.0 mg of ethinyl estradiol, 10 mg of gestodene and 25 mg of indomethacin in 1 ml of the star-shaped copolymer solution with a concentration of 30 wt % to prepare a drug-loaded vaginal release system. the

实施例5 Example 5

星形聚乙丙交酯（PLGA）-聚乙二醇单甲醚（mPEG）嵌段共聚物，其聚乙丙交酯（PLGA）嵌段中丙交酯摩尔比例为50%，乙交酯摩尔比 例为50%，将其完全溶解于2-4℃的模拟阴道液，配制成浓度为30wt%星形共聚物溶液。将8.0mg炔雌醇、20mg孕二烯酮及50mg吲哚美辛溶解于1ml浓度为30wt%上述星形共聚物溶液，制备出阴道载药控制释放系统。 Star-shaped polyethylene lactide (PLGA)-polyethylene glycol monomethyl ether (mPEG) block copolymer, the molar ratio of lactide in the polyglycolide (PLGA) block is 50%, glycolide The molar ratio is 50%, and it is completely dissolved in the simulated vaginal fluid at 2-4°C to prepare a star-shaped copolymer solution with a concentration of 30wt%. Dissolve 8.0 mg of ethinyl estradiol, 20 mg of gestodene and 50 mg of indomethacin in 1 ml of the star-shaped copolymer solution with a concentration of 30 wt % to prepare a vaginal drug-loaded controlled release system. the

实施例6-13 Example 6-13

实施例14 Example 14

实施例3中的阴道载药控制释放系统于37℃下20-30秒形成凝胶后，加入10毫升37℃的模拟阴道液作为释放介质。在特定时间点取样，同时补充 同体积的新鲜模拟液，持续取样35天。样品液药物浓度采用高效液相色谱（HPLC）检测。HPLC流动相为甲醇和水的混合液，图2确定了混合流动相的体积比为53:47，该条件下能够较好地将三种药物分开。图3确定了三种药物的出峰顺序，即吲哚美辛最早出峰，时间为11.12min，孕二烯酮其次出峰，时间为13.23min，炔雌醇最后出峰，时间为15.67min。三种药物在不同浓度梯度下检测的标准曲线呈现很好的线性关系，图4展示了三种药物的累积释放规律曲线，对曲线进行零级、一级与Higuchi模型拟合，发现Higuchi模型拟合表现最好的线性关系（图5为炔雌醇的拟合曲线），表明三种药物的释放规律符合Higuchi模型。在35天时，炔雌醇的累积释放分数为38%、孕二烯酮的累积释放分数为84%、吲哚美辛的累积释放分数为55%。 After the vaginal drug-loaded controlled release system in Example 3 forms a gel at 37° C. for 20-30 seconds, 10 ml of simulated vaginal fluid at 37° C. is added as a release medium. Samples were taken at specific time points, and the same volume of fresh simulating fluid was added at the same time, and samples were taken continuously for 35 days. The drug concentration of the sample solution was detected by high performance liquid chromatography (HPLC). The HPLC mobile phase is a mixture of methanol and water. Figure 2 confirms that the volume ratio of the mixed mobile phase is 53:47. Under this condition, the three drugs can be separated well. Figure 3 determines the peak sequence of the three drugs, that is, indomethacin is the first to peak at 11.12 minutes, gestodene is the second to peak at 13.23 minutes, and ethinylestradiol is the last to appear at 15.67 minutes . The standard curves of the three drugs detected under different concentration gradients showed a good linear relationship. Figure 4 shows the cumulative release curves of the three drugs. The curves were fitted with the Higuchi model at zero order and first order, and it was found that the Higuchi model fitted The linear relationship with the best performance (Figure 5 is the fitting curve of ethinyl estradiol), indicating that the release laws of the three drugs conform to the Higuchi model. At 35 days, the cumulative fractional release of ethinylestradiol was 38%, that of gestodene was 84%, and that of indomethacin was 55%. the

实施例15 Example 15

实施例4中的阴道载药控制释放系统于37℃下20-30秒形成凝胶后，加入10毫升37℃的模拟阴道液作为释放介质。在特定时间点取样，同时补充同体积的新鲜模拟液，持续取样35天。样品液药物浓度采用高效液相色谱（HPLC）检测。三种药物在不同浓度梯度下检测的标准曲线呈现很好的线性关系，对三种药物的累积释放规律曲线进行零级、一级与Higuchi模型拟合，发现Higuchi模型拟合表现最好的线性关系，表明三种药物的释放规律符合Higuchi模型。在35天时，炔雌醇的累积释放分数为32%、孕二烯酮的累积释放分数为58%、吲哚美辛的累积释放分数为38%。 After the vaginal drug-loaded controlled release system in Example 4 forms a gel at 37° C. for 20-30 seconds, 10 ml of simulated vaginal fluid at 37° C. is added as a release medium. Samples were taken at specific time points, and the same volume of fresh simulating fluid was added at the same time, and the sampling continued for 35 days. The drug concentration of the sample solution was detected by high performance liquid chromatography (HPLC). The standard curves of the three drugs tested at different concentration gradients showed a good linear relationship. The cumulative release curves of the three drugs were fitted with the Higuchi model at zero order and first order, and it was found that the Higuchi model fit the best linearity The relationship shows that the release laws of the three drugs conform to the Higuchi model. At 35 days, the cumulative fractional release of ethinylestradiol was 32%, that of gestodene was 58%, and that of indomethacin was 38%. the

实施例16 Example 16

实施例5中的阴道载药控制释放系统于37℃下20-30秒形成凝胶后，加入10毫升37℃的模拟阴道液作为释放介质。在特定时间点取样，同时补充同体积的新鲜模拟液，持续取样35天。样品液药物浓度采用高效液相色谱（HPLC）检测。三种药物在不同浓度梯度下检测的标准曲线呈现很好的线性关系，对三种药物的累积释放规律曲线进行零级、一级与Higuchi模型拟合，发现Higuchi模型拟合表现最 好的线性关系，表明三种药物的释放规律符合Higuchi模型。在35天时，炔雌醇的累积释放分数为20%、孕二烯酮的累积释放分数为30%、吲哚美辛的累积释放分数为21%。 After the vaginal drug-loaded controlled release system in Example 5 forms a gel at 37° C. for 20-30 seconds, 10 ml of simulated vaginal fluid at 37° C. is added as a release medium. Samples were taken at specific time points, and the same volume of fresh simulating fluid was added at the same time, and the sampling continued for 35 days. The drug concentration of the sample solution was detected by high performance liquid chromatography (HPLC). The standard curves of the three drugs tested at different concentration gradients showed a good linear relationship. The cumulative release curves of the three drugs were fitted with the Higuchi model at zero order and first order, and it was found that the Higuchi model fit the best linearity The relationship shows that the release laws of the three drugs conform to the Higuchi model. At 35 days, the cumulative fractional release of ethinylestradiol was 20%, that of gestodene was 30%, and that of indomethacin was 21%. the

当作为其它药物的控制释放系统，采用对应的水体模拟液（可以是水溶液、模拟阴道液或其它模拟液，如PBS缓冲液、模拟体液、模拟宫腔液），本发明也可以产生相同良好的技术效果，在室温或室温以下为自由流动的液态溶胶，而在人体温度下快速转变为不可自由流动的载药凝胶。 When used as a controlled release system for other drugs, the corresponding water body simulated liquid (which can be aqueous solution, simulated vaginal fluid or other simulated liquid, such as PBS buffer solution, simulated body fluid, simulated uterine cavity fluid) can also be produced by the present invention. Technical effect, it is a free-flowing liquid sol at room temperature or below room temperature, but rapidly transforms into a non-free-flowing drug-loaded gel at human body temperature. the

本领域的技术人员容易理解，以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。 It is easy for those skilled in the art to understand that the above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention, All should be included within the protection scope of the present invention. the

Claims (10)

1. a temperature sensitivity injectable medicine carrying Controlled Release System is characterized in that, star poly (glycolide-lactide)-poly glycol monomethyl ether block copolymer and human body simulation liquid, and the mass percentage content of said copolymer is 15-40%.

2. temperature sensitivity injectable medicine carrying Controlled Release System according to claim 1; It is characterized in that; Said human body simulation liquid is the simulation vaginal secretion, and contained medicine is the mixture of ethinylestradiol, gestodene and indomethacin, and contained medicine is the 0.01-8wt% of system's gross mass.

3. temperature sensitivity injectable medicine carrying Controlled Release System according to claim 1 and 2 is characterized in that in the said copolymer, the mass percentage content of poly (glycolide-lactide) is 55-85%, and the mass percentage content of poly glycol monomethyl ether is 15-45%.

4. temperature sensitivity injectable medicine carrying Controlled Release System according to claim 1 and 2 is characterized in that in the said copolymer, the mass percentage content of poly (glycolide-lactide) is 60-75%, and the mass percentage content of poly glycol monomethyl ether is 25-40%.

5. temperature sensitivity injectable medicine carrying Controlled Release System according to claim 1 and 2 is characterized in that in the block poly (glycolide-lactide) of said copolymer, lactide content is 0-100mol%, and surplus is an Acetic acid, hydroxy-, bimol. cyclic ester.

6. temperature sensitivity injectable medicine carrying Controlled Release System according to claim 4 is characterized in that in the block poly (glycolide-lactide) of said copolymer, lactide content is 0-100mol%, and surplus is an Acetic acid, hydroxy-, bimol. cyclic ester.

7. temperature sensitivity injectable medicine carrying Controlled Release System according to claim 1 and 2 is characterized in that in the block poly (glycolide-lactide) of said copolymer, lactide content is 50-90mol%, and surplus is an Acetic acid, hydroxy-, bimol. cyclic ester.

8. temperature sensitivity injectable medicine carrying Controlled Release System according to claim 6 is characterized in that in the block poly (glycolide-lactide) of said copolymer, lactide content is 50-90mol%, and surplus is an Acetic acid, hydroxy-, bimol. cyclic ester.

9. temperature sensitivity injectable medicine carrying Controlled Release System according to claim 1 and 2 is characterized in that the number-average molecular weight of the block poly glycol monomethyl ether of said copolymer is 350-1000, and more suitable molecular weight is 350-750.

10. temperature sensitivity injectable medicine carrying Controlled Release System according to claim 1 and 2 is characterized in that, said human body simulation liquid is aqueous solution, simulate vaginal secretion or comprise other simulated solution of PBS buffer, simulated body fluid and simulated uterine fluid.

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