CN1289066C - Glicetin -1 slow release microspheric preparation and its use - Google Patents
Glicetin -1 slow release microspheric preparation and its use Download PDFInfo
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- CN1289066C CN1289066C CN 03151059 CN03151059A CN1289066C CN 1289066 C CN1289066 C CN 1289066C CN 03151059 CN03151059 CN 03151059 CN 03151059 A CN03151059 A CN 03151059A CN 1289066 C CN1289066 C CN 1289066C
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Abstract
本发明涉及医药技术领域，是胰高血糖素样肽-1(GLP-1)的一种缓释微球制剂及其作为降糖药或控制体重的减肥药的用途。GLP-1是由小肠和大肠的分泌细胞及脑的神经细胞分泌的内源性多肽，具有刺激胰岛素分泌和抑制胰高血糖素分泌的作用，还有抑制食欲和延缓胃排空的作用，但其在体内的半衰期不到两分钟，从而制约了它作为药品的开发和利用。本发明以PLGA为基质，将GLP-1制成缓释微球制剂，缓释效果达4周以上，故可用作治疗糖尿病或控制体重的药品。The invention relates to the technical field of medicine, and relates to a slow-release microsphere preparation of glucagon-like peptide-1 (GLP-1) and its use as a hypoglycemic drug or weight-controlling weight-loss drug. GLP-1 is an endogenous polypeptide secreted by the secretory cells of the small intestine and large intestine and the nerve cells of the brain. It has the functions of stimulating insulin secretion and inhibiting glucagon secretion, as well as suppressing appetite and delaying gastric emptying. Its half-life in the body is less than two minutes, which restricts its development and utilization as a drug. The invention uses PLGA as a substrate to make GLP-1 into a sustained-release microsphere preparation, and the sustained-release effect can reach more than 4 weeks, so it can be used as a medicine for treating diabetes or controlling body weight.
Description
技术领域Technical field
本发明涉及医药技术领域，是胰高血糖素样肽-1(Glucagon-likepepide-1，GLP-1)的缓释微球制剂及其用途。The invention relates to the technical field of medicine, and relates to a sustained-release microsphere preparation of glucagon-like peptide-1 (GLP-1) and an application thereof.
背景技术 Background technique
胰高血糖素样肽-1(Glucagon-like pepide-1，GLP-1)是由小肠和大肠的分泌细胞及脑的神经细胞分泌的多肽，由37个氨基酸序列构成，其氨基酸序列为：His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Lle-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly。(Lopez LC，Frazier ML，Su C-J，et al.Mammalianpancreatic proglucangon contains three glucanguon-related peptides.Proc Nalt Acad Sci USA 1983，80：5485-5489)。GLP-1能刺激胰岛素的分泌，并能抑制胰高血糖素的分泌，降低空腹或餐后血糖，其作用已在健康人体和糖尿病病人的临床研究中得到证实{M.A.Nauck，D.Wollschlager，J.Werner，et al.Effects of subcutaneous glucagon-like peptide 1[GLP-1(7-36amide)]in patients with NIDDM .Diabetologia1996，39：1546-1553}。正因为GLP-1具有刺激胰岛素分泌和抑制胰高血糖素分泌的作用，故人们试图将其用作治疗糖尿病的药物。又因GLP-1可以抑制食欲，减缓胃排空，所以也有人拟将作其为控制体重的药物(Juris J.Meier，Baptist Gallwitz，Wolfgang E.Schmidt，et al.Glucagon-like peptide-1as a regulator of food intake and body weight：therapeutic perspectves.Eur J Pharm 2000，440：269-279)。GLP-1作为内源性多肽，安全性和药理作用是明确的，毒副作用很小，GLP-1的降血糖作用是依赖于血浆中葡萄糖的浓度，用于治疗糖尿病不会发生低血糖的副反应，对磺酰脲类降糖药治疗无效的糖尿病病人同样有良好的疗效。[Ritzel R，Orskov C，et al.Pharmacokietic，insulinotropic，and glucangonostatic properties ofGLP-1(7-36amide)after subcutaneous injection in healthy volunteers.dose-response-relationships.Diabetologia 199538：720-725]。然而，由于GLP-1在体内的半衰期很短(小于2分钟)(DeaconCF，Knudsen LB，MadsenK，et al.Dipeptidyl peptidase IV resistant analogues of glucagons-likepeptide-1 which have extended metabolic stability and improvedbiological activity.Diabetologia 1998 41：271-278)，这就制约了其作为药品的开发和利用，因此至今仍未应用于临床。Glucagon-like peptide-1 (GLP-1) is a polypeptide secreted by the secretory cells of the small intestine and large intestine and the nerve cells of the brain. It consists of 37 amino acid sequences, and its amino acid sequence is: His -Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys -Glu-Phe-Lle-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly. (Lopez LC, Frazier ML, Su C-J, et al. Mammalian pancreatic proglucangon contains three glucanguon-related peptides. Proc Nalt Acad Sci USA 1983, 80:5485-5489). GLP-1 can stimulate the secretion of insulin, and can inhibit the secretion of glucagon, reduce fasting or postprandial blood sugar, its role has been confirmed in clinical studies of healthy humans and diabetic patients {M.A.Nauck, D.Wollschlager, J .Werner, et al.Effects of subcutaneous glucagon-like peptide 1[GLP-1(7-36amide)]in patients with NIDDM.Diabetologia1996,39:1546-1553}. Just because GLP-1 has the function of stimulating insulin secretion and inhibiting glucagon secretion, people try to use it as a drug for treating diabetes. And because GLP-1 can suppress appetite and slow down gastric emptying, it is also intended to be used as a drug for weight control (Juris J.Meier, Baptist Gallwitz, Wolfgang E.Schmidt, et al.Glucagon-like peptide-1as a regulator of food intake and body weight: therapeutic perspectives. Eur J Pharm 2000, 440: 269-279). As an endogenous polypeptide, GLP-1 has clear safety and pharmacological effects, and has little toxic and side effects. The hypoglycemic effect of GLP-1 is dependent on the concentration of glucose in plasma, and it will not cause hypoglycemia as a side effect when used to treat diabetes. Response, diabetic patients who are ineffective to sulfonylurea hypoglycemic drugs also have good curative effect. [Ritzel R, Orskov C, et al. Pharmacokietic, insulinotropic, and glucangonostatic properties of GLP-1(7-36amide) after subcutaneous injection in healthy volunteers. dose-response-relationships. Diabetologia 199538:720-725]. However, due to the short half-life of GLP-1 in vivo (less than 2 minutes) (DeaconCF, Knudsen LB, MadsenK, et al. Dipeptidyl peptidase IV resistant analogues of glucagons-likepeptide-1 which have extended metabolic stability and improved biological activity. Diabetologia 1998 41:271-278), which restricts its development and utilization as a drug, so it has not been used clinically so far.
发明内容Contents of the invention
本发明提供一种GLP-1的缓释微球制剂，可持续释药达4周以上，从而使GLP-1有望成为可供临床使用的药物，用于治疗糖尿病或控制体重。近年来生物可降解的高分子材料广泛应用于蛋白多肽类药物缓释微球的制备，其中聚乳酸-羟基乙酸共聚物[poly(lactide-co-glycolide)，PLGA]，由于其良好的生物相容性及生物降解性已被美国FDA批准为药用高分子材料使用。以PLGA作为微球基质，体内外降解实验证明，在药物释放过程中，整个聚合物骨架呈均匀性降解，随着分子量的下降，骨架材料的亲水性增强，由于水分的不断渗入使蛋白多肽类药物持续释放出来(Wang YM，Sato H，Horikoshi.In vitro and in vivo evalution of taxol release from ploy(lactic-co-glycotic acid)microspheres containing isopropyl myristate anddegradation of the microspheres.J Control Rel，1997，49：157)。本发明就是使用PLGA作为基质制备GLP-1缓释微球制剂的。由于GLP-1第7至第36位氨基酸所组成的多肽片断[简称GLP-1(7-36)]与天然GLP-1具有同样的生物活性，并且较易制备，所以本发明以GLP-1(7-36)为主药，PLGA为基质，制备供皮下注射的GLP-1缓释微球制剂。The invention provides a sustained-release microsphere preparation of GLP-1, which can be released continuously for more than 4 weeks, so that GLP-1 is expected to become a clinically available drug for treating diabetes or controlling body weight. In recent years, biodegradable polymer materials have been widely used in the preparation of sustained-release microspheres of protein and polypeptide drugs, among which poly(lactide-co-glycolide), PLGA], due to its good biophase Capacitance and biodegradability have been approved by the US FDA as a pharmaceutical polymer material. Using PLGA as the microsphere matrix, the degradation experiments in vivo and in vitro proved that during the drug release process, the entire polymer skeleton was degraded uniformly. With the decrease of molecular weight, the hydrophilicity of the skeleton material was enhanced, and the protein and polypeptide (Wang YM, Sato H, Horikoshi. In vitro and in vivo evaluation of taxol release from ploy (lactic-co-glycotic acid) microspheres containing isopropyl myristate and degradation of the microspheres. J Control Rel, 1997, 49: 157). The present invention uses PLGA as a matrix to prepare GLP-1 sustained-release microsphere preparations. Since the polypeptide fragment composed of the 7th to 36th amino acids of GLP-1 [referred to as GLP-1 (7-36)] has the same biological activity as natural GLP-1 and is easier to prepare, the present invention uses GLP-1 (7-36) as the main drug and PLGA as the matrix, the GLP-1 sustained-release microsphere preparation for subcutaneous injection is prepared.
本发明缓释微球制剂制备方法有三种：There are three methods for preparing the sustained-release microsphere preparation of the present invention:
1.w/o/w溶剂挥发法：1.w/o/w solvent evaporation method:
(1)制备油相(1) Preparation of oil phase
将基质材料PLGA溶于有机溶剂二氯甲烷制成油相，浓度为50mg～300mg/ml；The matrix material PLGA is dissolved in the organic solvent dichloromethane to make an oil phase with a concentration of 50mg-300mg/ml;
(2)制备内水相(2) Preparation of the inner aqueous phase
取适量GLP-1和保护剂溶于水形成内水相，GLP-1浓度为1mg～10mg/ml，保护剂选自碳酸锌、人血清白蛋白、海藻糖和甘露醇等，其含量为1～5％；Dissolve an appropriate amount of GLP-1 and protective agent in water to form an inner water phase. The concentration of GLP-1 is 1 mg to 10 mg/ml. The protective agent is selected from zinc carbonate, human serum albumin, trehalose and mannitol, etc., and its content is 1 ~5%;
(3)制备微球(3) Preparation of microspheres
将内水相加入上述油相超声乳化形成初乳，将初乳迅速滴加在2～6％聚乙烯醇(PVA)水溶液中(还含有0～2％NaCl，或/和0.5％表面活性剂F-68)，机械搅拌充分匀化(搅拌速度为1000～1800rpm)，室温下继续低速搅拌4小时(搅拌速度为300～600rpm)，洗涤，收集，冷冻干燥即可。Add the inner water phase to the above-mentioned oil phase for ultrasonic emulsification to form colostrum, and quickly drop the colostrum into 2-6% polyvinyl alcohol (PVA) aqueous solution (also containing 0-2% NaCl, or/and 0.5% surfactant F-68), fully homogenize by mechanical stirring (stirring speed is 1000-1800rpm), continue to stir at low speed for 4 hours at room temperature (stirring speed is 300-600rpm), wash, collect, and freeze-dry.
2.s/o/o溶剂挥发法：2. s/o/o solvent evaporation method:
(1)制备油相(1) Preparation of oil phase
将基质材料PLGA溶于有机溶剂乙腈制成油相，浓度为50mg～300mg/ml；The matrix material PLGA is dissolved in the organic solvent acetonitrile to make an oil phase with a concentration of 50mg-300mg/ml;
(2)制备GLP-1微粉(2) Preparation of GLP-1 micropowder
将适量的聚乙二醇(PEG)和GLP-1及保护剂(其比例为8∶1∶2)分散于水中，为冷冻干燥后，用二氯甲烷洗涤、离心，除去PEG，得到6LP-1微粉，保护剂选自碳酸锌、海藻糖和甘露醇等；Disperse an appropriate amount of polyethylene glycol (PEG), GLP-1 and protective agent (the ratio is 8:1:2) in water, freeze-dry, wash with dichloromethane, centrifuge, remove PEG, and obtain 6LP- 1 Micropowder, the protective agent is selected from zinc carbonate, trehalose and mannitol, etc.;
(3)制备微球(3) Preparation of microspheres
将GLP-1微粉加入油相，超声分散，然后逐滴加在棉子油中，机械搅拌充分匀化(搅拌速度为600～800rpm)，室温下搅拌1小时，再加入适量的石油醚继续搅拌2小时(搅拌速度为300～600rpm)，可得6LP-1微球，洗涤，收集，冷冻干燥即可。Add GLP-1 micropowder into the oil phase, ultrasonically disperse, then add dropwise into cottonseed oil, mechanically stir to fully homogenize (stirring speed is 600-800rpm), stir at room temperature for 1 hour, then add an appropriate amount of petroleum ether and continue stirring After 2 hours (the stirring speed is 300-600 rpm), 6LP-1 microspheres can be obtained, which can be washed, collected and freeze-dried.
3.喷雾干燥法。3. Spray drying method.
(1)制备GLP-1微粉(1) Preparation of GLP-1 micropowder
取适量GLP-1和保护剂溶于水，喷雾冷冻干燥，得到微粉，保护剂选自碳酸锌、人血清白蛋白、海藻糖等，其含量为1～5％；Dissolve an appropriate amount of GLP-1 and protective agent in water, spray and freeze-dry to obtain micropowder, the protective agent is selected from zinc carbonate, human serum albumin, trehalose, etc., and its content is 1-5%;
(2)制备微球(2) Preparation of microspheres
将GLP-1微粉加入有机溶剂二氯甲烷，超声分散，喷雾干燥，即得微球，室温下真空干燥6小时后收集。Add GLP-1 micropowder into organic solvent dichloromethane, ultrasonically disperse, and spray dry to obtain microspheres, which are collected after vacuum drying at room temperature for 6 hours.
本发明所用的基质材料PL6A，分子量为3000～40000，聚乳酸(PLA)∶羟基乙酸(PGA)为25∶75～75∶25，浓度为50mg～300mg/ml。超声乳化，超声条件为：duty cycle％：40；output control：3档；timer：8次。喷雾干燥时进口温度为40℃、出口温度为30℃、喷雾压力5Pa。The matrix material PL6A used in the present invention has a molecular weight of 3000-40000, a ratio of polylactic acid (PLA):glycolic acid (PGA) of 25:75-75:25, and a concentration of 50mg-300mg/ml. For phacoemulsification, the ultrasonic conditions are: duty cycle%: 40; output control: 3 levels; timer: 8 times. During spray drying, the inlet temperature is 40°C, the outlet temperature is 30°C, and the spray pressure is 5Pa.
本发明缓释微球经体外释放实验，缓释达4周以上，释放符合近似零级模式，可用于治疗糖尿病和控制体重的皮下注射制剂。The sustained-release microspheres of the present invention have been released in vitro for more than 4 weeks, and the release conforms to an approximately zero-order model, and can be used as a subcutaneous injection preparation for treating diabetes and controlling body weight.
附图说明Description of drawings
图1为本发明GLP-1的缓释微球制剂给药后第1天血糖浓度～时间曲线图。Fig. 1 is a curve graph of blood glucose concentration-time on the first day after administration of the GLP-1 sustained-release microsphere preparation of the present invention.
图2为本发明GLP-1的缓释微球制剂给药后第5天血糖浓度～时间曲线图。Fig. 2 is a curve graph of blood glucose concentration-time on the 5th day after the administration of the sustained-release microsphere preparation of GLP-1 of the present invention.
图3为本发明GLP-1的缓释微球制剂给药后第10天血糖浓度～时间曲线图。Fig. 3 is a curve graph of blood glucose concentration-time on the 10th day after administration of the GLP-1 sustained-release microsphere preparation of the present invention.
图4为本发明GLP-1的缓释微球制剂给药后第15天血糖浓度～时间曲线图。Fig. 4 is a curve graph of blood glucose concentration-time on the 15th day after the administration of the sustained-release microsphere preparation of GLP-1 of the present invention.
图5为本发明GLP-1的缓释微球制剂给药后第20天血糖浓度～时间曲线图。Fig. 5 is a curve graph of blood glucose concentration-time on the 20th day after administration of the GLP-1 sustained-release microsphere preparation of the present invention.
图6为本发明GLP-1的缓释微球制剂给药后第25天血糖浓度～时间曲线图。Fig. 6 is a curve graph of blood glucose concentration-time on the 25th day after administration of the GLP-1 sustained-release microsphere preparation of the present invention.
图7为本发明GLP-1的缓释微球制剂给药后第30天血糖浓度～时间曲线图。Fig. 7 is a curve graph of blood glucose concentration-time on the 30th day after administration of the GLP-1 sustained-release microsphere preparation of the present invention.
具体实施方式 Detailed ways
实施例1：w/o/w溶剂挥发法制备GLP-1缓释微球制剂Embodiment 1: GLP-1 sustained-release microsphere preparation prepared by w/o/w solvent volatilization method
将PLGA(RG502H，PLA∶PGA＝50∶50，Mw＝34000)100mg溶于1.0ml二氯甲烷制成油相，GLP-13mg溶于0.1ml的重蒸溜水中(内含3％海藻糖、5％甘露醇)形成内水相，将其加入上述油相，超声乳化，形成w/o的初乳，将含3％PVA溶液30ml(含NaCl 2％和F-680.5％)置于搅拌容器中，将初乳在高速搅拌(1000rpm)下快速加入外水相中充分匀化，三分钟后，将转速下调至400rpm同时外水相加入30ml蒸馏水，室温下搅拌4小时，微球硬化后离心分离并洗涤，冷冻干燥。密封分装后辐照消毒即可。GLP-l微球的包封率为92％，粒径＜100μm。Dissolve 100 mg of PLGA (RG502H, PLA:PGA=50:50, M w =34000) in 1.0 ml of dichloromethane to make an oil phase, and dissolve GLP-13 mg in 0.1 ml of double-distilled water (containing 3% trehalose, 5% mannitol) to form the inner water phase, add it to the above oil phase, ultrasonic emulsification, form w/o colostrum, put 30ml of 3% PVA solution (containing NaCl 2% and F-680.5%) in the stirring vessel In the process, quickly add colostrum into the external water phase under high-speed stirring (1000rpm) and fully homogenize. After three minutes, reduce the rotation speed to 400rpm and add 30ml distilled water to the external water phase, stir at room temperature for 4 hours, and centrifuge after the microspheres harden. Separated and washed, freeze-dried. After sealing and dispensing, it can be irradiated and sterilized. The encapsulation efficiency of GLP-1 microspheres is 92%, and the particle size is less than 100 μm.
实施例2：s/o/o溶剂挥发法制备GLP-1缓释微球制剂Embodiment 2: s/o/o solvent volatilization method prepares GLP-1 sustained-release microsphere preparation
将PEG(PEG6000)24mg和GLP-13mg及保护剂(碳酸锌5mg)分散于lml重蒸溜水中，旋涡混合3分钟左右，冷冻干燥后，用二氯甲烷洗涤、离心，除去PEG，得到GLP-1微粉。将PLGA(RG502H，PLA∶PGA＝50∶50，Mw＝34000)200mg溶于乙腈1.0ml制成油相，将微粉加入上述油相，超声分散，将其逐滴加入棉子油中充分匀化，搅拌(600rpm)1小时，再加入适量的石油醚继续搅拌(400rpm)2小时，可得GLP-1微球，离心，用石油醚洗涤，收集，冷冻干燥，密封分装后辐照消毒即可。GLP-1微球的包封率为90％，粒径＜100μm。Disperse PEG (PEG6000) 24 mg, GLP-13 mg and protective agent (zinc carbonate 5 mg) in 1 ml double distilled water, vortex and mix for about 3 minutes, freeze-dry, wash with dichloromethane, centrifuge, remove PEG, and obtain GLP-1 Micronized. Dissolve 200 mg of PLGA (RG502H, PLA:PGA=50:50, Mw =34000) in 1.0 ml of acetonitrile to make an oil phase, add the micropowder to the above oil phase, disperse it by ultrasonic, add it drop by drop into the cottonseed oil and fully evenly melt, stir (600rpm) for 1 hour, then add an appropriate amount of petroleum ether and continue stirring (400rpm) for 2 hours to obtain GLP-1 microspheres, centrifuge, wash with petroleum ether, collect, freeze-dry, seal and sub-package, and then irradiate and sterilize That's it. The encapsulation efficiency of GLP-1 microspheres is 90%, and the particle size is less than 100 μm.
实施例3：喷雾干燥法制备GLP-1缓释微球制剂Embodiment 3: Preparation of GLP-1 sustained release microsphere preparation by spray drying method
将GLP-18mg及保护剂(人血清白蛋白30mg)溶于10ml的重蒸溜水中，喷入液氮中，将液氮在低温下挥发，得到GLP-1微粉。将PLGA(RG502H，PLA∶PGA＝50∶50，Mw＝34000)600mg溶于二氯甲烷10ml制成油相，将微粉加入油相中超声分散，喷雾干燥，进口温度为40℃、出口温度为30℃、喷雾压力5Pa，喷嘴直径0.5mm，流速1～2ml/min。将收集的微球在室温下真空干燥6小时，密封分装后辐照消毒即可。GLP-1微球的包封率为80％，粒径＜60μm。GLP-18mg and protective agent (human serum albumin 30mg) were dissolved in 10ml of double distilled water, sprayed into liquid nitrogen, and the liquid nitrogen was volatilized at low temperature to obtain GLP-1 micropowder. Dissolve 600mg of PLGA (RG502H, PLA:PGA=50:50, Mw =34000) in 10ml of dichloromethane to make an oil phase, add the fine powder into the oil phase to ultrasonically disperse, spray dry, the inlet temperature is 40°C, the outlet temperature The temperature is 30°C, the spray pressure is 5Pa, the nozzle diameter is 0.5mm, and the flow rate is 1-2ml/min. The collected microspheres were vacuum-dried at room temperature for 6 hours, and then sterilized by irradiation after sealing and dispensing. The encapsulation efficiency of GLP-1 microspheres is 80%, and the particle size is less than 60 μm.
动物试验：选取成年wister大鼠16只，体重200g左右，雌雄各半，随机分成给药组和空白组，给药组皮下注射适量微球(依实施例1制得160mg微球，含6LP-1约4.5mg)，空白组皮下注射同体积的生理盐水。分别于给药后的第1、5、10、15、20、25、30天的同一时间，给每只大鼠腹腔注射18mmol/kg葡萄糖，注射前每鼠先采空白血样，然后在5、10、15、20、30和50分钟眼眶取血，测定注射前后的血糖。血糖测定参照葡萄糖测定试剂盒(葡萄糖氧化酶法，北京化工厂)的说明书进行。制作血糖浓度和时间的曲线图(见图1至图7)，有图可见，空白对照组腹腔注射葡萄糖，五分钟后血糖明显升高，回落缓慢，五十分钟时仍未达到基态血糖浓度。给药组在第1、5、10、15、20、25、30天都可以观察到明显的降血糖作用，三十分钟内即回落到基态浓度。说明GLP-1微球在体内有明显的缓释和降血糖作用，所以本发明可作为GLP-1的缓释剂型用于治疗糖尿病或控制体重。Animal experiment: choose 16 adult wister rats, body weight about 200g, half male and half male, randomly divided into administration group and blank group, administration group subcutaneous injection of appropriate amount of microspheres (160mg microspheres made according to embodiment 1, containing 6LP- 1 about 4.5 mg), and the blank group was subcutaneously injected with the same volume of normal saline. At the same time on the 1st, 5th, 10th, 15th, 20th, 25th, and 30th days after the administration, each rat was given intraperitoneal injection of 18mmol/kg glucose. Blood was collected from the orbit at 10, 15, 20, 30 and 50 minutes to measure blood glucose before and after injection. Blood glucose was determined according to the instructions of the glucose determination kit (glucose oxidase method, Beijing Chemical Plant). Make the graph (seeing Fig. 1 to Fig. 7) of blood glucose concentration and time, as shown in Fig. 1, blank control group intraperitoneal injection of glucose, blood glucose obviously rises after five minutes, falls slowly, and has not yet reached baseline blood glucose concentration in fifty minutes. In the administration group, obvious hypoglycemic effects could be observed on the 1st, 5th, 10th, 15th, 20th, 25th, and 30th day, and the concentration returned to the base state within 30 minutes. It shows that the GLP-1 microspheres have obvious slow-release and hypoglycemic effects in the body, so the present invention can be used as a slow-release dosage form of GLP-1 for treating diabetes or controlling body weight.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105769771A (en) * | 2014-12-25 | 2016-07-20 | 四川科伦药物研究院有限公司 | Exenatide slow-release microsphere composition and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100344323C (en) * | 2004-09-30 | 2007-10-24 | 华东师范大学 | Human glucagon-like peptide-1 compound and its preparing method |
| US20080125361A1 (en) * | 2004-11-12 | 2008-05-29 | Novo Nordisk A/S | Stable Formulations Of Peptides |
| CN101292951B (en) * | 2007-04-23 | 2012-03-28 | 江苏先声药物研究有限公司 | Recombinant human endostatin long-acting preparation and its preparation method and application |
| CN102198103B (en) * | 2011-05-30 | 2014-07-23 | 深圳翰宇药业股份有限公司 | Stable exenatide sustained-release microsphere preparation and preparation method thereof |
| CN105878191B (en) * | 2016-04-26 | 2021-01-22 | 广州帝奇医药技术有限公司 | Preparation method of sustained-release microparticles, prepared sustained-release microparticles and application thereof |
| CN105878190B (en) * | 2016-04-26 | 2021-01-22 | 广州帝奇医药技术有限公司 | Preparation method of sustained-release microparticles, prepared sustained-release microparticles and application thereof |
| CN106074376A (en) * | 2016-06-27 | 2016-11-09 | 江苏师范大学 | A glucagon-like peptide-1 sustained-release nano-preparation, preparation method and application |
| CA3137895A1 (en) * | 2019-04-24 | 2020-10-29 | Ra Pharmaceuticals, Inc. | Compositions and methods for modulating complement activity |
| BR112022009974A2 (en) | 2019-11-25 | 2022-08-16 | Regeneron Pharma | METHODS OF PRODUCTION OF A POLYMER OR POLYMER-COATED MICROPARTICLES, TO PRODUCE POLYMERIC OR POLYMER-COATED MICROSPHERES, AND TO PRODUCE MICROPARTICLES, SUSTAINED RELEASE COMPOSITION, MICROPARTICLES, AND, PHARMACEUTICAL COMPOSITION |
| WO2024011218A1 (en) * | 2022-07-08 | 2024-01-11 | Brown University | Polymeric nanoparticles for long acting delivery of a peptide and methods of making and using thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105769771A (en) * | 2014-12-25 | 2016-07-20 | 四川科伦药物研究院有限公司 | Exenatide slow-release microsphere composition and preparation method thereof |
| CN105769771B (en) * | 2014-12-25 | 2019-02-01 | 四川科伦药物研究院有限公司 | A kind of Exenatide release microsphere composition and preparation method thereof |
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| CN1524516A (en) | 2004-09-01 |
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Assignee: Hainan Shuang Cheng Pharmaceutical Co., Ltd. Assignor: Army Medical Univ. No.2, Chinese PLA Contract fulfillment period: 2008.10.16 to 2013.10.16 Contract record no.: 2008460000017 Denomination of invention: Glicetin -1 slow release microspheric preparation and its use Granted publication date: 20061213 License type: Exclusive license Record date: 20081112 |
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