CN101057849A - Slow-releasing preparation containing metformin hydrochloride and glipizide and its preparation method - Google Patents

Slow-releasing preparation containing metformin hydrochloride and glipizide and its preparation method Download PDF

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CN101057849A
CN101057849A CN 200710071832 CN200710071832A CN101057849A CN 101057849 A CN101057849 A CN 101057849A CN 200710071832 CN200710071832 CN 200710071832 CN 200710071832 A CN200710071832 A CN 200710071832A CN 101057849 A CN101057849 A CN 101057849A
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pellets
min
release
metformin
glipizide
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CN 200710071832
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刘吉成
牛英才
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齐齐哈尔医学院
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Abstract

The invention discloses a diabecron and glipizide -containing slow-release agent and the method for preparing the same. The glipizide micro-pill takes blank micro-pill as carrier, and combines glipizide and other medical findings with it. The diabecron-containing slow-release micro-pill comprises diabetosan pill, slow-release coating membrane material or other medical findings. The method for preparing diabecron-containing slow-release micro-pill takes extrusion rolling method or blank micro-pill loading method. The product is characterized by safety, high efficient, low toxicity and convenient usage. It can be used to treat non-insulin-dependent diabetes mellitus.

Description

含有盐酸二甲双胍和格列吡嗪的缓释制剂及其制备方法 Containing sustained-release formulation of metformin hydrochloride and its preparation method glipizide

技术领域 FIELD

:本发明涉及一种含有盐酸二甲双胍和格列吡嗪的缓释制剂,本发明还涉及一种该缓释制剂的制备方法。 : The present invention relates to sustained release formulations containing glipizide and metformin hydrochloride, and the present invention also relates to a process for preparing the sustained-release formulation.

背景技术 Background technique

:目前,II型糖尿病的主要治疗方法为注射胰岛素和口服磺脲类、双胍类等降糖药物。 : Currently, the main method of treatment of Type II diabetes and insulin injections to oral sulfonylurea, biguanide hypoglycemic drugs and the like. 由于胰岛素剂量的难控制性和使用不方便,国内在临床上双胍类及磺脲类药物仍然被作为治疗II型糖尿病一线用药。 Due to the difficulty of controlling the insulin dose and inconvenient to use, domestic biguanide and sulfonylurea drugs in clinical practice is still used as first-line treatment of type II diabetes drugs.

盐酸二甲双胍的降糖机制主要是增加无糖酵解,抑制肝糖异生、降低肝糖输出和增加周围组织对胰岛素的敏感性,适用于II型糖尿病尤其是肥胖、血浆胰岛素偏高者、继发性磺脲类失效和I型糖尿病胰岛素治疗血糖控制不佳者。 Hypoglycemic mechanism of metformin hydrochloride is to increase non-glycolytic, suppress of hepatic gluconeogenesis, reduce hepatic glucose output and increasing the sensitivity of peripheral tissues to insulin, suitable especially in obese type II diabetes, the plasma insulin were high, following the sulfonylureas failure onset diabetes and insulin treatment in poor glycemic control of type I. 由于二甲双胍不刺激胰岛素分泌,且能改善血脂代谢,减轻体重,对心血管有保护作用,因此是肥胖II型糖尿病患者首选药。 Because metformin does not stimulate insulin secretion, and can improve lipid metabolism, lose weight, have a protective effect on the cardiovascular, therefore obese type II diabetes drug of choice. 二甲双胍对正常血糖无影响,通过抑制葡萄糖吸收等途径降糖,因此对预防糖耐量异常病人的病情发展也有重要作用。 Metformin no impact on normal blood sugar, glucose absorption inhibition by way hypoglycemic, so the development of the disease prevention in patients with abnormal glucose tolerance also play an important role. 盐酸二甲双胍也有其自身的缺点,就是其在体内的半衰期较短,为了维持有效的血药浓度,临床口服普通制剂需一日三次,这就给患者带来诸多不便。 Metformin hydrochloride has its own drawbacks, is its short half-life in the body, in order to maintain an effective blood concentration, general clinical oral formulation three times a day, which brings inconvenience to the patient. 而且直接使用双胍类药品,容易引起消化道不良反应。 And direct use of biguanide drugs, likely to cause gastrointestinal adverse reactions. 另外,由于普通的双胍类药品在胃液的损耗下生物利用度比较低,也不利于糖尿病治疗。 Further, since the conventional biguanide drugs bioavailability at a relatively low loss of juice, is not conducive to treatment of diabetes.

格列吡嗪降血糖的机制是其与β细胞膜上的磺酰脲受体特异性结合,从而使K+通道关闭,引起膜电位改变,Ca2+通道开启,胞液内Ca2+升高,促使胰岛素分泌。 Hypoglycemic glipizide mechanism is that specifically binds to β sulfonylurea receptor on the cell membrane, so that the K + channel is closed, causing changes in membrane potential, Ca2 + channel opening, Ca2 + increased the intracellular fluid to promote insulin secretion. 临床上主要用于经饮食和体育锻炼不能控制的II型糖尿病患者,其β细胞有一定分泌功能。 Mainly used in clinical patients with Type II diabetes can not be controlled diet and physical exercise, which have a β cell secretion. 格列吡嗪对II型糖尿病疗效显著,能逆转早期糖尿病患者微血管病变;预防视网膜和肾小球的病变;降低血清胆固醇和甘油三脂水平,预防冠心病。 Glipizide significant effect on type II diabetes, early stage diabetes can reverse the microvascular complications; prevention of retinal and glomerular lesions; reduce serum cholesterol and triglyceride levels, preventing coronary heart disease. 格列吡嗪临床上主要用于轻中度非胰岛素依赖型糖尿病患者,口服每日用量2.5~30mg不等,格列吡嗪的缺点是容易引起低血糖,长期大量服用很多人会形成继发性失效。 Clinically Glipizide is mainly used for diabetic patients with mild to moderate non-insulin dependent, oral daily dosage ranging from 2.5 ~ 30mg, glipizide shortcomings are likely to cause low blood sugar, a lot of people will take large doses of the formation of secondary of failure.

综上所述,无论是从降糖机制,还是从治疗功能、作用方面看,盐酸二甲双胍和格列吡嗪都是两种完全不同的降糖药物,因此以往这两种药物也都是单一型制剂,二者也分别拥有各自不同的适用群体。 In summary, both from hypoglycemic mechanism, or from the treatment of functional role of view, metformin and glipizide are two completely different hypoglycemic drugs, so the past two drugs are also single type preparations, respectively, both also have their own different applicable groups. 临床上只有当出现以单纯用磺脲类药物控制疗效不满意或磺脲类药物继发性失效的病人,医生才建议将二者配伍使用,以加强疗效。 Only when the patient is not satisfied to simply control the effect of sulfonylurea or with sulfonylurea secondary failure Clinically, the doctor will recommend their compatibility before use, to enhance efficacy.

在这种配伍使用过程中人们陆续发现,也解决了不少问题。 In the course of this compatibility of people it has been discovered, but also solve many problems. 第一问题是两种单一制剂配伍服用起来太麻烦,漏服现象常有发生。 The first issue are two single formulation compatibility taking up too much trouble, missed phenomenon often occurs. 为了解决这一问题,国外有些厂家将上述两种成分合在一起制成了复方制剂。 To solve this problem, some foreign manufacturers of the above two components together is made of a compound preparation. 目前美国FDA于2002年批准了Bristol-Myers Squibb公司的关于复方盐酸二甲双胍/格列吡嗪普通片剂。 The US FDA approved the Bristol-Myers Squibb Company's ordinary pyrazine compound metformin hydrochloride tablets on / Gregory in 2002. 这就大大地方便了患者的服用。 This greatly facilitates the taking of patients. 第二个问题是除了方便了患者的服用的优点外,人们还发现了复方制剂还具有以下优点:一是发现通过药物作用机制之间的互补可以提高疗效,即在两种药物之间存在着一定的协同作用;二是各单一组分的用量可以因此而减少,从而使药物的毒副作用也大大降低;三是使用固定配比的复方制剂,有利于提高患者的依从性,这一点对于长期慢性疾病的治疗是尤为重要的。 The second problem is that in addition to taking advantage of the convenience of the patient, but it is also found that the compound preparation has the following advantages: First, the discovery may improve efficacy by complementation between the mechanism of drug action, i.e. there are between the two drugs synergistic effect; the second is the amount of each single component may thus be reduced, so that the drug side effects are greatly reduced; third fixed ratio of compound preparation used, help to improve patient compliance, which is long-term the treatment of chronic diseases is particularly important. 这样一来,显然也就扩大了将两种药物配伍使用的适用对象,改变了原来使用的被动性。 As a result, it is clear that the expansion of the applicable target of two drugs combined use, changing the original use of the passive. 第三个问题是已有的复方盐酸二甲双胍、格列吡嗪普通片剂服用以后在人体内的血药浓度保持、药物释放的均匀性还不够理想,影响了降糖过程的平稳性。 The third problem is that conventional compound metformin hydrochloride, glipizide after taking the tablets in normal plasma concentration in humans is maintained, drug release is not ideal uniformity, stability affects the hypoglycemic process. 于是,国内又有人推出了这类复方药物的缓释剂型设计,只是从这些设计方案的具体内容来看,有些设计的目前现状还不能起到药物缓释的作用,还有的设计则就是直接地将两种药物与缓释材料混合在一起制成的。 As a result, domestic someone launched a sustained release dosage form design of such compound drugs, but the specifics of the design point of view, the current status of some of the design can not play a role in drug delivery, as well as the design is a direct mixing the two drugs together with the slow release material is formed. 其服用后在人体内的血药浓度、释放的均匀性要想达到特别理想的程度也是很不太容易的。 After taking its plasma concentration in humans, the release of especially desirable in order to achieve uniformity degree is also not easy.

发明内容 SUMMARY

:本发明的目的在于提供一种含有盐酸二甲双胍和格列吡嗪的缓释制剂,该缓释制剂能在体内24h维持有效的血药浓度,释放均匀。 : Object of the present invention is to provide a sustained release formulation comprising glipizide and metformin hydrochloride in the sustained release formulation can maintain 24h effective blood concentration in vivo, uniform release. 本发明的另一个发明目的还在于提供一种该缓释制剂的制备方法。 Another object of the present invention is to provide a method for preparing the sustained release formulation a.

本发明所采用的具体技术方案是:该缓释制剂其剂型为微丸,由盐酸二甲双胍缓释微丸和格列吡嗪常释微丸,按两种微丸中的药物的活性成分之比为1∶50-100的重量比混合制成,剂型品种为片剂或胶囊。 Particular aspect of the present invention is employed: the dosage form is sustained release formulation which pellets, and the pellets Metformin Hydrochloride often glipizide release pellet, the ratio of the active ingredient of the drug in two pellets is 1:50-100 blend weight ratio, the dosage form is a tablet or capsule varieties.

格列吡嗪常释微丸是以空白微丸为载体,加载格列吡嗪及其它可药用辅料制成。 Glipizide is a white release pellets Pellets normally as a carrier, and loading glibenclamide made pyrazine other pharmaceutically acceptable excipients. 含盐酸二甲双胍缓释微丸由含二甲双胍药素丸、缓释包衣成膜材料或还含有其它可药用辅料制成,其中的含盐酸二甲双胍药素丸采用挤出滚圆法或空白微丸加载法制备。 Metformin hydrochloride sustained-release pellets containing, sustained release coating or film-forming material may also contain other pharmaceutically acceptable excipients is made of a prime drug pellets metformin, metformin hydrochloride in which the drug-containing pellets by extrusion spheronization element or blank loaded pellets Preparation.

本发明中含盐酸二甲双胍缓释微丸和格列吡嗪常释微丸是由以下重量百分比的药用组分和此外工艺量的稀释剂水制备而成的。 The present invention containing metformin hydrochloride sustained-release pellets and glipizide release pellets is often the percentage by weight of the pharmaceutical composition and preparation of addition amount of diluent water formed.

(1)格列吡嗪常释微丸格列吡嗪3-5% 分散剂15-20% 粘合剂1--15% 空白丸芯70--85 (1) often glipizide release pellets glipizide dispersant 3-5% 15-20% binder pareil 70--85 1--15%

其中空白丸芯的组成为:填充剂70-100% 粘合剂0---15% 润滑剂0---15%(2)含盐酸二甲双胍缓释微丸A含二盐酸甲双胍药素丸含盐酸二甲双胍药素丸可采用a或b两种方法制备:a、挤出滚圆法盐酸二甲双胍 50-70% 填充剂20---30% 粘合剂3-10%b、空白微丸加载法盐酸二甲双胍60-75% 分散剂2-20% 粘合剂1---5%空白丸芯20--30%B缓释包衣液层缓释成膜材料60-90% 润滑剂10---40% 活性剂0-1%含二盐酸甲双胍药素丸与缓释包衣层的制备比例为1∶0.5---1.0;上述的缓释成膜材料可选取自纤维素酯衍生物、纤维素醚衍生物、纤维素酯的醚衍生物、丙烯酸类高分子、乙烯类高分子中的至少一种;上述的填充剂选自淀粉、及其衍生物、糖类、糊精、纤维素及其衍生物、乙烯类高分子中至少一种;上述的粘合剂为聚维酮和羟丙甲纤维素中至少一种。 Pareil wherein the composition is: 70-100% adhesive filler 15% Lubricant 0 --- 0 --- 15% (2) A sustained-release pellets containing metformin hydrochloride-containing drug metformin dihydrochloride hormone pellets hormone pellets containing the drug metformin hydrochloride can be prepared in two ways a or b: a, metformin hydrochloride extrusion spheronization filler 20 is 50 to 70% --- 30% binder 3-10% b, white pellets loading method metformin hydrochloride dispersant 2-20% 60-75% binder 1 --- 5% pareil 20--30% B sustained-release coating solution film forming material layer of 60-90% release lubricant 10-- -40% 0-1% proportion of the active agent dihydrochloride prepared containing the drug metformin extended release coating layer and the pigment pellet is 0.5 --- 1.0; and the sustained-release material may be selected from a cellulose ester forming derivatives , cellulose ether derivatives, ester derivatives of cellulose ether, an acrylic polymer, at least one of ethylene-based polymer; said filler is selected from starch, its derivatives, saccharides, dextrin, cellulose and its derivatives, at least one ethylene-based polymer; and the binder is povidone, hypromellose, and at least one.

本发明药物的制备工艺(1)空白丸芯的制备调解离心造粒机的挡板和喷枪的位置及角度,使物料在离心桶内呈现最大扇面,喷枪喷出的粘合剂正好喷于此扇面上。 Pharmaceutical preparation of the present invention (1) Preparation of the position and angle of the mediation pareil centrifugal granulator baffle and the lance, the material exhibits a maximum in the centrifugal fan barrel, just spray adhesive spray gun thereto fan on. 调节使喷气压力0.3Mpa,鼓风流量100~150L·min-1,主机离心速度448~705r·min-1,最初3~5min喷浆流量为7~9ml·min-1,然后调节喷浆流量为5~7ml·min-1,此过程持续3~5min,最后阶段为供粉阶段,润滑剂、填充剂供粉速度5~10g·min-1,喷浆流量不变,此阶段时间较长,视母核长大到合适大小后关机。 Adjusted so that air pressure 0.3Mpa, the blast flow rate of 100 ~ 150L · min-1, the host centrifugation speed 448 ~ 705r · min-1, the initial flow rate of 3 ~ 5min spraying 7 ~ 9ml · min-1, then the flow regulating spray is 5 ~ 7ml · min-1, the process continued 3 ~ 5min, the final stage is the stage for the powder, a lubricant, a filler powder supply rate 5 ~ 10g · min-1, spraying flow constant for a long time at this stage , depending on the nucleus grows to the appropriate size after shutdown. 结束后开启出料口,取出成品,室温晾干,取出过筛分级即得。 After opening the discharge port, remove the finished, dried at room temperature, extraction was sieved to obtain.

(2)格列吡嗪常释微丸的制备将空白丸芯置离心包衣造粒机内,以格列吡嗪和分散剂混合物供粉,粘合剂调浆,按下列参数开动离心包衣造粒机:主机转速150r·min-1,鼓风流量20L·min-1,喷气流量15~20L·min-1,喷气压力0.5Mpa,喷浆速度7~10ml·min-1,供粉速度5~10g·min-1,至粉末全部层积在母核上为止,60℃烘干,收集18~24目含药丸芯。 (2) Preparation of glipizide release pellets will often pareil opposing the centrifugal coating granulator, to a mixture of glibenclamide pyrazine and dispersant for the powder, the binder mixing, centrifugal start packet following parameters coating granulator: revolution speed of 150r · min-1, the blast flow rate of 20L · min-1, jet flow rate 15 ~ 20L · min-1, air pressure 0.5Mpa, spray rate 7 ~ 10ml · min-1, the toner supply speed of 5 ~ 10g · min-1, all laminated to the powder up in the nucleus, 60 deg.] C and drying, collecting 18 to 24 mesh pellets containing core.

(3)二甲双胍药素丸的制备A、挤出滚圆法称取盐酸二甲双胍、填充剂,将盐酸二甲双胍、填充剂和粘合剂过筛后混匀,按水与微晶纤维素之比为1.1∶1的比例加入适量的水,制成适宜的软材,经挤出滚圆机制得微丸,挤出转速为50r·min-1,滚圆转速为1100r·min-1,滚圆时间为4min,滚圆后于55℃烘箱中干燥5h后,过筛取18~24目间的微丸备用。 Preparation of (3) A pigment pellet drug metformin, extrusion spheronization weighed metformin hydrochloride, a filler, metformin hydrochloride, a binder and a filler mixed, sieved, according to the ratio of water to microcrystalline cellulose 1.1 :1 proportion of added amount of water into the suitable soft material, obtained by extrusion spheronization pellets, extrusion speed was 50r · min-1, spheronization speed of 1100r · min-1, spheronization time 4min, rounded after 55 ℃ oven dried after 5h, sieved pellets take alternate between 18 to 24 mesh.

B、空白微丸加载法取空白丸芯置离心造粒机内,将二甲双胍,分散剂、填充剂混合后过120目筛后置于供粉料室内,粘合剂调浆,调节喷气压力0.3Mpa,鼓风流量100~150L·min-1,主机离心速度448~705r·min-1,最初3~5min喷浆流量为7~9ml·min-1,然后调节喷浆流量为5~7ml·min-1,此过程持续3~5min,最后阶段为供粉阶段,供粉速度5~10g·min-1,喷浆流量不变,此阶段时间较长,视母核长大到合适大小后关机。 B, white pellets loading method takes pareil opposite a centrifugal granulator, metformin, a dispersing agent, the mixed filler was placed through a 120 mesh sieve chamber for powder, the binder mixing, adjust air pressure 0.3 mpa, flow rate of the blower 100 ~ 150L · min-1, the host centrifugation speed 448 ~ 705r · min-1, the initial flow rate of 3 ~ 5min spraying 7 ~ 9ml · min-1, then adjusting the flow rate of spray 5 ~ 7ml · after min-1, the process continued 3 ~ 5min, the final stage for the powder phase, the toner supply speed 5 ~ 10g · min-1, spraying flow constant for a long time at this stage, depending on the nucleus grows to the appropriate size shutdown. 结束后开启出料口,取出成品,室温晾干即得。 After opening the discharge port, remove the finished, dried at room temperature to obtain.

(4)二甲双胍缓释微丸的制备取一定量二甲双胍素丸和包衣液,将二甲双胍常释微丸置于离心室中,开动主机,调节挡板和喷枪位置及角度,设定包衣温度为21~24℃,主机转速为150r·min-1~180r·min-1,喷浆泵转速为10r·min-1~20r·min-1,鼓风流量为8L·min-1~10L·min-1,喷气流量为6L·min-1~8L·min-1,气源压力为0.4Mpa~0.7Mpa,喷气压力0.3Mpa。 (4) Preparation of sustained release pellets Metformin certain amount of metformin hormone pellets and the coating solution, the release pellets Metformin often placed in a centrifuge chamber, starting main regulating baffles and spray gun position and angle, the coating temperature is set 21 ~ 24 ℃, host speed of 150r · min-1 ~ 180r · min-1, spraying speed of the pump 10r · min-1 ~ 20r · min-1, the blast flow rate of 8L · min-1 ~ 10L · min -1 jet flow 6L · min-1 ~ 8L · min-1, air pressure is 0.4Mpa ~ 0.7Mpa, air pressure 0.3Mpa. 开动喷浆泵,在包衣过程中不断搅拌包衣液使其均匀,至一定量的包衣液包完后停止包衣,并将微丸继续在包衣机中沸腾干燥5~10min,关闭风机,取出包衣微丸在40~50℃熟化24h即可。 Actuated spray pump, constantly stirring the coating process the coating solution uniformly, to a certain quantity of coating liquid coated stop after the packet, and will continue to boil dried pellets in 5 ~ 10min coater, closed fan, to remove the coated pellets was aged 24h at 40 ~ 50 ℃.

(5)复合缓释制剂的制备将二甲双胍缓释微丸和格列吡嗪常释微丸按比例装入胶囊或压片,即得复合二甲双胍缓释胶囊或复合二甲双胍缓释片。 Preparation of sustained release formulations compound (5) Pellets of metformin and glipizide sustained release pellets proportionally often encapsulated or compressed tablets, sustained release capsules to obtain a composite or a composite metformin metformin tablets.

本发明的优点是所设计的产品首次使用了微丸剂型,这种缓释微丸属多剂量剂型,将药物分隔在多个隔室中,与单剂量剂型相比,具有较好的疗效重现性和较小的不良反应发生率,其优越性还在于:一是微丸在胃肠道内分布均匀,局部刺激小;二是由于面积大,吸收效果良好,不受胃排空因素影响;三是吸收速度规则、均匀,个体间的生物利用度差异小,重现性较好;四是不易破碎,球粒大小均匀,容易包衣制成缓控释或定位制剂;五是由许多小丸组成,个别小丸在制备上的失误或缺陷不止对整体制剂的释药行为产生较大影响;六是由不同药物的微丸组成的复方胶囊,可增加药物的稳定性,提高疗效,减少不良反应;七是生产中便于质量控制和含量测定,而且微丸适合复方制剂的配伍。 Advantage of the invention is designed for the first time the product pellets dosage forms, some species such sustained release pellets dosage forms, the drug in a plurality of separated compartments, compared to a single dosage form, with good effect weight now and less incidence of adverse reactions, which further advantages: First, the pellets evenly distributed within the gastrointestinal tract, local irritation; the second is due to the large area, good absorption, factors affected by gastric emptying; Third, absorption rate rule, a uniform, small differences in bioavailability between individuals, good reproducibility; four is not broken, the pellets of uniform size, easy positioning or slow release coating formulation prepared; five is composed of many pellets composition, individual errors or defects in the pellets produced have a greater impact than the overall release behavior of the formulation; six pellets of different drugs capsules were composed, increase the stability of the drug, improve efficacy, reduce side effects ; seven facilitate quality control and determination of the production, and the compatibility of pellets suitable for the combination. 近年来,由于新辅料的开发和生产,使缓释微丸在缓控释领域显示了独特的优越性,迄今被公认为是较理想的缓释剂型之一。 In recent years, development and production of new materials, the sustained-release pellets shows the unique advantages in the field of controlled release, it has so far been recognized as one of the more desirable sustained release dosage forms.

另外,虽然以往的有些微丸也都含有多种药物组分,但是在加工中都是将全部药物组分混合在一起的,现有的缓释剂型药物的制备采用的也是同样的方法。 Moreover, although some conventional pellets also contain a variety of pharmaceutical ingredients, but in the process are all mixed together drug component, it is prepared in the same manner as conventional pharmaceutical sustained release dosage form employed. 本发明则根据两种药物在体内的不同释放速度采用了二甲双胍缓释,格列吡嗪常释的区别设计,即施行了一种“一方两制”的作法,这样更能真正实现药物在体内保持24h维持有效的血药浓度,药物的释放也更加均匀。 According to the present invention, the two drugs at different release rates in vivo using release metformin, glipizide release distinction is often designed so that the implementation of a "one of two systems" approach, so that the drug is more real in vivo for 24h maintain effective blood concentration, more uniform drug release. 不仅提高了患者的顺应性,适合了临床用药发展的需要,而且还具有安全、高效、低毒和服用方便等方面的诸多优点。 Not only improve patient compliance, the need for clinical drug development, but also has many advantages safe, efficient, low toxicity and easy administration and other aspects.

具体实施方式 Detailed ways

:实施例11、制备含盐酸二甲双胍药素丸称取盐酸二甲双胍210g、填充剂微晶纤维素80g和粘合剂乳糖50g,将盐酸二甲双胍、微晶纤维素和乳糖过筛后混匀,按水与微晶纤维素之比为1.1∶1的比例加入适量的水,制成适宜的软材,经挤出滚圆机制得微丸,挤出转速为50r·min-1,滚圆转速为1100r·min-1,滚圆时间为4min,滚圆后于55℃烘箱中干燥5h后,过筛取18~24目间的微丸备用。 : Example 11, metformin hydrochloride prepared containing hormone drug pellets weighed 210g metformin hydrochloride, a binder and a filler microcrystalline cellulose 80g lactose 50g, metformin hydrochloride, microcrystalline cellulose and lactose sieved mix, based on the water ratio of the microcrystalline cellulose and an appropriate amount of water for the 1.1 ratio, made of suitable soft material, obtained by extrusion spheronization pellets, extrusion speed was 50r · min-1, spheronization speed of 1100r · min -1 4min spheronization time, after spheronization and dried in an oven at 55 ℃ 5h, sieved pellets take alternate between 18 to 24 mesh.

2、制备盐酸二甲双胍缓释微丸取上述含盐酸二甲双胍素丸500g,置于离心室中,开动主机,调节挡板和喷枪位置及角度,设定包衣温度为23℃,主机转速为150r·min-1,喷浆泵转速为15r·min-1,鼓风流量为10L·min-1,喷气流量为8L·min-1,气源压力为0.5Mpa,喷气压力0.3Mpa。 2. Preparation of Metformin Hydrochloride Sustained Release Pellets of metformin hydrochloride-containing pigment take pills 500g, placed in a centrifuge chamber, the host actuated, adjusting the position and angle baffles and spray gun, temperature of the coating 23 is set deg.] C, the rotation speed of the host 150r · min-1, spraying speed of the pump 15r · min-1, the blast flow rate of 10L · min-1, the jet flow of 8L · min-1, air pressure is 0.5Mpa, air pressure 0.3Mpa. 开动喷浆泵,在包衣过程中不断搅拌包衣液使其均匀,至由缓释成膜材料Eudragit NE 30D 200g、EudragitL30D-55 20g、润滑剂滑石粉68.2g、活性剂十二烷基硫酸钠0.55g和水262ml组成的包衣液包完后停止包衣,将微丸继续在包衣机中沸腾干燥5min,关闭风机,取出包衣微丸在50℃熟化24h,即可得盐酸二甲双胍缓释微丸。 Actuated spray pump, constantly stirring the coating process the coating solution uniformly, to release the film-forming material Eudragit NE 30D 200g, EudragitL30D-55 20g, 68.2 g talc lubricants, agents dodecylsulfate sodium and 0.55g water 262ml pack coating liquid composition stop after coating, the dried pellets boiling is continued for 5min coater, turn off the fan, remove the coated pellets was aged 24h at 50 ℃, to give metformin hydrochloride sustained-release pellets.

3、制备空白丸芯将100g填充剂微晶纤维素和蒸馏水以质量比1∶1(w/w)的比例混合并加入挤出机,使挤出转速为40r·min-1。 3. Preparation pareil filler microcrystalline cellulose and 100g of distilled water at a mass ratio 1:1 (w / w) proportions and added to the extruder, the speed of the extruded 40r · min-1. 用竹板向挤出机料斗内加药坯,药坯通过螺旋输送到出料口筛板(孔径0.9mm)挤出,成为条状物料。 Dosing parison into the hopper of the extruder with bamboo, drugs delivered to the blank through the discharge opening Spiral sieve (0.9mm aperture) extruded strip material becomes. 用容器全部接出后,一次性置于滚圆机内刀盘上,调节转速为1200r·min-1,开风机,滚圆时间为3min,滚圆后于50℃烘箱中干燥3h,取出过筛分级即得。 After receiving a full container, placed on a spheronizer disposable inner cutter, adjusting the rotational speed of 1200r · min-1, open fan, spheronization time 3min, rounded oven at 50 deg.] C after dried 3h, remove sieved i.e. too.

4、制备格列吡嗪常释微丸将空白丸芯96g置离心包衣造粒机内,以格列吡嗪5g、填充剂微晶纤维素20g和分散剂乳糖24g混合物供粉,粘合剂为5%羟丙甲纤维素水溶液,按下列参数开动离心包衣造粒机:主机转速150rpm,鼓风流量20L·min-1,喷气流量18L·min-1,喷气压力0.5Mpa,喷浆速度8ml·min-1,供粉速度7g·min-1,至粉末全部层积在母核上为止,60℃烘干即得,收集18~24目含药丸芯。 4. Preparation of glipizide release pellets often inner pareil 96g opposing centrifugal coating granulator, glipizide to 5g, a mixture of 24g lactose, 20g of microcrystalline cellulose filler and a dispersing agent for the powder adhesive agent is hypromellose 5% aqueous solution, the following parameters centrifugal coating granulator start: host speed 150 rpm, flow rate of the blower 20L · min-1, the jet flow 18L · min-1, air pressure 0.5Mpa, spray rate 8ml · min-1, the toner supply speed 7g · min-1, all laminated to the powder up in the nucleus, and drying to obtain 60 deg.] C, collecting 18 to 24 mesh pellets containing core.

5、制备复合盐酸二甲双胍缓释胶囊。 5, preparing a composite metformin hydrochloride sustained release capsules.

将盐酸二甲双胍缓释微丸和格列吡嗪常释微丸按比例装入胶囊,即得复合盐酸二甲双胍缓释胶囊。 Metformin hydrochloride sustained-release pellets and glipizide release pellets often encapsulated in proportion, to obtain the compound metformin hydrochloride sustained release capsules.

实施例21、制备空白丸芯采用离心造粒法制备空白丸芯,称取微晶纤维素500g置离心造粒机内,造粒条件为喷气压力0.3Mpa,鼓风流量125L·min-1,主机离心速度550r·min-1,最初4min喷浆流量为8ml·min-1,然后调节喷浆流量为6ml·min-1,此过程持续4min,最后阶段为供粉阶段,供粉机转速为20r·min-1,喷浆流量不变,视母核长大到合适大小后关机。 Example 21 was prepared using a centrifugal granulator pareil Preparation pareil seeds, to take the said opposite microcrystalline cellulose 500g centrifugal granulator, the granulation conditions are air pressure 0.3Mpa, the blast flow rate of 125L · min-1, host centrifugation speed 550r · min-1, the initial flow rate of 4min spray 8ml · min-1, then adjusting the flow rate of spray 6ml · min-1, 4min this process continues, the final stage for the powder phase, as the toner supply rotational speed 20r · min-1, spraying flow constant, depending on the nucleus grows to the appropriate size after shutdown. 结束后开启出料口,取出成品,室温晾干,过筛分级即得。 After opening the discharge port, remove the finished, dried at room temperature, was sieved to obtain.

2、制备含盐酸二甲双胍素丸取40~60目的微晶纤维素空白微丸芯80g置离心造粒机内,将盐酸二甲双胍250g、微晶纤维素7.5g和乳糖12.5g混合,过120目筛后置于供粉料室内,以5%羟丙甲基纤维素水溶液为粘合剂,采用离心造粒法制备盐酸二甲双胍素丸,造粒条件为调节喷气压力0.3Mpa,鼓风流量150L·min-1,主机离心速度500r·min-1,最初4min喷浆流量为8ml·min-1,然后调节喷浆流量为6ml·min-1,此过程持续4min,最后阶段为供粉阶段,供粉速度为7g·min-1,喷浆流量不变,视母核长大到合适大小后关机。 2. Preparation of pellets containing metformin hydrochloride prime object takes within 40 to 60 Pellets of Microcrystalline Cellulose core 80g opposing centrifugal granulator, metformin hydrochloride 250g, 7.5g lactose, microcrystalline cellulose and mixing 12.5g, through a 120 mesh sieve after the powder supply chamber disposed with 5% aqueous solution of hydroxypropyl methylcellulose as a binder, using a centrifugal granulating metformin hydrochloride prepared pellets, granulated condition to adjust air pressure 0.3Mpa, the blast flow rate of 150L · min -1, host centrifugation speed 500r · min-1, the initial flow rate of 4min spray 8ml · min-1, then adjusting the flow rate of spray 6ml · min-1, 4min this process continues, the final stage is the stage for the powder for the powder rate of 7g · min-1, spraying flow constant, depending on the nucleus grows to the appropriate size after shutdown. 结束后开启出料口,取出成品,室温晾干即得。 After opening the discharge port, remove the finished, dried at room temperature to obtain.

3、制备盐酸二甲双胍缓释微丸取500g含盐酸二甲双胍素丸,置于离心室中,开动主机,调节挡板和喷枪位置及角度,设定包衣温度为23℃,主机转速为150r·min-1,喷浆泵转速为15r·min-1,鼓风流量为10L·min-1,喷气流量为8L·min-1,气源压力为0.5Mpa,喷气压力0.3Mpa。 3, Metformin hydrochloride sustained-release pellets prepared containing 500g of metformin hydrochloride take hormone pellets, placed in a centrifuge chamber, the host actuated, adjusting the position and angle baffles and spray gun, temperature of the coating 23 is set deg.] C, the rotation speed of the host 150r · min -1, spraying speed of the pump 15r · min-1, the blast flow rate of 10L · min-1, the jet flow of 8L · min-1, air pressure is 0.5Mpa, air pressure 0.3Mpa. 开动喷浆泵,在包衣过程中不断搅拌包衣液使其均匀,至由Eudragit NE 30D 200g、EudragitL30D-55 20g、滑石粉68.2g、十二烷基硫酸钠0.55g和水262ml组成的包衣液包完后停止包衣,将微丸继续在包衣机中沸腾干燥5~10min,关闭风机,取出包衣微丸在40~50℃熟化24h,即可得盐酸二甲双胍缓释微丸。 Actuated spray pump, with constant stirring to evenly coating liquid during the coating process, to the Eudragit NE 30D 200g, EudragitL30D-55 20g, 68.2 g talc, sodium lauryl sulfate and 0.55g water 262ml package consisting package coating liquid stop after coating, the dried pellets boiling is continued in the 5 ~ 10min coater, turn off the fan, remove the coated pellets was aged 24h at 40 ~ 50 ℃, to give metformin hydrochloride sustained release pellets.

4、制备格列吡嗪常释微丸将微晶纤维素母核96g置离心包衣造粒机内,以格列吡嗪5g、微晶纤维素20g和乳糖24g混合物供粉,以5%羟丙甲纤维素水溶液为粘合剂,按下列参数开动离心包衣造粒机:主机转速150rpm,鼓风流量20L·min-1,喷气流量18L·min-1,喷气压力0.5Mpa,喷浆速度8ml·min-1,供粉速度7g·min-1。 4. Preparation of glipizide release pellets often inner nucleus Microcrystalline cellulose 96g opposing centrifugal coating granulator, glipizide to 5g, 24g microcrystalline cellulose 20g lactose and for the powder mixture, 5% hypromellose as a binder solution, coating the following parameters centrifugal granulator start: host speed 150 rpm, flow rate of the blower 20L · min-1, the jet flow 18L · min-1, air pressure 0.5Mpa, spray rate 8ml · min-1, the toner supply speed 7g · min-1. 至粉末全部层积在母核上为止。 All to the powder layered up in the nucleus. 60℃烘干即得。 60 deg.] C to obtain dried. 收集18~24目含药丸芯。 18 ~ 24 mesh was collected pellets containing core.

5、制备复合盐酸二甲双胍缓释胶囊。 5, preparing a composite metformin hydrochloride sustained release capsules.

将盐酸二甲双胍缓释微丸和格列吡嗪素丸按比例压片,即得复合盐酸二甲双胍缓释片。 Metformin hydrochloride sustained-release pellets and glipizide scale tableting hormone pellets, i.e. to obtain a composite of metformin hydrochloride tablets.

例3本例为本发明产品的动物药代动物学试验,通过建立测定狗血浆中盐酸二甲双胍浓度的HPLC法,以盐酸二甲双胍普通缓释片为标准对照,用面积法估算本发明的复方盐酸二甲双胍缓释微丸的相对生物利用度为97.9%。 Example 3 This Example zoological animal pharmacokinetic test product of the present invention, by establishing the concentration of metformin hydrochloride measuring dog plasma by HPLC to normal release tablets of metformin hydrochloride standard control, metformin hydrochloride Compound estimated by the area method of the present invention, the relative bioavailability of sustained release pellets was 97.9%. 给狗服入本发明产品盐酸二甲双胍缓释微丸250mg后,估算的末端半衰期为10.97±2.36小时,峰时间和峰浓度分别为5.8±1.7小时和1114.37±27.23ng/ml;平均保留时间为11.54±1.49小时,曲线下面积为1419.524±246.5ng/ml。 Ingestion dog product of the present invention the pellets Metformin hydrochloride 250mg, estimated terminal half-life was 10.97 ± 2.36 h, peak time and peak concentrations were 5.8 ± 1.7 in hours and 1114.37 ± 27.23ng / ml; mean retention time 11.54 ± 1.49 hours, the area under the curve 1419.524 ± 246.5ng / ml. 给狗服用10mg盐酸二甲双胍普通缓释片,估算的末端半衰期为2.09±1.22小时,峰时间和峰浓度分别为1.39±0.52小时和248.4±12.37ng/ml;平均保留时间为6.47±0.42小时,曲线下面积为952.369±250.6ng/ml。 Normal dogs taking metformin hydrochloride sustained release tablets 10mg, estimated terminal half-life was 2.09 ± 1.22 h, peak time and peak concentrations of the hour and 1.39 ± 0.52 248.4 ± 12.37ng / ml; mean retention time was 6.47 ± 0.42 h, the curve area under 952.369 ± 250.6ng / ml. 经t试验分析显示t1/2、平均滞留时间显著大于盐酸二甲双胍普通缓释片(p<0.05),达峰时间延长(p<0.01),峰浓度显著低于盐酸二甲双胍普通缓释片(p<0.01),两制曲线下的面积无显著差异(p<0.05),说明了本发明产品的优良效果。 By t-test analysis showed t1 / 2, the average residence time is significantly greater than the normal release of metformin hydrochloride tablets (p <0.05), time to peak extension (p <0.01), peak concentrations significantly lower than normal metformin hydrochloride sustained release tablets (p < 0.01), no significant difference (p <0.05) area under the curve of two systems, the excellent effect described products of the invention.

Claims (5)

1.一种含有盐酸二甲双胍和格列吡嗪的缓释制剂,该缓释制剂其剂型为微丸,由盐酸二甲双胍缓释微丸和格列吡嗪常释微丸按两种微丸中的药物的活性成分之比为1∶50-100的重量比混合制成,剂型品种为片剂或胶囊。 A sustained release formulation comprising glipizide and metformin hydrochloride in the dosage form is a sustained release formulation which pellets often release pellets Pellets of metformin hydrochloride sustained release glipizide and in two pharmaceutical Pellets ratio of active ingredient weight ratio is 1:50-100 made varieties dosage tablets or capsules.
2.根据权利要求1所述的一种含有盐酸二甲双胍和格列吡嗪的缓释制剂,其特征是所述的格列吡嗪常释微丸是以空白微丸为载体,加载格列吡嗪及其它可药用辅料制成;所述的含盐酸二甲双胍缓释微丸由含二甲双胍药素丸、缓释包衣成膜材料或还含有其它可药用辅料制成,其中的含盐酸二甲双胍药素丸采用挤出滚圆法或空白微丸加载法制备。 According to one of the claim 1 comprising metformin hydrochloride and sustained release formulations of glipizide, wherein said constant glipizide release pellets Pellets carrier is empty, loading glibenclamide pyrazol oxazin-made and other pharmaceutically acceptable excipients; the metformin hydrochloride-containing sustained-release pellets containing the drug metformin hormone pills, sustained release coating or film-forming material can be made also contain other pharmaceutical excipients, wherein the metformin hydrochloride-containing hormone drug pellets by extrusion spheronization pellets loaded or empty prepared.
3.根据权利要求2所述的一种含有盐酸二甲双胍和格列吡嗪的缓释制剂,其特征在于所述的盐酸二甲双胍缓释微丸和格列吡嗪常释微丸是由以下重量百分比的药用组分和除此之外工艺量的稀释剂水制备而成:(1)格列吡嗪常释微丸格列吡3-5% 分散剂15-20% 粘合剂1--15% 空白丸芯70--85%其中空白丸芯的组成为:填充剂70-100% 粘合剂0---15% 润滑剂0---15%(2)含盐酸二甲双胍缓释微丸A含二盐酸甲双胍药素丸含盐酸二甲双胍药素丸可采用a或b两种方法制备:a、挤出滚圆法盐酸二甲双胍50-70% 填充剂20---30% 粘合剂3-10b、空白微丸加载法盐酸二甲双胍60-75% 分散剂2-20% 粘合剂1--5% 空白丸芯20--30%B缓释包衣液层缓释成膜材料60-90% 润滑剂10---40% 活性剂0-1%含二盐酸甲双胍药素丸与缓释包衣层的配制比例为1∶0.5---1.0;上述的缓释成膜材料可选取自纤 According to one of the claim 2 comprising a sustained release formulation of metformin hydrochloride and glipizide, characterized in that the pellets release metformin hydrochloride and glipizide release pellets is usually represented by the following percentages by weight pharmaceutical composition and amount of diluent in addition to the process water prepared from: (1) often glipizide release pellets glitazone pyrazol dispersant 3-5% 15-20% binder 1--15 composition% pareil pareil wherein 70--85% is: 70-100% adhesive filler 15% lubricant 0 --- 0 --- 15% (2) metformin hydrochloride sustained-release pellets containing A drug-containing biguanide dihydrochloride A pill prime prime drug metformin hydrochloride pellets can be prepared both methods a or b: a, metformin hydrochloride extrusion spheronization 50-70% filler adhesive 20 is 30% 3- --- 10b, metformin hydrochloride pellets blank loading method dispersant 2-20% 60-75% binder 1--5% pareil 20--30% B sustained-release coating layer is a sustained release film-forming liquid material 60-90 10 --- 40% proportion of the active agent containing 0-1% drug metformin dihydrochloride prime pellets with sustained-release coating layer is formulated lubricant 0.5 --- 1.0%; and the sustained-release film-forming material can be selected from fiber 维素酯衍生物、纤维素醚衍生物、纤维素酯的醚衍生物、丙烯酸类高分子、乙烯类高分子中的至少一种;上述的填充剂选自淀粉、及其衍生物、糖类、糊精、纤维素及其衍生物、乙烯类高分子中至少一种;上述的粘合剂为聚维酮和羟丙甲纤维素中至少一种。 Cellulose ester derivatives, cellulose ether derivatives, ester derivatives of cellulose ether, an acrylic polymer, at least one of ethylene-based polymer; said filler is selected from starch, its derivatives, saccharides , dextrin, cellulose and derivatives thereof, at least one ethylene-based polymer; said at least one binder is povidone and hydroxypropyl methyl cellulose.
4.一种制备如权利要求1所述的含有盐酸二甲双胍和格列吡嗪的缓释制剂的方法,其特征是:(1)空白丸芯的制备调解离心造粒机的挡板和喷枪的位置及角度,使物料在离心桶内呈现最大扇面,喷枪喷出的粘合剂或分散剂及润湿剂正好喷于此扇面上。 The method of sustained-release preparation containing metformin hydrochloride and glipizide claim 1 for the preparation as claimed in claim 4, characterized in that: (1) Preparation pareil mediation baffle and the lance centrifugal granulator position and angle, so that the material exhibits a maximum in the centrifugal fan barrel, the spray gun or adhesive dispersing agent and wetting agent on the sector just sprayed thereto. 调节使喷气压力0.3Mpa,鼓风流量100~150L·min-1,主机离心速度448~705r·min-1,最初3~5min喷浆流量为7~9ml·min-1,然后调节喷浆流量为5~7ml·min-1,此过程持续3~5min,最后阶段为供粉阶段,填充剂供粉速度5~10g·min-1,喷浆流量不变,此阶段时间较长,视母核长大到合适大小后关机。 Adjusted so that air pressure 0.3Mpa, the blast flow rate of 100 ~ 150L · min-1, the host centrifugation speed 448 ~ 705r · min-1, the initial flow rate of 3 ~ 5min spraying 7 ~ 9ml · min-1, then the flow regulating spray is 5 ~ 7ml · min-1, the process continued 3 ~ 5min, the final stage is the stage for the powder, the filler powder supply speed of 5 ~ 10g · min-1, spraying flow constant for a long time at this stage, depending on the parent nucleation and growth to the appropriate size after shutdown. 结束后开启出料口,取出成品,室温晾干,取出过筛分级即得;(2)格列吡嗪常释微丸的制备将空白丸芯置离心包衣造粒机内,以格列吡嗪和分散剂混合物供粉,粘合剂调浆,按下列参数开动离心包衣造粒机:主机转速150r·min-1,鼓风流量20L·min-1,喷气流量15~20L·min-1,喷气压力0.5Mpa,喷浆速度7~10ml·min-1,供粉速度5~10g·min-1,至粉末全部层积在母核上为止,60℃烘干,收集18~24目含药丸芯;(3)含二甲双胍药素丸的制备含盐酸二甲双胍药素丸采用空白微丸加载法,其具体工艺是:取空白丸芯置离心造粒机内,将二甲双胍,分散剂、填充剂混合后过120目筛后置于供粉料室内,粘合剂调浆,调节喷气压力0.3Mpa,鼓风流量100~150L·min-1,主机离心速度448~705r·min-1,最初3~5min喷浆流量为7~9ml·min-1,然后调节喷浆流量为5~7ml·min-1,此过程持续3~5min,最 After opening the discharge port, remove the finished, dried at room temperature, extraction was sieved to obtain; (2) Preparation of glipizide release pellets will often pareil opposing the centrifugal coating granulator to Gleevec pyrazine and dispersant mixture for the powder, the binder mixing, the following parameters centrifugal coating granulator start: host speed 150r · min-1, the blast flow rate of 20L · min-1, jet flow rate 15 ~ 20L · min -1 0.5Mpa air pressure, spray rate 7 ~ 10ml · min-1, the toner supply speed of 5 ~ 10g · min-1, all laminated to the powder up in the nucleus, 60 deg.] C dry, 18 to 24 were collected mesh pellets containing the core; (3) preparation of pigment-containing pellets containing the drug metformin metformin hydrochloride pellets hormone drug loading method using white pellets, the specific process is: take pareil opposite a centrifugal granulator, metformin, dispersants, after mixing the filler disposed for the powder through a 120 mesh sieve chamber slurried adhesive, adjusting air pressure 0.3Mpa, the blast flow rate of 100 ~ 150L · min-1, the host centrifugation speed 448 ~ 705r · min-1, initially spray a flow rate of 3 ~ 5min 7 ~ 9ml · min-1, then adjusting the flow rate of spray 5 ~ 7ml · min-1, 3 ~ 5min this process continues, the most 阶段为供粉阶段,供粉速度5~10g·min-1,喷浆流量不变,此阶段时间较长,视母核长大到合适大小后关机。 Stage for the powder phase, the toner supply speed 5 ~ 10g · min-1, spraying flow constant, the longer this period of time, depending on the nucleus grows to the appropriate size after shutdown. 结束后开启出料口,取出成品,室温晾干即得;(4)二甲双胍缓释微丸的制备取一定量二甲双胍素丸和包衣液,将二甲双胍常释微丸置于离心室中,开动主机,调节挡板和喷枪位置及角度,设定包衣温度为21~24℃,主机转速为150r·min-1~180r·min-1,喷浆泵转速为10r·min-1~20r·min-1,鼓风流量为8L·min-1~10L·min-1,喷气流量为6L·min-1~8L·min-1,气源压力为0.4Mpa~0.7Mpa,喷气压力0.3Mpa。 After opening the discharge port, remove the finished, dried at room temperature to obtain; (4) Preparation of sustained release pellets Metformin certain amount of metformin hormone pellets and the coating solution, the release pellets Metformin often placed in a centrifuge chamber, actuated host adjusting position and angle of baffles and spray gun, the coating temperature is set to 21 ~ 24 ℃, host speed of 150r · min-1 ~ 180r · min-1, spraying speed of the pump 10r · min-1 ~ 20r · min -1 blast flow rate of 8L · min-1 ~ 10L · min-1, the jet flow of 6L · min-1 ~ 8L · min-1, air pressure is 0.4Mpa ~ 0.7Mpa, air pressure 0.3Mpa. 开动喷浆泵,在包衣过程中不断搅拌包衣液使其均匀,至一定量的包衣液包完后停止包衣,并将微丸继续在包衣机中沸腾干燥5~10min,关闭风机,取出包衣微丸在40~50℃熟化24h即可;(5)复合缓释制剂的制备将二甲双胍缓释微丸和格列吡嗪常释微丸按比例装入胶囊或压片,即得复合二甲双胍缓释胶囊或复合二甲双胍缓释片。 Actuated spray pump, constantly stirring the coating process the coating solution uniformly, to a certain quantity of coating liquid coated stop after the packet, and will continue to boil dried pellets in 5 ~ 10min coater, closed fan, to remove the coated pellets was aged 24h at 40 ~ 50 ℃; sustained release formulations prepared compound (5) pellets of metformin and glipizide sustained release pellets proportionally often encapsulated or compressed tablets, i.e., A composite or a composite capsules release metformin metformin tablets.
5.根据权利要求4所述的含有盐酸二甲双胍和格列吡嗪的缓释制剂的方法,其特征是:所述的含盐酸二甲双胍药素丸采用挤出滚圆法,具体工艺是:称取盐酸二甲双胍、填充剂,将盐酸二甲双胍、填充剂和粘合剂过筛后混匀,按水与微晶纤维素之比为1.1∶1的比例加入适量的水,制成适宜的软材,经挤出滚圆机制得微丸,挤出转速为50r·min-1,滚圆转速为1100r·min-1,滚圆时间为4min,滚圆后于55℃烘箱中干燥5h后,过筛取18~24目间的微丸备用。 The sustained-release formulation comprising glipizide and metformin hydrochloride according to claim 4, characterized in that: the prime drug metformin hydrochloride-containing pellets by extrusion spheronization, the specific process is: Weigh hydrochloride metformin, fillers, metformin hydrochloride, a binder and a filler mixed, sieved, according to the ratio of water to microcrystalline cellulose ratio of 1.1 for the amount of water is added, suitably made of a soft material, by squeezing the spheronization pellets obtained, extrusion speed was 50r · min-1, spheronization speed of 1100r · min-1, 4min spheronization time, after the spheronization oven dried 55 ℃ 5h, sieved take between 18 to 24 mesh alternate pellets.
CN 200710071832 2007-02-27 2007-02-27 Slow-releasing preparation containing metformin hydrochloride and glipizide and its preparation method CN101057849A (en)

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