CN101912375A - Metformin controlled release tablet - Google Patents

Metformin controlled release tablet Download PDF

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CN101912375A
CN101912375A CN2010102636403A CN201010263640A CN101912375A CN 101912375 A CN101912375 A CN 101912375A CN 2010102636403 A CN2010102636403 A CN 2010102636403A CN 201010263640 A CN201010263640 A CN 201010263640A CN 101912375 A CN101912375 A CN 101912375A
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metformin
tablet
release
tablets
controlled release
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CN2010102636403A
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Chinese (zh)
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冯岩
卢骏
吴涛
师键鑫
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冯岩
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Abstract

The invention relates to a metformin controlled release tablet compound which contains an effective dose of metformin and polyoxyethylene and selectively contains or excludes one or more pharmaceutically acceptable auxiliary materials. The invention also relates to a metformin controlled release tablet which comprises a single-layer tablet core and a coating membrane covering the tablet core, wherein medicine release hole(s) is/are arranged on one side or two sides of each tablet, the tablet core contain an effective dose of the metformin and the polyoxyethylene and selectively contains one or more pharmaceutically acceptable auxiliary materials, and the coating membrane is a semi-permeable membrane.

Description

一种二甲双胍控释片 One kind of controlled-release tablets of metformin

技术领域 FIELD

[0001] 本发明涉及药物制剂技术。 [0001] The present invention relates to a pharmaceutical formulation techniques. 更具体地,本发明涉及一种二甲双胍控释片组合物、一种二甲双胍控释片以及它们的制备方法。 More particularly, the present invention relates to a controlled release tablet of metformin composition A controlled release tablets of metformin and methods for their preparation.

背景技术 Background technique

[0002] 二甲双胍(Metformin),属于双胍类降糖药,具有提高2型糖尿病患者的血糖耐受性,降低基础和餐后血糖的作用。 [0002] Metformin (Metformin), belonging to the biguanide hypoglycemic agents, have improved glucose tolerance in patients with type 2 diabetes, reducing postprandial blood sugar and base. 盐酸二甲双胍的作用机理不同于其它类型的口服抗血糖药,它可减少肝糖的产生,降低肠对糖的吸收,并且可通过增加外周糖的摄取和利用而提高胰岛素的敏感性,与磺酰脲类药物不同的是,盐酸二甲双胍不会对2型糖尿病患者或正常血糖的患者产生低血糖症。 Mechanism of action of metformin hydrochloride is different from other types of oral anti-hyperglycemic agent, which reduces the production of glycogen, reduce intestinal absorption of sugar, and may increase insulin sensitivity by increasing peripheral glucose uptake and utilization of an outer, with sulfuryl urea different drugs is metformin hydrochloride does not produce hypoglycaemia in patients with type 2 diabetes or normoglycemia. 盐酸二甲双胍治疗后,胰岛素的分泌保持不变,而降低空腹胰岛素水平及每日血浆胰岛素水平。 Metformin hydrochloride treatment, insulin secretion remains unchanged while fasting insulin levels and decreased plasma insulin levels daily. 盐酸二甲双胍化学名称是1,1_ 二甲基双胍盐酸盐,结构式如下: Metformin hydrochloride has the chemical name 1,1_ dimethyl biguanide hydrochloride, the following structural formula:

[0003] [0003]

HgC \ HgC \

)N —O — NH-O — _ · HCI ) N -O - NH-O - _ · HCI

H9C ' U [I H9C 'U [I

NH NH NH NH

[0004] 缓控释制剂同普通制剂相比有很多优越性,例如,缓控释制剂能较长时间维持治疗所需的血药浓度,同时降低血药浓度的峰谷变化,降低毒副作用的发生率和严重程度。 [0004] The controlled release formulations as compared with ordinary formulation has many advantages, for example, controlled release formulations maintain a longer time required for the treatment of plasma concentration, while reducing the peak plasma concentration variation, reduced side effects of The incidence and severity. 缓控释制剂还可以通过减少服用次数,提高病人的依从性。 Controlled release formulations can also reduce the number of doses, improve patient compliance. 二甲双胍由于半衰期较短,普通制剂需要每天服用2次或3次,。 Since the short half-life of metformin, Common formulations need to take two or three times a day. 因此1天1次的二甲双胍缓控释制剂对糖尿病病人的临床治疗具有重要意义,在相关患者中具有广泛需求。 Therefore, once a day metformin controlled release formulations is important for clinical treatment of diabetic patients with extensive demand in the relevant patients.

[0005] 中国专利申请cn99804134. 3公开了一种以高分子材料HPMC作为亲水性凝胶骨架的二甲双胍缓释片。 [0005] Chinese Patent Application cn99804134. 3 discloses a sustained release tablet of metformin kind HPMC as the hydrophilic polymer material gel skeleton. 采用双相控释递送系统延长二甲双胍药物释放时间,该双相控释递送系统包含(1)由基本上均勻的颗粒形成的内部固体颗粒相,(2)外部固体连续相,其中上述内部固体颗粒相的颗粒分散和包埋在所述外部固体连续相中,然后将所述递送系统可压制成片或装入胶囊中。 Biphasic controlled release delivery system using the drug metformin extended release time, the biphasic controlled release delivery system comprises (1) inside the solid particles are formed from a substantially homogeneous phase particles, (2) the outer solid continuous phase, wherein the inner solid particulate phase and embedded particles are dispersed in said outer solid continuous phase, and then the delivery system may be compressed into tablets or filled into capsules. 该项专利的缺点在于该种技术制得的二甲双胍缓释片释放一般不是恒速释放,其次体内释放行为受环境PH值、胃肠蠕动等体内环境影响较大,从而导致治疗效果之间的差异较大。 The disadvantage of this patent is prepared by techniques of Metformin is generally not constant release release sheet, followed by the in vivo release behavior of the environment PH value, and other gastrointestinal motility in vivo greater environmental impact, resulting in a difference between treatment larger.

[0006] 渗透泵片是由药物、半透膜包衣材料、渗透压活性物质和推动剂等组成的,以渗透压作为释药能源的控释片。 [0006] The osmotic pump tablet is a pharmaceutical, a semipermeable membrane coating material, the active material and the osmotic push composition, and the like, to release energy as osmotic controlled release tablets. 美国专利申请US6866866公开了一种渗透泵型二甲双胍控释片,2004年美国批准由ANDRX LABS LLC公司生产。 US Patent Application US6866866 discloses an osmotic pump controlled release tablets of metformin in 2004, the United States approved for production by the ANDRX LABS LLC company. 采用该原理及方法制备的是单室单层渗透泵片。 It prepared using the method and the principle of a single chamber monolayer osmotic pump tablet. 这种单室单层渗透泵控释片片芯组成为二甲双胍、增溶剂以及粘合剂,片芯外采用高分子材料进行包衣,然后包衣膜上进行打孔。 Such single-chamber osmotic pump controlled release single core piece consisting of metformin, and a binder outer solubilizers, tablet cores are coated with polymer, then coated film is punctured. 该项技术的缺点是由于片芯中的二甲双胍易溶于水,且片芯中含有促进二甲双胍溶解的增溶剂,故在释放过程中易出现片芯内局部二甲双胍溶解过快从而使包衣膜内渗透压升高较快,在此情况下二甲双胍的释放量会突然 Disadvantage of this technique is due to the metformin core soluble in water, and the core contains a solubilizer to promote dissolution of metformin, it is prone during the release of metformin partial dissolution of the inner core so that the coating film too osmotic pressure quickly, in which case the sudden release of metformin

3增多,易增加不良反应的发生率。 3 increase, likely to increase the incidence of adverse reactions.

[0007] 本发明提供了不同于现有技术的一种二甲双胍控释片组合物、一种二甲双胍控释片,以及它们的制备方法。 [0007] The present invention differs from the prior art provides a controlled release tablet of metformin composition A controlled release tablets of metformin, as well as methods for their preparation.

发明内容 SUMMARY

[0008] 1、本发明的目的之一是提供一种二甲双胍控释片组合物,它含有有效量的二甲双胍和聚氧乙烯,并选择性地含有一种或多种药学上可接受的辅料。 [0008] 1, object of the present invention is to provide a controlled release tablet of metformin composition comprising an effective amount of a metformin and polyoxyethylene, and optionally containing one or more pharmaceutically acceptable excipient.

[0009] 2、本发明的另一目的是提供了一种二甲双胍控释片,包括单层片心和包裹在片心上的包衣膜,并在片剂一侧或两侧有释药孔,其中片心含有有效量的二甲双胍和聚氧乙烯, 并选择性地含有一种或多种药学上可接受的辅料,包衣膜是半渗透膜。 [0009] 2, a further object of the present invention is to provide a controlled release tablets of metformin, comprising a single core sheet and film coated tablet cores wrapped, and the tablet has a release hole in one or both sides wherein the tablet core containing an effective amount of metformin and polyoxyethylene, and optionally containing one or more pharmaceutically acceptable excipient, the coating film is a semi-permeable membrane.

[0010] 3、本发明的再一目的是提供了二甲双胍控释片的制备方法。 [0010] 3, a further object of the present invention is to provide a method for preparing a controlled release tablets of metformin.

具体实施方式 Detailed ways

[0011] 本发明的二甲双胍控释片是单室单层的渗透泵型控释片。 Metformin Controlled Release Tablet [0011] The present invention is a single chamber of a single-layer osmotic pump tablet.

[0012] 渗透泵控释制剂作为控释制剂的典型代表,具有零级释药特征明显,释药行为不受介质环境PH值、胃肠蠕动和食物等因素的影响,以及体内外释药相关性好等特点。 [0012] As a typical representative of a controlled release formulation osmotic pump controlled release formulation, significantly having zero-order release characteristics, the drug release behavior is not affected by environmental factors medium PH, stomach and intestines, and other foods, as well as the relevant in vivo and in vitro release and good characteristics.

[0013] 已有的二甲双胍控释片同样是采用单室单层双面打孔的渗透泵型控释片。 [0013] Also conventional controlled release tablet of metformin is single-sided single-chamber osmotic pump perforated sheet. 由上市产品FORTAMET®说明书可以看出,片芯由二甲双胍、增溶剂和粘合剂组成,外部包衣两侧进行打孔。 FORTAMET® market can be seen from the description, the metformin tablet core, solubilizing agents and binder, both punctured outer coating. 由于片芯中的二甲双胍易溶于水,且片芯中含有促进二甲双胍溶解的增溶剂, 故在释放过程中易出现片芯内局部二甲双胍溶解过快从而使包衣膜内渗透压升高较快,在此情况下二甲双胍的释放量会突然增多,易增加不良反应的发生率。 Since the core metformin soluble in water, and the core contains a solubilizer to promote dissolution of metformin, it is prone to the fast dissolving metformin tablet core localized in the release process so that the coating film osmolality faster in this case, the release of metformin will suddenly increase, likely to increase the incidence of adverse reactions. 对上市产品的释放度测定结果如下: Determination of the release-to-market results are as follows:

[0014] [0014]

[0015] 另外按照下列处方分别制备了盐酸二甲双胍控释片并测定释放度。 [0015] Further according to the following formulation are controlled release tablets of metformin hydrochloride is prepared and measured release.

[0016] 片心处方:单位(mg/片) [0016] The tablet core formulation: Unit (mg / tablet)

[0017] [0017]

[0018] 制粒、压片、包衣、打孔步骤均与实施例1中方法相同。 [0018] granulating, tableting, coating, perforating method steps are the same as in Example 1. 参照实施例1中释放度测定方法对制得的片剂进行测定。 Reference Example 1 Determination of the release of the prepared tablets were measured.

[0019] 测定结果 [0019] Measurement results

[0020] 处方1释放度测定结果 [0020] Formulation 1 results in the release rates

[0021] [0021]

[0022] 处方2释放度测定结果 [0022] Prescription 2 release measurement result

[0023] [0023]

[0024] 处方3释放度测定结果 [0024] Release of the measurement result Prescription 3

[0025] [0025]

[0026] 处方4释放度测定结果 [0026] Release of the measurement result Prescription 4

[0027] [0027]

[0028] 由上述试验结果可见,按已有技术制备的二甲双胍控释片易于突释,各片释放不一致。 [0028] apparent from the above test results, metformin controlled release tablets prepared according to prior art is easy to burst, releasing the sheets inconsistent.

[0029] 本发明研究人员在大量试验的基础上,惊奇地发现片芯中加入适宜的聚氧乙烯后,可以有效的解决二甲双胍控释片易于突释或释放不一致的难题,通过相对简单的工艺实现了产品质量的稳定一致。 After [0029] Researchers present invention, in a large number of experiments, surprisingly found that the addition of suitable core polyoxyethylene, can effectively solve the metformin controlled release tablet inconsistent easily burst or release problems, by a relatively simple process to achieve a stable and consistent product quality.

[0030] 本发明提供了一种二甲双胍控释片组合物,它含有有效量的二甲双胍和适宜的聚氧乙烯,并选择性地含有一种或多种药学上可接受的辅料。 [0030] The present invention provides a controlled release tablet of metformin composition comprising an effective amount of a metformin and a suitable polyoxyethylene, and optionally containing one or more pharmaceutically acceptable excipient.

[0031] 聚氧乙烯(Polyethylene oxide)是-(0CH2CH2)_n的非离子均聚物,其中η代表氧乙基的平均数目,通常在2,000到约100,000之间。 [0031] polyoxyethylene (Polyethylene oxide) is - (0CH2CH2) _n nonionic homopolymers, wherein η represents the number average oxide group, typically between 2,000 to about 100,000. 它是水溶性树脂,分子量一般在约100, 000到约7,000,000之间,根据分子量的不同在水溶液中具有不同的黏度。 It is a water-soluble resin, a molecular weight generally from about 100, between about 000 to 7,000,000, in an aqueous solution having a different viscosity depending on the molecular weight. 商业化的聚氧乙烯常根据平均分子量的不同被划分为不同型号。 Commercial polyoxyethylene often depending on the average molecular weight is divided into different types. 例如,Dow化学公司的POLYOXtm 系列产品中,WSR N-10NF的分子量为约100,000,WSR N-80NF的分子量为约200,000, WSR N-750NF 的分子量为约300,000, WSR-205NF 的分子量为约600,000, WSR-1105NF 的分子量为约900,000,WSR Ν-12Κ NF的分子量为约1,000,000,WSR N-60KNF的分子量为约2,000,000,WSR-301NF 的分子量为约4,000,000,WSRCoagulant NF 的分子量为约5,000,000,WSR-303NF 的分子量为约7,000,000。 For example, Dow Chemical Company POLYOXtm series of products, WSR N-10NF molecular weight of about 100,000, WSR N-80NF molecular weight of about 200,000, WSR N-750NF molecular weight of about 300,000, WSR-205NF molecular weight of about 600,000, WSR-1105NF molecular weight of about 900,000, WSR Ν-12Κ NF molecular weight of about 1,000,000, WSR N-60KNF molecular weight of about 2,000,000, WSR-301NF molecular weight of about 4 , 000,000, WSRCoagulant NF molecular weight of about 5,000,000, WSR-303NF a molecular weight of about 7,000,000.

[0032] 本发明中聚氧乙烯选自分子量100,000〜7,000, 000中的一种或多种,优选分子量100,000〜300,000中的一种或多种,更优选分子量为20,000的一种聚氧乙烯。 [0032] In the present invention, the molecular weight of the polyoxyethylene selected 100,000~7,000, 000 of one or more, preferably a molecular weight of one or more 100,000~300,000, more preferably a molecular weight of one kind of polyoxyethylene 20,000.

[0033] 本发明中聚氧乙烯的用量根据所采用聚氧乙烯的分子量和预期达到的控释效果来决定,用量范围一般占片剂重量的0. 〜20%,优选占片剂重量的0. 5%〜10%。 [0033] In the present invention, the amount of polyoxyethylene is determined according to the molecular weight of polyoxyethylene and expected to achieve a controlled release effect employed in an amount ranging usually accounts for 0.5 ~ 20% by weight of the tablet, the tablet weight is preferably from 0 5% ~ 10%.

[0034] 本发明中的聚氧乙烯还可以是与其他渗透压活性的高分子材料合用的形式。 [0034] Polyoxyethylene in the present invention may be a polymer material in combination with other forms of osmotic activity. 其他渗透压活性的高分子材料包括羟丙甲纤维素、阿拉伯胶、聚维酮、海藻酸钠等。 Other polymeric materials include osmotic activity hypromellose, arabic gum, povidone, sodium alginate and the like.

[0035] 一种或多种药学可接受的辅料选自任何可用于控释片的药用辅料,包括但不限于填充剂、促渗剂、增溶剂、粘合剂、润滑剂等。 [0035] one or more pharmaceutically acceptable excipients may be selected from any pharmaceutically acceptable excipients for controlled release tablets, including but not limited to, fillers, permeation enhancers, solubilizers, binders, lubricants and the like.

[0036] 其中填充剂和促渗剂选自乳糖、甘露醇、氯化钠等,优选乳糖。 [0036] wherein the filler and the penetration enhancer is selected from lactose, mannitol, sodium chloride, and the like, preferably lactose.

[0037] 其中增溶剂选自十二烷基硫酸钠、十二烷基磺酸钠、吐温-80等,优选十二烷基硫酸钠。 [0037] wherein the solubilizing agent is selected from sodium lauryl sulfate, sodium dodecyl sulfate, Tween-80 and the like, preferably sodium lauryl sulfate.

[0038] 其中粘合剂选自聚维酮、预胶化淀粉、淀粉浆、低分子量羟丙甲纤维素等,优选聚维酮。 [0038] wherein the binder is selected from povidone, pregelatinized starch, starch paste and low molecular weight hydroxypropyl methylcellulose and the like, preferably povidone.

[0039] 其中润滑剂选自硬脂酸镁、硬脂酸、硬脂醇、氢化蓖麻油等,优选硬脂酸镁。 [0039] wherein the lubricant is selected from magnesium stearate, stearic acid, stearyl alcohol, hydrogenated castor oil and the like, preferably magnesium stearate.

[0040] 本发明的二甲双胍控释片组合物可用于糖尿病的治疗,制备成二甲双胍控释片后,具有释药速度稳定,释药速度不受胃肠道环境影响,患者依顺性高的特点。 Metformin controlled release tablet composition [0040] The present invention is useful for the treatment of diabetes, the controlled release tablets of metformin prepared, having a stable release rate, release rate from the gastrointestinal tract environmental impact, high The compliance characteristics of patients.

[0041] 本发明提供了一种二甲双胍控释片,包括单层片心和包裹在片心上的包衣膜,并在片剂一侧或两侧各有一释药孔。 [0041] The present invention provides a controlled release tablets of metformin, comprising a single core sheet and film coated tablet cores wrapping of the tablet and release one or both sides each having a hole. 片心含有有效量的二甲双胍和聚氧乙烯,并选择性地含有一种或多种药学上可接受的辅料。 Tablet core containing an effective amount of metformin and polyoxyethylene, and optionally containing one or more pharmaceutically acceptable excipient. 包衣膜是半透膜。 The coating film is a semi-permeable membrane.

[0042] 优选片心中含有二甲双胍、聚氧乙烯、粘合剂和增溶剂。 [0042] The substrate preferably contains metformin heart, polyoxyethylene, binder and solubilizer.

[0043] 本发明二甲双胍控释片中包衣膜是半透膜,主要含有包衣成膜材料。 [0043] The controlled-release metformin tablets coated film of the present invention is a semipermeable membrane, primarily comprises a coating film-forming material. 包衣成膜材 Coating material to be deposited

7料多为对水等液体具有半渗透性而对药物并不具有渗透作用的高分子材料。 7 feed the polymer material having a plurality of semi-permeable to water and other liquid does not have effect on the drug permeation. 为增加包衣膜的柔韧性,防止药物外泄而使片剂本身溶蚀,以及保证片剂内外有较大渗透压差,可加入增塑剂。 To increase the flexibility of the coated film, preventing the leakage of the drug dissolution tablet itself, and ensuring a greater osmotic pressure difference inside and outside the tablets, a plasticizer may be added. 若包衣膜采用非激光开孔,还需加入致孔剂。 If the non-film-coating of the laser piercing, need to join porogen.

[0044] 本发明中包衣成膜材料选自醋酸纤维素、丙烯酸树脂、乙基纤维素等,优选醋酸纤会佳ο [0044] In the present invention, a coating film forming material is selected from cellulose acetate, acrylic resin, ethyl cellulose, acetate fiber will preferably good ο

[0045] 增塑剂选自柠檬酸三乙酯、蓖麻油、吐温80、邻苯二甲酸酯等,优选柠檬酸三乙酯。 [0045] The plasticizer is selected from triethyl citrate, castor oil, Tween 80, phthalate, preferably triethyl citrate.

[0046] 致孔剂选自聚乙二醇400、聚乙二醇600、聚乙二醇1000和聚乙二醇1500等,优选聚乙二醇1500。 [0046] The porogen selected from polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000 and polyethylene glycol 1500 and the like, preferably polyethylene glycol 1500.

[0047] 本发明的二甲双胍控释片在包衣膜的表面,有一个或两个释药孔。 Metformin Controlled Release Tablet [0047] the present invention on the surface of the coating film, one or two release holes.

[0048] 本发明提供了本发明二甲双胍控释片的制备方法。 [0048] The present invention provides a method for preparing a controlled release metformin tablets according to the present invention.

[0049] 二甲双胍与聚氧乙烯、粘合剂、增溶剂等混勻后制粒、干燥,压成片心后包衣,最后在片剂的一面或双面打孔,制得二甲双胍控释片。 [0049] The metformin with polyoxyethylene, binder, solubilizer After mixing granulated, dried, pressed into tablet cores after coating, and finally punching one or both sides of the tablet, controlled release tablet of metformin prepared .

[0050] 打孔可以采用激光或机械的方式进行。 [0050] The puncturing may be performed using a laser or mechanical means. 早期文献曾报道用机械钻孔来制备渗透泵片,这种方法不适用机械化大生产,仅限于实验室小量试制;目前工业生产中常采用激光打孔的方式,该方法使用激光作为致孔的能量来源,对包衣膜的损伤小,工作效率高;也有文献报道采用改进了的冲头,在包衣前的片心上形成凹痕,包衣后直接形成释药孔。 Early literature has reported osmotic pump tablets were prepared by mechanical drilling, this method is not suitable mechanized production, is limited to a small laboratory trial; industrial production often uses laser drilling mode, the method uses a laser as a porogen energy source, little damage on the coating film, high efficiency; have reported improved using a punch, dents formed tablet cores before coating, the release hole is formed directly after coating.

[0051] 本发明中“有效量的二甲双胍”中的“有效量”是指服用片剂后能在体内形成有效治疗血药浓度的量。 [0051] In the present invention, "effective amount of metformin" in "an effective amount" refers to an amount effective therapeutic blood concentration after taking the tablets can be formed in vivo.

[0052] 本发明的二甲双胍控释片属于缓控释片剂。 Metformin Controlled Release Tablet [0052] The present invention belongs to the slow-release tablets. 由于有时控释片和缓释片难于区分, 虽然本发明的二甲双胍控释片释药更接近于零级动力学,但也可能被称为二甲双胍缓释片,此种情况下的二甲双胍缓释片仍属于本发明范围之内。 Since controlled-release tablets and sustained release tablets is sometimes difficult to distinguish, although the release of metformin controlled release tablets of the present invention is closer to zero order kinetics, but may also be referred to as a release metformin tablets, sustained release tablets of metformin in this case It falls within the scope of the present invention.

[0053] 实施例 [0053] Example

[0054] 下述实施例进一步介绍和阐述本发明,但不以任何方式限制本发明。 [0054] The following examples further illustrate the invention and described, but do not limit the present invention in any way.

[0055] 实施例中聚氧乙烯N80指Dow化学公司的POLYOX WSR N-80NF,分子量为约200, 000 ;聚氧乙烯WO指Dow化学公司的WSR N-10NF,分子量为约100,000。 [0055] Example N80 refers to polyoxyethylene Dow Chemical Company POLYOX WSR N-80NF, molecular weight of about 200, 000; WO polyoxyethylene refers Dow Chemical Company WSR N-10NF, molecular weight of about 100,000. 聚氧乙烯205 指Dow化学公司的WSR-205NF,分子量为约600,000。 Polyoxyethylene 205 refers to The Dow Chemical Company WSR-205NF, a molecular weight of about 600,000.

[0056] 实施例1 [0056] Example 1

[0057] 片心处方: [0057] prescription tablet core:

[0058] [0058]

[0059] 片心制备方法: Preparation [0059] The method of tablet core:

[0060] 1、取二甲双胍过80目筛; [0060] 1, taking metformin over 80 mesh sieve;

[0061] 2、按处方量称取二甲双胍、聚氧乙烯、聚维酮k90、十二烷基硫酸钠,混合均勻,加入适量的水制软材,过20目筛制粒,40°C鼓风干燥完全; [0061] 2, by prescription weighed metformin, polyethylene oxide, povidone K90, sodium lauryl sulfate, mixed, water was added q.s. made of soft material, granulated through a 20 mesh sieve, 40 ° C drum wind dried completely;

[0062] 3、待颗粒干燥完全后,20目筛整粒,与处方量的硬脂酸镁混合均勻,压片。 [0062] 3. After the granules were dried completely, 20 mesh sieve, mixed with the prescribed amount of magnesium stearate uniformly, tabletting.

[0063] 包衣液处方(1000ml包衣液用量) [0063] The coating solution formulation (1000ml amount of coating solution)

[0064] 醋酸纤维素 30g [0064] 30g of cellulose acetate

[0065]聚乙二醇 1500 4g [0065] Polyethylene glycol 1500 4g

[0066] 柠檬酸三乙酯 3g [0066] Triethyl citrate 3g

[0067] 丙酮 900ml [0067] 900ml of acetone

[0068] 水 IOOml [0068] Water IOOml

[0069] 配制方法: [0069] Preparation method:

[0070] 1、称取4g聚乙二醇1500,加水100ml,浸泡使之溶解完全,得溶液A ; [0070] 1. Weigh 4g polyethylene glycol 1500, water 100ml, soaked and dissolved completely to obtain a solution A;

[0071] 2、称取30g醋酸纤维素加900ml丙酮,搅拌至溶解完全,得溶液B ; [0071] 2. Weigh 30g of cellulose acetate in acetone 900ml was added and stirred until completely dissolved to obtain a solution B;

[0072] 3、将溶液A加入溶液B中,待溶液澄清后,加入3g的柠檬酸三乙酯,搅拌均勻,即得。 [0072] 3 and the solution A was added solution B, until the solution is clear, 3g of triethyl citrate was added, stirred uniformly, ie.

[0073] 包衣操作: [0073] The coating operation:

[0074] 采用薄膜包衣的常规操作方式进行包衣操作,以片剂包衣增重达到3.0%〜 5. 0%,包衣结束后,于40°C下固化24小时,即得。 [0074] The film-coating operation using a conventional coating operation is performed to the tablet coating weight gain of 3.0% ~ 5.0%, after coating, cured for 24 hours at 40 ° C, that is, too.

[0075]打孔: [0075] Punch:

[0076] 取包衣后的片剂,采用激光或机械方式在片剂的两侧各打一直径0. 4〜0. 8mm的小孔,即得二甲双胍控释片成品。 [0076] After taking the tablets coated using a laser or mechanical means to play each hole having a diameter 0. 4~0. 8mm on both sides of the tablet, controlled release tablet of metformin to obtain the finished product.

[0077] 释放度的测定 Determination of dissolution [0077]

[0078] 取样品,照释放度测定法(中国药典2010年版二部附录XD第一法)(采用溶出度测定法第一法的装置),以PH7. 4的磷酸盐缓冲溶液900ml为溶剂,转速为每分钟100转, 依法操作,在第2小时、4小时、6小时、8小时、10小时、12小时、14小时、16小时分别取溶液10ml,滤过,并即时在操作容器中补充pH7. 4的磷酸盐缓冲溶液10ml,取续滤液作为供试液。 [0078] Samples were taken, according to the release assay (Chinese Pharmacopoeia 2010 Appendix XD method) (a first method of using the apparatus dissolution assay), phosphate buffer solution to 900ml PH7. 4 is the solvent, speed of 100 revolutions per minute, according to operations in the first 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, respectively, take the solution 10ml, filtered, and instant operation supplemented vessel phosphate buffer solution 10ml pH7. 4, the filtrate taken as the test solution. 另精密称取二甲双胍对照品适量,加PH7. 4的磷酸盐缓冲溶液配制成30μ g/ml溶液, 作为对照品溶液。 Another accurately weighed metformin reference standard amount of phosphate buffer solution PH7. 4 is formulated to 30μ g / ml solution, as the reference solution. 取供试品与对照品溶液,照紫外分光光度法在250nm的波长处测定吸收度,按外标法计算每片不同时间的释放量。 For the test and reference solution, according to the UV spectrophotometric determination of spectral absorption at a wavelength of 250nm is calculated for each sheet release at different times by the external standard method.

[0079] 测定结果 [0079] The measurement result

[0080] [0080]

[0081] 实施例2 [0081] Example 2

[0082] 片心处方: [0082] prescription tablet core:

[0083] [0083]

[0084] 根据片心处方量按照实施例1的片心制备方法制备片心,采用与实施例1相同的包衣液,并使用与实施例1相同的包衣和打孔方法制备本实施例二甲双胍控释片成品。 [0084] The tablet core The tablet cores prepared according to prescriptions method for preparing the tablet cores of Example 1, using the same coating solution in Example 1, and coating was prepared using the same method of Example 1 and puncturing the present embodiment controlled release tablets of metformin finished.

[0085] 释放度测定结果 [0085] Release of the measurement result

[0086] [0086]

[0087] 实施例3 [0087] Example 3

[0088] 片心处方: [0088] prescription tablet core:

[0089] [0089]

[0090] 根据片心处方量按照实施例1的片心制备方法制备片心,采用与实施例1相同的包衣液,并使用与实施例1相同的包衣和打孔方法制备本实施例二甲双胍控释片成品。 [0090] The tablet core The tablet cores prepared according to prescriptions method for preparing the tablet cores of Example 1, using the same coating solution in Example 1, and coating was prepared using the same method of Example 1 and puncturing the present embodiment controlled release tablets of metformin finished.

[0091] 释放度测定结果 [0091] Release of the measurement result

[0092] [0092]

[0093] 实施例4 [0093] Example 4

[0094] 片心处方: [0094] prescription tablet core:

[0095] [0095]

[0096] 根据片心处方量按照实施例1的片心制备方法制备片心,采用与实施例1相同的包衣液进行包衣。 [0096] coated with the same coating liquid as in Example 1 according to the amount of tablet cores according to formulation preparation method of the tablet core The tablet cores of Example 1, using.

[0097] 打孔:取包衣后的片剂,采用激光或机械方式在片剂的一侧打一直径0. 4〜0. 8mm 的小孔,即得二甲双胍控释片成品。 [0097] Punch: after taking the tablets coated using a laser or mechanical means to play a hole diameter of 0. 4~0 8mm on one side of the tablet, controlled release tablet of metformin to obtain the finished product.

[0098] 释放度测定结果 [0098] Release of the measurement result

[0099] [0099]

[0100] 实施例5 [0100] Example 5

[0101] 片心处方: [0101] prescription tablet core:

[0102] [0102]

[0103] 根据片心处方量按照实施例1的片心制备方法制备片心,采用与实施例1相同的包衣液,并使用与实施例1相同的包衣和打孔方法制备本实施例二甲双胍控释片成品。 [0103] The tablet core The tablet cores prepared according to prescriptions method for preparing the tablet cores of Example 1, using the same coating solution in Example 1, and coating was prepared using the same method of Example 1 and puncturing the present embodiment controlled release tablets of metformin finished.

[0104] 释放度测定结果 [0104] Release of the measurement result

[0105] [0105]

[0106] 实施例6 [0106] Example 6

[0107] 片心处方: [0107] prescription tablet core:

[0108] [0108]

[0109] 根据片心处方量按照实施例1的片心制备方法制备片心,采用与实施例1相同的包衣液,并使用与实施例1相同的包衣和打孔方法制备本实施例二甲双胍控释片成品。 [0109] The tablet core The tablet cores prepared according to prescriptions method for preparing the tablet cores of Example 1, using the same coating solution in Example 1, and coating was prepared using the same method of Example 1 and puncturing the present embodiment controlled release tablets of metformin finished.

[0110] 释放度测定结果 [0110] Release of the measurement result

[0111] [0111]

[0112] 实施例7 [0112] Example 7

[0113] 片心处方: [0113] prescription tablet core:

[0114] [0114]

[0115] 根据片心处方量按照实施例1的片心制备方法制备片心,采用与实施例1相同的包衣液,并使用与实施例1相同的包衣和打孔方法制备本实施例二甲双胍控释片成品。 [0115] The tablet core The tablet cores prepared according to prescriptions method for preparing the tablet cores of Example 1, using the same coating solution in Example 1, and coating was prepared using the same method of Example 1 and puncturing the present embodiment controlled release tablets of metformin finished.

[0116] 释放度测定结果 [0116] Release of the measurement result

[0117] [0117]

[0118] 实施例8 [0118] Example 8

[0119] 片心处方: [0119] prescription tablet core:

[0120] [0120]

[0121] 根据片心处方量按照实施例1的片心制备方法制备片心,采用与实施例1相同的包衣液,并使用与实施例1相同的包衣和打孔方法制备本实施例二甲双胍控释片成品。 [0121] The tablet core The tablet cores prepared according to prescriptions method for preparing the tablet cores of Example 1, using the same coating solution in Example 1, and coating was prepared using the same method of Example 1 and puncturing the present embodiment controlled release tablets of metformin finished.

[0122] 释放度测定结果 [0122] Release of the measurement result

[0123] [0123]

Claims (9)

  1. 一种二甲双胍控释片,包括单层片心和包裹在片心上的包衣膜,并在片剂一侧或两侧有释药孔,其中片心含有有效量的二甲双胍和重量比为0.1%‑10%的聚氧乙烯,并选择性地含有或不含有一种或多种药学上可接受的辅料。 One kind of controlled release tablets of metformin, comprising a single core sheet and wrapped in a film coated tablet cores, and there are pores in the tablets release one or both sides, wherein the tablet core containing an effective amount of metformin and a weight ratio of 0.1 % -10% polyoxyethylene and optionally with or without one or more pharmaceutically acceptable excipient.
  2. 2.如权利要求1所述的控释片,其中包衣膜是半透膜,并在片剂一侧或两侧有释药孔。 The release sheet as claimed in claim 1, wherein the coating film is a semi-permeable membrane, and has pores in the tablets release one or both sides.
  3. 3.如权利要求1的控释片,片心由有效量的二甲双胍和重量比0. 的聚氧乙烯组成,并选择性地含有或不含有一种或多种药学上可接受的辅料。 The release sheet as claimed in claim 1, the tablet core an effective amount of metformin and the weight ratio of the polyoxyethylene 0. composition, and optionally containing or not containing one or more pharmaceutically acceptable excipient.
  4. 4.如权利要求2所述的控释片,半透膜由醋酸纤维素、增塑剂和致孔剂组成。 Controlled release tablets as claimed in claim 2, the semipermeable membrane of cellulose acetate, a plasticizer and a porogen.
  5. 5.如权利要求2所述的控释片,包衣膜中增塑剂是柠檬酸三乙酯,致孔剂是聚乙二醇1500。 5. The controlled release tablet according to claim 2, the plasticizer is triethyl citrate coating film, the porogen is polyethylene glycol 1500.
  6. 6.如权利要求3所述的控释片,片心中盐酸二甲双胍的重量在500mg-1000mg之间,平均分子量在100,000-600, 000的聚氧乙烯量为片剂重量的0. 〜20%。 6. The controlled-release tablets according to claim 3, the weight of metformin hydrochloride tablets heart between 500mg-1000mg, an average molecular weight of 100,000-600, 000 polyoxyethylene amount is 0.5 ~ 20 weight of the tablet %.
  7. 7.如权利要求3所述的控释片,片心中盐酸二甲双胍的重量在500mg-1000mg之间,平均分子量在100,000-600, 000的聚氧乙烯量优选为片剂重量的0. 5%〜10%。 7. The controlled-release tablets according to claim 3, the weight of metformin hydrochloride tablets heart between 500mg-1000mg, an average molecular weight of 100,000-600, 000 polyoxyethylene preferably in an amount of 0.5 wt tablet % ~ 10%.
  8. 8.如权利要求3所述的控释片,片心除含有有效量的二甲双胍和聚氧乙烯外,还含有增溶剂和润滑剂。 8. The controlled-release tablets according to claim 3, in addition to tablet core containing an effective amount of metformin and polyoxyethylene, also include a solubilizing agent and a lubricant.
  9. 9.如权利要求3所述的控释片,片心中含有的增溶剂为十二烷基硫酸钠,润滑剂为硬脂酸镁。 9. The controlled release tablet according to claim 3, solubilizers heart sheet contained sodium dodecyl sulfate, the lubricant is magnesium stearate.
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