WO2018177318A1 - 一种盐酸二甲双胍缓释片及其制备方法 - Google Patents

一种盐酸二甲双胍缓释片及其制备方法 Download PDF

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WO2018177318A1
WO2018177318A1 PCT/CN2018/080830 CN2018080830W WO2018177318A1 WO 2018177318 A1 WO2018177318 A1 WO 2018177318A1 CN 2018080830 W CN2018080830 W CN 2018080830W WO 2018177318 A1 WO2018177318 A1 WO 2018177318A1
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metformin hydrochloride
parts
sustained
components
ethyl cellulose
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PCT/CN2018/080830
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French (fr)
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冉诗念
陈用芳
何伟
杨绪凤
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重庆康刻尔制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the invention relates to an oral tablet, in particular to a metformin hydrochloride sustained release tablet and a preparation method thereof.
  • Metformin hydrochloride is a major diterpene hypoglycemic agent used clinically. It is also a basic drug used in combination therapy and combination therapy for type 2 diabetes in patients with type 2 diabetes recommended by many national diabetes guidelines. Metformin hydrochloride is a highly water-soluble drug with low bioavailability (50-60%), short half-life and large fluctuations (0.9-2.6 h). Clinically, large doses of repeated doses are needed to maintain effective blood concentration (3 times a day, 500 mg each time). Patients have poor compliance. The main side effect after taking the drug is gastrointestinal reaction, and lactic acidosis is caused by excess.
  • the sustained-release preparation can effectively reduce the side effects of metformin hydrochloride and reduce the accumulation of drugs.
  • the main absorption site of the drug is the small intestine, the absorption capacity of the colon is weak, and the common sustained-release preparation is mainly released in the colon, so the utilization rate is low. .
  • the solubility of metformin hydrochloride in water is >2.4mol/L. Therefore, the sustained-release dosage form is mainly composed of hydrophilic gel skeleton sustained-release tablets, but the usual skeleton sustained-release technology is difficult to control the release of drugs in the initial stage. When the weight of the control piece is less than 1g, the release in vitro is controlled to be more than 12h.
  • Patent No. CN200810140349.X discloses a metformin hydrochloride sustained-release tablet and a preparation method thereof, specifically, pulverizing and mixing a prescribed amount of metformin hydrochloride, a sustained-release material and a filler, adding a soft material made of a binder, granulating, and drying, The whole granules are mixed with a lubricant and compressed into tablets.
  • the sustained release tablets prepared by this method have an in vitro release rate of 20-40% and 40-65% in vitro (2015 Pharmacopoeia standard requirements: 2h, 10-35%; 6h, 40-70%), with burst release. phenomenon.
  • Oral metformin sustained-release preparation and preparation method thereof are disclosed in the application No. 02133574.5, and the process outline is to form a gel by absorbing water and swelling of a high-viscosity polymer material to prepare a sustained-release tablet which is taken only once a day.
  • This patent has the following problems: 1 The main drug component metformin hydrochloride is large (up to 500mg), the tablet is significant, which is not conducive to the compliance of patients taking drugs; the in vitro release rate of 21-3h is 10-60%, and there is a burst phenomenon.
  • Patent No. 200910104099.9 discloses a metformin hydrochloride sustained-release tablet which mainly relies on a film coating technique to achieve a sustained release effect, and the metformin hydrochloride sustained-release tablet prepared by the preparation method of the patent is released after being accelerated for 6 months and 24 months.
  • the degree is close to the standard value, there is a quality risk, and the tablet is easily contaminated.
  • the object of the present invention is to provide a metformin hydrochloride sustained-release tablet which can slowly release a drug in the body, maintain an effective blood drug concentration, and improve the compliance and safety of a patient's medication.
  • Another object of the present invention is to provide a safe, reliable, and large-scale production process of metformin hydrochloride sustained-release tablets.
  • metformin hydrochloride sustained-release tablet characterized in that the metformin hydrochloride sustained-release tablet is sustained release-released by a sustained release agent and a coating, wherein each component is in the following parts by weight for:
  • the components in the metformin hydrochloride sustained-release tablet are: in the following parts by weight: 150 parts of metformin hydrochloride, 8 parts of sodium carboxymethylcellulose, 15 parts of pregelatinized starch, 1.5 parts of hypromellose, and B. 3 parts of cellulose, 1.5 parts of polyethylene glycol 6000 and 1.5 parts of hexadecanol.
  • metformin hydrochloride sustained-release tablet has a hardness of 10 kgf to 18 kgf and a friability of ⁇ 1%.
  • a preparation method of metformin hydrochloride sustained-release tablets comprising the following steps:
  • Metformin hydrochloride, sodium carboxymethylcellulose, pregelatinized starch and hypromellose are weighed according to the ratio, and the ratio of each group to weight is 120-180 parts of metformin hydrochloride. 10-20 parts of cellulose sodium, 20-60 parts of pregelatinized starch, 2-4 parts of hypromellose;
  • step S2 taking the hypromellose weighed in step S1 to prepare a binder solution, wherein the solvent is purified water, and the mass fraction of the binder is 3-5%;
  • Metformin hydrochloride, sodium carboxymethylcellulose and pregelatinized starch are uniformly pulverized through a 85 mesh sieve, placed in a blender, stirred and uniformly mixed, added with a binder to make a soft material, sieved, granulated, and dried, and dried.
  • the granules are placed in a granulator for granulation, total mixing, tableting, and tableting, inspection;
  • the mass fraction of the binder solution is a 4% aqueous solution of hydroxypropylmethylcellulose.
  • the solute of the coating liquid is ethyl cellulose and
  • the solvent is a 95% ethanol solution.
  • step S4 the stirring and mixing time is 30 minutes, boiling and drying until the moisture content of the pellet is 2.8%-3.0%, the rotation speed of the granulator is 12-17HZ, and the whole pellet is passed through the 12-16 mesh sieve, and the total mixing is performed. The time is 15 minutes.
  • step S5 the rotation speed of the coating pan is 4-6 rpm, and the flow rate of the spray gun is 200-250 mL/min.
  • preparation method of the metformin hydrochloride sustained-release tablet comprises the following steps:
  • Metformin hydrochloride, sodium carboxymethylcellulose, pregelatinized starch, hypromellose are weighed according to the ratio, and the components are divided into: 100 parts by weight of metformin hydrochloride and 8 parts of sodium carboxymethylcellulose. , 15 parts of pregelatinized starch, 1.5 parts of hypromellose;
  • Metformin hydrochloride, sodium carboxymethylcellulose and pregelatinized starch are uniformly pulverized through a 85 mesh sieve, stirred and mixed for 30 minutes, added with a soft material made of a binder, sieved through a 15 mesh sieve, boiled and dried, and boiled and dried hot air.
  • the temperature is 55-65 ° C, dried to a moisture content of 2.8%, and the dried granules are granulated.
  • the speed of the granulator is 12-17 Hz, the whole granules are passed through a 15 mesh sieve, and the total mixing is 15 minutes.
  • the invention is based on the further improvement of the patent number CN200910104099.9, aiming at optimizing the formula of the patent, the ratio of the coating liquid and the preparation process of the metformin hydrochloride sustained-release tablet, mainly embodied in the following points: 1) the viscosity is changed in the formula The type of the mixture is selected from a 3-5% aqueous solution of hypromellose sodium as a binder to reduce the gap between the product particles and reduce the release rate of the product in vitro; 2) adjust the ratio of the coating liquid to expand the coating The proportion of other components in the liquid, and increased the weight proportion of the porogen PEG 6000 in other components, so that the prepared metformin hydrochloride sustained release tablets accelerated in the stability test for 6 months and 24 long periods.
  • the release rate of the month can be maintained at the middle value of the release standard, and there is no quality risk; 3)
  • the method of the invention strictly controls the end point of the boiling drying, so that the moisture content of the particles is 2.8-3.0%, which can effectively improve the product qualification. Rate, reduce loose edges and missing edges.
  • the invention not only has the patent CN200910104099.9, but also has the advantages of low material selection, low cost, high yield, simple method, easy control and mass production, and further optimizes the formulation and the preparation process of the sustained release sheet, and solves the present problem.
  • problems in the technology of sustained release tablets or the release of quality risks There are problems in the technology of sustained release tablets or the release of quality risks.
  • a preparation method of metformin hydrochloride sustained-release tablets comprising the following steps:
  • Metformin hydrochloride, sodium carboxymethylcellulose, pregelatinized starch and hypromellose are weighed according to the ratio, and the ratio of each group to weight is 120-180 parts of metformin hydrochloride. 10-20 parts of cellulose sodium, 20-60 parts of pregelatinized starch, 2-4 parts of hypromellose;
  • step S2 taking the hypromellose weighed in step S1 to prepare a binder solution, wherein the solvent is purified water, and the mass fraction of the binder is 3-5%;
  • the solvent is an ethanol/water solution having a mass fraction of 95%;
  • Metformin hydrochloride, sodium carboxymethylcellulose and pregelatinized starch are uniformly pulverized through a 85 mesh sieve, mixed in a mixer for 30 minutes, added with a soft material made of a binder, sieved through 13-15 mesh, and dried by boiling.
  • the dry hot air temperature is 55-65 ° C, and the moisture content of the granules is 2.8%-3.0%.
  • the dried granules are placed in a granulator for granulation.
  • the granule speed is 12-17 Hz, and the whole granules are 12- 16 mesh sieve, total mixing for 15 minutes, tableting into tablets, inspection;
  • Example 1 A metformin hydrochloride sustained-release tablet, wherein the weight ratio of each component is shown in Table 1.
  • the yield of metformin hydrochloride sustained-release tablets in Example 1 was 99.5%.
  • Example 2 Metformin hydrochloride sustained-release tablets, wherein the weight ratio of each component is shown in Table 2.
  • Example 3 Metformin hydrochloride sustained-release tablets, wherein the weight ratio of each component is shown in Table 3.
  • Example 4 Metformin hydrochloride sustained-release tablets, wherein the weight ratio of each component is shown in Table 4.
  • the yield of metformin hydrochloride sustained-release tablets in Example 4 was 99.5%.
  • Metformin hydrochloride sustained-release tablets were prepared according to the formulation and preparation method of the patent CN200910104099.9, wherein the weight ratio of each component is shown in Table 5.
  • metformin hydrochloride, compressible starch and lactose were crushed separately and passed through a 120 mesh sieve for use. After taking ethylcellulose and an appropriate amount of 95% ethanol (refrigerated overnight), 95% ethanol was added according to the above ratio. Make 5% of the coating solution, spare;
  • the granules are sieved by 14 mesh, dried at 55-60 ° C, and the controlled water content is less than 3%;
  • the tablet is placed in a coating pan for coating, and the flow rate of the coating liquid is adjusted to 200-250 ml/min, the speed of the coating machine is 4-6 rpm, and the inlet air temperature is 50-60 ° C.
  • the outlet air temperature is 40-50 ° C and the spray gun pressure is about 4 kpa.
  • the continuous spray flow rate control at 200 ml/min
  • the mixture is cooled to room temperature.
  • the yield of metformin hydrochloride sustained-release tablets prepared in the comparative example was 98.5%.
  • Examples 1-4 and corresponding in vitro release test results show that the dimethylhydrazine hydrochloride sustained-release tablet prepared by the formulation and method of the invention has high quality, perfect appearance and can meet the in vitro release standard and other items. Quality indicators and less weight gain, easy for patients to accept;
  • Example 7 shows that during the storage process, the release of each time point increases with the increase of time, and the increase is more obvious at 2h and 6h.
  • the products obtained in Example 1 and Example 4 of the present invention increased by about 2-6% at 2h and 6h, and the comparison value was worth about 9% in 2h and 6h, and after being placed for 24 months in a long time, Examples 1 and 4
  • the product release rate is within the standard range, and the release rate of the comparative product is close to the standard limit, and there is a quality risk.

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Abstract

本发明公开了一种盐酸二甲双胍缓释片及其制备方法，该缓释片是通过缓释剂和包衣达到缓释效果，所述缓释剂为羧甲纤维素钠和预胶化淀粉的组合，所述包衣液由乙基纤维素及其他组分溶解在质量分数95％乙醇中配制而成，所述其他组分为聚乙二醇6000和十六醇；所述羟丙甲纤维素溶于纯化水中制备为粘合剂。通过本发明得到的盐酸二甲双胍缓释片能使药物在体内缓慢释放，维持有效血药浓度，提高患者用药的顺应性及安全性。本发明产品的制备方法安全、可靠，能规模化生产。

Description

一种盐酸二甲双胍缓释片及其制备方法 技术领域
本发明涉及一种口服药片，特别涉及一种盐酸二甲双胍缓释片及其制备方法。
背景技术
盐酸二甲双胍是临床使用的主要双胍类降糖药，因不良反应小，也是多个国家糖尿病指南中推荐的Ⅱ型糖尿病患者控制高血糖的一线用药和联合用药中的基础用药。盐酸二甲双胍为极易水溶性药物，其生物利用度低(50-60％)，半衰期短且波动较大(0.9-2.6h)。临床上需要大剂量反复用药以维持有效血药浓度(每日3次，每次500mg)，患者顺应性差，服药后主要副作用为胃肠道反应，过量后引起乳酸中毒。
缓释制剂可有效降低盐酸二甲双胍的毒副作用，减少药物蓄积，但由于该药的主要吸收部位为小肠，结肠处的吸收能力很弱，而普通缓释制剂主要在结肠释药，因此利用率低。盐酸二甲双胍在水中的溶解度﹥2.4mol/L，因此其缓释剂型以亲水凝胶骨架缓释片为主，但采用通常的骨架缓释技术，对开始段的药物释放难以控制，很难在控制片重在1g以下的同时，控制体外释放达到12h以上。
专利号为CN200810140349.X公开了盐酸二甲双胍缓释片及其制备方法，具体为将处方量的盐酸二甲双胍、缓释材料和填充剂粉碎混匀，加入粘合剂制软材，制粒，干燥，整粒，加入润滑剂混合，压片得素片。通过该方法制得的缓释片1h、3h体外释放度为20-40％、40-65％(2015年药典标准要求：2h，10-35％；6h，40-70％)，有突释现象。
申请号为02133574.5公开了口服二甲双胍缓释剂及其制备方法，其工艺概要为利用高粘度高分子材料吸水膨胀形成凝胶，制成每天只需服用一次的缓释片。此专利存在如下问题：①主药成分盐酸二甲双胍占比大(高达500mg)，片重大，不利于患者服药的顺应性；②1-3h体外释放度为10-60％，有突释现象。
专利号为200910104099.9公开了一种主要依靠膜包衣技术达到缓释效果的盐酸二甲双胍缓释片，通过该专利中的制备方法制备的盐酸二甲双胍缓释片在加速6个月和24个月后释放度接近标准值，存在质量风险，且片剂易被污染。
发明内容
针对上述现有技术中存在的缺陷，本发明的目的旨在提供一种能使药物在体内缓慢释放，维持有效血药浓度，提高患者用药的顺应性及安全性的盐酸二甲双胍缓释片。
本发明的另一目的在于提供一种安全、可靠，能规模化生产的盐酸二甲双胍缓释片制备方法。
本发明的目的是这样实现的：一种盐酸二甲双胍缓释片，其特征在于：所述盐酸二甲双胍缓释片是通过缓释剂和包衣达到缓释效果，其中各组分按以下重量份计为：
Figure PCTCN2018080830-appb-000001
所述缓释剂为羧甲纤维素钠和预胶化淀粉的组合，所述包衣液由乙基纤维素及其他组分溶解在质量分数95％乙醇中配制而成，所述其他组分为聚乙二醇6000和十六醇；以乙基纤维素及其他组分为溶质，包衣液质量浓度为7-10％，其中，乙基纤维素:其他组分＝1:0.8-1，聚乙二醇6000:十六醇＝1:0.8-1.2；所述羟丙甲纤维素溶于纯化水中制备为粘合剂，所述粘合剂的质量分数为3-5％。
进一步的，所述盐酸二甲双胍缓释片中各组分按以下重量份计为：盐酸二甲双胍150份，羧甲纤维素钠8份，预胶化淀粉15份，羟丙甲纤维素1.5份，乙基纤维素3份，聚乙二醇6000 1.5份和十六醇1.5份。
进一步的，所述盐酸二甲双胍缓释片的硬度为10kgf-18kgf，脆碎度≤1％。
一种盐酸二甲双胍缓释片的制备方法，包括以下步骤：
S1：将盐酸二甲双胍、羧甲纤维素钠、预胶化淀粉、羟丙甲纤维素按配比称取，备用，其中，各组分配比按重量计比为：盐酸二甲双胍120-180份，羧甲纤维素钠10-20份，预胶化淀粉20-60份，羟丙甲纤维素2-4份；
S2：取步骤S1中称取的羟丙甲纤维素配制粘合剂溶液，其中溶剂为纯化水，粘合剂的质量分数为3-5％；
S3：将乙基纤维素、其他组分按配比称取，备用；所述其他组分为聚乙二醇6000和十六醇，其中，乙基纤维素∶其他组分＝1∶0.8-1.0，聚乙二醇6000∶十六醇＝1∶0.8-1.2，将称取完成的上述原料加入到质量分数为95％的乙醇/水溶液中配制成质量浓度为7-10％的包衣液，过125目筛，备用；所述包衣液的溶质为乙基纤维素和其他组分，溶剂为质量分数为95％的乙醇/水溶液；
S4：将盐酸二甲双胍、羧甲纤维素钠和预胶化淀粉统一粉碎过85目筛，放 入搅拌机搅拌混合均匀，加入粘合剂制软材，过筛制粒、沸腾干燥，将干燥后的颗粒放入整粒机进行整粒，总混，压片得素片，检验；
S5：素片检验合格后，将素片倒入包衣锅包衣，调整喷枪高度为140-200mm，对素片进行预热，热风温度为30-40℃,开启喷枪，开始喷浆，喷浆完成后，继续在30-40℃热风下干燥，冷至室温，包衣完成，检测、包装。
进一步的，在步骤S2中，粘合剂溶液的质量分数为4％的羟丙基甲纤维素水溶液。
进一步的，在步骤S3中，将乙基纤维素、其他组分按配比称取，备用；所述其他组分为聚乙二醇6000和十六醇，其中，乙基纤维素∶其他组分＝1∶0.8-1.0，聚乙二醇6000∶十六醇＝1∶0.8-1.2，在搅拌下，依次将称取完成的乙基纤维素、聚乙二醇6000、十六醇加入到浓度为95％的乙醇溶液中，搅拌至完全溶解，配制成质量浓度为7-10％的包衣液，浸泡过夜，过125目筛，备用；所述包衣液的溶质为乙基纤维素和其他组分，溶剂为浓度为95％的乙醇溶液。
进一步的，在步骤S4中，搅拌混合时间为30分钟，沸腾干燥至颗粒水分含量为2.8％-3.0％，整粒机的转速为12-17HZ，整粒后过12-16目筛，总混时间为15分钟。
进一步的，在步骤S5中，包衣锅体的转速为4-6转/分，喷枪的流量为200-250mL/分钟。
进一步的，所述盐酸二甲双胍缓释片的制备方法，包括下述步骤：
S1：将盐酸二甲双胍、羧甲纤维素钠、预胶化淀粉、羟丙甲纤维素按配比称取，备用，其中组分按重量计份为：盐酸二甲双胍150份，羧甲纤维素钠8 份，预胶化淀粉15份，羟丙甲纤维素1.5份；
S2：取S1中称取的羟丙甲纤维素配制粘合剂溶液，其中溶剂为纯化水，粘合剂的质量分数为4％；
S3：将乙基纤维素、其他组分按配比称取，备用，其他组分为聚乙二醇6000和十六醇，在搅拌下，依次将称取完成的乙基纤维素、聚乙二醇6000和十六醇加入95％的乙醇溶液，继续搅拌至完全溶解，浸泡过夜，过125目筛，备用，其中，按重量计份，乙基纤维素3份，聚乙二醇6000 1.5份，十六醇1.5份。
S4：将盐酸二甲双胍、羧甲纤维素钠和预胶化淀粉统一粉碎过85目筛，搅拌混合30分钟，加入粘合剂制软材，过15目筛制粒、沸腾干燥，沸腾干燥的热风温度为55-65℃，干燥至颗粒水分含量为2.8％，将干燥后的颗粒进行整粒，整粒机转速为12-17Hz，整粒过15目筛，总混15分钟，压片得素片，检验；
S5：素片检验合格后，将素片倒入包衣锅包衣，调整喷枪高度为140-200mm，对素片进行预热，锅体的转速为5转/分，热风温度为30-40℃,开启喷枪，开始喷浆，喷浆流量控制在200-250mL/分，锅体的转速为4-6转/分，喷浆完成后，继续在30-40℃热风下干燥，锅体的转速为5转/分，干燥完成后，冷至室温，包衣完成，检测、包装。
本发明是基于专利号CN200910104099.9的进一步改进，旨在优化专利中的配方、包衣液的配比及盐酸二甲双胍缓释片制备工艺，主要体现在以下几点：1)配方中改变了粘合剂的种类，选用质量分数为3-5％羟丙甲纤维素钠水溶液为粘合剂，减小产品颗粒间隙，降低产品体外释放速度；2)调整包衣液的配比，扩大包衣液中其他组分的占比，并且增加了其他组分中致孔剂聚乙二醇6000的重量占比，使得制备的盐酸二甲双胍缓释片在稳定性测试中加速6个月和长期 24个月的释放度都能保持在释放度标准的中间值,不存在质量风险；3)本发明方法，严格控制沸腾干燥的终点，使颗粒的水分含量为2.8-3.0％，能有效提高产品的合格率，减少松边和缺边现象。
总之，本发明不仅具备专利CN200910104099.9的选料价廉，成本低，收率高，方法简单、易控及可大批量生产等优势，而且进一步优化配方及缓释片制备工艺，解决了现有技术中缓释片突释或不释及质量风险等问题。
具体实施方式
下面结合具体实施例详述本发明，实施例1,2,3,4中盐酸二甲双胍缓释片的制备方法参见如下。
一种盐酸二甲双胍缓释片的制备方法，包括以下步骤：
S1：将盐酸二甲双胍、羧甲纤维素钠、预胶化淀粉、羟丙甲纤维素按配比称取，备用，其中，各组分配比按重量计比为：盐酸二甲双胍120-180份，羧甲纤维素钠10-20份，预胶化淀粉20-60份，羟丙甲纤维素2-4份；
S2：取步骤S1中称取的羟丙甲纤维素配制粘合剂溶液，其中溶剂为纯化水，粘合剂的质量分数为3-5％；
S3：将乙基纤维素、其他组分按配比称取，备用；所述其他组分为聚乙二醇6000和十六醇，其中，乙基纤维素∶其他组分＝1∶0.8-1.0，聚乙二醇6000∶十六醇＝1∶0.8-1.2；在搅拌下，依次将称取完成的乙基纤维素，聚乙二醇6000和十六醇加入到质量分数为95％的乙醇/水溶液中，继续搅拌至完全溶解，浸泡过夜，配制成质量浓度为7-10％的包衣液，过125目筛，备用；所述包衣液的溶质为乙基纤维素和其他组分，溶剂为质量分数为95％的乙醇/水溶液；
S4：将盐酸二甲双胍、羧甲纤维素钠和预胶化淀粉统一粉碎过85目筛，放 入搅拌机混合搅拌30分钟，加入粘合剂制软材，过13-15目筛制粒、沸腾干燥，干燥热风温度为55-65℃，干燥至颗粒水分含量为2.8％-3.0％，将干燥后的颗粒放入整粒机进行整粒，整粒机转速为12-17Hz，整粒过12-16目筛，总混15分钟，压片得素片，检验；
S5：素片检验合格后，将素片倒入包衣锅包衣，调整喷枪高度为140-200(170)mm，对素片进行预热，锅体的转速为4-6转/分，热风温度为30-40℃,开启喷枪，开始喷浆，喷浆流量控制在200-250mL/分，喷浆完成后，继续在30-40℃热风下干燥，冷至室温，包衣完成，检测、包装。
实施例1：一种盐酸二甲双胍缓释片，其中各组分重量配比见表一。
表                                                  一
Figure PCTCN2018080830-appb-000002
实施例1中盐酸二甲双胍缓释片的合格率为99.5％。
实施例2：盐酸二甲双胍缓释片，其中各组分重量配比见表二。
表                                              二
素片组分 重量分配比
盐酸二甲双胍 180
羧甲纤维素钠 10
预胶化淀粉 60
羟丙甲纤维素 2
包衣液组分 重量分配比
乙基纤维素 30
聚乙二醇6000 14
十六醇 16
95％乙醇 适量，加乙醇至包衣液浓度为7％，(包衣液-溶剂)/包衣液。
实施例2中盐酸二甲双胍缓释片的合格率为99.3％。
实施例3：盐酸二甲双胍缓释片，其中各组分重量配比见表三。
表                                                      三
素片组分 重量分配比
盐酸二甲双胍 150
羧甲纤维素钠 8
预胶化淀粉 15
羟丙甲纤维素 1.5
包衣液组分 重量分配比
乙基纤维素 3
聚乙二醇6000 1.5
十六醇 1.5
95％乙醇 适量，加乙醇至包衣液浓度为10％，(包衣液-溶剂)/包衣液。
实施例3中盐酸二甲双胍缓释片的合格率为99.8％。
实施例4：盐酸二甲双胍缓释片，其中各组分重量配比见表四。
表                                                     四
素片组分 重量分配比
盐酸二甲双胍 150
羧甲纤维素钠 15
预胶化淀粉 35
羟丙甲纤维素 4
包衣液组分 重量分配比
乙基纤维素 25
聚乙二醇6000 10
十六醇 10
95％乙醇 适量，加乙醇至包衣液浓度为10％，(包衣液-溶剂)/包衣液。
实施例4中盐酸二甲双胍缓释片的合格率为99.5％。
对比例：按照专利CN200910104099.9中的配方及制备方法制备盐酸二甲双胍缓释片，其中各组分重量配比见表五。
表                                                      五
素片组分 重量分配比
盐酸二甲双胍 150
乳糖 12
7％可压性淀粉浆 3.6
硬脂酸镁 3
包衣液组分 重量分配比
乙基纤维素 4.5
羟丙基纤维素 1.5
聚维酮 0.9
十六醇 1.2
95％乙醇 适量，加乙醇至包衣液浓度为5％，(包衣液-溶剂)/包衣液。
具体制备过程如下：
按上表配比将盐酸二甲双胍、可压性淀粉、乳糖分别粉碎，过120目筛，备用；取乙基纤维素和适量的95％乙醇(冷藏过夜)后，按上述配比补足95％乙醇使成5％的包衣液，备用；
取可压性淀粉，配制成7％的淀粉浆液，备用；
取盐酸二甲双胍、乳糖粉末，按等量递加原则混合均匀，用7％的淀粉浆液制成软材；
以14目筛制粒，于55-60℃干燥，控制含水量小于3％；
以16目筛整粒后，加入处方量的硬脂酸镁，混匀、压素片；
素片检查合格后，将片剂置于包衣锅中进行包衣，调节包衣液喷浆流量200-250ml/分钟，包衣机转速4-6转/分钟，进风温度50-60℃，出风温度40-50℃和喷枪压力约4kpa在素片不粘结的情况下，连续喷雾(流量控制在200ml/分钟)，喷浆完毕，冷却至室温出料。
对比例中制备的盐酸二甲双胍缓释片的合格率为98.5％。
表六 本发明各实施例制备的盐酸二甲双胍缓释片释放度测定结果
Figure PCTCN2018080830-appb-000003
表七 本发明各实施例及对比例中盐酸二甲双胍缓释片放置0天、加速6个月、长期24个月样品释放度检测结果
Figure PCTCN2018080830-appb-000004
由上述各实施例可得出如下结论：
1)实施例1-4及对应的体外释放度检测结果表明，通过本发明配方及方法制备的盐酸二甲胍缓释片产品质量高，外观光洁完美，能达到体外释放度标准及其他各项质量指标且增重较小，易于患者接受；
2)表七可以看出产品在存储过程中，随着时间的增加，各个时间点的释放度有所增加，其中在2h和6h增幅较明显。本发明实施例1、实施例4所得产品在2h和6h增幅约为2-6％，对比例值得产品在2h和6h增幅约为9％，在长期放置24个月后，实施例1及4产品释放度均在标准范围内，对比例产品释放度接近标准限度，存在质量风险。
以上所述仅为本发明的具体实施例而已，并不用于限制本发明，对于本领域的技术人员来说，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (9)

  1. 一种盐酸二甲双胍缓释片，其特征在于：所述盐酸二甲双胍缓释片是通过缓释剂和包衣达到缓释效果，其中，各组分按以下重量份计为：
    Figure PCTCN2018080830-appb-100001
    所述缓释剂为羧甲纤维素钠和预胶化淀粉的组合，所述包衣液由乙基纤维素及其他组分溶解在质量分数95％乙醇中配制而成，所述其他组分为聚乙二醇6000和十六醇；以乙基纤维素及其他组分为溶质，包衣液质量浓度为7-10％，其中，乙基纤维素:其他组分＝1:0.8-1，聚乙二醇6000:十六醇＝1:0.8-1.2；所述羟丙甲纤维素溶于纯化水中制备为粘合剂，所述粘合剂的质量分数为3-5％。
  2. 如权利要求1所述的一种盐酸二甲双胍缓释片，其特征在于：所述盐酸二甲双胍缓释片中各组分按以下重量份计为：盐酸二甲双胍150份，羧甲纤维素钠8份，预胶化淀粉15份，羟丙甲纤维素1.5份，乙基纤维素3份，聚乙二醇60001.5份和十六醇1.5份。
  3. 如权利要求1所述的一种盐酸二甲双胍缓释片，其特征在于： 所述盐酸二甲双胍缓释片的硬度为10kgf-18kgf，脆碎度≤1％。
  4. 如权利要求1-3任一项所述的一种盐酸二甲双胍缓释片的制备方法，其特征在于：包括以下步骤：
    S1：将盐酸二甲双胍、羧甲纤维素钠、预胶化淀粉、羟丙甲纤维素按配比称取，备用，其中，各组分配比按重量计比为：盐酸二甲双胍120-180份，羧甲纤维素钠10-20份，预胶化淀粉20-60份，羟丙甲纤维素2-4份；
    S2：取步骤S1中称取的羟丙甲纤维素配制粘合剂溶液，其中溶剂为纯化水，粘合剂的质量分数为3-5％；
    S3：将乙基纤维素、其他组分按配比称取，备用；所述其他组分为聚乙二醇6000和十六醇，其中，乙基纤维素∶其他组分＝1∶0.8-1.0，聚乙二醇6000∶十六醇＝1∶0.8-1.2，将称取完成的上述原料加入到质量分数为95％的乙醇/水溶液中配制成质量浓度为7-10％的包衣液，过125目筛，备用；所述包衣液的溶质为乙基纤维素和其他组分，溶剂为质量分数为95％的乙醇/水溶液；
    S4：将盐酸二甲双胍、羧甲纤维素钠和预胶化淀粉统一粉碎过85目筛，放入搅拌机搅拌混合均匀，加入粘合剂制软材，过筛制粒、沸腾干燥，将干燥后的颗粒放入整粒机进行整粒，总混，压片得素片，检验；
    S5：素片检验合格后，将素片倒入包衣锅包衣，调整喷枪高度为140-200mm，对素片进行预热，热风温度为30-40℃,开启喷枪，开始喷浆，喷浆完成后，继续在30-40℃热风下干燥，冷至室温，包衣 完成，检测、包装。
  5. 如权利要求4所述的一种盐酸二甲双胍缓释片的制备方法，其特征在于：在步骤S2中，粘合剂溶液的质量分数为4％的羟丙基甲纤维素水溶液。
  6. 如权利要求4所述的一种盐酸二甲双胍缓释片的制备方法，其特征在于：在步骤S3中，将乙基纤维素、其他组分按配比称取，备用；所述其他组分为聚乙二醇6000和十六醇，其中，乙基纤维素∶其他组分＝1∶0.8-1.0，聚乙二醇6000∶十六醇＝1∶0.8-1.2，在搅拌下，依次将称取完成的乙基纤维素、聚乙二醇6000、十六醇加入到浓度为95％的乙醇溶液中，搅拌至完全溶解，配制成质量浓度为7-10％的包衣液，浸泡过夜，过125目筛，备用；所述包衣液的溶质为乙基纤维素和其他组分，溶剂为浓度为95％的乙醇溶液。
  7. 如权利要求4所述的一种盐酸二甲双胍缓释片的制备方法，其特征在于：在步骤S4中，搅拌混合时间为30分钟，沸腾干燥至颗粒水分含量为2.8％-3.0％，整粒机的转速为12-17HZ，整粒后过12-16目筛，总混时间为15分钟。
  8. 如权利要求4所述的一种盐酸二甲双胍缓释片的制备方法，其特征在于：在步骤S5中，包衣锅体的转速为4-6转/分，喷枪的流量为200-250mL/分钟。
  9. 如权利要求4所述的一种盐酸二甲双胍缓释片的制备方法，其特征在于：所述盐酸二甲双胍缓释片的制备方法，包括下述步骤：
    S1：将盐酸二甲双胍、羧甲纤维素钠、预胶化淀粉、羟丙甲纤维 素按配比称取，备用，其中组分按重量计份为：盐酸二甲双胍150份，羧甲纤维素钠8份，预胶化淀粉15份，羟丙甲纤维素1.5份；
    S2：取S1中称取的羟丙甲纤维素配制粘合剂溶液，其中溶剂为纯化水，粘合剂的质量分数为4％；
    S3：将乙基纤维素、其他组分按配比称取，备用，其他组分为聚乙二醇6000和十六醇，在搅拌下，依次将称取完成的乙基纤维素、聚乙二醇6000和十六醇加入95％的乙醇溶液，继续搅拌至完全溶解，浸泡过夜，过125目筛，备用，其中，按重量计份，乙基纤维素3份，聚乙二醇6000 1.5份，十六醇1.5份。
    S4：将盐酸二甲双胍、羧甲纤维素钠和预胶化淀粉统一粉碎过85目筛，搅拌混合30分钟，加入粘合剂制软材，过15目筛制粒、沸腾干燥，沸腾干燥的热风温度为55-65℃，干燥至颗粒水分含量为2.8％，将干燥后的颗粒进行整粒，整粒机转速为12-17Hz，整粒过15目筛，总混15分钟，压片得素片，检验；
    S5：素片检验合格后，将素片倒入包衣锅包衣，调整喷枪高度为140-200mm，对素片进行预热，锅体的转速为5转/分，热风温度为30-40℃,开启喷枪，开始喷浆，喷浆流量控制在200-250mL/分，锅体的转速为4-6转/分，喷浆完成后，继续在30-40℃热风下干燥，锅体的转速为5转/分，干燥完成后，冷至室温，包衣完成，检测、包装。
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