WO2021258683A1 - 一种盐酸小檗碱谷维素片剂在治疗糖尿病中的应用 - Google Patents

一种盐酸小檗碱谷维素片剂在治疗糖尿病中的应用 Download PDF

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WO2021258683A1
WO2021258683A1 PCT/CN2020/137539 CN2020137539W WO2021258683A1 WO 2021258683 A1 WO2021258683 A1 WO 2021258683A1 CN 2020137539 W CN2020137539 W CN 2020137539W WO 2021258683 A1 WO2021258683 A1 WO 2021258683A1
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oryzanol
berberine hydrochloride
berberine
granules
hydrochloride
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PCT/CN2020/137539
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English (en)
French (fr)
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李琎杰
熊洪峰
杨春艳
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宜春万申制药机械有限公司
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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
    • A61K9/2072—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
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention belongs to the field of medicine, and relates to a prescription and preparation process of a berberine hydrochloride oryzanol tablet, and the application of the tablet in the treatment of diabetes.
  • Berberine hydrochloride is an isoquinoline alkaloid isolated from the traditional Chinese medicine Rhizoma Coptidis, and it is the main effective component of Coptidis antibacterial. It is yellow needle-like crystal with bitter taste. It is widely distributed in the plant kingdom. Berberine hydrochloride is often used for intestinal infections,
  • Oryzanol is a vitamin medicine extracted from rice bran oil. Its main components are cycloxylene alcohol ferulate and 2,4-methylene cycloxylamino alcohol ferulate. my country is a large rice producer in the world, and the source of raw materials used to extract oryzanol is extremely rich. Oryzanol mainly improves autonomic nerve function, reduces endocrine disorders, and improves symptoms of mental nerve disorders.
  • berberine hydrochloride and oryzanol have significant blood sugar lowering, lipid-lowering, weight loss and blood sugar lowering effects, and the combination of the two has a synergistic effect.
  • a combination of existing oryzanol preparations and berberine hydrochloride preparations is usually used to treat related diseases. If a compound preparation can be developed, it will greatly improve patient compliance.
  • oryzanol is a poorly soluble drug, almost insoluble in water, and its bioavailability is very low.
  • Berberine hydrochloride is poorly absorbed in the body and its bioavailability is also very low.
  • the preparation of the two into a compound preparation not only has to overcome the problems of low dissolution rate and low bioavailability of the drug, but also, because different drug materials have different properties, preparing them in the same preparation will inevitably face technical difficulties in the preparation of excipients, etc. . Therefore, if a compound preparation of berberine hydrochloride oryzanol with simple prescription process and high drug solubility and bioavailability can be provided, it will have a good market prospect.
  • the purpose of the present invention is to provide a berberine hydrochloride oryzanol compound preparation with simple preparation process, convenient use, and significantly improved bioavailability.
  • the invention disperses the drug in the surface active agent and the dispersant by mixing the surfactant, the dispersant and the drug, and then performs airflow pulverization and dry granulation, thereby improving the specific surface area and dispersibility of the drug. Further coating the coating liquid containing surfactants, dispersants, and hydrophilic film coating materials to form a hydrophilic coating layer on the surface of the drug particles, further improving the dispersibility and dissolution of the drug, and greatly improving the hydrochloric acid content.
  • the present invention provides a berberine hydrochloride oryzanol tablet, which comprises berberine hydrochloride oryzanol granules, a filler, a disintegrant, and a lubricant.
  • the berberine hydrochloride oryzanol granules are composed of berberine hydrochloride, oryzanol, surfactants, dispersants, and hydrophilic film coating materials, wherein the weight ratio of the berberine hydrochloride and oryzanol is 1:0.2- 0.8.
  • the weight ratio of berberine hydrochloride and oryzanol is 1:0.2-0.6.
  • the surfactant is selected from one of sodium lauryl sulfate and polysorbate 80 or a combination of both.
  • the dispersant is selected from one or more of microcrystalline cellulose, hypromellose, and poloxamer.
  • the hydrophilic film coating material is selected from one or more of hydroxyethyl cellulose and hydroxyethyl methyl cellulose.
  • the filler is one or more of microcrystalline cellulose, lactose, pregelatinized starch, and mannitol.
  • the disintegrant is one or more of croscarmellose sodium, crospovidone, hypromellose, and corn starch.
  • the lubricant is one or more of magnesium stearate and silicon dioxide.
  • Another object of the present invention is to provide a method for preparing oryzanol berberine hydrochloride tablets, which includes the following steps:
  • modified berberine hydrochloride oryzanol granules are mixed with fillers, disintegrants, and lubricants in a certain proportion and then compressed into tablets.
  • the particle size of the mixture after jet pulverization is D90 ⁇ 20 ⁇ m.
  • the weight gain of the coating is 3% to 5%.
  • the present invention has the following advantages and beneficial effects:
  • the prescription and preparation process are simple.
  • the combined application of berberine hydrochloride and oryzanol has the effect of synergistic treatment of diabetes.
  • the composition of the prescription is simple, which greatly improves the patient's compliance.
  • test methods in the following examples are all conventional methods, and the raw materials, reagent materials, etc. used in the following examples, unless otherwise specified, are all commercially available products.
  • the amount used in each example is a percentage by weight.
  • a berberine hydrochloride oryzanol tablet which has the following composition:
  • the berberine hydrochloride, oryzanol, internally added polysorbate 80, internally added hypromellose are mixed, and are subjected to jet pulverization and dry granulation.
  • Adding polysorbate 80 and adding hypromellose are dissolved in a 3% hydroxyethyl cellulose aqueous solution to obtain a coating solution.
  • the coating liquid is sprayed onto the particles obtained by dry granulation, and the weight gain of the coating is 3% to obtain modified particles of berberine hydrochloride oryzanol.
  • the above modified berberine hydrochloride oryzanol granules are mixed with lactose, croscarmellose sodium, and magnesium stearate and then compressed into tablets.
  • a berberine hydrochloride oryzanol tablet which has the following composition:
  • the berberine hydrochloride, oryzanol, sodium lauryl sulfate, and poloxamer are added to mix, and they are subjected to jet pulverization and dry granulation. Adding sodium lauryl sulfate and adding poloxamer are dissolved in a 5% hydroxyethyl methyl cellulose aqueous solution to obtain a coating solution. Using a fluidized bed spray method, the coating liquid is sprayed onto the particles obtained by dry granulation, and the weight gain of the coating is 3% to obtain modified particles of berberine hydrochloride oryzanol.
  • the above modified berberine hydrochloride oryzanol granules are mixed with lactose, croscarmellose sodium, and magnesium stearate and then compressed into tablets.
  • a berberine hydrochloride oryzanol tablet which has the following composition:
  • the berberine hydrochloride, oryzanol, sodium lauryl sulfate and hypromellose are added to the mixture, and the mixture is subjected to airflow pulverization and dry granulation. Adding sodium lauryl sulfate and adding hypromellose are dissolved in a 3% hydroxyethyl methylcellulose aqueous solution to obtain a coating solution. Using a fluidized bed spray method, the coating liquid is sprayed onto the particles obtained by dry granulation, and the weight gain of the coating is 3% to obtain modified particles of berberine hydrochloride oryzanol.
  • the above modified berberine hydrochloride oryzanol granules are mixed with microcrystalline cellulose, lactose, crospovidone, and magnesium stearate and then compressed into tablets.
  • a berberine hydrochloride oryzanol tablet which has the following composition:
  • the berberine hydrochloride, oryzanol, internally added polysorbate 80, internally added microcrystalline cellulose are mixed, airflow pulverized, and dry granulation is performed.
  • the externally added polysorbate 80 and the externally added microcrystalline cellulose are dissolved in a 3% hydroxyethyl cellulose aqueous solution to obtain a coating solution.
  • the coating liquid is sprayed onto the particles obtained by dry granulation, and the weight gain of the coating is 3% to obtain modified particles of berberine hydrochloride oryzanol.
  • the above modified berberine hydrochloride oryzanol granules are mixed with lactose, crospovidone, and magnesium stearate and then compressed into tablets.
  • a berberine hydrochloride oryzanol tablet which has the following composition:
  • the berberine hydrochloride, oryzanol, internal polysorbate 80, internal poloxamer are mixed, airflow pulverization, and dry granulation are performed.
  • Adding polysorbate 80 and adding poloxamer are dissolved in a 3% hydroxyethyl cellulose aqueous solution to obtain a coating solution.
  • the coating liquid is sprayed onto the particles obtained by dry granulation, and the weight gain of the coating is 3% to obtain modified particles of berberine hydrochloride oryzanol.
  • the above modified berberine hydrochloride oryzanol granules are mixed with lactose, croscarmellose sodium, and magnesium stearate and then compressed into tablets.
  • Comparative Example 1 Tablets after direct mixing.
  • the formulation is the same as in Example 1, and the preparation method is as follows: mix berberine hydrochloride, oryzanol, polysorbate 80, hypromellose, lactose, croscarmellose sodium, and magnesium stearate and directly compress the tablets .
  • Comparative Example 2 Tablets without coating.
  • composition of the prescription is the same as that of Example 1, and the preparation method is as follows: mix berberine hydrochloride, oryzanol, polysorbate 80, and hypromellose, perform jet pulverization, and dry granulation.
  • the granules are mixed with lactose, croscarmellose sodium, and magnesium stearate and then compressed into tablets.
  • the formulation is the same as in Example 1, and the preparation method is as follows: mix berberine hydrochloride, oryzanol, polysorbate 80, and hypromellose, and dry granulate. Adding polysorbate 80 and adding hypromellose are dissolved in a 3% hydroxyethyl cellulose aqueous solution to obtain a coating solution. Using a fluidized bed spray method, the coating liquid is sprayed onto the particles obtained by dry granulation, and the coating weight gain is 3%. The granules are mixed with lactose, croscarmellose sodium, and magnesium stearate and then compressed into tablets.
  • Example 1 Except that it does not contain berberine hydrochloride, the rest of the prescription composition and preparation method are the same as in Example 1.
  • the preparation method is as follows:
  • Example 1-5 and Comparative Examples 1-3 The content uniformity of oryzanol in the tablets of Examples 1-5 and Comparative Examples 1-3 was measured. Take 6 tablets each prepared in Example 1-5 and Comparative Example 1-3, grind with about 30ml of n-heptane, transfer to a 50ml measuring flask, heat in a water bath at 70°C for 10 minutes to dissolve, leave to cool, and add n-heptane Dilute the alkane to the mark, shake it, take 1ml of the additional filtrate, put it in a 10ml measuring flask, add n-heptane to the mark, shake it, measure the absorbance at a wavelength of 315nm, and bring it into the regression equation calculation. The results are shown in Table 1.
  • Comparative Example 2 does not include the step of coating a hydrophilic material, and no hydrophilic coating is formed on the surface of the particles, resulting in that the roundness and hydrophilicity of the particles are not as good as the examples of this application, and the friability is poor, and the content of the tablet Poor uniformity.
  • Table 1 The cumulative dissolution percentage of the tablets prepared in Examples 1 to 5
  • mice SPF mice aged 4-6 weeks, male, weighing 18-22g.
  • mice After adaptive feeding of the mice for 7 days, fasting without water for 24 hours, 10 mice were randomly selected as normal control group, and the same amount of normal saline was injected intraperitoneally, and each of the remaining mice was injected intraperitoneally with 200 mg/kg alloxan. Saline was prepared into a 2% solution, and normal eating was restored after injection. After 72 hours, the mice were cut off the tail tip to take blood, and the fasting blood glucose was measured by the blood glucose meter. Before the measurement, the fasting blood glucose value was higher than 11.1mmol/L and the mice with fasting blood glucose value greater than 11.1mmol/L were successfully modeled hyperglycemic mice.
  • the first group (negative control group): normal mice, fed with normal saline;
  • the second group (diabetes model group): hyperglycemia mice, gavage normal saline
  • the third group (positive control group): glimepiride, 5mg/kg
  • Control group berberine hydrochloride tablets of comparative example 4, oryzanol tablets of comparative example 5;
  • Examples 1-5 of the present invention can significantly reduce the hypoglycemia level of experimental animals after administration, which is similar to the positive control glibenclamide at low doses, and the blood glucose of animals decreases significantly at high doses.
  • the blood sugar lowering effect is not as good as the combination of the two, indicating that the combination of the two achieves a synergistic effect.

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Abstract

一种盐酸小檗碱（I）谷维素片剂及其在治疗糖尿病中的应用，盐酸小檗碱谷维素片剂由一定比例的改性盐酸小檗碱谷维素颗粒和其他辅料混合压片而成，所述改性颗粒由药物，表面活性剂，分散剂组成，该改性颗粒能够很好的改善盐酸小檗碱和谷维素的溶解度，提高药物的溶出度和生物利用度。该片剂通过药物的配伍，合理的处方和制备工艺，达到了很好的治疗糖尿病的效果。

Description

一种盐酸小檗碱谷维素片剂在治疗糖尿病中的应用 技术领域
本发明属于医药领域，涉及一种盐酸小檗碱谷维素片剂的处方及制备工艺，及该片剂在治疗糖尿病药物中的应用。
背景技术
盐酸小檗碱(黄连素，Berberine)是从中药黄连中分离的一种异喹啉生物碱，是黄连抗菌的主要有效成分。为黄色针状结晶，味苦。在植物界中分布较广。盐酸小檗碱常用于肠道感染，
Figure PCTCN2020137539-appb-000001
谷维素(Oryzanol，OZ)是从米糠油提取的一种维生素类药物，其主要成分是环木菠萝烯醇阿魏酯、2，4-亚甲基环木菠萝醇阿魏酸酯。我国是世界稻米生产大国，用于提取谷维素的原料来源极其丰富。谷维素主要改善自主神经功能，可减少内分泌紊乱，改善精神神经失调症状。
现有技术证明盐酸小檗碱和谷维素均有显著的降血糖、调脂、减重和降糖效应，两者联用具有协同作用。现有技术中通常采用将现有的谷维素制剂和盐酸小檗碱制剂联用，治疗相关疾病。若能开发出一种复方制剂，将大大提高病人的顺应性。
然而，谷维素属于难溶性药物，几乎不溶于水，生物利用度很低。盐酸小檗碱在体内吸收差，生物利用度也非常低。将两者制备成复方制剂不仅要克服药物的溶出度低，生物利用度低的问题，同时，不同药物原料药性质不同，将其制备在同一制剂中必然也面临辅料选择等制剂上的技术困难。因此，若能提供一种处方工艺简单，药物溶解度和生物利用度高的盐酸小檗碱谷维素复方制剂，将具有很好的市场前景。
发明内容
本发明的目的是提供一种制备工艺简单、使用方便，生物利用度显著提高的盐酸小檗碱谷维素复方制剂。
本发明通过将表面活性剂、分散剂与药物混合后进行气流粉碎，干法制粒，将药物分散在表面活性剂和分散剂中，提高药物的比表面积和分散性。进一步包衣含有表面活性剂、分散剂、亲水性薄膜包衣材料的包衣液，在药物颗粒表面形成亲水性包衣层，进一步提高药物的分散性和溶出度，大大提高了盐酸小檗碱和谷维素的生物利用度。
本发明提供一种盐酸小檗碱谷维素片剂，包含盐酸小檗碱谷维素颗粒，填充剂，崩解剂，润滑剂。
所述盐酸小檗碱谷维素颗粒由盐酸小檗碱，谷维素，表面活性剂，分散剂，亲水性薄膜包衣材料组成，其中，所述盐酸小檗碱和谷维素的重量比为1：0.2-0.8。
优选的，所述盐酸小檗碱和谷维素的重量比为1：0.2-0.6。
所述表面活性剂选自十二烷基硫酸钠，聚山梨酯80中的一种或两者的组合。
所述分散剂选自微晶纤维素，羟丙甲纤维素，泊洛沙姆中的一种或多种。
所述亲水性薄膜包衣材料选自羟乙基纤维素，羟乙基甲基纤维素中的一种或多种。
所述填充剂为微晶纤维素，乳糖，预胶化淀粉，甘露醇中的一种或多种。
所述崩解剂为交联羧甲基纤维素钠，交联聚维酮，羟丙甲纤维素，玉米淀粉中的一种或多种。
所述润滑剂为硬脂酸镁，二氧化硅中的一种或多种。
本发明的另一目的是提供一种制备谷维素盐酸小檗碱片剂的制备方法，包括如下步骤：
(1)盐酸小檗碱谷维素颗粒的制备：将盐酸小檗碱、谷维素、部分表面活性剂、分散剂混合，进行气流粉碎，干法制粒，得到颗粒；
(2)将剩余的表面活性剂，分散剂溶于亲水性薄膜包衣材料溶液中，搅拌至溶解，得到包衣液；采用流化床喷雾的方式，将包衣液喷雾到颗粒上，即得改性盐酸小檗碱谷维素颗粒；
(3)将改性盐酸小檗碱谷维素颗粒按照一定的比例与填充剂，崩解剂，润滑剂混合后压片。
优选的，气流粉碎后混合物的粒径为D90≤20μm。
优选的，包衣增重为3％-5％。
与现有技术相比，本发明具有如下优点和有益效果：
(1)选择具有增溶作用的表面活性剂，以及具有强烈亲水性的分散剂，能够显著提高盐酸小檗碱和谷维素的分散性和溶出度。
(2)将表面活性剂、分散剂与盐酸小檗碱和谷维素混合后进行气流粉碎，干法制粒，能够很好的将盐酸小檗碱和谷维素分散在表面活性剂和分散剂中，提高盐酸小檗碱或谷维素的比表面积和分散性。
(3)将表面活性剂和分散剂溶解在亲水性薄膜包衣材料溶液中，采用流化床喷雾的方法包衣盐酸小檗碱谷维素颗粒上，能够在颗粒表面形成亲水性包衣层，表面活性剂和分散剂遇水后迅速溶解，进一步提高亲水性和溶出度，进而提高药物的生物利用度。
(4)处方和制备工艺简单，盐酸小檗碱和谷维素两者联合应用具有协同治疗糖尿病的效果，处方组成简单，大大提高了病人的顺应性。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细阐述，给出的实施例仅为了阐述本发明，而不是为了限制本发明的范围。下述实施例中的试验方法，如无特殊说明，均为常规方法，下述实施例中所用的原料、试剂材料等，如无特殊说明，均为市售购买产品。各实施例中用量均为重量百分含量。
实施例1
一种盐酸小檗碱谷维素片剂，其组成如下：
Figure PCTCN2020137539-appb-000002
制备方法：
(1)盐酸小檗碱谷维素颗粒的制备
将盐酸小檗碱、谷维素、内加聚山梨酯80，内加羟丙甲纤维素混合，进行气流粉碎，干法制粒。将外加聚山梨酯80，外加羟丙甲纤维素溶于3％羟乙基纤维素水溶液中，得到包衣溶液。采用流化床喷雾的方式，将上述包衣液喷雾到干法制粒得到的粒子上，包衣增重为3％，得盐酸小檗碱谷维素改性颗粒。
(2)片剂的制备
将上述盐酸小檗碱谷维素改性颗粒与乳糖，交联羧甲基纤维素钠，硬脂酸镁混合后压片。
实施例2：
一种盐酸小檗碱谷维素片剂，其组成如下：
Figure PCTCN2020137539-appb-000003
制备方法：
(1)盐酸小檗碱谷维素颗粒的制备
将盐酸小檗碱、谷维素、内加十二烷基硫酸钠，内加泊洛沙姆混合，进行气流粉碎，干法制粒。将外加十二烷基硫酸钠，外加泊洛沙姆溶于5％羟乙基甲基纤维素水溶液中，得到包衣溶液。采用流化床喷雾的方式，将上述包衣液喷雾到干法制粒得到的粒子上，包衣增重为3％，得盐酸小檗碱谷维素改性颗粒。
(2)片剂的制备
将上述盐酸小檗碱谷维素改性颗粒与乳糖，交联羧甲基纤维素钠，硬脂酸镁混合后压片。
实施例3：
一种盐酸小檗碱谷维素片剂，其组成如下：
Figure PCTCN2020137539-appb-000004
制备方法：
(1)盐酸小檗碱谷维素颗粒的制备
将盐酸小檗碱、谷维素、内加十二烷基硫酸钠，内加羟丙甲纤维素混合，进行气流粉碎，干法制粒。将外加十二烷基硫酸钠，外加羟丙甲纤维素溶于3％羟乙基甲基纤维素水溶液中，得到包衣溶液。采用流化床喷雾的方式，将上述包衣液喷雾到干法制粒得到的粒子上，包衣增重为3％，得盐酸小檗碱谷维素改性颗粒。
(2)片剂的制备
将上述盐酸小檗碱谷维素改性颗粒与微晶纤维素，乳糖，交联聚维酮，硬脂酸镁混合后压片。
实施例4：
一种盐酸小檗碱谷维素片剂，其组成如下：
Figure PCTCN2020137539-appb-000005
制备方法：
(2)盐酸小檗碱谷维素颗粒的制备
将盐酸小檗碱、谷维素、内加聚山梨酯80，内加微晶纤维素混合，进行气流粉碎，干法制粒。将外加聚山梨酯80，外加微晶纤维素溶于3％羟乙基纤维素水溶液中，得到包衣溶液。采用流化床喷雾的方式，将上述包衣液喷雾到干法制粒得到的粒子上，包衣增重为3％，得盐酸小檗碱谷维素改性颗粒。
(2)片剂的制备
将上述盐酸小檗碱谷维素改性颗粒与乳糖，交联聚维酮，硬脂酸镁混合后压片。
实施例5：
一种盐酸小檗碱谷维素片剂，其组成如下：
Figure PCTCN2020137539-appb-000006
制备方法：
(1)盐酸小檗碱谷维素颗粒的制备
将盐酸小檗碱、谷维素、内加聚山梨酯80，内加泊洛沙姆混合，进行气流粉碎，干法 制粒。将外加聚山梨酯80，外加泊洛沙姆溶于3％羟乙基纤维素水溶液中，得到包衣溶液。采用流化床喷雾的方式，将上述包衣液喷雾到干法制粒得到的粒子上，包衣增重为3％，得盐酸小檗碱谷维素改性颗粒。
(2)片剂的制备
将上述盐酸小檗碱谷维素改性颗粒与乳糖，交联羧甲基纤维素钠，硬脂酸镁混合后压片。
对比例1：直接混合后压片。
处方组成同实施例1，制备方法如下：将盐酸小檗碱、谷维素、聚山梨酯80、羟丙甲纤维素，乳糖，交联羧甲基纤维素钠，硬脂酸镁混合后直接压片。
对比例2：不包衣压片。
处方组成同实施例1，制备方法如下：将盐酸小檗碱、谷维素、聚山梨酯80、羟丙甲纤维素混合，进行气流粉碎，干法制粒。将该颗粒与乳糖，交联羧甲基纤维素钠，硬脂酸镁混合后压片。
对比例3：不进行气流粉碎后压片
处方组成同实施例1，制备方法如下：将盐酸小檗碱、谷维素、聚山梨酯80、羟丙甲纤维素混合，干法制粒。将外加聚山梨酯80，外加羟丙甲纤维素溶于3％羟乙基纤维素水溶液中，得到包衣溶液。采用流化床喷雾的方式，将上述包衣液喷雾到干法制粒得到的粒子上，包衣增重为3％。将该颗粒与乳糖，交联羧甲基纤维素钠，硬脂酸镁混合后压片。
对比例4：盐酸小檗碱单独压片
除了不含谷维素外，其余的处方组成和制备方法同实施例1。
对比例5：谷维素单独压片
除了不含盐酸小檗碱外，其余的处方组成和制备方法同实施例1，制备方法如下：
实验例1：
标准曲线的绘制
1.谷维素标准曲线的绘制
精密称取谷维素原料药20mg，置100mL的量瓶中，加正庚烷适量，于70℃的水浴中加热10min使溶解，放冷，再加正庚烷至刻度，摇匀，制成浓度为0.2mg/ml的标准贮备液。精密量取1，2，3，4，5ml，分别置于50ml量瓶中，加正庚烷稀释至刻度，摇匀，测定在315nm波长处的吸收度(A)。以A(Y)对浓度C(X，μg/mL)进行线性回归，得谷维素吸光度和浓度的回归方程和标准曲线。
2.盐酸小檗碱标准曲线的绘制
精确称取盐酸小檗碱20mg，置于50ml的量瓶中，以适量的80％乙醇溶解后定容。准确吸取1，2，3，4，5ml上述标准液，用80％乙醇稀释并定容至50ml，测定在348nm处的吸光度(A)，以A(Y)对浓度C(X，μg/mL)进行线性回归，得盐酸小檗碱吸光度和浓度的回归方程和标准曲线。
实验例2：
含量均匀度测定
测量实施例1-5，对比例1-3的片剂中谷维素的含量均匀度。取实施例1-5，对比例1-3制备得到的片剂各6片，用正庚烷约30ml研磨，转移到50ml量瓶中，70℃水浴加热10min 使溶解，放冷，加正庚烷稀释至刻度，摇匀，取续滤液1ml，置10ml量瓶中，加正庚烷至刻度，摇匀，在315nm波长处测定吸收度，并带入回归方程计算，结果如表1显示。
表1片剂的含量均匀度
Figure PCTCN2020137539-appb-000007
由上表可以看出：本发明实施例1-5制备得到的盐酸小檗碱谷维素片剂含量均一，然而，对比例1-3制备得到的片剂不同片剂之间差异很大。其主要原因是对比例1直接混合，对比例3未进行气流粉碎后即进行干法制粒，谷维素溶解度和分散性差，与表面活性剂和分散剂混合不均匀。对比例2不包含包裹亲水性材料包衣步骤，颗粒表面没有形成亲水性包衣，导致颗粒的圆整度和亲水性不如本申请实施例，脆碎度差，进而片剂的含量均匀度差。
实验例2
片剂溶出度的测定
参照《中国药典》2010版二部附录XC第二法,于温度(37±0.5)、转速100r/min下分别测定本发明实施例1-6，对比例1、4的盐酸小檗碱和谷维素体外溶出曲线。为了提高谷维素在溶出介质的溶解性，选取500mL含0.5％聚山梨酯-80的磷酸缓冲盐溶液(pH 7.4)为溶出介质，于转篮中进行试验,在0，15，30，45，60，90，120min各取样5mL，同时补加5mL同等温度的新鲜溶出介质。样品经0.22μm滤膜过滤后，测定盐酸小檗碱和谷维素的溶出量，并计算累计溶出百分率。
表1实施例1～5制备的片剂累计溶出百分率
Figure PCTCN2020137539-appb-000008
Figure PCTCN2020137539-appb-000009
由上表可以看出，本发明实施例1-5制备得到的片剂溶出度良好，均在120min内达到80％以上。而对比例1-3制备得到的片剂，溶出度在120min时均在65％以下。原因为：对比例1直接混合，对比例2不包含亲水性包衣，对比例3未进行气流粉碎后即进行干法制粒，盐酸小檗碱和谷维素在片剂中分散性差，含量均匀度差，进而导致溶出速率低。生物利用度低，
实验例3：
药效学实验
实验动物：4-6周龄SPF级别小鼠，雄性，体重在18-22g。
1.四氧嘧啶诱导小鼠糖尿病模型的建立。
将小鼠适应性喂养7天后，禁食不禁水24h，随机取10只作为正常对照组，腹腔注射等量生理盐水,其余小鼠每只腹腔注射200mg/kg四氧嘧啶，临用前用生理盐水配制成2％的溶液，注射后恢复正常进食。72h后，小鼠剪尾尖取血，血糖仪测量空腹血糖值，测定前禁食不禁水12h，空腹血糖值大于11.1mmol/L的小鼠为成功造模的高血糖小鼠。
2.实验组别
第一组(阴性对照组)：正常小鼠，灌胃生理盐水；
第二组(糖尿病模型组)：高血糖小鼠，灌胃生理盐水
第三组(阳性对照组)：格列美脲，5mg/kg
实验组：本发明实施例1-5的盐酸小檗碱谷维素片剂；
对照组：对比例4的盐酸小檗碱片剂，对比例5的谷维素片剂；
每组8只。
3.降血糖实验
给药方式：灌胃，每天2次，每次间隔12小时。连续给药14天，各组饲喂基础饲料和自由饮水，给药7天和14天后测定小鼠空腹血糖值。实验结果如下：
表2实施例1～5制备的片剂对高血糖模型小鼠血糖浓度的影响
Figure PCTCN2020137539-appb-000010
Figure PCTCN2020137539-appb-000011
由上表可知，本发明实施例1-5能够在给药后显著降实验动物低血糖水平，在低剂量时与阳性对照格列本脲类似，高剂量时动物血糖显著下降。而单独使用盐酸小檗碱或谷维素，降血糖效果均不如两者组合，说明两者的组合达到了协同增效的效果。
以上所述仅为本发明的优选实施例，并不用于限制本发明，对本领域技术人员来说，本发明可以有各种更改和变化，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围内。

Claims (7)

  1. 一种盐酸小檗碱谷维素片剂，其特征在于，处方组成如下：盐酸小檗碱谷维素颗粒，填充剂，崩解剂，润滑剂；
    所述盐酸小檗碱谷维素颗粒由盐酸小檗碱，谷维素，表面活性剂，分散剂，亲水性薄膜包衣材料组成，其中，所述盐酸小檗碱和谷维素的重量比为1：0.2-0.8。
  2. 如权利要求1所述的谷维素盐酸小檗碱片剂，其特征在于，所述表面活性剂选自十二烷基硫酸钠，聚山梨酯80中的一种或两者的组合；所述分散剂选自微晶纤维素，羟丙甲纤维素，泊洛沙姆中的一种或多种；所述亲水性薄膜包衣材料选自羟乙基纤维素，羟乙基甲基纤维素中的一种或多种。
  3. 如权利要求1所述的谷维素盐酸小檗碱片剂，其特征在于，所述填充剂为微晶纤维素，乳糖，预胶化淀粉，甘露醇中的一种或多种；所述崩解剂为交联羧甲基纤维素钠，交联聚维酮，羟丙甲纤维素，玉米淀粉中的一种或多种；所述润滑剂为硬脂酸镁，二氧化硅中的一种或多种。
  4. 如权利要求1所述的谷维素盐酸小檗碱片剂，其特征在于，所述盐酸小檗碱，谷维素重量比为1：0.2-0.6。
  5. 一种制备如权利要求1-4所述的谷维素盐酸小檗碱片剂的制备方法，其特征在于：
    盐酸小檗碱谷维素颗粒的制备：将盐酸小檗碱、谷维素、内加表面活性剂、内加分散剂混合，进行气流粉碎，干法制粒，得到颗粒；
    将外加表面活性剂，外加分散剂溶于亲水性薄膜包衣材料溶液中，搅拌至溶解，得到包衣液；采用流化床喷雾的方式，将包衣液喷雾到颗粒上，即得改性盐酸小檗碱谷维素颗粒；
    (3)将改性盐酸小檗碱谷维素颗粒按照一定的比例与填充剂，崩解剂，润滑剂混合后压片。
  6. 如权利要求7所述的制备方法，其特征在于，气流粉碎后混合物的粒径为D90≤20μm。
  7. 如权利要求7所述的制备方法，其特征在于，步骤(2)中包衣增重为3-5％。
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