WO2014063596A1

WO2014063596A1 - Oral formulation for treating diabetes

Info

Publication number: WO2014063596A1
Application number: PCT/CN2013/085588
Authority: WO
Inventors: 金方; 范颖; 俞雄; 彭程
Original assignee: 中国医药工业研究总院; 上海医药工业研究院
Priority date: 2012-10-23
Filing date: 2013-10-21
Publication date: 2014-05-01
Also published as: CN103768071A; CN103768071B

Abstract

An oral formulation, preparation method therefor and use thereof. The oral formulation comprises a pharmaceutically acceptable carrier and 17α-ethynyl-androst-5-ene-3β, 7β, 17β-triol as active ingredient; the formulation is not released or is substantially not released in an acidic medium.

Description

一种治疗糖尿病的口服制剂技术领域 Oral preparation for treating diabetes

本发明涉及一种 17 α -乙炔基雄^ -5-烯 -3 β， 7 β， 17 β -三醇（ΗΕ3286)的口服制剂，以及所述制剂的制法和用途。背景技术 The present invention relates to an oral preparation of 17α-ethynylandrost-5-ene-3β,7β,17β-triol (ΗΕ3286), and a process for the preparation and use of the preparation. Background technique

已知 ΗΕ3286, 化学名为17(1 -乙炔基雄甾-5-烯-3|3，7|3，17|3-三醇，用于预防和治疗 II型糖尿病（参见中国专利申请 200780022449.6)。 It is known that ΗΕ3286, chemical name 17 (1-ethynylandrost-5-ene-3|3,7|3,17|3-triol, is used for the prevention and treatment of type 2 diabetes (see Chinese Patent Application No. 200780022449.6).

中国专利申请 200980112162.1中提供和描述了 17 α -乙炔基雄甾 -5-烯 -3 β， 7 β，17 β -三醇的固体形式，包括无定形和晶体形式及其特定的多晶型物，脱水物，溶剂合物。本发明进一步涉及包含以所述固体形式存在的 17 a -乙炔基雄 -5-烯 -3 β , 7 β , 17 β -三醇的固体和混悬制剂的制备。发明说明中指出该制剂包含药物和一种或多种药学可接受的载体的组合物，实施例中列举了含有微粉化 ΗΕ3286、月桂基硫酸钠、微晶纤维素、交联维酮、硬脂酸镁的处方，该处方混合物装于硬明胶胶囊壳中。 A solid form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol, including amorphous and crystalline forms and specific polymorphs thereof, is provided and described in Chinese Patent Application No. 200980112162.1, Anhydrate, solvate. The invention further relates to the preparation of solid and suspension formulations comprising 17 a-ethynylandrost-5-ene-3β, 7β, 17β-triol in the solid form. The invention indicates that the formulation comprises a composition of a drug and one or more pharmaceutically acceptable carriers, examples of which include micronized mash 3286, sodium lauryl sulfate, microcrystalline cellulose, crosslinked ketone, and stearin. A prescription for magnesium sulfate, which is contained in a hard gelatin capsule shell.

上述专利（CN200980112162.1)未提及 ΗΕ3286固体制剂口服后的生物利用度，也没有实施例提供数据支持。此外，硬胶囊处方中表面活性剂月桂基硫酸钠用量大（占处方总量的 20%)，而月桂基硫酸钠是中等毒性物质，对胃、黏膜、眼睛、上呼吸道、皮肤产生剌激等急性毒性反应。动物静脉注射试验结果表明，月桂基硫酸钠对肺、肾、肝有明显的毒性反应。因此，上述硬胶囊处方在生产过程中可能会对人体将产生毒性反应，药物制剂经口服后还可能对胃肠道产生剌激而导致不同程度的毒副反应。 The above patent (CN200980112162.1) does not mention the bioavailability of the ΗΕ3286 solid preparation after oral administration, nor does the embodiment provide data support. In addition, the amount of surfactant sodium lauryl sulfate in the hard capsule formulation is large (20% of the total prescription), while sodium lauryl sulfate is a moderately toxic substance that stimulates the stomach, mucous membranes, eyes, upper respiratory tract, and skin. Acute toxicity. The results of intravenous injection test showed that sodium lauryl sulfate had obvious toxicity to lung, kidney and liver. Therefore, the above hard capsule prescription may have a toxic reaction to the human body during the production process, and the pharmaceutical preparation may cause irritation to the gastrointestinal tract after oral administration, resulting in various degrees of toxic side effects.

PCT专利申请 WO/2010/036822中提供了一种治疗高血糖或糖尿病的方法，该治疗方案包括给予 17 α -乙炔基雄 -5-烯 -3 β ,7β , 17β -三醇和二甲双胍或格列苯脲中的一种。发明说明中描述了由 a -乙炔基雄甾 -5-烯 -3 β，7β， 17 β -三醇以及一种或多种可药用辅料组成的口服药物制剂，该制剂可在给药后 2〜4小时使病人血浆药物浓度维持在 0.5ng/mL〜200 ng/mL，该处方由两种或多种辅料组成，润滑剂包括月桂基硫酸钠或硬脂酸镁，其它可药用辅料包括微晶纤维素或交联聚维酮，以及17(1 -乙炔基雄甾-5-烯-33，7 ，17 -三醇。该处方在口服给药后迅速释放药物。实施例中列举了 II期双盲对照试验结果，与安慰剂组相比，口服 17(1 - 乙炔基雄甾-5-烯-3 3，7 ^ ， 17 ^ -三醇制剂后的药效，当日剂量为 l Omg (5mg/次， 2 次 /天）时某些临床指标（糖化血红蛋白，空腹血糖水平）明显减小，但某些临床指标（空腹血浆 C肽水平，空腹胰岛素水平，果糖胺， H0MA2胰岛素抵抗， H0MA2胰岛素敏感度， Η0ΜΑ2 β细胞功能）没有明显改善。 A method for the treatment of hyperglycemia or diabetes comprising administration of 17α-ethynylandrost-5-ene-3β,7β,17β-triol and metformin or glibenclamide is provided in PCT patent application WO/2010/036822. One of the ureas. An oral pharmaceutical formulation consisting of a-ethynylandrost-5-ene-3β,7β,17β-triol and one or more pharmaceutically acceptable excipients is described in the description of the invention, which may be administered after administration 2 The patient's plasma drug concentration is maintained at 0.5 ng/mL to 200 ng/mL for ~4 hours. The prescription consists of two or more excipients. The lubricant includes sodium lauryl sulfate or magnesium stearate. Other pharmaceutically acceptable excipients include Microcrystalline cellulose or crospovidone, and 17(1-ethynylandrost-5-ene-33,7,17-triol. This formulation rapidly releases the drug after oral administration. II is listed in the examples. Results of a double-blind controlled trial, compared with placebo, oral 17 (1 - The efficacy of ethinylandrost-5-ene-3 3,7 ^ , 17 ^ -triol preparation, the daily dose is l Omg (5mg / time, 2 times / day) when certain clinical indicators (glycated hemoglobin, fasting Blood glucose levels were significantly reduced, but some clinical indicators (fasting plasma C-peptide levels, fasting insulin levels, fructosamine, H0MA2 insulin resistance, H0MA2 insulin sensitivity, Η0ΜΑ2 beta cell function) did not significantly improve.

因此，本领域迫切需要开发一种有较高稳定性和有效性，并且安全、副作用小的 ΗΕ3286制剂。发明内容 Therefore, there is an urgent need in the art to develop a ΗΕ3286 preparation which has high stability and effectiveness, and which is safe and has few side effects. Summary of the invention

本发明的目的就是提供一种稳定、有效、安全、且副作用小的 ΗΕ3286口服制剂。在本发明的第一方面，提供了一种口服制剂，所述的口服制剂含有药学上可接受的载体和作为活性成分的 17 α -乙炔基雄^ -5-烯 -3 β， 7 β， 17 β -三醇 It is an object of the present invention to provide a ΗΕ3286 oral preparation which is stable, effective, safe, and has few side effects. In a first aspect of the invention, there is provided an oral preparation comprising a pharmaceutically acceptable carrier and 17 α -ethynylandro-5-ene-3 β, 7 β, 17 as an active ingredient Beta-triol

(ΗΕ3286) ,并且所述口服制剂具有以下特性：所述制剂在酸性介质中不释放或基本不释放。 (ΗΕ 3286), and the oral preparation has the property that the preparation does not release or is substantially not released in an acidic medium.

在另一优选例中，所述的酸性介质是 0. 1M的盐酸水溶液。 In another preferred embodiment, the acidic medium is 0.1 M aqueous hydrochloric acid.

在另一优选例中，所述制剂的相对生物利用度可提高 50%以上（参比制剂为速释胶囊），优选的相对生物利用度提高 60%以上。 In another preferred embodiment, the relative bioavailability of the formulation can be increased by more than 50% (the reference formulation is an immediate release capsule), and the preferred relative bioavailability is increased by more than 60%.

在另一优选例中，在酸性介质中不释放或基本不释放指：所述制剂在酸性介质中放置（或溶出） 2小时，活性成分 ΗΕ3286的释放量不大于标示量的 10%，优选地不大于标示量的 5%。 In another preferred embodiment, the release or non-release in the acidic medium means: the preparation is placed (or dissolved) in an acidic medium for 2 hours, and the release amount of the active ingredient ΗΕ3286 is not more than 10% of the labeled amount, preferably Not more than 5% of the indicated amount.

在另一优选例中，将所述制剂置于缓冲液（如 ρΗ = 6.8磷酸盐缓冲液）中放置（或溶出） 45min，活性成分 HE3286的释放量 70%，优选地 80%，更佳地 85%。 In another preferred embodiment, the preparation is placed (or dissolved) in a buffer (e.g., ρ Η = 6.8 phosphate buffer) for 45 minutes, and the release amount of the active ingredient HE3286 is 70%, preferably 80%, more preferably 85%.

在另一优选例中，所述制剂为肠溶制剂。 In another preferred embodiment, the formulation is an enteric formulation.

在另一优选例中，所述制剂的剂型包括：片剂、胶囊剂、或微丸剂。 In another preferred embodiment, the dosage form of the formulation comprises: a tablet, a capsule, or a pellet.

在另一优选例中，所述制剂选自下组： In another preferred embodiment, the formulation is selected from the group consisting of:

a) 肠溶片剂，所述的片剂包括片芯、隔离层、肠溶包衣，其中所述的片芯含有 17 α -乙炔基雄甾 -5-烯 -3 β， 7 β， 17 β -三醇； a) enteric tablet, the tablet comprising a core, a barrier layer, an enteric coating, wherein the core comprises 17 α -ethynylandrost-5-ene-3 β, 7 β, 17 β -triol;

b) 肠溶胶囊剂，所述的胶囊包括肠溶胶囊以及位于肠溶胶囊内的药物颗粒或粉末，其中所述的药物颗粒或粉末包括 17 α -乙炔基雄 -5-烯 -3 β , 7 β , 17 β - 三醇； b) enteric capsules, the capsules comprising enteric capsules and drug particles in enteric capsules Or a powder, wherein the pharmaceutical granule or powder comprises 17 α -ethynyl androst-5-ene-3 β , 7 β , 17 β -triol;

c) 肠溶微丸剂，所述的微丸剂包括肠溶微丸剂或填充于胶囊内的肠溶微丸，其中所述的肠溶微丸包括微丸药芯、微丸隔离层、微丸肠溶包衣，其中药芯包括 17 α -乙炔基雄甾- 5-烯- 3 β， 7 β， 17 β -三醇。 c) enteric pellets, the pellets comprising enteric pellets or enteric pellets filled in a capsule, wherein the enteric pellets comprise a pellet core, a pellet isolation layer, and an pellet enteric solution. The coating, wherein the core comprises 17α-ethynylandrost-5-ene-3β, 7β, 17β-triol.

在另一优选例中，所述制剂具有选自下组的一个或多个特征： In another preferred embodiment, the formulation has one or more characteristics selected from the group consisting of:

(i) a)或 b)或 c)中所述的药学上可接受的载体包括增溶剂、提供局部碱性环境的惰性物质、填充剂、崩解剂、粘合剂、润滑剂； (i) The pharmaceutically acceptable carrier described in a) or b) or c) includes a solubilizing agent, an inert substance providing a local alkaline environment, a filler, a disintegrant, a binder, a lubricant;

(i i) a)或 c)中所述的隔离层包括羟丙基甲基纤维素、聚乙烯吡咯烷酮、羟丙基纤维素、羟甲基纤维素、甲基纤维素、乙基纤维素、聚乙烯醇、聚乙酸乙烯酯化、聚乙二醇、甘露醇或其组合，优选的采羟丙基甲基纤维素和 /或聚乙烯吡咯烷酮用； (ii) The barrier layer described in a) or c) includes hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, ethylcellulose, poly Vinyl alcohol, polyvinyl acetate, polyethylene glycol, mannitol or a combination thereof, preferably hydroxypropylmethylcellulose and/or polyvinylpyrrolidone;

(i i i ) a)或 c)中所述的肠溶包衣包括甲基丙烯酸 -甲基丙烯酸甲酯共聚物、邻苯二甲酸醋酸纤维素、醋酸羟丙基甲基纤维素琥珀酸酯、邻苯二甲基羟丙基甲基纤维素、醋酸纤维素钛酸酯、羧甲基乙烯纤维素、乙酸苯三酸纤维素、聚乙酸邻苯二甲基乙烯酯、乙酸琥珀酸羟丙基甲基纤维素、乙酸邻苯二甲酸纤维素、虫胶或其组合，优选的采用甲基丙烯酸 -甲基丙烯酸甲酯共聚物、邻苯二甲基羟丙基甲基纤维素、醋酸羟丙基甲基纤维素琥珀酸酯。 (iii) The enteric coating described in a) or c) includes methacrylic acid-methyl methacrylate copolymer, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, adjacent Benzyl hydroxypropyl methylcellulose, cellulose acetate titanate, carboxymethyl vinyl cellulose, cellulose acetate triacetate, phthalic acid poly(vinyl phthalate), hydroxypropyl propyl succinate Base cellulose, cellulose acetate phthalate, shellac or a combination thereof, preferably using methacrylic acid-methyl methacrylate copolymer, phthalyl hydroxypropyl methylcellulose, hydroxypropyl acetate Methylcellulose succinate.

(iv) 隔离层增重为片芯或药芯重量的 1-30%，优选的采用 2-15%; (iv) the weight gain of the barrier layer is 1-30% of the weight of the core or core, preferably 2-15%;

(V)肠溶层包衣的增重为片芯或药芯重量的 1-30%，优选的为 4-15%。 (V) The weight gain of the enteric layer coating is from 1 to 30%, preferably from 4 to 15% by weight of the core or core.

在另一优选例中，所述的提供局部碱性环境的惰性物质包括氧化钙、氢氧化钙、氢氧化镁、碱性无机镁盐（如碳酸镁、重质碳酸镁）、色氨酸、组氨酸、赖氨酸、精氨酸、色氨酸钠、组氨酸钠、赖氨酸钠、精氨酸钠、色氨酸钾、组氨酸钾、赖氨酸钾、精氨酸钾、色氨酸镁、组氨酸镁、赖氨酸镁、精氨酸镁或其组合，优选的采用氢氧化镁、碳酸镁、组氨酸；和 /或 In another preferred embodiment, the inert substance providing a local alkaline environment includes calcium oxide, calcium hydroxide, magnesium hydroxide, basic inorganic magnesium salt (such as magnesium carbonate, heavy magnesium carbonate), tryptophan, Histidine, lysine, arginine, sodium tryptophan, sodium histidine, sodium lysinate, sodium arginate, potassium tryptophan, potassium histidine, potassium lysine, arginine Potassium, magnesium tryptophan, magnesium histidine, magnesium lysine, magnesium arginate or a combination thereof, preferably using magnesium hydroxide, magnesium carbonate, histidine; and/or

所述惰性物质的用量是组合物中活性成分重量的 0〜50%，优选为 0%〜40%。在另一优选例中，所述制剂还具有一个或多个选自下组的特性： The inert substance is used in an amount of from 0 to 50% by weight, preferably from 0% to 40%, based on the total weight of the active ingredient in the composition. In another preferred embodiment, the formulation further has one or more properties selected from the group consisting of:

(vi)每个制剂中 17 α -乙炔基雄甾 -5-烯 -3 β， 7 β， 17 β -三醇的含量为 0.5mg〜100mg，较佳地每剂中活性成分含量为 2mg、 5mg、 10mg、 25mg、 50mg、 lOOmg;(vi) 17 α -ethynylandrost-5-ene-3 β, 7 β, 17 β -triol in each preparation 0.5mg~100mg, preferably the active ingredient content per dose is 2mg, 5mg, 10mg, 25mg, 50mg, lOOmg;

(vii)所述的活性成分包括药学上可接受的 17 α -乙炔基雄 -5-烯 -3 β， 7 β， 17 β -三醇的晶型、无定形物、脱水物、溶剂化物、水合物、和对映体； The active ingredient according to (vii) includes pharmaceutically acceptable crystalline form of 17 α -ethynyl andrhen-5-ene-3 β, 7 β, 17 β -triol, amorphous form, anhydrate, solvate, hydrated And enantiomers;

(viii)所述的甲基丙烯酸-甲基丙烯酸甲酯共聚物包括 Eudragit L系列、 Eudragit S系列、 Eudragit 系列、 Eudragit RS系列、 Eudragit FS系列、 (viii) The methacrylic acid-methyl methacrylate copolymer includes Eudragit L series, Eudragit S series, Eudragit series, Eudragit RS series, Eudragit FS series,

EudragitNE系列、肠溶型 II号、肠溶型 III号、欧巴代、或其组合； EudragitNE series, enteric type II, enteric type III, Opadry, or a combination thereof;

(ix)所述的增溶剂包括：月桂基硫酸钠、泊洛沙姆、聚山梨酯、聚氧乙烯烷基醚、环糊精、聚乙二醇、聚氧乙烯氢化蓖麻油、或其组合； The solubilizing agent of (ix) includes: sodium lauryl sulfate, poloxamer, polysorbate, polyoxyethylene alkyl ether, cyclodextrin, polyethylene glycol, polyoxyethylene hydrogenated castor oil, or a combination thereof ;

(X)所述的填充剂包括微晶纤维素、乳糖、蔗糖、淀粉、预胶化淀粉、甘露醇、糖粉、糊精、或其组合；和 /或所述填充剂的用量是活性成分重量的 10〜5000%，优选为 50〜3000%，优选的采用微晶纤维素、乳糖、蔗糖、淀粉、或其组合； The filler according to (X) includes microcrystalline cellulose, lactose, sucrose, starch, pregelatinized starch, mannitol, powdered sugar, dextrin, or a combination thereof; and/or the filler is used as an active ingredient. 10 to 5000% by weight, preferably 50 to 3000%, preferably using microcrystalline cellulose, lactose, sucrose, starch, or a combination thereof;

(xi)所述的崩解剂包括交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素、干淀粉、或其组合；和 /或所述崩解剂的用量是片芯或药芯总重的 0.5〜50%，优选为 1〜40%； (xi) the disintegrant comprises crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, dry starch, or a combination thereof; and/or The disintegrant is used in an amount of 0.5 to 50%, preferably 1 to 40%, based on the total weight of the core or core;

(xii)所述的粘合剂包括聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羧甲基纤维素、共聚维酮、乙基纤维素、聚乙烯醇、聚乙二醇、黄原胶、海藻酸、海藻酸盐、或其组合；和 /或所述粘合剂浓度为 0.5%〜50%(w/v)，用量是载体总重的 0.1-80%； (xii) The binder includes polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, copolyvidone, ethylcellulose, polyethylene Alcohol, polyethylene glycol, xanthan gum, alginic acid, alginate, or a combination thereof; and/or the binder concentration is 0.5% to 50% (w/v), and the amount is 0.1 of the total weight of the carrier. -80%;

(xiii)所述的润滑剂包括硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸、单硬脂酸甘油酯、微粉硅胶、滑石粉、水合硅铝酸钠、聚乙二醇、氢化植物油、硬脂酸富马酸钠、聚氧乙烯单硬脂酸酯、单月桂蔗糖酸酯、月桂醇硫酸钠、月桂醇硫酸镁、十二烷基硫酸镁、滑石粉、或其组合；和 /或所述润滑剂的用量是片芯或药芯总重的 0.1〜20%，优选为 0.5〜5%； (xiii) The lubricant includes magnesium stearate, calcium stearate, zinc stearate, stearic acid, glyceryl monostearate, silica gel, talc, hydrated sodium aluminosilicate, polyethylene. Alcohol, hydrogenated vegetable oil, sodium fumarate, polyoxyethylene monostearate, monolauryl sucrose, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium lauryl sulfate, talc, or Combining; and/or the lubricant is used in an amount of 0.1 to 20%, preferably 0.5 to 5%, based on the total weight of the core or core;

(xiv) 所述的活性成分是微粉化的 17 α -乙炔基雄甾 -5-烯 -3 β ,7β , 17β - 三醇，其平均粒径（D50)为 0.1 μ η！〜 10μ m，优选地 0· 5 μ m〜5 μ m。 (xiv) The active ingredient is micronized 17 α -ethynylandrost-5-ene-3β,7β,17β-triol with an average particle size (D50) of 0.1 μηη! 〜10 μm, preferably 0·5 μm~5 μm.

在另一优选例中，增溶剂的用量为 0〜1000% (以活性成分的重量计），优选的增溶剂用量为 5 ~ 30% (以活性成分的重量计）； In another preferred embodiment, the solubilizer is used in an amount of from 0 to 1000% by weight based on the weight of the active ingredient, preferably from 5 to 30% by weight of the active ingredient;

在另一优选例中，所述的口服制剂不含增溶剂。 In another preferred embodiment, the oral preparation contains no solubilizer.

在另一优选例中， a)或 c)中所述的肠溶包衣还含有增塑剂，其中所述的增塑剂包括柠檬酸三乙酯、聚乙二醇、苯二甲酸二乙酯、癸二酸二丁酯、三甘油醋酸酯、蓖麻油，较佳地，为柠檬酸三乙酯、聚乙二醇，更佳地，为柠檬酸三乙酯。在本发明的第二方面，提供了一种本发明第一方面中所述的口服制剂的制备方法，所述方法选自下组： In another preferred embodiment, the enteric coating described in a) or c) further comprises a plasticizer, wherein said plasticizing The agent includes triethyl citrate, polyethylene glycol, diethyl phthalate, dibutyl sebacate, triglycerin acetate, castor oil, preferably triethyl citrate, polyethylene glycol More preferably, it is triethyl citrate. In a second aspect of the invention, there is provided a process for the preparation of an oral preparation according to the first aspect of the invention, which is selected from the group consisting of:

(a)方法一，所述方法包括步骤： (a) Method 1, the method comprising the steps of:

将 HE3286和药学上可接受的载体混合，并制成药芯； Mixing HE3286 with a pharmaceutically acceptable carrier and forming a drug core;

将药芯压制为片芯并逐层包裹隔离层及肠溶包衣，从而形成肠溶片剂；和 / 或 Pressing the core into a core and wrapping the barrier layer and the enteric coating layer by layer to form an enteric tablet; and/or

(b)方法二，所述方法包括步骤： (b) Method 2, the method comprising the steps of:

将 HE3286颗粒或粉末填装在肠溶胶囊中，从而形成肠溶胶囊剂，其中所述颗粒或粉末包括 HE3286和药学上可接受的载体； The HE3286 granule or powder is filled in an enteric capsule to form an enteric capsule, wherein the granule or powder comprises HE3286 and a pharmaceutically acceptable carrier;

(c)方法三，所述方法包括步骤： (c) Method 3, the method comprising the steps of:

将肠溶微丸填装入胶囊，形成肠溶微丸剂，其中所述的肠溶微丸包括微丸药芯、微丸隔离层、微丸肠溶包衣，其中微丸药芯包括 HE3286和药学上可接受的载体。 The enteric pellets are filled into capsules to form enteric pellets, wherein the enteric pellets include a pellet core, a pellet isolation layer, and a pellet enteric coating, wherein the pellet core comprises HE3286 and pharmacy. Acceptable carrier.

在另一优选例中，所述的片芯或药芯可通过湿法制粒、干法制粒、混合粉末压制法制得。 In another preferred embodiment, the core or core may be prepared by wet granulation, dry granulation, or mixed powder compaction.

在另一优选例中，所述的片芯或药芯的硬度在 4〜15kg，崩解时间为 1〜15 分钟。 In another preferred embodiment, the core or core has a hardness of 4 to 15 kg and a disintegration time of 1 to 15 minutes.

在另一优选例中，所述的药芯还包括制备口服制剂前体的步骤，其中所述前体是将活性成分和药学上可接受的载体混合，并包裹隔离层； In another preferred embodiment, the drug core further comprises the step of preparing an oral preparation precursor, wherein the precursor is a mixture of the active ingredient and a pharmaceutically acceptable carrier, and wrapping the barrier layer;

所述的活性成分指药学上可接受的 17 α -乙炔基雄甾 -5-烯 -3 β , 7 β , 17 β - 三醇的晶型、无定形物、脱水物、溶剂化物、水合物、对映体；和 /或 The active ingredient refers to a pharmaceutically acceptable crystalline form of 17α-ethynylandrost-5-ene-3β, 7β, 17β-triol, an amorphous form, an anhydrate, a solvate, a hydrate, Enantiomers; and/or

所述的药学上可接受的载体包括增溶剂、提供局部碱性环境的惰性物质、填充剂、崩解剂、粘合剂、润滑剂；和 /或 The pharmaceutically acceptable carrier includes a solubilizing agent, an inert substance providing a local alkaline environment, a filler, a disintegrant, a binder, a lubricant; and/or

所述的隔离层包括羟丙基甲基纤维素、羟丙基纤维素、羟甲基纤维素、甲基纤维素、乙基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、聚乙酸乙烯酯化、聚乙二醇、甘露醇或其组合；其中隔离层增重为片芯或药芯的 1-30%，优选的采用 2-15%。在另一优选例中，所述的微丸药芯是将 17 α -乙炔基雄甾 -5-烯 -3 β , 7 β , 17 β -三醇和药学上可接受的载体混合形成，平均粒径为 100〜2000 μ ηι。 The separator comprises hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, ethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, Polyethylene glycol, mannitol or a combination thereof; wherein the weight of the separator is 1-30% of the core or core, preferably 2-15%. In another preferred embodiment, the pellet core is formed by mixing 17α-ethynylandrost-5-ene-3β, 7β, 17β-triol and a pharmaceutically acceptable carrier, and the average particle size is 100~2000 μ ηι.

在本发明的第三方面，提供了本发明第一方面所述的口服制剂的用途，所述的制剂被用于制备预防和治疗 Π型糖尿病、类风湿性关节炎、溃疡性结肠炎的药物。应理解，在本发明范围内中，本发明的上述各技术特征和在下文（如实施例）中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。附图说明 In a third aspect of the invention, there is provided the use of the oral preparation of the first aspect of the invention for the preparation of a medicament for the prevention and treatment of diabetes, rheumatoid arthritis, ulcerative colitis . It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here. DRAWINGS

图 1显示了本发明一个实施例中口服制剂的释放曲线。 Figure 1 shows the release profile of an oral formulation in one embodiment of the invention.

图 2显示了本发明一个实施例中口服制剂的释放曲线。 Figure 2 shows the release profile of an oral formulation in one embodiment of the invention.

图 3显示了本发明一个实施例中口服制剂的释放曲线。具体实施方式 Figure 3 shows the release profile of an oral formulation in one embodiment of the invention. detailed description

本发明人经过广泛而深入的研究，意外地发现了 ΗΕ3286在酸性环境下或酸存在下极易分解，导致口服制剂的生物利用度极低。本发明人首次开发了在酸性介质比如胃液中基本不释放活性成分而主要在肠道中释放活性成分的口服制剂，从而显著提高了活性成分的相对生物利用度（以速释胶囊为参比，相对生物利用度至少提高 50%以上）。此外，本发明人还进一步改进了配方，通过减少或消除了现有制剂中较大毒副作用的成分（如某些表面活性剂）以及添加惰性物质，提供了一种安全性好、生物利用度高的 ΗΕ3286口服制剂。在此基础上，完成了本发明。 The inventors have extensively and intensively studied and unexpectedly found that ΗΕ3286 is easily decomposed in an acidic environment or in the presence of an acid, resulting in extremely low bioavailability of an oral preparation. The present inventors have for the first time developed an oral preparation which does not substantially release the active ingredient in an acidic medium such as gastric juice and mainly releases the active ingredient in the intestinal tract, thereby remarkably improving the relative bioavailability of the active ingredient (in terms of immediate release capsules as a reference, relative Bioavailability is increased by at least 50%). In addition, the inventors have further improved the formulation to provide a safe, bioavailable ingredient by reducing or eliminating the large toxic side effects of existing formulations (such as certain surfactants) and by adding inert materials. High ΗΕ3286 oral preparation. On the basis of this, the present invention has been completed.

经实验证明，本发明制剂有效地改善了药物的稳定性，并提高了药物的生物利用度，减少药物用量，降低毒副作用。活性成分 It has been experimentally proved that the preparation of the invention effectively improves the stability of the medicine, improves the bioavailability of the medicine, reduces the dosage of the medicine, and reduces the side effects. Active ingredient

如本文所用，术语 "本发明活性成分" 、 " ΗΕ3286 " 或 "活性成分" 可互换使用，指化合物 ΗΕ3286 ,其化学名为 17 α -乙炔基雄甾 -5-烯 -3 β , 7 β , 17 β -三醇。本发明的活性成分可以为药学上可接受的 ΗΕ3286的各种晶型、无定形、脱水物、溶剂化物、水合物、对映体，本发明中 ΗΕ3286即指本发明的活性成分。 As used herein, the terms "active ingredient of the invention", "ΗΕ3286" or "active ingredient" are used interchangeably and refer to the compound ΗΕ3286 having the chemical name 17α-ethynylandrost-5-ene-3β, 7β, 17 β-triol. The active ingredient of the present invention may be various crystalline forms, amorphous forms, anhydrates, solvates, hydrates, and enantiomers of pharmaceutically acceptable oxime 3286. In the present invention, ΗΕ3286 refers to the active ingredient of the present invention.

ΗΕ3286为新型的治疗与自身免疫性相关的^体类化合物，在 II型糖尿病、类风湿性关节炎、溃疡性结肠炎等疾病的治疗中有广泛的应用前景。 ΗΕ3286 is a novel treatment for autoimmune-related compounds, in type II diabetes, It has broad application prospects in the treatment of diseases such as rheumatoid arthritis and ulcerative colitis.

可用于本发明的 HE3286可以是粉末、颗粒或晶体等各种形式。尤其是微粉化的 HE3286。 The HE3286 which can be used in the present invention may be in various forms such as powder, granules or crystals. Especially the micronized HE3286.

通常 HE3286经微粉化处理后，平均粒径（D50) 0. Ι μ η！〜 10 μ ηι，优选的采用平均粒径（D50) 0. 5 μ ηι〜5 μ ηι。其中，代表性的微粉化处理方法包括（但并不限于）：气流粉碎、超临界流体粉碎、机械粉碎等。药学上可接受的载体 Usually, after the micronization of HE3286, the average particle size (D50) is 0. Ι μ η! 〜 10 μ ηι, preferably using an average particle diameter (D50) 0. 5 μ ηι 5 μ ηι. Among them, representative micronization treatment methods include, but are not limited to, jet milling, supercritical fluid pulverization, mechanical pulverization, and the like. Pharmacologically acceptable carrier

为在药物制剂中除主药以外的附加物，一般要求性质稳定，与主药无配伍禁忌，不产生副作用，不影响疗效，在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用、不与主药产生理化作用、不影响主药的含量测定。 In addition to the main drug in the pharmaceutical preparations, the general requirements are stable, no compatibility with the main drug, no side effects, no effect, no deformation, cracking, mildew, insects, no human body at normal temperature Harmful, no physiological effects, no physical and chemical effects with the main drug, does not affect the determination of the content of the main drug.

可用于本发明的载体没有特别限制，可以为任何药学上可接受的载体，包括增溶剂、提供局部碱性环境的惰性物质、填充剂、崩解剂、粘合剂、润滑剂。 The carrier which can be used in the present invention is not particularly limited and may be any pharmaceutically acceptable carrier, including a solubilizing agent, an inert substance providing a local alkaline environment, a filler, a disintegrating agent, a binder, and a lubricant.

1.增溶剂 Solubilizer

可用于本发明的增溶剂没有特别限制，可以为任何增加 ΗΕ3286溶解性的化合物，包括月桂基硫酸钠、泊洛沙姆、聚山梨酯、聚氧乙烯烷基醚、环糊精、聚乙二醇、聚氧乙烯氢化蓖麻油或其组合物。 The solubilizing agent usable in the present invention is not particularly limited and may be any compound which increases the solubility of ΗΕ3286, including sodium lauryl sulfate, poloxamer, polysorbate, polyoxyethylene alkyl ether, cyclodextrin, polyethylene. Alcohol, polyoxyethylene hydrogenated castor oil or a combination thereof.

其中增溶剂的用量是组合物中 ΗΕ3286重量的 0〜1000%。 The amount of solubilizer used is from 0 to 1000% by weight based on the weight of ΗΕ3286 in the composition.

较佳地，所述的口服制剂不含增溶剂或增溶剂含量很低，如小于制剂总重量的 8%，较佳地小于 2%。 Preferably, the oral formulation contains no solubilizer or solubilizer content, such as less than 8%, preferably less than 2%, by total weight of the formulation.

2.提供局部碱性环境的惰性物质 2. Provide inert substances in a local alkaline environment

可用于本发明的提供局部碱性环境的惰性物质没有特别限制，可以为任何提供局部碱性环境以确保 ΗΕ3286不分解的惰性物质，优选的有氧化钙、氢氧化钙、氧化镁、氢氧化镁、碱性无机镁盐（如碳酸镁、重质碳酸镁）、色氨酸、组氨酸、赖氨酸、精氨酸、色氨酸钠、组氨酸钠、赖氨酸钠、精氨酸钠、色氨酸钾、组氨酸钾、赖氨酸钾、精氨酸钾、色氨酸镁、组氨酸镁、赖氨酸镁、精氨酸镁或其组合。其中惰性物质的用量是组合物中 ΗΕ3286重量的 0〜40%，优选为 0%〜30%。 The inert substance which can be used in the present invention to provide a local alkaline environment is not particularly limited, and may be any inert substance which provides a local alkaline environment to ensure that ΗΕ3286 does not decompose, and preferably calcium oxide, calcium hydroxide, magnesium oxide, magnesium hydroxide. , basic inorganic magnesium salts (such as magnesium carbonate, heavy magnesium carbonate), tryptophan, histidine, lysine, arginine, sodium tryptophan, sodium histidine, sodium lysine, refined ammonia Sodium, potassium tryptophan, potassium histidine, potassium lysine, potassium arginine, magnesium tryptophan, magnesium histidine, magnesium lysine, magnesium arginate or a combination thereof. The inert substance is used in an amount of from 0 to 40%, preferably from 0% to 30% by weight based on the weight of ΗΕ3286 in the composition.

3.填充剂可用于本发明的填充剂没有特别限制，可以为任何在 HE3286制剂中起到填充、稀释或增加药物分散效果的化合物，包括微晶纤维素、乳糖、淀粉、预胶化淀粉、甘露醇、糖粉、糊精或其组合。 3. Filler The filler which can be used in the present invention is not particularly limited, and may be any compound which functions to fill, dilute or increase the drug dispersion effect in the HE3286 preparation, including microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, sugar. Powder, dextrin or a combination thereof.

其中填充剂的用量是组合物中 HE3286重量的 10〜5000%，优选为 50〜3000%。 The filler is used in an amount of 10 to 5000% by weight, preferably 50 to 3000% by weight based on the weight of the HE3286 in the composition.

4.崩解剂 4. Disintegrant

可用于本发明的崩解剂没有任何限制，可以为任何使 HE3286在肠液中迅速膨胀并崩解为细小颗粒的化合物，优选的包括交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素、干淀粉或其组合。 The disintegrant which can be used in the present invention is not limited in any way, and may be any compound which rapidly swells and disintegrates HE3286 into intestinal granules, preferably crospovidone, croscarmellose sodium, carboxy Sodium methyl starch, low substituted hydroxypropyl cellulose, dry starch or a combination thereof.

其中崩解剂的用量是片芯或药芯总重的 0. 5〜50%，优选为 1〜40%。 5〜50%优选优选为1〜40%。 The amount of the disintegrating agent is 0. 5~50%, preferably 1~40%.

5.粘合剂 5. Binder

可用于本发明的黏合剂没有特别限制，可以为任何使 HE3286粉末或颗粒在制剂中聚集粘结的化合物，包括聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羧甲基纤维素、共聚维酮、乙基纤维素、聚乙烯醇、聚乙二醇、黄原胶、海藻酸、海藻酸盐或其组合。 The adhesive which can be used in the present invention is not particularly limited and may be any compound which causes aggregation or adhesion of HE3286 powder or granules in a preparation, including polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose. , carboxymethylcellulose, copovidone, ethylcellulose, polyvinyl alcohol, polyethylene glycol, xanthan gum, alginic acid, alginate or a combination thereof.

其中粘合剂浓度为 0. 5%〜50% (w/v)，用量是片芯或药芯总重的 0. 1-80%。 01至80百分比。 The adhesive concentration is 0. 5% ~ 50% (w / v), the amount is 0.1-80% of the total weight of the core or core.

6.润滑剂 Lubricant

可用于本发明的润滑剂没有特别限制，可以为任何降低 HE3286粉末或颗粒之间以及 HE3286与制药机械之间摩擦力从而改善粉末或颗粒流动性的化合物，包括硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸、单硬脂酸甘油酯、微粉硅胶、滑石粉、水合硅铝酸钠、聚乙二醇、氢化植物油、硬脂酸富马酸钠、聚氧乙烯单硬脂酸酯、单月桂蔗糖酸酯、月桂醇硫酸钠、月桂醇硫酸镁、十二烷基硫酸镁、滑石粉或其组合。 The lubricant which can be used in the present invention is not particularly limited and may be any compound which reduces the friction between the HE3286 powder or particles and between HE3286 and a pharmaceutical machine to improve the fluidity of the powder or the particles, including magnesium stearate and calcium stearate. , zinc stearate, stearic acid, glyceryl monostearate, micronized silica gel, talc, hydrated sodium aluminosilicate, polyethylene glycol, hydrogenated vegetable oil, sodium stearate fumarate, polyoxyethylene single hard Fatty acid ester, monolauric sucrose ester, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium lauryl sulfate, talc or a combination thereof.

其中润滑剂的用量是片芯或药芯总重的 0. 1〜20%，优选为 0. 5〜5%。药芯或片芯 5〜5%。 The amount of the total weight of the core or the core of the core is 0. 1~20%, preferably 0. 5~5%. Drug core or core

本发明中的药芯由 HE3286粉末或颗粒与药学上可接受的载体混合形成。本发明中的片芯为药芯压制成片状，并应用于肠溶片剂的制作，压片设备包括单冲压片机、高速旋转压片机等。 The core of the present invention is formed by mixing HE3286 powder or granules with a pharmaceutically acceptable carrier. The core of the present invention is pressed into a sheet shape by a core, and is applied to the preparation of an enteric tablet. The tableting apparatus includes a single punching machine, a high speed rotary tableting machine, and the like.

可用于本发明的片芯或药芯可通过湿法制粒、干法制粒、混合粉末压制法制得，并具有以下特性：硬度在 4〜15kg，崩解时间在 1〜15分钟。 The core or core which can be used in the present invention can be prepared by wet granulation, dry granulation, mixed powder compaction It has the following characteristics: hardness is 4~15kg, and disintegration time is 1~15 minutes.

在本发明中，药芯可经压制成片剂后，逐层包裹隔离层、肠溶包衣制成 HE3286 肠溶片剂。通常，药芯的直径为 0. 6〜lcm，药芯质量为 50〜2000mg; 和 /或 In the present invention, the drug core can be compressed into a tablet, and the release layer and the enteric coating are coated layer by layer to form an HE3286 enteric tablet. Usually, the core diameter is 0. 6~lcm, the core quality is 50~2000mg; and / or

微丸药芯为小粒径的药芯，微丸药芯可逐层包裹微丸隔离层、微丸肠溶包衣后填充入胶囊，并制得肠溶微丸剂，其中药芯的粒径为平均 100〜2000 μ ηι，或药芯质量为 50〜2000mg。隔离层、肠溶包衣、和肠溶胶囊 The pellet core is a small particle size core, and the pellet core can be wrapped layer by layer with the pellet isolation layer, the pellet is enteric coated, and then filled into the capsule, and the enteric pellet is prepared, wherein the particle diameter of the core is average 100~2000 μ ηι, or the core weight is 50~2000mg. Separation layer, enteric coating, and enteric capsule

HE3286是一种在酸性介质中容易被破坏的物质，其在酸性介质如人工胃液中的降解半衰期约为 40分钟，为了避免 HE3286与强酸性胃内容物的接触，并将活性物质即 HE3286完整地传递到 pH近中性且活性物质能被迅速吸收的肠道部分，故在药芯或片芯的外层包裹一层肠溶包衣层或者肠溶胶囊可以较好地防止制剂中对酸不稳定的活性药物与酸性胃内容物的接触。但是，常用的肠溶包衣或肠溶胶囊组分大多带有酸性基团，如果直接用肠溶衣包裹上述片芯，容易导致对酸不稳定的活性药物的降解。因此，在包裹肠溶衣层之前需要包裹一层隔离层。所述的隔离层、肠溶包衣以及肠溶胶囊均可通过市售获得。 HE3286 is a substance that is easily destroyed in an acidic medium. Its degradation half-life in an acidic medium such as artificial gastric juice is about 40 minutes. In order to avoid contact of HE3286 with strongly acidic gastric contents, the active substance, HE3286, is completely intact. It is delivered to the part of the intestine where the pH is near neutral and the active substance can be quickly absorbed. Therefore, coating the outer layer of the core or core with an enteric coating layer or enteric capsule can better prevent the acid in the preparation. Stable active drug contact with acidic gastric contents. However, most of the commonly used enteric coatings or intestinal sac components have acidic groups. If the core is coated directly with an enteric coating, it tends to cause degradation of the acid-labile active drug. Therefore, it is necessary to wrap a barrier layer before wrapping the enteric coating layer. The barrier layer, the enteric coating, and the enteric capsule are all commercially available.

1.隔离层 Isolation layer

可用于本发明的隔离层，用于隔离药芯和呈酸性的肠溶包衣，包括羟丙基甲基纤维素、羟丙基纤维素、羟甲基纤维素、甲基纤维素、乙基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、聚乙酸乙烯酯化、聚乙二醇、甘露醇或其组合；其中隔离层增重为片芯或药芯质量的 1-30%，优选的采用 2-15%。 A barrier layer useful in the present invention for isolating the core and the acidic enteric coating, including hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, ethyl Cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polyethylene glycol, mannitol or a combination thereof; wherein the weight gain of the separator is 1-30% of the mass of the core or core, preferably 2 -15%.

所述的隔离层还可选用抗粘剂、防静电剂、色素、色淀等，其中所选用的抗粘剂和防静电剂包括滑石粉、硬脂酸镁、微粉硅胶、甲基硅油、硅油，或其组合。 The release layer may also be selected from an anti-adhesive agent, an antistatic agent, a pigment, a lake, etc., wherein the selected anti-adhesive agent and antistatic agent include talc, magnesium stearate, micro-silica gel, methyl silicone oil, silicone oil. , or a combination thereof.

2.肠溶包衣 2. Enteric coating

可用于本发明的肠溶包衣没有特别限制，可以为任何在酸性介质中不溶解，但在肠道内才溶解的药物外部包衣结构，丙烯酸树脂类、邻苯二甲基羟丙基甲基纤维素、醋酸纤维素钛酸酯、羧甲基乙烯纤维素、乙酸苯三酸纤维素、聚乙酸邻苯二甲基乙烯酯、乙酸琥珀酸羟丙基甲基纤维素、乙酸邻苯二甲酸纤维素、虫胶或其组合；其中肠溶层的包衣增重为片芯或药芯质量的 1-30%，优选的为 2-20% 其中优选的肠溶包衣为丙烯酸树脂类，包括 Eudragi t L系列、 Eudragi t S 系列、 Eudragi t 系列、 Eudragi t RS系列、 Eudragi t FS系列、 Eudragi tNE 系列、肠溶型 I I号、肠溶型 I I I号、欧巴代或其组合。 The enteric coating which can be used in the present invention is not particularly limited, and may be any external coating structure of a drug which does not dissolve in an acidic medium but dissolves in the intestinal tract, acrylic resin, phthalyl hydroxypropyl methyl group. Cellulose, cellulose acetate titanate, carboxymethyl ethylene cellulose, cellulose acetate triacetate, phthalic acid polyvinyl acetate, hydroxypropyl methyl cellulose acetate succinate, phthalic acid acetate Cellulose, shellac or a combination thereof; wherein the coating weight of the enteric layer is 1-30%, preferably 2-20%, of the core or core mass Among the preferred enteric coatings are acrylics, including Eudragi t L series, Eudragi t S series, Eudragi t series, Eudragi t RS series, Eudragi t FS series, Eudragi tNE series, enteric type II, enteric type No. III, Opad or a combination thereof.

所述的肠溶包衣还含有增塑剂作为其辅料，可用于本发明的增塑剂没有特别限制，可以为药学中可接受的用以增加 HE3286的材料柔靭性的化合物，包括柠檬酸三乙酯、聚乙二醇、苯二甲酸二乙酯、癸二酸二丁酯、三甘油醋酸酯、蓖麻油，较佳地，为柠檬酸三乙酯、聚乙二醇，更佳地，为柠檬酸三乙酯。 The enteric coating further contains a plasticizer as an auxiliary material thereof, and the plasticizer to be used in the present invention is not particularly limited, and may be a pharmaceutically acceptable compound for increasing the flexibility of the material of HE3286, including citric acid three. Ethyl ester, polyethylene glycol, diethyl phthalate, dibutyl sebacate, triglycerin acetate, castor oil, preferably triethyl citrate, polyethylene glycol, more preferably, It is triethyl citrate.

所述的肠溶包衣还可选用抗粘剂、防静电剂、色素、色淀等，其中所选用的抗粘剂和防静电剂包括滑石粉、硬脂酸镁、微粉硅胶、甲基硅油、硅油，或其组合。 The enteric coating may also be selected from an anti-adhesive agent, an antistatic agent, a pigment, a lake, etc., wherein the selected anti-adhesive agent and antistatic agent include talc, magnesium stearate, micro-silica gel, methyl silicone oil. , silicone oil, or a combination thereof.

3.肠溶胶囊 3. Enteric capsules

可用于本发明的肠溶胶囊没有特别限制，可以选用任何市售可得的肠溶胶囊壳，包括明胶和肠溶材料共同制成的胶囊壳、植物肠溶胶囊壳，或将片芯或药芯或微丸经肠溶包衣后填充于明胶空心胶囊中。口服制剂 The enteric capsule which can be used in the present invention is not particularly limited, and any commercially available enteric capsule shell can be selected, including a capsule shell made of gelatin and an enteric material, a vegetable enteric capsule shell, or a core or a medicine. The core or pellet is filled in a gelatin hollow capsule after enteric coating. Oral preparation

本发明的口服制剂具有高生物利用度且具有在酸性介质中不释放或基本不释放等特性。通常，本发明口服制剂的相对生物利用度提高 50%以上（参比制剂为速释胶囊）并且在酸性介质中 2小时以内无释放或基本不释放药物（释放率 10%，较佳地 5%)；在磷酸盐缓冲液中 60min释放率大于 75%。 The oral preparation of the present invention has high bioavailability and has characteristics such as no release or substantially no release in an acidic medium. In general, the relative bioavailability of the oral preparation of the present invention is increased by more than 50% (the reference preparation is an immediate release capsule) and there is no release or substantially no release of the drug within 2 hours in an acidic medium (release rate 10%, preferably 5%) ); release rate in phosphate buffer for 60 min is greater than 75%.

酸性介质和 pH=6. 8磷酸盐缓冲液或 pH=7.5 ~ 8.0磷酸盐缓冲液可按照中国药典或美国药典或欧洲药典或日本药典进行配制，或按照中国药典或美国药典或欧洲药典或日本药典配制含有胃蛋白酶的人工胃液和含有胰酶的人工肠液。 Acid medium and pH=6.8 phosphate buffer or pH=7.5 ~ 8.0 phosphate buffer can be formulated according to Chinese Pharmacopoeia or US Pharmacopoeia or European Pharmacopoeia or Japanese Pharmacopoeia, or according to Chinese Pharmacopoeia or US Pharmacopoeia or European Pharmacopoeia or Japan The pharmacopoeia prepares artificial gastric juice containing pepsin and artificial intestinal juice containing trypsin.

在本发明中，代表性的口服制剂包括：肠溶片剂、肠溶胶囊和肠溶微丸剂。通常，每剂口服制剂含活性成分 0. 5mg〜100mg，优选的为 lmg、 2mg、 5mg、 10mg、 25mg、 50mg、 100mg。 In the present invention, representative oral preparations include: enteric tablets, enteric capsules, and enteric pellets. Usually, each oral preparation contains the active ingredient 0.5 mg to 100 mg, preferably 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg.

1.肠溶片剂 Enteric tablet

所述的片剂包括片芯以及逐层包裹的隔离层和肠溶包衣，其中所述片芯为药芯经压片后形成，所述药芯包括 HE3286和药学上可接受的载体。 2.肠溶胶囊剂 The tablet comprises a core and a layer-by-layer barrier layer and an enteric coating, wherein the core is formed by compressing a core comprising HE3286 and a pharmaceutically acceptable carrier. 2. Enteric capsules

所述的胶囊剂包括肠溶胶囊和位于肠溶胶囊内的药芯，所述的药芯包括 HE3286和药学上可接受的载体。 The capsule comprises an enteric capsule and a core located in the enteric capsule, the core comprising HE3286 and a pharmaceutically acceptable carrier.

3.肠溶微丸剂 3. Enteric pellets

所述的肠溶微丸剂包括胶囊以及位于胶囊内的肠溶微丸，其中所述的肠溶微丸包括微丸药芯以及逐层包裹的微丸隔离层和微丸肠溶包衣，所述的微丸药芯为小粒径的药芯（粒径为 100〜 2000 μ m)，所述的药芯包括 HE3286和药学上可接受的载体。制法 The enteric pellets include a capsule and an enteric pellet in a capsule, wherein the enteric pellet comprises a pellet core and a layer-by-layer coated pellet isolation layer and a pellet enteric coating, The pellet core is a small particle size core (particle size of 100 to 2000 μm), and the core comprises HE3286 and a pharmaceutically acceptable carrier. System of law

本发明的口服制剂可用本领域常规方法和设备进行制造。以肠溶制剂为例，代表性的制法包括（但并不限于）： Oral formulations of the invention can be made using conventional methods and equipment in the art. Taking enteric preparations as an example, representative methods include (but are not limited to):

a)肠溶片剂的制备方法，通常包括制粒、压片、包衣等步骤。 a) A method for preparing an enteric tablet, which usually comprises the steps of granulation, tableting, coating, and the like.

通常，活性成分（如微粉化处理后的 HE3286)可与药学上可接受的载体混合形成药芯，并经压制成片剂、包裹隔离层、肠溶包衣等步骤，制成肠溶片剂。 Usually, the active ingredient (such as HE3286 after micronization treatment) can be mixed with a pharmaceutically acceptable carrier to form a core, and is compressed into a tablet, a coated layer, an enteric coating, etc. to prepare an enteric tablet. .

b)肠溶胶囊剂的制备方法，通常包括制粒、装胶囊等步骤。 b) A method for preparing an enteric capsule, which usually comprises the steps of granulation, capsule filling and the like.

通常，将药物颗粒（或药芯）直接填充入肠溶胶囊，制成 HE3286肠溶胶囊剂。 c)肠溶微丸剂的制备方法，通常包括包衣法、离心层积法、球晶造粒法、乳化法、挤出滚圆法、沸腾床制粒包衣、振荡滴制法等方法。 Usually, the drug particles (or core) are directly filled into an enteric capsule to prepare an enteric capsule of HE3286. c) A method for preparing an enteric pellet, which generally comprises a coating method, a centrifugal layering method, a spherulite granulation method, an emulsification method, an extrusion spheronization method, a fluidized bed granulation coating method, an oscillating dropping method, and the like.

通常，将活性成分（如微粉化处理后的 HE3286)与药学上可接受的载体混合形成微丸药芯。然后，包裹微丸隔离层和微丸肠溶包衣后，填充入胶囊中，可制成肠溶微丸剂。 Typically, the active ingredient (e.g., HE3286 after micronization) is mixed with a pharmaceutically acceptable carrier to form a pellet core. Then, after the pellet-separating layer and the pellets are enteric coated, they are filled into capsules to prepare enteric pellets.

其中制粒包括经制粒设备制粒和不经制粒设备制粒。经制粒设备制粒包括干燥，整粒，加入润滑剂等常规步骤，制粒设备包括三相切割混合制粒机、离心造粒包衣机、高速搅拌制粒机、挤出-滚圆造粒机、摇摆制粒机、流化床一步制粒机等，较佳地为三相切割混合制粒机、流化床一步制粒机。 The granulation includes granulation by a granulation apparatus and granulation by a granulation apparatus. The granulation equipment comprises the following steps of drying, granulating, adding a lubricant, etc., and the granulating equipment comprises a three-phase cutting and mixing granulator, a centrifugal granulation coating machine, a high-speed stirring granulator, and extrusion-spheronizing granulation. The machine, the swing granulator, the fluidized bed one-step granulator, etc., are preferably a three-phase cutting mixing granulator and a fluidized bed one-stage granulator.

压片设备包括（但并不限于）：单冲压片机、高速旋转压片机。 Tableting equipment includes (but is not limited to): single punching machine, high speed rotary tablet press.

包衣设备包括（但并不限于）：传统型包衣锅、高效包衣锅、流化床、造粒包衣机，优选采用高效包衣锅、流化床等。本发明的主要有益效果 Coating equipment includes, but is not limited to, a conventional coating pan, a high-efficiency coating pan, a fluidized bed, a granulation coating machine, preferably a high-efficiency coating pan, a fluidized bed, and the like. The main beneficial effects of the invention

1.稳定性强：根据 HE3286的酸不稳定性特性，本发明的 HE3286肠溶制剂含有一种或多种隔离层和肠溶包衣层，所采用的惰性材料可在片芯或药芯中提供局部碱性环境，通过上述制剂手段可减弱或避免 HE3286在酸性介质中降解。惰性材料、隔离层、肠溶包衣材料不与 HE3286发生化学反应， HE3286与所用载体相容性好，所述制剂在酸性介质中稳定性高、不降解，相比原口服制剂有更高的稳定性。 1. Strong stability: According to the acid instability characteristics of HE3286, the HE3286 enteric preparation of the present invention contains one or more barrier layers and an enteric coating layer, and the inert material used may be in the core or core. Providing a local alkaline environment, the degradation of HE3286 in an acidic medium can be reduced or avoided by the above-mentioned formulation means. The inert material, the barrier layer, and the enteric coating material do not chemically react with HE3286. HE3286 has good compatibility with the carrier used. The formulation has high stability and no degradation in acidic medium, and is higher than the original oral preparation. stability.

2.生物利用度高：本发明的肠溶制剂在 pH=6. 8磷酸盐缓冲液或 pH=7.5 ~ 8.0 磷酸盐缓冲液或含有胰酶的模拟肠液中充分释放药物，即到达吸收部位（肠道）的活性药物更多，药物可被迅速吸收，并且能够产生治疗应用所需的药物释放曲线，较原制剂生物利用度更高，药物用量可更少。 2. High bioavailability: The enteric preparation of the present invention fully releases the drug in the pH=6.8 phosphate buffer or pH=7.5 ~ 8.0 phosphate buffer or simulated intestinal juice containing trypsin, that is, reaches the absorption site ( The intestinal tract has more active drugs, the drug can be quickly absorbed, and can produce the drug release profile required for therapeutic applications, with higher bioavailability than the original formulation, and less drug use.

3.安全性高：本发明的 HE3286肠溶口服制剂不含或仅含有少量增溶剂（如月桂基硫酸钠），从而减小生产过程中对人体的剌激，相比原制剂能避免组合物经口服后增溶剂对胃肠道的剌激，降低组合物应用中毒副作用出现的可能。 3. High safety: The HE3286 enteric oral preparation of the invention does not contain or only contains a small amount of solubilizing agent (such as sodium lauryl sulfate), thereby reducing the stimulation of the human body during the production process, and avoiding the composition compared with the original preparation. After oral administration, the solubilizing agent stimulates the gastrointestinal tract and reduces the possibility of toxic side effects in the composition.

4.工艺简单、重现性好、适于工业化生产：本发明所用的制剂工艺及设备均为本领域常规制剂及设备，调整适当的制剂比例即可获得符合规格要求的肠溶制剂。下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件（如中国药典 (2010版)），或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。实施例 1 HE3286在人工胃液溶液中的降解半衰期 4. Simple process, good reproducibility, and suitable for industrial production: The preparation process and equipment used in the present invention are conventional preparations and equipments in the field, and an appropriate amount of the preparation can be adjusted to obtain an enteric preparation which meets the specifications. The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in the following examples that do not specify the specific conditions are usually in accordance with conventional conditions (such as the Chinese Pharmacopoeia (2010 edition)), or in accordance with the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight and parts by weight. Example 1 Degradation half-life of HE3286 in artificial gastric juice solution

称取 HE3286 62. 5mg置 25mL容量瓶，甲醇溶解并定容，得到 2. 5mg/mL HE3286 贮备液。分别移取 2mL HE3286贮备液至 11个 25mL容量瓶中，分别加入 ImL 人工胃液，分另 ll于 lOmiru 20min^ 30min、 40min^ 50min^ 60min、 90min、 120min^ ISOmiru 240min加入 1ml lmol/L氢氧化钠溶液中和，甲醇定容至刻度；同时移取 2mL HE3286 贮备液至 25mL容量瓶中，加入 2mL纯水，甲醇定容至刻度，作为未降解对照组。高效液相色谱法记录 HE3286峰面积，计算 HE3286浓度。同法测定 HE3286在 pH=4. 5、 6. 0、 6. 8的人工肠液及纯水中的稳定性。 Weighed HE3286 62. 5mg placed in a 25mL volumetric flask, dissolved in methanol and volume, to obtain 2. 5mg / mL HE3286 stock solution. Pipette 2mL of HE3286 stock solution into 11 25mL volumetric flasks, add ImL artificial gastric juice, respectively, l llmiru 20min^ 30min, 40min^ 50min^ 60min, 90min, 120min^ ISOmiru 240min add 1ml lmol/L sodium hydroxide Neutralize in solution, make up to volume of methanol; remove 2mL HE3286 at the same time The stock solution was placed in a 25 mL volumetric flask, 2 mL of pure water was added, and the volume of methanol was adjusted to the mark to serve as an undegraded control group. The peak area of HE3286 was recorded by high performance liquid chromatography, and the concentration of HE3286 was calculated. The stability of HE3286 in artificial intestinal juice and pure water at pH=4.5, 6. 0, and 6. 8 was determined by the same method.

HE3286含量测定 HPLC方法为：色谱柱 Ult imate™ XB-C18 3. 5 μ m4. 6 X 150mm, 流动相为乙腈：纯水 =30 : 70，检测波长 210nm PAD。 Determination of HE3286 HPLC method: Column Ult imateTM XB-C18 3. 5 μ m4. 6 X 150mm, mobile phase acetonitrile: pure water = 30: 70, detection wavelength 210nm PAD.

结果显示， HE3268在 pH=4. 5、 6. 0、 6. 8的人工肠液及纯水中 24h含量几乎无变化，药物没有发生降解，而 HE3286在人工胃液中的降解半衰期仅为约 40min，说明 HE3286在酸性环境下非常容易降解， HE3286在药物制剂经口服后过早与酸性的胃内容物接触将导致药物降解，降低口服生物利用度，同时可能导致病人间个体差异增大，不利于发挥药效。 The results showed that HE3268 had almost no change in the content of artificial intestine and pure water at pH=4.5, 6. 0, 6. 8 for 24 h, and the degradation of HE3286 in artificial gastric juice was only about 40 min. It shows that HE3286 is very easy to degrade under acidic conditions. The early contact of HE3286 with acidic gastric contents after oral administration of the drug preparation will lead to drug degradation, reduce oral bioavailability, and may lead to an increase in individual differences among patients, which is not conducive to exerting Drug effect.

与之相反，其他一些类似化合物在酸存在下仍然较为稳定。实施例 2 HE3286原制剂的制备及成型性测试 In contrast, some other similar compounds are still relatively stable in the presence of acid. Example 2 Preparation and Formability Test of Original Preparation of HE3286

本实施例所述的 HE3286原制剂为片剂，其中含有增溶剂以及其他药学上可接受的其他辅料，组合物组成与中国专利 200980112162. 1中胶囊剂相同。 The original preparation of HE3286 described in this example is a tablet containing a solubilizing agent and other pharmaceutically acceptable other excipients, and the composition of the composition is the same as that of the capsule of Chinese Patent 200980112162.

制备工艺为：药物及辅料混合物经制粒设备制粒，干燥，整粒，压片，得到直径约 7讓的片芯，重量约 150mg。 The preparation process is as follows: The drug and the auxiliary material mixture are granulated by a granulating device, dried, granulated, and tableted to obtain a core having a diameter of about 7 and a weight of about 150 mg.

对上述产物按中国药典 2010版二部附录 XG片剂脆碎度检査法进行成型性测试。制备原料（按 10000片计)及成型性测试结果如表 1所示： The above products were tested for formability according to the Chinese Pharmacopoeia 2010 edition two appendix XG tablet friability test method. The raw materials (based on 10,000 sheets) and the moldability test results are shown in Table 1:

表 1 Table 1

结果表明，按中国专利 200980112162. 1中组合物组成制备片剂，片剂硬度偏低，脆碎度不符合要求，该处方组成不适宜用作 HE3286肠溶制剂的片芯。实施例 3 本发明 HE3286肠溶片剂的制备及成型性测试

The results showed that the tablets were prepared according to the composition of the composition of Chinese Patent 200980112162. 1 and the hardness of the tablets was low. The friability does not meet the requirements, and the prescription composition is not suitable for use as the core of the HE3286 enteric preparation. Example 3 Preparation and Formability Test of HE3286 Enteric Tablets of the Invention

本实施例所述的 HE3286肠溶片剂规格为 5mg (以 HE3286含量计）。制备步骤如下： 3. 1 片芯的制备： The HE3286 enteric tablet described in this example has a specification of 5 mg (based on the HE3286 content). The preparation steps are as follows: 3. 1 Core preparation:

a)将微粉化 HE3286、月桂基硫酸钠、微晶纤维素 Γ¾101、乳糖、交联聚维酮 XL-10、共聚乙烯吡咯烷酮 VA64混合均匀，加入 3%羟丙基甲基纤维素溶液将混合粉末制成颗粒，该过程是在三相切割混合制粒机中完成的； a) Mix micronized HE3286, sodium lauryl sulfate, microcrystalline cellulose Γ3⁄4101, lactose, crospovidone XL-10, and polyvinylpyrrolidone VA64, and add 3% hydroxypropyl methylcellulose solution to mix the powder. Made into granules, the process is completed in a three-phase cutting and mixing granulator;

b)当混合粉末粘结为颗粒后，用电热恒温鼓风干燥机 5CTC下干燥。整粒后，将硬脂酸镁加入到干燥的小颗粒中混合均匀； b) After the mixed powder is bonded to the granules, it is dried by an electric thermostatic blast dryer 5CTC. After the whole granules, magnesium stearate is added to the dried small granules and mixed uniformly;

c)使用高速旋转压片机压制所得混合物，得到直径约 8mm的片芯，片芯重量约 330mg, 硬度 5〜9kg。 c) The resulting mixture was pressed using a high speed rotary tableting machine to obtain a core having a diameter of about 8 mm, a core weight of about 330 mg, and a hardness of 5 to 9 kg.

3. 2隔离层的制备：将欧巴代溶于水中，搅拌过夜，将所得产物喷在片芯表面进行沉淀。此操作高效包衣锅在中完成。 3. 2 Preparation of barrier layer: Opadry was dissolved in water, stirred overnight, and the obtained product was sprayed on the surface of the core to precipitate. This operation is done in a highly efficient coating pan.

3. 3 肠溶层的制备： 3. 3 Preparation of enteric layer:

a)将柠檬酸三乙酯溶于一部分水中，加到 Eudragit L30D-55的水分散体中，搅拌所得混合物 lh_; a) Dissolving triethyl citrate in a portion of water, adding to an aqueous dispersion of Eudragit L30D-55, and stirring the resulting mixture for 1 h _;

b)将超细滑石粉在剩余部分的水中匀化得到超细滑石粉混悬液； b) homogenizing the ultrafine talc powder in the remaining part of the water to obtain an ultrafine talc powder suspension;

c)将上述超细滑石粉混悬液加入到上述柠檬酸三乙酯 / Eudragit L30D-55混合溶液中； c) adding the above ultrafine talc powder suspension to the above triethyl citrate / Eudragit L30D-55 mixed solution;

d)将所述混合物通过喷雾而沉淀在包裹隔离层包衣的片芯表面，此操作高效包衣锅在中完成，然后用电热恒温鼓风干燥机使肠溶层包衣老化，温度优选保持在 40°C，保持 2h。 d) precipitating the mixture by spraying onto the surface of the core coated with the release layer, in which the high-efficiency coating pan is completed, and then the enteric layer coating is aged by an electric thermostatic blast dryer, and the temperature is preferably maintained. At 40 ° C, hold for 2 h.

3. 4 成型性测试 3. 4 Formability test

按照中国药典 2010版二部附录 XG片剂脆碎度检査法进行成型性测试。 The moldability test was carried out according to the Chinese Pharmacopoeia 2010 edition two appendix XG tablet friability test method.

制备原料（按 10000片计)及成型性结果如表 2所示： The raw materials (based on 10,000 sheets) and the moldability results are shown in Table 2:

表 2 Table 2

使用量 (g) /增重比 (%) / 原料成分原料名称 Usage (g) / weight gain ratio (%) / raw material ingredients

结果 Result

HE3286 HE3286 50g HE3286 HE3286 50g

增溶剂月桂基硫酸钠 250g (占处方量的 7. 60%) 惰性物质无无 Solubilizer sodium lauryl sulfate 250g (accounting for 7.60% of the prescription) Inert matter without

微晶纤维素 raioi 595g Microcrystalline cellulose raioi 595g

填充剂 Filler

乳糖 1785g Lactose 1785g

崩解剂交联聚维酮 XL-10 300g Disintegrant crospovidone XL-10 300g

共聚乙烯吡咯烷酮 Copolyvinylpyrrolidone

300g 300g

VA64 VA64

粘合剂 Adhesive

3%羟丙基甲基纤维素 3% hydroxypropyl methylcellulose

适量 Moderate amount

溶液 Solution

润滑剂硬脂酸镁 7. 3g Lubricant Magnesium stearate 7. 3g

隔离层欧巴代增重 5% Isolation layer Opadry weight gain 5%

肠溶层 Eudragit L30D-55 增重 6% Enteric layer Eudragit L30D-55 gain 6%

硬度 5 9kg Hardness 5 9kg

片芯片芯 Chip core

脆碎度符合要求由此制得的 HE3286片芯质量为 330mg，硬度为 5 9kg，脆碎度符合要求，由此制得的 HE3286肠溶片剂每剂质量为 370mg，含 HE3286 5mg 实施例 4对实施例 3中制备的产物进行药物释放特性测试 The friability is as follows. The quality of the HE3286 core is 330mg, the hardness is 59kg, and the friability meets the requirements. The HE3286 enteric tablet prepared by this method has a mass of 370mg per agent and contains HE3286 5mg. Drug release characteristics test of the product prepared in Example 3

按照《中国药典（2010版）》附录 XD释放度测定第二法对实施例 3中制备的 HE3286 肠溶片剂的脆碎度及药物释放特性进行测试。具体步骤为： The friability and drug release characteristics of the HE3286 enteric tablet prepared in Example 3 were tested in accordance with the Chinese Pharmacopoeia (2010 Edition) Appendix XD Release Determination Method. The specific steps are:

1)将 HE3286肠溶制剂在 0. lmol/L盐酸水溶液 (模拟人工胃液）中溶出 2小时，然后将 0. lmol/L盐酸水溶液更换为 pH=6. 8的磷酸盐缓冲液 (模拟人工肠液），分别于 10min 20min 30min 45min 60min取样 10ml，过滤取续滤液为供试品； The phosphate buffer solution (simulated artificial intestinal juice) was replaced with a 0.1 mol/L hydrochloric acid aqueous solution in a pH of 6.8. 10 ml, 10 ml, 10 min, 30 min, 45 min, 60 min, respectively, and the filtrate was filtered to obtain a test sample;

2)高效液相色谱法记录供试品中 HE3286峰面积：色谱柱 Ultimate™ XB-C18 3. 5 u m4. 6 X 150mm, 流动相为乙腈：纯水 =30 : 70，检测波长 210nm PAD; 2) Record the HE3286 peak area in the test sample by high performance liquid chromatography: Column UltimateTM XB-C18 3. 5 u m4. 6 X 150mm, mobile phase is acetonitrile: pure water = 30: 70, detection wavelength 210nm PAD;

3)计算供试品中 HE3286含量，进一步计算释放度 Q，计算公式如下： 3) Calculate the content of HE3286 in the test sample, and further calculate the release degree Q. The calculation formula is as follows:

€x ¥ €x ¥

Q = v . X 1關％其中， C为 HE3286浓度 g/ml V为释放介质体积 (ml) W为制剂中活性成分标示量 (mg) Q = v . X 1 Guan% where C is the concentration of HE3286 g/ml V is the volume of the release medium (ml) W is the active ingredient in the preparation (mg)

本实施例的释放曲线见图 1 The release curve of this embodiment is shown in Fig. 1.

结果如表 3所示： The results are shown in Table 3:

表 3 测试例结果 table 3 Test case result

释放度 Release

酸性介质中 2h后组合物表面没有裂缝、崩解或 There was no crack, disintegration or surface on the surface of the composition after 2 h in an acidic medium.

人工胃 Artificial stomach

软化现象，无药物释放 Softening, no drug release

液 Liquid

释放度 Release

pH=6. 8磷酸盐缓冲液中 45min药物释放度为 pH=6. 8 phosphate buffer solution 45min drug release rate is

人工肠 Artificial intestine

85. 95%。 85. 95%.

液结果显示， HE3286肠溶制剂在酸性介质中没有释放药物，提示口服 HE3286肠溶片剂后可避免药物与酸性胃内容物过早接触，具有高度稳定性； HE3286肠溶片剂在 pH=6. 8磷酸盐缓冲液中逐渐崩解并释放药物，提示 HE3286肠溶片剂可在肠道部位释放药物，利于药物吸收。 The results showed that the HE3286 enteric preparation did not release the drug in the acidic medium, suggesting that the oral administration of HE3286 enteric tablets can avoid premature contact with the acidic gastric contents and has high stability; HE3286 enteric tablets at pH=6 8. Phosphate buffer gradually disintegrates and releases the drug, suggesting that HE3286 enteric tablets can release drugs in the intestinal tract, which is beneficial for drug absorption.

因此，通过改变组合物处方组成，片芯成型性明显改善，片芯硬度适宜，脆碎度符合要求， HE3286肠溶制剂的体外释放度符合要求。实施例 5 测定原制剂和实施例 3中制备的产物在比格犬体内的生物利用度测定中国专利 200980112162. 1中原制剂和实施例 3中制备的产物在比格犬体内的生物利用度，步骤如下 Therefore, by changing the composition of the composition, the core formability is obviously improved, the core hardness is suitable, the friability is in accordance with the requirements, and the in vitro release degree of the HE3286 enteric preparation meets the requirements. Example 5 Determination of the bioavailability of the original preparation and the product prepared in Example 3 in Beagle dogs The bioavailability of the product prepared in the original preparation and the preparation of Example 3 in Beagle dogs, the procedure as follows

1)取比格犬 8只禁食 12h后随即分为两组，分别给予中国专利 200980112162. 1 中所述 HE3286胶囊剂和实施例 3中制备的 HE3286肠溶片剂； 1) Take the Beagle dogs and fasten them for 12 hours and then divide them into two groups, respectively, and give HE3286 capsules as described in Chinese Patent 200980112162. 1 and HE3286 enteric tablets prepared in Example 3;

2)分别在给药后的 0 h、 0. 5 h、 1 h、 1. 25 h、 1. 5 h、 1. 75 h、 2 h、 2. 25 h、 2. 5 h、 2. 75 h、 3 h、 3. 33 h、 3. 66 h、 4 h、 4· 5 h、 5 h、 6 h、 8 h、 12 h、 24h 取血； 2) 0 h, 0.5 h, 1 h, 1. 25 h, 1. 5 h, 1. 75 h, 2 h, 2. 25 h, 2. 5 h, 2. 75 after administration, respectively Blood was taken at h, 3 h, 3. 33 h, 3. 66 h, 4 h, 4 · 5 h, 5 h, 6 h, 8 h, 12 h, 24 h;

3)处理血浆样品：取 50 L内标溶液 ISD置于聚丙烯小管，加入 200 血浆样品，涡旋混匀，加入 0. 5mL乙酸乙酯，并涡旋提取 3分钟， 10600 X g、 4°C下离心 5 分钟，精密吸取 400 上清液至 96孔板中，在约 35 ° C的氮气下吹干，加入 100 μ L甲醇：水（2 : 8)复溶，涡旋混匀 3分钟； 3) Treatment of plasma samples: Take 50 L of the internal standard solution ISD in a polypropylene tube, add 200 plasma samples, vortex and mix, add 0.5 mL of ethyl acetate, and vortex for 3 minutes, 10600 X g, 4 ° Centrifuge for 5 minutes at C, accurately draw 400 supernatant into 96-well plate, dry it under nitrogen at about 35 ° C, reconstitute with 100 μL of methanol: water (2: 8), and vortex for 3 minutes. ;

4)使用 LC-MS/MS进行色谱分析；使用岛津 UFLC 20-AD XR超快速液相***与美国应用生物***公司 ΑΡΙ-5000三重四级杆质谱联用，色谱柱为 Luna 5μ C₈， 50 X 2. 0 mm, 流动相为 0. 4%甲酸水溶液：甲醇， HE3286离子对为 313. 2/295. 2。 HE3286线性范围为 2. 00〜1000 ng/mL, 线性相关系数 r>0. 9930。 5)将 HE3286峰面积代入标准曲线求算血浆 HE3286浓度。 4) Chromatographic analysis using LC-MS/MS; using Shimadzu UFLC 20-AD XR ultra-fast liquid phase system combined with Applied Biosystems ΑΡΙ-5000 triple quadrupole mass spectrometer, the column is Luna 5μ C ₈ , 5之间。 The water phase was 0. 4% aqueous solution of formic acid: methanol, HE3286 ion pair was 313. 2/295. 2. The linear range of the HE3286 is 2. 00~1000 ng/mL, and the linear correlation coefficient r>0. 5) Substituting the peak area of HE3286 into the standard curve to calculate the plasma HE3286 concentration.

HE3286胶囊剂和 HE3286肠溶片剂的药代动力学参数如表 4: The pharmacokinetic parameters of HE3286 capsules and HE3286 enteric tablets are shown in Table 4:

表 4 Table 4

*ρ〈0. 05，与胶囊剂组相比存在显著差异结果显示，与原制剂相比，实施例 3中制备的 ΗΕ3286肠溶片剂相对生物利用度为 173% (ρ〈0. 05)； ΗΕ3286肠溶片剂可显著提高血浆药物峰浓度，但对药物代谢半衰期没有显著影响。 *ρ<0.05, there was a significant difference compared with the capsule group. The results showed that the relative bioavailability of the ΗΕ3286 enteric tablet prepared in Example 3 was 173% (ρ<0.05) compared with the original preparation. ΗΕ3286 enteric tablets can significantly increase plasma drug peak concentration, but has no significant effect on drug metabolism half-life.

因此，与原制剂相比，实施例 3中制备的 ΗΕ3286肠溶制剂的生物利用度得到显著提高，提示在不改变处方组成的情况下，通过剂型选择 (本发明为 ΗΕ3286肠溶片剂) 可显著提高制剂生物利用度，合理的剂型有利于药效的发挥。 Therefore, the bioavailability of the ΗΕ3286 enteric preparation prepared in Example 3 was significantly improved as compared with the original preparation, suggesting that the dosage form selection (the present invention is ΗΕ3286 enteric tablet) can be carried out without changing the prescription composition. Significantly improve the bioavailability of the preparation, a reasonable dosage form is conducive to the efficacy of the drug.

鉴于实施例 3中 ΗΕ3286肠溶片剂具有很高的体内生物利用度，因此以该组合物的制剂特征，即片芯成型性和释放度为标准，对 ΗΕ3286肠溶制剂的处方组成进行筛选，筛选目的在于减少处方中增溶剂 (尤其是表面活性剂）的用量，减小制剂对人体胃肠道粘膜的剌激，从而减轻副作用。实施例 6 不含增溶剂的 ΗΕ3286肠溶片剂的制备及成型性测试 In view of the high in vivo bioavailability of the ΗΕ3286 enteric tablet in Example 3, the formulation composition of the ΗΕ3286 enteric preparation is screened according to the formulation characteristics of the composition, that is, core formability and release rate. The purpose of the screening is to reduce the amount of solubilizer (especially surfactant) in the prescription, and to reduce the stimulation of the gastrointestinal mucosa of the human body, thereby reducing side effects. Example 6 Preparation and Formability Test of ΗΕ3286 Enteric Tablets Without Solubilizer

本实施例所述的 ΗΕ3286肠溶片剂不含增溶剂，规格为 2mg。制备及测试步骤同实施例 3，区别在于片芯重量为 150mg The ΗΕ3286 enteric tablet described in this example does not contain a solubilizing agent and has a specification of 2 mg. The preparation and testing procedures are the same as in Example 3, except that the core weight is 150 mg.

制备原料（按 10000片计)及成型性结果如表 5所示： The raw materials (in 10,000 sheets) and the moldability results are shown in Table 5:

表 5 table 5

原料成分原料名称使用量 (g) /增重比 (%) /结果 Raw material ingredients Raw material name Usage (g) / weight gain ratio (%) / result

HE3286 HE3286 20g HE3286 HE3286 20g

增溶剂无无 Solubilizer no

惰性物质无无 Inert material None

填充剂淀粉 444g Filler starch 444g

乳糖 889g Lactose 889g

崩解剂交联羧甲基纤维素钠 66g 粘合剂 5%PVP乙醇溶液适量润滑剂滑石粉 33 Disintegrating agent croscarmellose sodium 66g Adhesive 5% PVP ethanol solution appropriate amount of lubricant talcum powder 33

隔离层欧巴代增重 5% Isolation layer Opadry weight gain 5%

肠溶层邻苯二甲基醋酸纤维素增重 10% Enteric layer phthalate cellulose weight gain 10%

片芯片芯硬度 5〜9kg 脆碎度符合要求由此制得的 HE3286片芯质量约 150mg，硬度 5〜9kg，脆碎度符合要求，由此制得的肠溶片剂每剂质量为 165mg，含 HE3286 2mg。实施例 7 对实施例 6中制备的产物进行药物释放特性测试 The core hardness of the chip core is 5~9kg. The friability is as follows. The quality of the HE3286 core is about 150mg, the hardness is 5~9kg, and the friability is in accordance with the requirements. The quality of the enteric tablet prepared by this method is 165mg. Contains 2 mg of HE3286. Example 7 The drug release characteristics test was carried out on the product prepared in Example 6.

测试方法与步骤同实施例 4，释放曲线见图 2，其区别与结果如表 6所示: The test method and procedure are the same as those in Embodiment 4. The release curve is shown in Figure 2. The difference and result are shown in Table 6:

表 6 Table 6

结果显示， HE3286肠溶制剂在人工胃液中没有释放药物，提示不含增溶剂的 HE3286肠溶片剂可避免药物与酸性胃内容物过早接触，具有高度稳定性；不含增溶剂的 HE3286肠溶片剂在 pH=6. 8人工肠液中逐渐崩解并释放药物，提示 HE3286肠溶片剂可在小肠部位释放药物，利于药物吸收。 The results showed that the HE3286 enteric preparation did not release the drug in the artificial gastric juice, suggesting that the HE3286 enteric tablet without the solubilizing agent can prevent the drug from premature contact with the acidic stomach contents, and has high stability; HE3286 sausage without the solubilizer The dissolved tablet gradually disintegrated and released the drug in the pH=6.8 artificial intestinal juice, suggesting that the HE3286 enteric tablet can release the drug in the small intestine, which is beneficial to the absorption of the drug.

因此，本实施例显示的不含增溶剂 (尤其是表面活性剂）的肠溶片剂，片芯成型性良好，片芯硬度适宜，脆碎度符合要求， HE3286肠溶制剂的体外释放度符合要求，且对人体毒副作用更小。实施例 8 不含增溶剂、含惰性物质的 HE3286肠溶片剂的制备及成型性测试本实施例所述的 HE3286肠溶片剂不含增溶剂，含有提供局部碱性环境的惰性物质，规格为 10mg。制备及测试步骤同实施例 3，区别在于片芯重量为 100mg。 Therefore, the enteric tablet without the solubilizing agent (especially surfactant) shown in the present embodiment has good core formability, suitable core hardness, and friability meets the requirements, and the in vitro release of the HE3286 enteric preparation conforms to the requirements. Requirements, and the side effects of the human body are smaller. Example 8 Preparation and Formability Test of HE3286 Enteric Tablets Containing No Solubilizer and Inert Containing Substance The HE3286 enteric tablet described in this example contains no solubilizing agent and contains an inert substance providing a local alkaline environment. It is 10mg. The preparation and test procedures were the same as in Example 3 except that the core weight was 100 mg.

制备原料（按 10000片计)及成型性结果如表 7所示： The raw materials (in 10,000 sheets) and the moldability results are shown in Table 7:

表 7 原料成使用量 (g) /增重比 (%) / 原料名称 Table 7 Raw material usage (g) / weight gain ratio (%) / raw material name

分结果 Result

HE3286 HE3286 100g HE3286 HE3286 100g

增溶剂无无 Solubilizer no

惰性物 Inert

氢氧化镁 40g Magnesium hydroxide 40g

质 Quality

蔗糖 340g Sucrose 340g

填充剂 Filler

乳糖 340g Lactose 340g

崩解剂羧甲基淀粉钠 150g Disintegrant sodium carboxymethyl starch 150g

粘合剂 10%淀粉浆溶液适量 Adhesive 10% starch slurry solution

硬脂酸镁 15g Magnesium stearate 15g

润滑剂 Lubricant

微粉硅胶 15g Micro-silica gel 15g

隔离层 10%欧巴代 II型溶液增重 3% Isolation layer 10% Opadry II solution Weight gain 3%

醋酸羟丙基甲基纤维素琥珀 Hydroxypropyl methylcellulose acetate

肠溶层增重 3% Enteric layer weight gain 3%

酸酯由此制得的 HE3286片芯质量约 100mg，硬度 5〜9kg，脆碎度符合要求，由此制得的肠溶片剂每剂质量为 106mg，含 HE3286 10mg。实施例 9 对实施例 8中制备的产物进行药物释放特性测试 Ethyl ester The thus obtained HE3286 core has a mass of about 100 mg, a hardness of 5 to 9 kg, and a friability of the requirements. The enteric tablet thus obtained has a mass of 106 mg per capsule and contains 10 mg of HE3286. Example 9 The drug release characteristic test was carried out on the product prepared in Example 8.

测试方法与步骤同实施例 4，释放曲线见图 3，其区别与结果如表 8所示：表 8 The test method and procedure are the same as those in the embodiment 4. The release curve is shown in Fig. 3. The difference and result are shown in Table 8: Table 8

结果显示， HE3286肠溶制剂在人工胃液中没有释放药物，提示不含增溶剂、含惰性物质的 HE3286肠溶片剂可避免药物与酸性胃内容物过早接触，具有高度稳定性; 不含增溶剂、含惰性物质的 HE3286肠溶片剂在 pH=6. 8人工肠液中逐渐崩解并释放药物，提示 HE3286肠溶片剂可在小肠部位释放药物，利于药物吸收。因此，本实施例显示的不含增溶剂 (尤其是表面活性剂）的肠溶片剂，片芯成型性良好，片芯硬度适宜，脆碎度符合要求， HE3286肠溶制剂的体外释放度符合要求，且对人体毒副作用更小。实施例 10 不含增溶剂、含惰性物质的 HE3286肠溶片剂的制备及成型性测试本实施例所述的 HE3286肠溶片剂不含增溶剂，含有提供局部碱性环境的惰性物质，规格为 10mg。制备及测试步骤同实施例 3，区别在于片芯重量为 120mg。

The results showed that the HE3286 enteric preparation did not release the drug in the artificial gastric juice, suggesting that the HE3286 enteric tablet containing no solubilizing agent and inert substance can prevent the drug from premature contact with the acidic stomach contents, and has high stability; The solvent and the HE3286 enteric tablet containing the inert substance gradually disintegrated and released the drug in the pH=6.8 artificial intestinal juice, suggesting that the HE3286 enteric tablet can release the drug in the small intestine, which is beneficial to the absorption of the drug. Therefore, the enteric tablet without the solubilizing agent (especially surfactant) shown in the present embodiment has good core formability, suitable core hardness, and friability meets the requirements, and the in vitro release of the HE3286 enteric preparation conforms to the requirements. Requirements, and the side effects of the human body are smaller. Example 10 Preparation and Formability Test of HE3286 Enteric Tablets Without Solubilizer and Inert Substance The HE3286 enteric tablet described in this example does not contain a solubilizing agent and contains an inert substance providing a local alkaline environment. It is 10mg. The preparation and testing procedures were the same as in Example 3 except that the core weight was 120 mg.

制备原料（按 10000片计)及成型性结果如表 9所示： The raw materials (based on 10,000 sheets) and the moldability results are shown in Table 9:

表 9 Table 9

由此制得的 HE3286片芯质量约 120mg，硬度 5〜9kg，脆碎度符合要求，由此制得的肠溶片剂每剂质量为 133mg，含 HE3286 10mg。实施例 11 不含增溶剂、含惰性物质的 HE3286肠溶片剂的制备及成型性测试本实施例所述的 HE3286肠溶片剂不含增溶剂，含有提供局部碱性环境的惰性物质，规格为 10mg。制备及测试步骤同实施例 3，区别在于片芯重量为 150mg。

The HE3286 core thus obtained has a core mass of about 120 mg and a hardness of 5 to 9 kg, and the friability is in accordance with the requirements. The enteric tablet thus obtained has a mass of 133 mg per agent and contains 10 mg of HE3286. Example 11 Preparation and Formability Test of HE3286 Enteric Tablets Containing No Solubilizer and Inert Containing Substance The HE3286 enteric tablet described in this example does not contain a solubilizing agent and contains an inert substance providing a local alkaline environment. It is 10mg. The preparation and testing procedures were the same as in Example 3 except that the core weight was 150 mg.

制备原料（按 10000片计)及成型性结果如表 10所示： The raw materials (in 10,000 sheets) and the moldability results are shown in Table 10:

表 10 Table 10

原料成分原料名称使用量 (g) /增重比 (%) /结果 HE3286 HE3286 100g Raw material ingredient raw material name usage (g) / weight gain ratio (%) / result HE3286 HE3286 100g

增溶剂无无 Solubilizer no

惰性物质组氨酸钠 15g Inert substance sodium histidine 15g

微晶纤维素 650g Microcrystalline cellulose 650g

填充剂 Filler

丄^^ ^ 650g 丄^^ ^ 650g

崩解剂低取代羟丙基纤维素 50g Disintegrant Low-substituted hydroxypropyl cellulose 50g

粘合剂 10%淀粉浆溶液适量 Adhesive 10% starch slurry solution

硬脂酸镁 15g Magnesium stearate 15g

润滑剂 Lubricant

微粉硅胶 15g Micro-silica gel 15g

隔离层 5%HPMC溶液增重 5% Isolation layer 5% HPMC solution weight gain 5%

肠溶层 Eudragi t L 100 增重 12% 由此制得的 HE3286片芯质量约 150mg，硬度 5〜9kg，脆碎度符合要求，由此制得的肠溶片剂每剂质量为 176mg，含 HE3286 10mg。实施例 12 肠溶胶囊剂的制备 Enteric layer Eudragi t L 100 Weight gain 12% The HE3286 core thus obtained has a core mass of about 150 mg and a hardness of 5 to 9 kg. The friability is in accordance with the requirements. The quality of the enteric tablet thus obtained is 176 mg per dose. HE3286 10mg. Example 12 Preparation of Enteric Capsules

本实施例所述的 HE3286肠溶胶囊剂，含有提供局部碱性环境的惰性物质，规格为 10mg。制备步骤为： The HE3286 enteric capsule according to the present embodiment contains an inert substance which provides a local alkaline environment and has a specification of 10 mg. The preparation steps are:

a) 将微粉化 HE3286、氢氧化镁、微晶纤维素 1¾101、乳糖、交联聚维酮 XL-10 混合均匀，加入 3%羟丙基甲基纤维素溶液将混合粉末制成颗粒状药芯，粒径约为 100 ~ 2000 μ m₀ a) Mix micronized HE3286, magnesium hydroxide, microcrystalline cellulose 13⁄4101, lactose, crospovidone XL-10, and add 3% hydroxypropyl methylcellulose solution to make the powder into a granular drug core. , particle size is about 100 ~ 2000 μ m ₀

b) 将上述药芯灌装入肠溶胶囊，形成肠溶胶囊剂。 b) The above drug core is filled into an enteric capsule to form an enteric capsule.

制备原料（按 10000片计）如表 11所示： The raw materials (according to 10,000 pieces) are shown in Table 11:

表 11 Table 11

由此制得的 HE3286胶囊剂每剂内容物质量约为 150mg，其中含 HE3286 10mg，灌装于肠溶明胶空心胶囊中。实施例 13 对实施例 12中制备的产物进行药物释放特性测试

The HE3286 capsule thus obtained has a content of about 150 mg per dose, and contains 10 mg of HE3286, which is filled in an enteric gelatin hollow capsule. Example 13 Drug release characteristics test of the product prepared in Example 12

测试方法与步骤同实施例 4，其区别与结果如表 12所示： The test methods and steps are the same as those in Embodiment 4. The differences and results are shown in Table 12:

表 12 Table 12

结果显示， HE3286肠溶制剂在人工胃液中没有释放药物，提示 HE3286肠溶胶囊剂同样可避免药物与酸性胃内容物过早接触，在 pH=6. 8人工肠液中逐渐崩解并释放药物，说明 HE3286肠溶胶囊剂可在小肠部位释放药物，利于药物吸收。

The results showed that the HE3286 enteric preparation did not release the drug in the artificial gastric juice, suggesting that the HE3286 enteric capsule can also prevent the drug from premature contact with the acidic stomach contents, gradually disintegrating and releasing the drug in the pH=6.8 artificial intestinal juice. It shows that HE3286 enteric capsule can release drugs in the small intestine, which is beneficial to drug absorption.

因此，本实施例显示的肠溶胶囊剂，药芯成型性良好， HE3286肠溶制剂的体外释放度符合要求，且对人体毒副作用更小，生物利用度更高。实施例 14肠溶微丸剂 Therefore, the enteric capsules shown in this embodiment have good core formability, and the in vitro release degree of the HE3286 enteric preparation meets the requirements, and the human side has less toxic side effects and higher bioavailability. Example 14 Enteric pellets

本实施例所述的 HE3286肠溶微丸剂，系将肠溶微丸灌装于胶囊中，肠溶微丸由空白丸芯、主药层、隔离层、肠溶层组成，每粒胶囊含有 HE3286 2mg。具体制备方法如下：空白丸芯：市售粒径范围为 0. 3〜0. 5讓的空白惰性微丸 2000g; 主药层： HE3286 20g，聚乙烯吡咯烷酮 30g，滑石粉 2g; 溶剂为 90%乙醇 1000ml ; The HE3286 enteric pellets of the present embodiment are filled with enteric pellets, and the enteric pellets are composed of a blank pellet core, a main drug layer, a separation layer and an enteric layer, and each capsule contains HE3286. 2mg. The specific preparation method is as follows: blank pellet core: commercially available particle size range of 0. 3~0. 5 let blank inert pellets 2000g; main drug layer: HE3286 20g, polyvinylpyrrolidone 30g, talc powder 2g; solvent is 90% 1000ml of ethanol;

隔离层：羟丙甲基纤维素 50g，滑石粉 250g Isolation layer: hydroxypropylmethylcellulose 50g, talcum powder 250g

肠溶层： HPMCAS 390g，柠檬酸三乙酯 95g，滑石粉 115g Enteric layer: HPMCAS 390g, triethyl citrate 95g, talcum powder 115g

肠溶微丸剂的制备工艺如下： The preparation process of enteric pellets is as follows:

含药层的制备：将 HE3286混悬于粘合剂 (聚乙烯吡咯烷酮）中，药物浓度为 2%，使用流化床将 HE3286涂覆于空白丸芯上，干燥得到含药微丸，在流化床中干燥。 Preparation of drug-containing layer: HE3286 was suspended in a binder (polyvinylpyrrolidone) at a drug concentration of 2%, HE3286 was applied to a blank pellet core using a fluidized bed, and dried to obtain a drug-containing pellet, in a stream Dry in the chemical bed.

隔离层的制备：将隔离层羟丙甲基纤维素水溶液涂覆到含药小丸上，干燥得含隔离层微丸。 Preparation of the separation layer: the isolation layer of hydroxypropylmethylcellulose aqueous solution is applied to the drug-containing pellets, and is dried to contain Separation pellets.

肠溶层的制备：将肠溶包衣液 HPMCAS (醋酸羟丙基甲基纤维素琥珀酸酯）涂覆至上述小丸中，干燥得肠溶微丸。 Preparation of enteric layer: An enteric coating liquid HPMCAS (hydroxypropylmethylcellulose acetate succinate) was applied to the above pellets, and dried to obtain enteric pellets.

肠溶微丸剂的制备：将干燥的肠溶微丸灌装于明胶空心胶囊中。结果显示， HE3286肠溶微丸剂在人工胃液中没有释放药物，提示肠溶微丸剂同样可避免药物与酸性胃内容物过早接触，在 pH=6. 8人工肠液中逐渐崩解并释放药物。这表明该肠溶微丸剂可在小肠部位释放药物，利于药物吸收。在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。 Preparation of enteric pellets: The dried enteric pellets are filled in gelatin hollow capsules. The results showed that the HE3286 enteric pellets did not release the drug in the artificial gastric juice, suggesting that the enteric pellets can also prevent premature contact between the drug and the acidic gastric contents, and gradually disintegrate and release the drug in the pH=6.8 artificial intestinal juice. This indicates that the enteric pellets can release drugs in the small intestine, which is beneficial for drug absorption. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it is to be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims

权利要求 Rights request

1. 一种口服制剂，其特征在于，所述的口服制剂含有药学上可接受的载体和作为活性成分的 17 α -乙炔基雄甾 -5-烯 -3 β , 7 β , 17 β -三醇（ΗΕ3286)，并且所述口服制剂具有以下特性：所述制剂在酸性介质中不释放或基本不释放。 An oral preparation comprising a pharmaceutically acceptable carrier and 17 α -ethynylandrost-5-ene-3 β , 7 β , 17 β -triol as an active ingredient (ΗΕ3286), and the oral preparation has the following characteristics: The preparation is not released or substantially not released in an acidic medium.

2. 如权利要求 1所述的制剂，其特征在于，所述的酸性介质是 0. 1M的盐酸水溶液，以及所述制剂在酸性介质中不释放或基本不释放指：所述口服制剂在酸性介质中放置 2小时，所述活性成分的释放量不大于 10%，优选地不大于 5%。 2. The preparation according to claim 1, wherein the acidic medium is 0.1 M aqueous hydrochloric acid, and the preparation is not released or substantially released in an acidic medium: the oral preparation is acidic The active ingredient is released in an amount of not more than 10%, preferably not more than 5%, in the medium for 2 hours.

3. 如权利要求 1所述的制剂，其特征在于，将所述口服制剂置于 ρΗ = 6.8磷酸盐缓冲液中溶出 45min，活性成分的释放量 70%，优选地 80%。 The preparation according to claim 1, wherein the oral preparation is dissolved in ρΗ = 6.8 phosphate buffer for 45 minutes, and the release amount of the active ingredient is 70%, preferably 80%.

4. 如权利要求 1所述的制剂，其特征在于，所述制剂为肠溶制剂。 4. The preparation according to claim 1, wherein the preparation is an enteric preparation.

5. 如权利要求 1或 4所述的制剂，其特征在于，所述制剂的剂型包括：片剂、胶囊剂、或微丸剂。 5. The preparation according to claim 1 or 4, wherein the dosage form of the preparation comprises: a tablet, a capsule, or a pellet.

6. 如权利要求 1所述的口服制剂，其特征在于，所述制剂选自下组： a) 肠溶片剂，所述的片剂包括片芯、隔离层、肠溶包衣，其中所述的片芯含有 17 α -乙炔基雄甾 -5-烯 -3 β， 7 β， 17 β -三醇； 6. The oral preparation according to claim 1, wherein the preparation is selected from the group consisting of: a) an enteric tablet, the tablet comprising a core, a release layer, an enteric coating, wherein The core of the film contains 17 α -ethynylandrost-5-ene-3 β, 7 β, 17 β -triol;

b) 肠溶胶囊剂，所述的胶囊包括肠溶胶囊以及位于肠溶胶囊内的药物颗粒或粉末，其中所述的药物颗粒或粉末包括 17 α -乙炔基雄 -5-烯 -3 β， 7 β， 17 β -三醇； b) enteric capsules comprising an enteric capsule and a pharmaceutical granule or powder in an enteric capsule, wherein the pharmaceutical granule or powder comprises 17 α -ethynylandrost-5-ene-3 β, 7 ,, 17 β-triol;

c) 肠溶微丸剂，所述的微丸剂包括肠溶微丸剂或填充于胶囊内的肠溶微丸，其中所述的肠溶微丸包括微丸药芯、微丸隔离层、微丸肠溶包衣，其中药芯包括 17 α -乙炔基雄甾 -5-烯- 3 β， 7 β， 17 β -三醇。 c) enteric pellets, the pellets comprising enteric pellets or enteric pellets filled in a capsule, wherein the enteric pellets comprise a pellet core, a pellet isolation layer, and an pellet enteric solution. The coating, wherein the core comprises 17α-ethynylandrost-5-ene-3β, 7β, 17β-triol.

7. 如权利要求 6所述的制剂，其特征在于，所述制剂具有选自下组的一个或多个特征： 7. The formulation of claim 6 wherein the formulation has one or more characteristics selected from the group consisting of:

(i i) a)或 c)中所述的隔离层包括羟丙基甲基纤维素、聚乙烯吡咯烷酮、羟丙基纤维素、羟甲基纤维素、甲基纤维素、乙基纤维素、聚乙烯醇、聚乙酸乙烯酯化、聚乙二醇、甘露醇或其组合，优选的采羟丙基甲基纤维素和 /或聚乙烯吡咯烷酮用； (i i i) a)或 c)中所述的肠溶包衣包括甲基丙烯酸 -甲基丙烯酸甲酯共聚物、邻苯二甲酸醋酸纤维素、醋酸羟丙基甲基纤维素琥珀酸酯、邻苯二甲基羟丙基甲基纤维素、醋酸纤维素钛酸酯、羧甲基乙烯纤维素、乙酸苯三酸纤维素、聚乙酸邻苯二甲基乙烯酯、乙酸琥珀酸羟丙基甲基纤维素、乙酸邻苯二甲酸纤维素、虫胶或其组合，优选的采用甲基丙烯酸 -甲基丙烯酸甲酯共聚物、邻苯二甲基羟丙基甲基纤维素、醋酸羟丙基甲基纤维素琥珀酸酯。 (ii) The barrier layer described in a) or c) includes hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, ethylcellulose, poly Vinyl alcohol, polyvinyl acetate, polyethylene glycol, mannitol or a combination thereof, preferably hydroxypropylmethylcellulose and/or polyvinylpyrrolidone; (iii) The enteric coating described in a) or c) includes methacrylic acid-methyl methacrylate copolymer, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, adjacent Benzyl hydroxypropyl methylcellulose, cellulose acetate titanate, carboxymethyl vinyl cellulose, cellulose acetate triacetate, phthalic acid poly(vinyl phthalate), hydroxypropyl propyl succinate Base cellulose, cellulose acetate phthalate, shellac or a combination thereof, preferably using methacrylic acid-methyl methacrylate copolymer, phthalyl hydroxypropyl methylcellulose, hydroxypropyl acetate Methylcellulose succinate.

8. 如权利要求 7所述的制剂，其特征在于，所述制剂具有选自下组的一个或多个特征： 8. The formulation of claim 7, wherein the formulation has one or more characteristics selected from the group consisting of:

(V) 肠溶层包衣的增重为片芯或药芯重量的 1-30%，优选的为 4-15%。 (V) The weight gain of the enteric layer coating is from 1 to 30% by weight of the core or core, preferably from 4 to 15%.

9. 如权利要求 7所述的制剂，其特征在于，所述的提供局部碱性环境的惰性物质包括氧化钙、氢氧化钙、氢氧化镁、碱性无机镁盐（如碳酸镁、重质碳酸镁）、色氨酸、组氨酸、赖氨酸、精氨酸、色氨酸钠、组氨酸钠、赖氨酸钠、精氨酸钠、色氨酸钾、组氨酸钾、赖氨酸钾、精氨酸钾、色氨酸镁、组氨酸镁、赖氨酸镁、精氨酸镁或其组合，优选的采用氢氧化镁、碳酸镁、组氨酸；和 /或 9. The preparation according to claim 7, wherein the inert substance providing a local alkaline environment comprises calcium oxide, calcium hydroxide, magnesium hydroxide, basic inorganic magnesium salt (such as magnesium carbonate, heavy substance). Magnesium carbonate), tryptophan, histidine, lysine, arginine, sodium tryptophan, sodium histidine, sodium lysinate, sodium arginate, potassium tryptophan, potassium histidine, Potassium lysine, potassium arginate, magnesium tryptophan, magnesium histidine, magnesium lysine, magnesium arginate or a combination thereof, preferably using magnesium hydroxide, magnesium carbonate, histidine; and/or

所述惰性物质的用量是组合物中活性成分重量的 0〜50%，优选为 0%〜40%。 The inert substance is used in an amount of from 0 to 50% by weight, preferably from 0% to 40%, based on the total weight of the active ingredient in the composition.

10.如权利要求 1或 7所述的制剂，其特征在于，所述制剂还具有一个或多个选自下组的特性： 10. The formulation of claim 1 or 7, wherein the formulation further has one or more properties selected from the group consisting of:

(vi)每个制剂中 17 α -乙炔基雄甾 -5-烯 -3 β， 7 β， 17 β -三醇的含量为 (vi) 17 α -ethynylandrost-5-ene -3 β, 7 β, 17 β -triol in each preparation

0. 5mg〜100mg，较佳地每剂中活性成分含量为 2mg、 5mg、 10mg、 25mg、 50mg、 lOOmg; 0mg〜100mg, preferably the active ingredient content per dose is 2mg, 5mg, 10mg, 25mg, 50mg, lOOmg;

(vi i)所述的活性成分包括药学上可接受的 17 α -乙炔基雄 -5-烯 -3 β， 7 β， 17 β -三醇的晶型、无定形物、脱水物、溶剂化物、水合物、和对映体； (vi i) The active ingredient comprises a crystalline form, an amorphous form, an anhydrate, a solvate, pharmaceutically acceptable 17 α -ethynyl andrhen-5-ene-3 β, 7 β, 17 β-triol, Hydrates, and enantiomers;

(vi i i)所述的甲基丙烯酸-甲基丙烯酸甲酯共聚物包括 Eudragi t L系列、 Eudragi t S系列、 Eudragi t 系列、 Eudragi t RS系列、 Eudragi t FS系列、 Eudragi tNE系列、肠溶型 I I号、肠溶型 I I I号、欧巴代、或其组合； The methacrylic acid-methyl methacrylate copolymer described in (vi ii) includes Eudragi t L series, Eudragi t S series, Eudragi t series, Eudragi t RS series, Eudragi t FS series, Eudragi tNE series, enteric type II, enteric type III, Opadry, or a combination thereof;

(X)所述的填充剂包括微晶纤维素、乳糖、蔗糖、淀粉、预胶化淀粉、甘露醇、糖粉、糊精、或其组合；和 /或所述填充剂的用量是活性成分重量的 10〜5000%，优选为 50〜3000%，优选的采用微晶纤维素、乳糖、蔗糖、淀粉、或其组合；The filler according to (X) includes microcrystalline cellulose, lactose, sucrose, starch, pregelatinized starch, mannitol, powdered sugar, dextrin, or a combination thereof; and/or the filler is used as an active ingredient. 10 to 5000% of the weight, Preferably it is 50 to 3000%, preferably using microcrystalline cellulose, lactose, sucrose, starch, or a combination thereof;

(xi)所述的崩解剂包括交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素、干淀粉、或其组合；和 /或所述崩解剂的用量是片芯或药芯总重的 0. 5— 50%, 优选为 1〜40%； (xi) the disintegrant comprises crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, dry starch, or a combination thereof; and/or 5〜 50%优选优选为1〜40%; The amount of the tablet or the core of the core is 0.5 to 50%, preferably 1 to 40%;

(xi i)所述的粘合剂包括聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羧甲基纤维素、共聚维酮、乙基纤维素、聚乙烯醇、聚乙二醇、黄原胶、海藻酸、海藻酸盐、或其组合；和 /或所述粘合剂浓度为 0. 5%〜50% (w/v)，用量是载体总重的 0. 1-80%； (xi i) The binder includes polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, copovidone, ethylcellulose, poly 5%〜50% (w/v), The amount is the total carrier, the concentration of the binder is 0.5%~50% (w/v), and the amount of the binder is 0.5%~50% (w/v) 0. 1-80%;

(xi i i)所述的润滑剂包括硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸、单硬脂酸甘油酯、微粉硅胶、滑石粉、水合硅铝酸钠、聚乙二醇、氢化植物油、硬脂酸富马酸钠、聚氧乙烯单硬脂酸酯、单月桂蔗糖酸酯、月桂醇硫酸钠、月桂醇硫酸镁、十二烷基硫酸镁、滑石粉、或其组合；和 /或所述润滑剂的用量是片芯或药芯总重的 0. 1〜20%，优选为 0. 5〜5%； (xi ii) The lubricants include magnesium stearate, calcium stearate, zinc stearate, stearic acid, glyceryl monostearate, silica gel, talc, hydrated sodium aluminosilicate, polyethyl b. Glycol, hydrogenated vegetable oil, sodium fumarate, polyoxyethylene monostearate, monolauryl sucrose, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium lauryl sulfate, talc, or 5〜5%; Preferably, the amount is 0. 1~20%, preferably 0. 5~5%;

(xiv) 所述的活性成分是微粉化的 17 α -乙炔基雄甾 -5-烯 -3 β， 7 β， 17 β -三醇，其平均粒径（D50)为 0. 1 μ η！〜 10 μ m，优选地 0. 5 μ m〜5 μ m。 (xiv) The active ingredient is micronized 17 α -ethynylandrost -5-ene -3 β, 7 β, 17 β -triol having an average particle diameter (D50) of 0.1 μηη! 〜 10 μ m, preferably 0. 5 μ m~5 μ m.

11. 如权利要求 7所述的口服制剂，其特征在于， a)或 c)中所述的肠溶包衣还含有增塑剂，其中所述的增塑剂包括柠檬酸三乙酯、聚乙二醇、苯二甲酸二乙酯、癸二酸二丁酯、三甘油醋酸酯、蓖麻油，较佳地，为柠檬酸三乙酯、聚乙二醇，更佳地，为柠檬酸三乙酯。 The oral preparation according to claim 7, wherein the enteric coating described in a) or c) further contains a plasticizer, wherein the plasticizer comprises triethyl citrate, poly Ethylene glycol, diethyl phthalate, dibutyl sebacate, triglycerin acetate, castor oil, preferably triethyl citrate, polyethylene glycol, more preferably citric acid three Ethyl ester.

12. 一种权利要求 1所述的口服制剂的制备方法，其特征在于，所述方法选自下组： 12. A method of preparing an oral preparation according to claim 1, wherein the method is selected from the group consisting of:

将药芯压制为片芯并逐层包裹隔离层及肠溶包衣，从而形成肠溶片剂；和 /或 (b)方法二，所述方法包括步骤： Pressing the core into a core and wrapping the release layer and the enteric coating layer by layer to form an enteric tablet; and/or (b) method 2, the method comprising the steps of:

将肠溶微丸填装入胶囊，形成肠溶微丸剂，其中所述的肠溶微丸包括微丸药芯、微丸隔离层、微丸肠溶包衣，其中微丸药芯包括 HE3286和药学上可接受的载体。The enteric pellets are filled into capsules to form enteric pellets, wherein the enteric pellets include a pellet core, Pellets isolation layer, pellet enteric coating, wherein the pellet core comprises HE3286 and a pharmaceutically acceptable carrier.

13. 如权利要求 12所述的方法，其特征在于，所述的片芯或药芯通过湿法制粒、干法制粒、混合粉末压制法制得。 13. The method according to claim 12, wherein the core or core is obtained by wet granulation, dry granulation, and mixed powder compaction.

14. 如权利要求 12所述的方法，其特征在于，所述的药芯还包括制备口服制剂前体的步骤，其中所述前体是将活性成分和药学上可接受的载体混合，并包裹隔离层； 14. The method of claim 12, wherein the core further comprises the step of preparing an oral formulation precursor, wherein the precursor is a mixture of the active ingredient and a pharmaceutically acceptable carrier, and is packaged Isolation layer;

所述的活性成分指药学上可接受的 17 α -乙炔基雄甾 -5-烯 -3 β， 7 β， 17 β -三醇的晶型、无定形物、脱水物、溶剂化物、水合物、对映体；和 /或 The active ingredient refers to a pharmaceutically acceptable crystalline form of 17 α -ethynylandrost-5-ene-3 β, 7 β, 17 β -triol, an amorphous form, an anhydrate, a solvate, a hydrate, Enantiomers; and/or

所述的隔离层包括羟丙基甲基纤维素、羟丙基纤维素、羟甲基纤维素、甲基纤维素、乙基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、聚乙酸乙烯酯化、聚乙二醇、甘露醇或其组合；其中隔离层增重为片芯或药芯的 1-30%，优选的采用 2-15%。 The separator comprises hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, ethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, Polyethylene glycol, mannitol or a combination thereof; wherein the weight of the separator is 1-30% of the core or core, preferably 2-15%.

15. 一种权利要求 1所述的口服制剂的用途，其特征在于，所述的制剂用于制备预防和治疗 II型糖尿病、类风湿性关节炎、溃疡性结肠炎的药物。 Use of an oral preparation according to claim 1, wherein the preparation is for the preparation of a medicament for preventing and treating type II diabetes, rheumatoid arthritis, and ulcerative colitis.