WO2023173460A1 - 一种sglt-2抑制剂的药物组合物 - Google Patents

一种sglt-2抑制剂的药物组合物 Download PDF

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WO2023173460A1
WO2023173460A1 PCT/CN2022/082706 CN2022082706W WO2023173460A1 WO 2023173460 A1 WO2023173460 A1 WO 2023173460A1 CN 2022082706 W CN2022082706 W CN 2022082706W WO 2023173460 A1 WO2023173460 A1 WO 2023173460A1
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parts
pharmaceutical composition
sglt
inhibitor
weight
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PCT/CN2022/082706
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French (fr)
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王克艳
吴世斌
丁备
王程程
王飞
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江苏万邦生化医药集团有限责任公司
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    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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 present invention relates to the field of pharmaceutical preparations. Specifically, the present invention relates to a novel pharmaceutical composition of SGLT-2 inhibitor.
  • Type 1 diabetes mellitus T1DM
  • T2DM insulin resistance
  • Type 2 diabetes is the most common type of diabetes, and its prevalence continues to increase worldwide. This type of diabetes accounts for about 90% of the total number of people with diabetes.
  • Type 2 diabetes is characterized by hyperglycemia, which can lead to macrovascular and microvascular complications, including retinopathy, nephropathy, neuropathy, and accelerated cardiovascular disease. Excessive hyperglycemia promotes glucotoxicity by increasing insulin resistance and interfering with cellular function. Despite various treatment options, many patients have inadequate glycemic control and remain at risk for chronic complications.
  • SGLT2 is a sodium-solute co-transporter located in the renal proximal tubule that reabsorbs most of the glucose filtered by the glomerulus.
  • SGLT2 Pharmacological sodium-glucose co-transporter 2
  • renal glucose reabsorption may be upregulated in patients with type 2 diabetes, and orally active selective SGLT2 inhibitors may improve glycemic control to a therapeutically useful extent.
  • the present invention aims to provide a novel SGLT-2 inhibitor pharmaceutical composition represented by formula (I).
  • the "SGLT2 inhibitor” or “active substance” in the present invention refers to (1R, 2R, 3S, 4S, 6R)-4-(4-chloro-3-(ethoxybenzyl)phenyl)-5, 5-Difluoro-6-(hydroxymethyl)cyclohexane-1,2,3-triol, its structure is shown in formula (I):
  • the pharmaceutical composition of an SGLT-2 inhibitor according to the present invention includes the following components by weight: 9-11 parts of the SGLT2 inhibitor represented by formula (I), 50-200 parts of filler, and 0.5 parts of lubricant. -5 parts, 0-15 parts of disintegrant and 0-10 parts of binder.
  • the pharmaceutical composition of the SGLT-2 inhibitor includes the following parts by weight: 10 parts of the SGLT2 inhibitor represented by formula (I), 80-190 parts of filler, and lubricant 1-2 parts, 0-15 parts of disintegrant and 0-10 parts of binder.
  • the pharmaceutical composition of the SGLT-2 inhibitor of the present invention includes the following parts by weight: 9-11 parts of the SGLT2 inhibitor represented by formula (I), and 50-11 parts of the filler. 200 parts, lubricant 0.5-5 parts, disintegrant 2-15 parts and binder 2-10 parts.
  • the pharmaceutical composition of the SGLT-2 inhibitor of the present invention includes the following parts by weight: 9-11 parts of the SGLT2 inhibitor represented by formula (I), filler 80-190 parts, 1-2 parts of lubricant, 5-10 parts of disintegrant and 3-6 parts of binder.
  • the filler of the present invention is selected from the group consisting of lactose, sucrose, fructose, starch, pregelatinized starch, corn starch, glucose, mannitol, xylitol, sorbitol, microcrystalline cellulose, and wood fiber.
  • lactose sucrose, fructose, starch, pregelatinized starch, corn starch, glucose, mannitol, xylitol, sorbitol, microcrystalline cellulose, and wood fiber.
  • the preferred weight ratio of lactose and microcrystalline cellulose is about 1:2 to 2:1; more preferably, it is 1 :1 ⁇ 2:1, most preferably 1:1.
  • the microcrystalline cellulose of the present invention is selected from one of PH101, PH102, PH301 or PH302, with PH102 being more preferred.
  • the lubricant of the present invention is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, carnauba wax, palm wax, stearic acid, and hydrogenated vegetable oil.
  • the preferred lubricant is magnesium stearate.
  • the disintegrant of the present invention is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, starch, low-substituted hydroxypropyl cellulose, preferably carboxymethyl Sodium starch.
  • the binder of the present invention is selected from one or more of hypromellose, hydroxypropyl cellulose, corn starch, pregelatinized starch, polyvinylpyrrolidone, and ethyl cellulose. mixture, preferably the binder is hypromellose.
  • the viscosity of hypromellose is 4mPa ⁇ s ⁇ 60mPa ⁇ s, more preferably 4mPa ⁇ s ⁇ 6mPa ⁇ s.
  • hypromellose can be hypromellose E5, hydroxypropylmethylcellulose Methylcellulose E30 or hypromellose 50, preferably hypromellose E5 or hypromellose E30; the inventor found that hypromellose under this viscosity or model has better dissolution.
  • the pharmaceutical composition of the present invention may further comprise an external coating.
  • the outer protective coating may include the following substances: one or more coating polymers, one or more plasticizers, one or more anti-adhesive agents, one or more glidants or one or more colorants.
  • the outer coating is Opadry.
  • the weight of Opadry accounts for 1 to 5 wt% of the weight of the uncoated tablet.
  • the SGLT-2 inhibitor pharmaceutical composition of the present invention is an oral preparation, for example, it can be in the form of tablets, granules or capsules.
  • the SGLT-2 inhibitor pharmaceutical composition of the present invention is an oral preparation, wherein Compound I is present in a daily dose ranging from 5 to 25 mg/day, and the daily dose is a single dose, divided dose or multiple doses. .
  • the invention relates to pharmaceutical compositions, wherein the amount of compound (I) is 5 mg per dose.
  • the present invention relates to pharmaceutical compositions, wherein the amount of compound (I) is 10 mg per dose.
  • the invention relates to pharmaceutical compositions, wherein the amount of compound (I) is 25 mg per dose.
  • SGLT2 inhibitors are available in daily doses ranging from 5 to 25 mg/day. They are convenient to administer, have high patient compliance, and can provide excellent efficacy within the safety window.
  • the invention also provides a method for preparing the SGLT2 inhibitor pharmaceutical composition of the invention, which includes the following steps:
  • the pretreatment in step (1) means that the particle size of the SGLT2 inhibitor of formula (I) is controlled at D90 ⁇ 60 ⁇ m, and more preferably D90 ⁇ 30 ⁇ m. The inventor found that the particle size is controlled within this range. Has better dissolution. Pretreatment methods can be conventional methods in the field, such as sieving, crushing, grinding, etc.
  • novel SGLT2 inhibitor pharmaceutical composition prepared by the present invention can be used for the treatment of II diabetes and related diseases.
  • compositions of the present invention may be administered in combination with one or more other therapeutic agents.
  • the other therapeutic agents include, but are not limited to, anti-diabetic agents, anti-hypertensive agents, and anti-hyperlipidemic agents.
  • the pharmaceutical composition of the present invention has good material fluidity, which is conducive to material transfer and ensures uniformity of filling.
  • the weight difference of the produced finished products is small, and it complies with the relevant regulations of quality control.
  • the pharmaceutical composition of the present invention dissolves rapidly, with more than 59% dissolution in 5 minutes, more than 85% dissolution in 10 minutes, and more than 90% dissolution in 15 minutes, and it can play a role quickly after entering the body.
  • the quality of the pharmaceutical composition of the present invention is stable, and the relevant substances, dissolution rate and content do not change significantly under conditions of high temperature, high humidity and strong light irradiation. It can meet the needs of clinical medication and provide new solutions for patients with diabetes and related diseases. medication choices.
  • Figure 3 shows the dissolution comparison of different lactose/microcrystalline cellulose ratios
  • Figure 4 shows the effect of different hypromellose models on dissolution.
  • the granules for filling were prepared with 10% raw material, 48.48% filler microcrystalline cellulose, 40.52% lactose, and 1% magnesium stearate (Table 1).
  • Example 1 used for capsule filling were packed into 4# opaque capsule shells at 100 mg/pellet to provide 10 mg capsules.
  • Example 4 25 mg (Example 4) and 10 mg (Example 5) granules containing SGLT2 inhibitors were prepared according to the prescription in Table 3 below.
  • Element mg/bag parts by weight active substance 25 10 microcrystalline cellulose 150 60 lactose 52.5 twenty one Croscarmellose sodium 12.5 5 Hydroxypropylcellulose E5 7.5 3 Magnesium stearate 2.5 1 total weight 250 100
  • Granulation Premix the active substance, microcrystalline cellulose, lactose, and croscarmellose sodium, then add the prescribed amount of binder solution to prepare a soft material, and sieve and granulate.
  • Drying and granulation Dry and granulate the wet granules.
  • Example 4 The granules of Example 4 used to prepare the granules 25 mg were bagged at 100 mg/bag to provide 10 mg granules.
  • microcrystalline cellulose 50 100 lactose 36 72 Croscarmellose sodium 5 10 Hydroxypropylcellulose E5 3 6 Magnesium stearate 1 2 total weight 100 100
  • Granulation Premix the active substance, microcrystalline cellulose, lactose, and croscarmellose sodium, then add the prescribed amount of binder solution to prepare a soft material, and sieve and granulate.
  • Drying and granulation Dry and granulate the wet granules.
  • Example 7 Effect of different microcrystalline cellulose models on material fluidity
  • Granulation Premix the active substance, microcrystalline cellulose, lactose, and croscarmellose sodium, then add the prescribed amount of binder solution to prepare a soft material, and sieve and granulate.
  • pH101, pH102, and pH302 were selected for three batches of granulation to examine the fluidity of the material.
  • Drying and granulation Dry and granulate the wet granules.
  • Tablet pressing Use a ⁇ 8.0mm mold to perform tableting based on the theoretical weight.
  • Coating Use Opadry coating powder to prepare a 10% coating liquid, and use a coating machine for coating.
  • Carr index (tap density - bulk density) / tap density ⁇ 100%.
  • Dissolution device paddle method; rotation speed: 75 rpm; temperature: 37 ⁇ 0.5°C; dissolution medium: containing 0.2% Tween80 0.1mol/L hydrochloric acid solution; medium volume: 900ml; sampling time: sampling at 5, 10, 15, 30, and 45 minutes respectively;
  • Determination method Determine according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Four General Chapters 0512), using Waters Symmetry shield RP18 (50mm ⁇ 4.6mm, 3.5 ⁇ m) or other chromatographic columns with equivalent performance, using acetonitrile-water (35:65 ) is the mobile phase, with isocratic elution for 10 minutes; the column temperature is 30°C; the flow rate is 1ml per minute; the detection wavelength is 224nm; the injection volume is 20 ⁇ l.
  • the dissolution of microcrystalline cellulose pH101, pH102 and pH302 can all achieve a rapid dissolution effect of greater than 85% in 15 minutes.
  • pH102 is selected as the filler
  • the dissolution rate is greater than 85% in 10 minutes, and oral administration can be rapid. Effective, cheaper and more fluid than pH302.
  • Tablets containing SGLT2 inhibitors of 25 mg (Example 8) and 10 mg (Example 9) were prepared as described in Table 8 below.
  • Granulation Premix the active substance, microcrystalline cellulose, lactose, and croscarmellose sodium, then add the prescribed amount of binder solution to prepare a soft material, and sieve and granulate.
  • Drying and granulation Dry and granulate the wet granules.
  • Tablet pressing Use a ⁇ 8.0mm mold to perform tableting based on the theoretical weight.
  • Coating Use Opadry coating powder to prepare a 10% coating liquid, and use a coating machine for coating.
  • Example 8 The granules of Example 8 used to prepare 25 mg tablets were compressed using a ⁇ 6.5 mm tableting mold at a weight of 100 mg/tablet to obtain 100 mg tablets. Use the same coating powder for coating.
  • Element Amount/mg parts by weight active substance 5 10 Microcrystalline Cellulose pH102 40 80 lactose 46 92 Croscarmellose sodium 5 10 hypromellose 3 6 Magnesium stearate 1 2 Film weight 100 100 Opadry Coated Powder (Red) 3 3(based on plain slices)
  • Granulation Premix the active substance, microcrystalline cellulose, lactose, and croscarmellose sodium, then add the prescribed amount of binder solution to prepare a soft material, and sieve and granulate.
  • Drying and granulation Dry and granulate the wet granules.
  • Tablet pressing Use a ⁇ 6.5mm mold to perform tableting based on the theoretical weight.
  • Coating Use Opadry coating powder to prepare a 10% coating liquid, and use a coating machine for coating.
  • Example 8 Take the tablets in the above-mentioned Example 8, Example 9, and Example 10, 6 tablets each, and measure them using the second method of the Chinese Pharmacopoeia 2020 edition of the four general chapters 0931.
  • the dissolution device paddle method; rotation speed: 75 rpm; temperature: 37 ⁇ 0.5°C; dissolution medium: 0.1mol/L hydrochloric acid solution containing 0.2% Tween80; medium volume: 900ml; sampling time: sampling at 5, 10, 15, 30, and 45 minutes respectively;
  • Determination method Determine according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Four General Chapters 0512), using Waters Symmetry shield RP18 (50mm ⁇ 4.6mm, 3.5 ⁇ m) or other chromatographic columns with equivalent performance, using acetonitrile-water (35:65 ) is the mobile phase, with isocratic elution for 10 minutes; the column temperature is 30°C; the flow rate is 1 ml per minute; the detection wavelength is 224 nm; the injection volume is 20 ⁇ l.
  • Example 10 5 61.1% 59.8% 62.4% 10 85.8% 85.0% 89.4% 15 91.5% 90.7% 93.3% 30 96.2% 95.3% 95.6% 45 97.5% 97.0% 96.5%
  • the dissolution results of the 25 mg, 10 mg, and 5 mg samples of the present invention are basically consistent.
  • the D90 of the active ingredient ⁇ 60 ⁇ m, more than 59% can be dissolved in 5 minutes, more than 85% can be dissolved in 10 minutes, and more than 90% can be dissolved in 15 minutes, indicating that the pharmaceutical composition of the present invention dissolves rapidly and can be rapidly dissolved after oral administration. Have a therapeutic effect.
  • Table 10 below shows the prescription information for different lactose/microcrystalline cellulose ratios.
  • Granulation Premix the active substance, microcrystalline cellulose, lactose, and croscarmellose sodium, then add the prescribed amount of binder solution to prepare a soft material, and sieve and granulate.
  • Drying and granulation Dry and granulate the wet granules.
  • Tablet pressing Use a ⁇ 8.0mm mold to perform tableting based on the theoretical weight.
  • Coating Use Opadry coating powder to prepare a 10% coating liquid, and use a coating machine for coating.
  • Lactose/microcrystalline cellulose approx. bulk density Tap density Carr Index % 1:2 0.383 0.625 38.7 1:1 0.383 0.527 27.3 2:1 0.375 0.560 33.0
  • Dissolution device paddle method; rotation speed: 75 rpm; temperature: 37 ⁇ 0.5°C; dissolution medium: containing 0.2% Tween80 0.1mol/L hydrochloric acid solution; medium volume: 900ml; sampling time: sampling at 5, 10, 15, 30, and 45 minutes respectively;
  • Determination method Determine according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Four General Chapters 0512), using Waters Symmetry shield RP18 (50mm ⁇ 4.6mm, 3.5 ⁇ m) or other chromatographic columns with equivalent performance, using acetonitrile-water (35:65 ) is the mobile phase, with isocratic elution for 10 minutes; the column temperature is 30°C; the flow rate is 1ml per minute; the detection wavelength is 224nm; the injection volume is 20 ⁇ l.
  • Granulation Premix the active substance, microcrystalline cellulose, lactose, and croscarmellose sodium, then add the prescribed amount of binder solution to prepare a soft material, and sieve and granulate.
  • Drying and granulation Dry and granulate the wet granules.
  • Tablet pressing Use a ⁇ 8.0mm mold to perform tableting based on the theoretical weight.
  • Coating Use Opadry coating powder to prepare a 10% coating liquid, and use a coating machine for coating.
  • Prescription 23 Prescription 24 Prescription 25 Bulk density (g/ml) 0.383 0.394 0.400 Tap density (g/ml) 0.527 0.618 0.611 Carr Index % 27.3 36.2 34.5
  • the dissolution rate reaches more than 85% within 10 minutes, while when hypromellose E50 is used, the dissolution is slower.
  • the dissolution rate can reach more than 90% in 15 minutes, it can take effect quickly, and the therapeutic effect can be quickly exerted after oral administration.
  • Example 8 The highest specification sample of Example 8 was investigated for influencing factors.
  • the influencing factors test conditions were: high temperature: 60°C; high humidity: 90% ⁇ 5%; illumination: 4500lx ⁇ 500lx, ultraviolet 90 ⁇ w.h/cm 2 .
  • the storage time is 30 days, and samples are taken on the 10th and 30th days respectively.
  • the key quality attributes of the small test samples are tested according to the draft quality standards for finished products.

Abstract

一种SGLT-2抑制剂的药物组合物，包括如下重量份数的成分：式(I)所示的SGLT2抑制剂9-11份，填充剂50-200份、润滑剂0.5-5份、崩解剂0-15份和粘合剂0-10份；该药物组合物质量稳定，在高温、高湿、强光照射条件下有关物质、溶出度、含量均未发生明显变化，能够满足临床用药需求，为糖尿病及其相关疾病的患者提供了新的用药选择。

Description

一种SGLT-2抑制剂的药物组合物 技术领域
本发明涉及药物制剂领域。具体而言，本发明涉及一种新型SGLT-2抑制剂的药物组合物。
背景技术
与糖尿病相关的高血糖是由胰岛素缺乏，即1型糖尿病(T1DM))或胰岛素分泌不足或胰岛素抵抗(T2DM)引起的。2型糖尿病是最常见的糖尿病类型，其患病率在全球范围内持续上升。这类糖尿病占糖尿病总人数的90％左右。2型糖尿病以高血糖为特征，可导致大血管和微血管并发症，包括视网膜病变、肾病、神经病变和加速心血管疾病。过量的高血糖通过增加胰岛素抵抗和干扰细胞功能促进糖毒性。尽管有各种治疗选择，许多患者血糖控制不充分，仍有慢性并发症的风险。
(1R,2R,3S,4S,6R)-4-(4-氯-3-(乙氧基苄基)苯基)-5,5-二氟-6-(羟基甲基)环己烷-1,2,3-三醇是一种新型口服选择性钠-葡萄糖共转运体2(SGLT2)抑制剂，专为治疗2型糖尿病而设计，其结构如下式(I)所示：
Figure PCTCN2022082706-appb-000001
(1R,2R,3S,4S,6R)-4-(4-氯-3-(乙氧基苄基)苯基)-5,5-二氟-6-(羟基甲基)环己烷-1,2,3-三醇通过SGLT2抑制肾脏葡萄糖的再吸收来改善高血糖。SGLT2是一种钠-溶质共转运蛋白，位于肾近端小管，重吸收大部分肾小球滤过的葡萄糖。药理上钠-葡萄糖共转运体2(SGLT2)抑制，在2型糖尿病患者中，肾脏葡萄糖再吸收可能上调，口服活性选择性SGLT2抑制剂可改善血糖控制，达到治疗有用的程度。
发明内容
本发明旨在提供一种式(I)所示的新型的SGLT-2抑制剂的药物组合物。
本发明中的“SGLT2抑制剂”或者“活性物质”是指(1R,2R,3S,4S,6R)-4-(4-氯-3-(乙氧基苄基)苯基)-5,5-二氟-6-(羟基甲基)环己烷-1,2,3-三醇，其 结构如式(I)所示：
Figure PCTCN2022082706-appb-000002
本发明所述的一种SGLT-2抑制剂的药物组合物，包括如下重量份数的成分：式(I)所示的SGLT2抑制剂9-11份，填充剂50-200份、润滑剂0.5-5份、崩解剂0-15份和粘合剂0-10份。
在一些具体的实例中，所述的SGLT-2抑制剂的药物组合物，包括如下重量份数的成分：式(I)所示的SGLT2抑制剂10份，填充剂80-190份、润滑剂1-2份、崩解剂0-15份和粘合剂0-10份。
在一些更具体的实例中，本发明所述的SGLT-2抑制剂的药物组合物，包括如下重量份数的成分：式(I)所示的SGLT2抑制剂9-11份，填充剂50-200份，润滑剂0.5-5份，崩解剂2-15份和粘合剂2-10份。
进一步的在一些更具体的实例中，本发明所述的SGLT-2抑制剂的药物组合物，包括如下重量份数的成分：式(I)所示的SGLT2抑制剂9-11份，填充剂80-190份，润滑剂1-2份，崩解剂5-10份和粘合剂3-6份。
在一些实施例中，本发明所述的填充剂选自乳糖、蔗糖、果糖、淀粉、预胶化淀粉、玉米淀粉、葡萄糖、甘露醇、木糖醇、山梨醇、微晶纤维素、木纤维素、碳酸钙、磷酸氢钙中的一种或多种的混合物；优选的填充剂为乳糖和微晶纤维素的组合物。发明人发现采用乳糖和微晶纤维素的组合物作为填充剂可以获得很好的物料流动性，优选的乳糖和微晶纤维素的重量比约为1:2～2:1；更优选为1：1～2:1，最优选1:1。
在一些实施例中，本发明所述的微晶纤维素选自PH101、PH102、PH301或PH302中的一种，更优选PH102。
在一些实施例中，本发明所述的润滑剂选自硬脂酸镁、硬脂富马酸钠、巴西棕榈蜡、棕榈蜡、硬脂酸、氢化植物油，优选润滑剂是硬脂酸镁。
在一些实施例中，本发明所述的崩解剂选自交联羧甲基纤维素钠、羧甲淀粉钠、交联聚乙烯吡咯烷酮、淀粉、低取代羟丙基纤维素，优选羧甲基淀粉钠。
在一些实施例中，本发明所述的粘合剂选自羟丙甲纤维素、羟丙纤维素、玉米淀粉、预胶化淀粉、聚乙烯吡咯烷酮、乙基纤维素中的一种或多种的混合物，优选粘合剂为羟丙甲纤维素。在一些实施例中，其中羟丙甲纤维素的粘度为4mPa·s～60mPa·s，进一步优选4mPa·s～6mPa·s，例如羟丙甲纤维素可以为羟丙甲纤维素E5、羟丙甲纤维素E30或者羟丙甲纤维素50，优选羟丙甲纤维素E5或羟丙甲纤维素E30；发明人发现选用该粘度或型号下的羟丙甲纤维素，具有更好的溶出。
本发明所述的药物组合物可进一步包括外部包衣。优选的，所述外部保护包衣可以包含下列物质：一种或多种包衣聚合物、一种或多种增塑剂、一种或多种抗粘剂、一种或多种助流剂或者一种或多种着色剂。在一种实施例中，所述外部包衣为欧巴代，在一些实施例中，欧巴代的重量占未包衣片剂重量的1wt％～5wt％。
本发明所述的SGLT-2抑制剂药物组合物为口服制剂，例如可以为片剂、颗粒剂或胶囊的形式。
本发明所述的SGLT-2抑制剂药物组合物为口服制剂，其中化合物I以每日提供5～25mg/天范围内的日剂量存在，所述的日剂量为单剂量或分剂量或多剂量。在一些实施例中，本发明涉及的药物组合物，其中化合物(I)的量为每剂5mg。在一些实施例中，本发明涉及的药物组合物，其中化合物(I)的量为每剂10mg。在一些实施例中，本发明涉及的药物组合物，其中化合物(I)的量为每剂25mg。SGLT2抑制剂以每日提供5～25mg/天范围内的日剂量存在，用药方便，患者顺应性高，能够在安全窗范围内提供优异的疗效。
本发明还提供了本发明所述的SGLT2抑制剂药物组合物的制备方法，包含以下步骤：
(1)对式(I)SGLT2抑制剂进行预处理；预处理后与填充剂、润滑剂、粘合剂和崩解剂混合；
(2)进行压片或灌装胶囊。
在一些实施例中，步骤(1)中的预处理是指式(I)SGLT2抑制剂的粒径控制在D90≤60μm，更进一步优选D90≤30μm，发明人发现将粒径控制在该范围内具有更好的溶出。预处理的方法可以选择本领域的常规方法，例如过筛、粉碎、研磨等方式。
本发明所述的药物组合物进行压片后还可以使用本领域的常规方法对于片剂使用包衣材料进一步包衣保护。
本发明制备的新型SGLT2抑制剂药物组合物，可用于II糖尿病及其相关疾病的治疗。
本发明的药物组合物可以与一种或多种其他治疗剂联合施用。所述其他治疗剂包括但不限于抗糖尿病药、抗高血压药、降血脂药。
本发明相对于其他现有技术的优势：
本发明的药物组合物物料流动性好，有利于物料转移、确保装填均匀性，制得的成品重量差异小，符合质量控制的相关规定。
本发明的药物组合物溶出迅速，5分钟即可溶出59％以上，10分钟可溶出85％以上，15分钟可溶出90％以上，进入体内后可迅速发挥作用。
本发明的药物组合物质量稳定，在高温、高湿、强光照射条件下有关物质、溶出度、含量均未发生明显变化，能够满足临床用药需求，为糖尿病及其相关疾病的患者提供了新的用药选择。
附图说明
图1实施例7不同微晶纤维素型号对溶出的影响；
图2实施例8～10溶出曲线图；
图3为不同乳糖/微晶纤维素比例对溶出对比；
图4为不同羟丙甲纤维素型号对溶出影响。
具体实施方式
以下的实施例便于更好地理解本发明，但并不限定本发明。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。
以下实施例中所述的“活性物质”均是指其结构如式(I)所示的化合物：
Figure PCTCN2022082706-appb-000003
实施例1 硬胶囊剂(25mg)产品
制备用于填充用的颗粒，原料占比10％，填充剂微晶纤维素占比48.48％，乳糖占比40.52％，硬脂酸镁1％(表1)。
表1
成分 量/mg 重量份数
活性物质 25 10
微晶纤维素 121.2 48.48
乳糖 101.3 40.52
硬脂酸镁 2.5 1
总重 250 100
1)称取活性物质，放置在研磨中进行研磨，研磨至原料粒径符合要求(D90≤30μm)。
2)将活性成分、微晶纤维素、乳糖混合。
3)再加入硬脂酸镁进行混合。
4)将混合后颗粒灌装按250mg/粒装入至2#不透明胶囊中，以提供25mg胶囊。
实施例2 硬胶囊剂(10mg)产品
用于胶囊填充的实施例1颗粒，按100mg/粒装入4#不透明胶囊壳中，以提供10mg胶囊。
实施例3 硬胶囊剂(5mg)产品
按照表2处方制备硬胶囊剂5mg产品。
表2
成分 量/mg 重量份数
活性物质 5 10
微晶纤维素 50 100
乳糖 44 88
硬脂酸镁 1 2
总重 100 100
1)称取活性物质，放置在研磨中进行研磨，研磨至原料粒径符合要求(D90≤30μm)。
2)将活性成分、微晶纤维素、乳糖混合。
3)在加入硬脂酸镁进行混合。
4)将混合后颗粒灌装按100mg/粒装入至4#不透明胶囊中，以提供5mg胶囊。
实施例4 颗粒剂(25mg)
如下表3处方制备25mg(实施例4)、10mg(实施例5)含有SGLT2抑制剂的颗粒剂。
表3单剂量处方：
成分 mg/袋 重量份数
活性物质 25 10
微晶纤维素 150 60
乳糖 52.5 21
交联羧甲基纤维素钠 12.5 5
羟丙纤维素E5 7.5 3
硬脂酸镁 2.5 1
总重 250 100
1)称取活性物质，采用气流粉碎机进行粉碎，粉碎至原料粒径符合要求(D90≤30μm)。
2)制粒：将活性物质、微晶纤维素、乳糖、交联羧甲基纤维素钠进行预混合，然后加入处方量粘合剂溶液制软材，过筛制粒。
3)干燥整粒：将湿颗粒干燥、整粒。
4)取处方量硬脂酸镁与颗粒混合。
5)将混合颗粒按250mg/袋进行装袋。
实施例5 颗粒剂(10mg)
用于制备颗粒剂25mg的实施例4颗粒，按100mg/袋装入袋中，以提供10mg颗粒剂。
实施例6 颗粒剂(5mg)
颗粒剂5mg处方如表4所示：
表4
处方 mg/袋 重量份数
活性物质 5 10
微晶纤维素 50 100
乳糖 36 72
交联羧甲基纤维素钠 5 10
羟丙纤维素E5 3 6
硬脂酸镁 1 2
总重 100 100
1)称取活性物质，采用气流粉碎机进行粉碎，粉碎至原料粒径符合要求(D90≤30μm)。
2)制粒：将活性物质、微晶纤维素、乳糖、交联羧甲基纤维素钠进行预混合，然后加入处方量粘合剂溶液制软材，过筛制粒。
3)干燥整粒：将湿颗粒干燥、整粒。
4)取处方量硬脂酸镁与颗粒混合。
5)将混合颗粒按100mg/袋进行装袋。
实施例7 不同微晶纤维素型号对物料流动性影响
1、处方信息如表5所示：
表5
成分 量/mg 重量份数
活性物质 25 10
微晶纤维素 100 40
乳糖 102.5 41
交联羧甲基纤维素钠 12.5 5
羟丙甲纤维素E5 7.5 3
硬脂酸镁 2.5 1
片重 250 100
欧巴代包衣粉(黄色) 7.5 3(以素片计)
2、工艺：
1)称取活性物质，采用气流粉碎机进行粉碎，粉碎至原料粒径符合要求(D90≤30μm)。
2)制粒：将活性物质、微晶纤维素、乳糖、交联羧甲基纤维素钠进行预混合，然后加入处方量粘合剂溶液制软材，过筛制粒。其中微晶纤维素型号分别选择pH101、pH102、pH302进行三批制粒，考察物料的流动性。
3)干燥整粒：将湿颗粒干燥、整粒。
4)取处方量硬脂酸镁与颗粒混合。
5)压片：根据理论重量使用φ8.0mm模具进行压片。
6)包衣：使用欧巴代包衣粉配置成10％包衣液，使用包衣机进行包衣。
3、粉体性质：
取总混后物料，测定物料流动性，结果如下表6：
表6不同型号微晶纤维素制备总混物料粉体性质
微晶纤维素型号 松密度 振实密度 卡尔指数％
pH101 0.355 0.608 41.6
pH102 0.383 0.527 27.3
pH302 0.375 0.533 29.6
卡尔指数＝(振实密度-松密度)/振实密度×100％。
因此，使用压片机对三种物料进行压片，在压片机强制加料器作用下，三种物料均满足压片要求，但是为满足大生产放大需求，pH102微晶纤维素作为填充剂具有明显优势。
4、溶出曲线
取上述实施例7中片剂，各6片，采用中国药典2020版四部通则0931第二法进行测定，溶出装置：桨法；转速：75rpm；温度：37±0.5℃；溶出介质：含0.2％Tween80 0.1mol/L盐酸溶液；介质体积：900ml；取样时间：分别在5、10、15、30、45min取样；
测定方法：照高效液相色谱法(中国药典2020年版四部通则0512)测定，采用Waters Symmetry shield RP18(50mm×4.6mm，3.5μm)或其他性能相当的色谱柱，以乙腈-水(35：65)为流动相，等度洗脱10分钟；柱温为30℃；流速为每分钟1ml；检测波长为224nm；进样体积20μl。
表7不同型号的微晶纤维素对溶出的对比
时间 pH101 pH102 pH302
5min 58.4％ 76.8％ 75.2％
10min 80.1％ 87.2％ 86.5％
15min 87.0％ 91.2％ 92.6％
30min 90.1％ 93.6％ 94.0％
45min 94.7％ 96.5％ 94.9％
如表7和附图1所示，选用微晶纤维素pH101、pH102和pH302溶出均能实现15min大于85％的快速溶出效果，但是选择pH102作为填充剂，溶出10min大于85％，口服可快速起效，且相比pH302价格便宜、流动性更好。
实施例8 片剂(25mg)
如下表8所述制备25mg(实施例8)、10mg(实施例9)含有SGLT2抑制剂的片剂。
表8
成分 量/mg 重量份数
活性物质 25 10
微晶纤维素pH102 100 40
乳糖 102.5 41
交联羧甲基纤维素钠 12.5 5
羟丙甲纤维素 7.5 3
硬脂酸镁 2.5 1
片重 250 100
欧巴代包衣粉(黄色) 7.5 3(以素片计)
1)称取活性物质，采用气流粉碎机进行粉碎，粉碎至原料粒径符合要求(D90≤30μm)。
2)制粒：将活性物质、微晶纤维素、乳糖、交联羧甲基纤维素钠进行预混合，然后加入处方量粘合剂溶液制软材，过筛制粒。
3)干燥整粒：将湿颗粒干燥、整粒。
4)取处方量硬脂酸镁与颗粒混合。
5)压片：根据理论重量使用φ8.0mm模具进行压片。
6)包衣：使用欧巴代包衣粉配置成10％包衣液，使用包衣机进行包衣。
实施例9 片剂(10mg)
用于制备片剂25mg的实施例8颗粒，按100mg/片片重，采用φ6.5mm压片模具进行压片，以得到100mg片剂。使用同一包衣粉进行包衣。
实施例10 片剂(5mg)
片剂5mg处方如表9：
表9
成分 量/mg 重量份数
活性物质 5 10
微晶纤维素pH102 40 80
乳糖 46 92
交联羧甲基纤维素钠 5 10
羟丙甲纤维素 3 6
硬脂酸镁 1 2
片重 100 100
欧巴代包衣粉(红色) 3 3(以素片计)
1)称取活性物质，采用气流粉碎机进行粉碎，粉碎至原料粒径符合要求(D90≤60μm)。
2)制粒：将活性物质、微晶纤维素、乳糖、交联羧甲基纤维素钠进行预混合，然后加入处方量粘合剂溶液制软材，过筛制粒。
3)干燥整粒：将湿颗粒干燥、整粒。
4)取处方量硬脂酸镁与颗粒混合。
5)压片：根据理论重量使用φ6.5mm模具进行压片。
6)包衣：使用欧巴代包衣粉配置成10％包衣液，使用包衣机进行包衣。
溶出曲线测定
取上述实施例8、实施例9、实施例10中的片剂，各6片，采用中国药典2020版四部通则0931第二法进行测定，溶出装置：桨法；转速：75rpm；温度：37±0.5℃；溶出介质：含0.2％Tween80 0.1mol/L盐酸溶液；介质体积：900ml；取样时间：分别在5、10、15、30、45min取样；
测定方法：照高效液相色谱法(中国药典2020年版四部通则0512)测定， 采用Waters Symmetry shield RP18(50mm×4.6mm，3.5μm)或其他性能相当的色谱柱，以乙腈-水(35：65)为流动相，等度洗脱10分钟；柱温为30℃；流速为每分钟1ml；检测波长为224nm；进样体积20μl。
表10实施例8～10溶出曲线结果
时间(min) 实施例8 实施例9 实施例10
5 61.1％ 59.8％ 62.4％
10 85.8％ 85.0％ 89.4％
15 91.5％ 90.7％ 93.3％
30 96.2％ 95.3％ 95.6％
45 97.5％ 97.0％ 96.5％
如表10和附图2所示，本发明的25mg、10mg、5mg样品，溶出结果基本一致。当活性成分的D90≤60μm时，5分钟即可溶出59％以上，10分钟可溶出85％以上，15分钟可溶出90％以上，表明本发明的药物组合物溶出迅速，口服给药后可快速发挥治疗作用。
实施例10 不同乳糖/微晶纤维素比例考察
1、处方工艺信息
如下表10所示不同乳糖/微晶纤维素比例处方信息
表10不同乳糖/微晶纤维素比例对制粒流动性及溶出影响
Figure PCTCN2022082706-appb-000004
Figure PCTCN2022082706-appb-000005
1)称取活性物质，采用气流粉碎机进行粉碎，粉碎至原料粒径符合要求(D90≤30μm)。
2)制粒：将活性物质、微晶纤维素、乳糖、交联羧甲基纤维素钠进行预混合，然后加入处方量粘合剂溶液制软材，过筛制粒。
3)干燥整粒：将湿颗粒干燥、整粒。
4)取处方量硬脂酸镁与颗粒混合。
5)压片：根据理论重量使用φ8.0mm模具进行压片。
6)包衣：使用欧巴代包衣粉配置成10％包衣液，使用包衣机进行包衣。
2、粉体性质
取总混后物料，测定物料流动性，结果如下表11：
表11不同物料粉体性质
乳糖/微晶纤维素约 松密度 振实密度 卡尔指数％
1:2 0.383 0.625 38.7
1:1 0.383 0.527 27.3
2:1 0.375 0.560 33.0
3、溶出曲线
取上述实施10中片剂，各6片，采用中国药典2020版四部通则0931第二法进行测定，溶出装置：桨法；转速：75rpm；温度：37±0.5℃；溶出介质：含0.2％Tween80 0.1mol/L盐酸溶液；介质体积：900ml；取样时间：分别在5、10、15、30、45min取样；
测定方法：照高效液相色谱法(中国药典2020年版四部通则0512)测定，采用Waters Symmetry shield RP18(50mm×4.6mm，3.5μm)或其他性能相当的色谱柱，以乙腈-水(35：65)为流动相，等度洗脱10分钟；柱温为30℃；流速为每分钟1ml；检测波长为224nm；进样体积20μl。
表12不同乳糖/微晶纤维素比例对溶出的对比
Figure PCTCN2022082706-appb-000006
如表12和附图3所示，选用乳糖/微晶纤维素比例约1:2时，总混物料卡尔指数为38.7％，流动性可接受，但溶出较慢。乳糖/微晶纤维素比较约为1:1和2:1时，溶出差异较小，乳糖/微晶纤维素比例约为1:1更有利于后续生产放大需求。
实施例11 不同羟丙甲纤维素型号比例考察
1、处方工艺信息
表13不同粘合剂型号的处方组成
Figure PCTCN2022082706-appb-000007
1)称取活性物质，采用气流粉碎机进行粉碎，粉碎至原料粒径符合要求(D90≤30μm)。
2)制粒：将活性物质、微晶纤维素、乳糖、交联羧甲基纤维素钠进行预混合，然后加入处方量粘合剂溶液制软材，过筛制粒。
3)干燥整粒：将湿颗粒干燥、整粒。
4)取处方量硬脂酸镁与颗粒混合。
5)压片：根据理论重量使用φ8.0mm模具进行压片。
6)包衣：使用欧巴代包衣粉配置成10％包衣液，使用包衣机进行包衣。
2、粉体性质
表14不同粘合剂型号对中间体流动性影响
处方 处方23 处方24 处方25
松密度(g/ml) 0.383 0.394 0.400
振实密度(g/ml) 0.527 0.618 0.611
卡尔指数％ 27.3 36.2 34.5
3、使用实施例10中的溶出曲线检测方法对上述实施例11中样品进行溶出曲线检测，结果见表15。
表15不同粘合剂型号对溶出曲线影响
处方 羟丙甲纤维素E5 羟丙甲纤维素E30 羟丙甲纤维素E50
5min 76.8％ 70.8％ 67.2％
10min 87.2％ 85.1％ 80.5％
15min 91.2％ 88.2％ 82.6％
30min 93.6％ 90.6％ 87.0％
45min 96.5％ 92.5％ 89.9％
如表15和附图4所示，选用羟丙甲纤维素E5和E30时，溶出度在10min内达到85％以上，而使用羟丙甲纤维素E50时，溶出较慢。使用羟丙甲纤维素E5时物料流动性更优，溶出度在15min时可达到90％以上，可以快速起效，口服给药后可快速发挥治疗作用。
实施例12 影响因素试验
对实施例8最高规格的样品，进行影响因素考察，影响因素试验条件：高温：60℃；高湿：90％±5％；光照：4500lx±500lx，紫外90μw.h/cm 2。
放置时间30天，分别于10天、30天取样，根据成品质量标准草案对小试样品的关键质量属性进行检测。
表16实施例8质量测定结果
Figure PCTCN2022082706-appb-000008
结论：从表16试验结果可知，本发明制备的片剂样品在高温60℃、高湿RH90％±5％、强光照射放置30天，有关物质、溶出度和含量均未发生明显变化，说明本发现制备的新型SGLT2抑制剂药物组合物性质稳定。
本领域的普通技术人员在不偏离本发明的原理和精神的情况下，可以对本发明的药物组合物以及方法进行多种修饰和变化，以达到相同的技术效果，这些都属于与本发明相同或等同的范围。

Claims (10)

  1. 一种SGLT-2抑制剂的药物组合物，其特征在于，包括如下重量份数的成分：式(I)所示的SGLT2抑制剂9-11份，填充剂50-200份、润滑剂0.5-5份、崩解剂0-15份和粘合剂0-10份。
  2. 根据权利要求1所述的SGLT-2抑制剂的药物组合物，其特征在于，包括如下重量份数的成分：式(I)所示的SGLT2抑制剂10份，填充剂80-190份、润滑剂1-2份、崩解剂0-15份和粘合剂0-10份。
  3. 根据权利要求1所述的SGLT-2抑制剂的药物组合物，其特征在于，包括如下重量份数的成分：式(I)所示的SGLT2抑制剂9-11份，填充剂50-200份，润滑剂0.5-5份，崩解剂2-15份和粘合剂2-10份；优选的，包括如下重量份数的成分：式(I)所示的SGLT2抑制剂9-11份，填充剂80-190份，润滑剂1-2份，崩解剂5-10份和粘合剂3-6份。
  4. 根据权利要求1～3任一项所述的SGLT-2抑制剂的药物组合物，其特征在于，所述的填充剂选自乳糖、蔗糖、果糖、淀粉、预胶化淀粉、玉米淀粉、葡萄糖、甘露醇、木糖醇、山梨醇、微晶纤维素、木纤维素、碳酸钙、磷酸氢钙中的一种或多种的混合物；优选的填充剂为乳糖和微晶纤维素的组合物；优选的，乳糖和微晶纤维素的重量比为1:2～2:1；更优选1:1～2:1，最优选1:1。
  5. 根据权利要求1～3任一项所述的SGLT-2抑制剂的药物组合物，其特征在于，所述的微晶纤维素选自PH101、PH102、PH301或PH302中的一种，更优选PH102；所述的润滑剂选自硬脂酸镁、硬质富马酸钠、巴西棕榈蜡、棕榈蜡、硬脂酸、氢化植物油，优选润滑剂是硬脂酸镁；所述的崩解剂选自交联羧甲基纤维素钠、羧甲淀粉钠、交联聚乙烯吡咯烷酮、淀粉、低取代羟丙基纤维素，优选羧甲基淀粉钠；所述的粘合剂选自羟丙甲纤维素、羟丙纤维素、玉米淀粉、预胶化淀粉、聚乙烯吡咯烷酮、乙基纤维素中的一种或多种的混合物，优选粘合剂为羟丙甲纤维素；优先的，羟丙甲纤维素的粘度为4mPa·s～60mPa·s，进一步优选4mPa·s～6mPa·s。
  6. 根据权利要求1～3任一项所述的SGLT-2抑制剂的药物组合物，其特征在于，所述的药物组合物包括外部包衣；优选的，所述外部包衣为欧巴代，更优选的，欧巴代的重量占未包衣片剂重量的1wt％～5wt％。
  7. 根据权利要求1所述的SGLT-2抑制剂的药物组合物，其特征在于，所述药 物组合物为口服制剂，优选的为片剂、颗粒剂或胶囊。
  8. 根据权利要求1所述的SGLT-2抑制剂的药物组合物，其特征在于，所述药物组合物以化合物I每日提供5～25mg/天范围内的日剂量存在。
  9. 权利要求1所述的SGLT-2抑制剂的药物组合物的制备方法，其特征在于，包括以下步骤：
    (1)对式(I)SGLT2抑制剂进行预处理；预处理后与填充剂、润滑剂、粘合剂和崩解剂混合；
    (2)后进行压片或灌装胶囊。
    优选的，步骤(1)中的预处理是指式(I)SGLT2抑制剂的粒径控制在D90≤60μm，更进一步优选D90≤30μm。
  10. 权利要求1所述的SGLT-2抑制剂的药物组合物在用于制备II糖尿病及其相关疾病药物中的应用。
PCT/CN2022/082706 2022-03-14 2022-03-24 一种sglt-2抑制剂的药物组合物 WO2023173460A1 (zh)

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