WO2020155098A1 - 一种用于治疗糖尿病的药物组合物及其制备方法和用途 - Google Patents

一种用于治疗糖尿病的药物组合物及其制备方法和用途 Download PDF

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WO2020155098A1
WO2020155098A1 PCT/CN2019/074405 CN2019074405W WO2020155098A1 WO 2020155098 A1 WO2020155098 A1 WO 2020155098A1 CN 2019074405 W CN2019074405 W CN 2019074405W WO 2020155098 A1 WO2020155098 A1 WO 2020155098A1
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metformin hydrochloride
pharmaceutical composition
metformin
tyaggliflozin
preparation
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PCT/CN2019/074405
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English (en)
French (fr)
Inventor
任晓文
徐为人
赵桂龙
王玉丽
曹光
汤立达
邹美香
孟策
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天津药物研究院有限公司
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Priority to PCT/CN2019/074405 priority Critical patent/WO2020155098A1/zh
Publication of WO2020155098A1 publication Critical patent/WO2020155098A1/zh

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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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 medicines related to hypoglycemic preparations, in particular, to a pharmaceutical composition for treating diabetes and a preparation method and application thereof.
  • diabetes The incidence of diabetes continues to rise, and it has become one of the five diseases with the highest morbidity and mortality in the world, especially in developing countries such as China, the Indo-Chinese subcontinent and Africa. Diabetes can be divided into type I, namely insulin-dependent diabetes mellitus (IDDM), and type II, namely non-insulin-dependent diabetes mellitus (NIDDM).
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • vascular complications often occur, including macrovascular disease and microvascular disease, leading to chronic and progressive damage to the heart, brain, kidney, eyes and other organs. The harm of diabetes mainly comes from these complications.
  • NIDDM vascular complications of diabetes in China
  • therapeutic drugs for NIDDM include sulfonylureas, biguanides, ⁇ -glucosidase inhibitors, insulin sensitizers and prandial blood glucose regulators.
  • metformin The first choice for the treatment of type II diabetes recommended by my country's latest guidelines is metformin. If there are no contraindications, metformin should always be kept in the diabetes treatment plan. Those who are not suitable for metformin treatment can choose ⁇ -glucosidase inhibitors or insulin secretagogues. If metformin is used alone and the blood sugar is still not up to standard, ⁇ -glucosidase inhibitors, insulin secretagogues, DPP-4 inhibitors or thiazolidinedione (second-line treatment) can be added. Those who are not suitable for metformin can be treated with other oral drugs.
  • insulin therapy (basic insulin once a day or premixed insulin once or twice a day) or a combination of three oral drugs can be used.
  • GLP-1 receptor agonists can be used for third-line therapy. If the combined treatment of basal insulin or premixed insulin and oral drugs is still not up to standard, the treatment plan should be adjusted to multiple insulin treatments (basic insulin plus meals insulin or premixed insulin analogs 3 times a day). Insulin secretagogues should be discontinued during premixed insulin therapy and multiple insulin therapy.
  • the above-mentioned medication regimen is based on the clinical evidence in terms of pharmaceutical health economics, efficacy and safety, as well as my country's national conditions and other factors, which are recommended by the guidelines for the treatment of type II diabetes.
  • Sodium glucose cotransporter 2 (SGLT2) inhibitors include dapagliflozin, remogliflozin, sergliflozin, canagliflozin, and agliflozin ), among which dapagliflozin is the first SGLT2 inhibitor approved and marketed in Europe, and its diabetes treatment effect has been initially confirmed by clinical studies.
  • SGLT2 inhibitors have the advantages of reducing body weight, rarely causing hypoglycemia, and the therapeutic effect is independent of the existence of insulin.
  • SGLT2 inhibitors also have some "congenital" deficiencies: Compared with traditional hypoglycemic drugs, SGLT2 inhibitors have no evidence-based medical evidence in preventing or delaying diabetes complications, whether it causes long-term diabetes to be harmful to the kidneys The impact (such as urinary system infection, renal damage or worsening kidney disease) remains to be investigated.
  • SGLT2 inhibitors can control the progression of type II diabetes from many aspects such as blood sugar, weight, blood pressure, etc., and are used as additional drugs for patients with existing monotherapy, providing another option for clinical treatment.
  • Tianagliflozin (Tianagliflozin) is a new SGLT2 inhibitor with five chiral centers in the three-dimensional structure.
  • the marketed product is the combined application of pioglitazone hydrochloride and metformin hydrochloride.
  • the compound preparation has been developed and marketed by Takeda Pharmaceuticals, Japan. The specifications are 15/500mg and 15/850mg, and the trade name is ACTOPLUS MET.
  • the compound preparation of glimepiride and metformin hydrochloride was originally developed by Bristol-Myers Squibb, the specifications of which are 2.5/500mg and 5/500mg.
  • the US Food and Drug Administration approved a fixed combination of the SGLT2 inhibitor canagliflozin (canagliflozin) and metformin for the treatment of adult type 2 diabetes.
  • the drug is called Invokamet and includes 50 or 150 mg canagliflozin or 500 or 1000 mg metformin tablets.
  • the recommended dose is twice a day. It is the first fixed combination of canagliflozin and metformin on the US market.
  • Xigduo XR combines the SGLT2 inhibitor dapagliflozin (dapagliflozin, trade name Forxiga) with extended-release metformin hydrochloride for the first time; for adult patients with type II diabetes who need dapagliflozin combined with metformin treatment, the drug can be used as an adjuvant drug. Cooperate with diet and exercise to control blood sugar. Prior to this, Xigduo (dapagliflozin/immediate-release metformin hydrochloride) was approved by the European Union in January 2014 and is the first SGLT2 inhibitor and metformin compound product marketed in the European Union. The usage of Xigduo XR is to take it once a day with meals in the morning. Sustained-release preparations gradually release the drug ingredients in volume to reduce gastrointestinal adverse reactions caused by metformin. The maximum recommended daily dose is 10 mg of dapagliflozin/2000 mg of extended-release metformin hydrochloride.
  • EMEA approved Novartis's vildagliptin/metformin hydrochloride compound tablets on November 14, 2007, to treat type II diabetes, for the treatment of patients who cannot effectively control blood sugar with the maximum tolerated dose of metformin or currently combined Patients taking vildagliptin (Galvus) and metformin.
  • the dosage specification of the compound tablet is vildagliptin/metformin hydrochloride 50mg/850mg or 50mg/1000mg.
  • the compound preparation products of the marketed product and metformin hydrochloride show that the efficacy is better than the single preparation.
  • an object of the present invention is to provide a stable, effective blood sugar control and synergistic pharmaceutical composition for treating diabetes.
  • Another object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention.
  • Another object of the present invention is to provide a use of the pharmaceutical composition of the present invention.
  • Another object of the present invention is to provide a method for treating type II diabetes.
  • the present invention provides a pharmaceutical composition for the treatment of diabetes, which comprises typagliflozin and metformin hydrochloride, wherein the mass ratio of typagliflozin to metformin hydrochloride is 1:50 to 200, preferably 1: 50 ⁇ 170.
  • the content of tyaggliflozin per unit preparation is 2.5 mg-20 mg, preferably 2.5 mg-10 mg, most preferably 5 mg-10 mg; the content of metformin hydrochloride is 250 mg ⁇ 1000mg, preferably 500mg ⁇ 1000mg, most preferably 500mg ⁇ 850mg.
  • the pharmaceutical composition is an oral preparation, such as a tablet, a capsule, etc., preferably a tablet; preferably, the oral preparation is prepared by first combining metformin hydrochloride alone with a pharmaceutical Acceptable excipients are granulated together to obtain metformin hydrochloride granules, and then the metformin hydrochloride granules are mixed with tyaggliflozin and other pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are selected from one or more of fillers, disintegrants, binders and lubricants.
  • the filler is selected from one or more of microcrystalline cellulose, optimized microcrystalline cellulose and calcium hydrogen phosphate;
  • the disintegrant is selected from crospovidone One or more of croscarmellose sodium, carboxymethyl cellulose calcium and low-substituted hydroxypropyl cellulose;
  • the binder is selected from hydroxypropyl cellulose, povidone and hydroxypropyl cellulose One or more of methyl cellulose;
  • the lubricant is selected from magnesium stearate, calcium stearate, glyceryl behenate, sodium stearyl fumarate, silicon dioxide, micronized silica gel and One or more of talcum powder.
  • the present invention provides a method for preparing the pharmaceutical composition of the present invention, including the following steps:
  • step (1) The metformin hydrochloride granules obtained in step (1) are uniformly mixed with typagliflozin and other pharmaceutically acceptable excipients to prepare the pharmaceutical composition.
  • the wet granulation process is a high shear wet granulation process and/or a fluidized bed process, preferably a high shear wet granulation process.
  • the particle size of the metformin hydrochloride particles is D90 ⁇ 180 ⁇ m and/or the particle size of the typagliflozin before mixing is D10 ⁇ 5 ⁇ m, D50 ⁇ 25 ⁇ m, D90 ⁇ 70 ⁇ m, Preferably, D10 ⁇ 3 ⁇ m, D50 ⁇ 20 ⁇ m, and D90 ⁇ 55 ⁇ m, so as to ensure the uniformity of mixing of the two active ingredients, as well as the fluidity and compressibility of the particles.
  • the present invention provides the use of the pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of type II diabetes.
  • the present invention provides a method for treating type II diabetes, comprising administering a therapeutically effective amount of the pharmaceutical composition of the present invention to a subject in need.
  • the pharmaceutical composition of the present invention is composed of a combination of a specific ratio of SGLT2 inhibitor tyaggliflozin and metformin hydrochloride, which can more effectively control the productivity of blood sugar and achieve the effect of synergistic treatment of diabetes.
  • the pharmaceutical composition of the present invention can make it convenient for patients to take medicine, increase compliance, and have better synergistic effects.
  • the method for preparing the pharmaceutical composition of the present invention controls the particle diameters of metformin hydrochloride particles and tyaggliflozin, thereby ensuring the uniformity of the mixing of the two active ingredients, and the fluidity and compressibility of the particles. If the particle size is D90>70 ⁇ m, the dissolution rate is slow in the later stage, and the dissolution cannot be completed within 60 minutes, which affects the absorption in the body.
  • the preparation method of the invention is suitable for large-scale industrial production.
  • Figure 1 shows the UV absorption spectrum of Tyagliptin in 0.1mol/L hydrochloric acid solution
  • Figure 2 shows the UV absorption spectrum of metformin hydrochloride in 0.1 mol/L hydrochloric acid solution
  • Figure 3 shows the UV absorption spectrum of a mixture of Tyagliptin and metformin hydrochloride (1:1) in a 0.1mol/L hydrochloric acid solution;
  • Fig. 4 shows the dissolution test curve of tyaggliflozin and metformin pharmaceutical compositions in Examples 1, 2, 3, 4, 5, 6, and 10 of the present invention
  • Figure 5 shows the metformin hydrochloride dissolution measurement curve of the tyaggliflozin metformin pharmaceutical composition in Examples 1, 2, 3, 4, 5, 6, and 10 of the present invention
  • Figure 6 shows the comparison of the dissolution determination curves of tyaggliflozin and metformin pharmaceutical compositions prepared from tyaggliflozin with different particle sizes in Examples 7, 8, and 9 of the present invention
  • Figure 7 shows the comparison of the metformin hydrochloride dissolution test curves of the typagliflozin metformin pharmaceutical composition prepared from typagliflozin with different particle sizes in Examples 7, 8, and 9 of the present invention
  • Figure 8 shows the determination of tyaggliflozin related substances of the tyaggliflozin-metformin pharmaceutical composition in Example 1 of the present invention
  • FIG. 9 shows the determination spectrum of related substances of metformin hydrochloride in the typagliflozin metformin pharmaceutical composition in Example 1 of the present invention.
  • Figure 10 shows the determination spectrum of typagliflozin-related substances of the typagliflozin-metformin pharmaceutical composition in Example 2 of the present invention
  • FIG. 11 shows the determination spectrum of related substances of metformin hydrochloride in the typagliflozin metformin pharmaceutical composition in Example 2 of the present invention
  • Figure 12 shows the determination spectrum of typagliflozin-related substances of the typagliflozin-metformin pharmaceutical composition in Example 3 of the present invention
  • FIG. 13 shows the determination spectrum of related substances of metformin hydrochloride in the pharmaceutical composition of typagliflozin metformin in Example 3 of the present invention
  • Figure 14 shows the determination spectrum of typagliflozin related substances of the typagliflozin-metformin pharmaceutical composition in Example 4 of the present invention
  • Fig. 15 shows the determination spectrum of related substances of metformin hydrochloride of the typagliflozin metformin pharmaceutical composition in Example 4 of the present invention
  • Figure 16 shows the determination of typagliflozin-related substances of the typagliflozin-metformin pharmaceutical composition in Example 5 of the present invention
  • FIG. 17 shows the determination spectrum of related substances of metformin hydrochloride in the typagliflozin metformin pharmaceutical composition in Example 5 of the present invention
  • Figure 18 shows the determination of tyaggliflozin-related substances in the tyagliflozin-metformin pharmaceutical composition in Example 6 of the present invention
  • FIG. 19 shows a determination spectrum of related substances of metformin hydrochloride in the pharmaceutical composition of typagliflozin metformin in Example 6 of the present invention
  • FIG. 20 shows the determination spectrum of typagliflozin related substances of the typagliflozin-metformin pharmaceutical composition in Example 7 of the present invention
  • FIG. 21 shows a determination spectrum of related substances of metformin hydrochloride in the pharmaceutical composition of typagliflozin metformin in Example 7 of the present invention
  • Figure 22 shows the determination of tyaggliflozin related substances of the tyaggliflozin-metformin pharmaceutical composition in Example 8 of the present invention
  • FIG. 23 shows a determination spectrum of related substances of metformin hydrochloride in the pharmaceutical composition of typagliflozin metformin in Example 8 of the present invention
  • FIG. 24 shows a determination spectrum of typagliflozin-related substances of the typagliflozin-metformin pharmaceutical composition in Example 9 of the present invention.
  • FIG. 25 shows a determination spectrum of related substances of metformin hydrochloride in the pharmaceutical composition of typagliflozin metformin in Example 9 of the present invention
  • FIG. 26 shows a determination spectrum of typagliflozin related substances of the typagliflozin-metformin pharmaceutical composition in Example 10 of the present invention
  • FIG. 27 shows a determination pattern of related substances of metformin hydrochloride in the pharmaceutical composition of typagliflozin metformin in Example 10 of the present invention
  • Figure 28 shows the determination spectrum of tyaggliflozin related substances
  • Figure 29 shows the determination spectrum of related substances of metformin hydrochloride
  • Figure 30 shows the HPLC profile of the dicyandiamide reference substance.
  • the metformin hydrochloride particles are prepared by the following steps: mixing a prescription amount of metformin hydrochloride with a binder, adding an appropriate amount of ethanol water, and at a speed (mixing 450 rpm, shearing 470 rpm) Make wet granules for 3 to 5 minutes.
  • the wet granules are granulated with a swing granulator through a 20-mesh screen. After granulation, the wet granules are poured into the Glatt boiling fluidized bed machine, at the inlet temperature of 50-60°C, the material temperature is about 50°C, and the drying time is about 8-14 minutes. Controlling moisture ⁇ 3.5% is the end of drying.
  • the materials are granulated with a 20-mesh screen to prepare metformin hydrochloride granules.
  • the tyagliflozin metformin composition is prepared by the following steps: adding typagliflozin and metformin hydrochloride particles of a certain particle size and appropriate fillers, disintegrants, and lubricants into the mixer, and cover And lock the cover, turn on the multi-directional motion mixer, the mixing time is 3 to 5 minutes, after the mixing is finished, the material is discharged and weighed, and the content of tyaggliflozin and metformin hydrochloride in the intermediate particles is determined. Measure the moisture of the total mixed material ( ⁇ 3.5%).
  • the ratios and parts are weight ratios and parts by weight.
  • the raw materials are in grams, or parts by weight.
  • Figures 1 to 3 respectively show the UV absorption spectra of a mixture of typagliflozin, metformin hydrochloride, and a mixture of typagliflozin and metformin hydrochloride (1:1) in a 0.1 mol/L hydrochloric acid solution.
  • the prescription amount of metformin hydrochloride and polyvinylpyrrolidone were passed through an 80-mesh sieve, and then put into the silo of the wet granulator, and dry blended at a speed (stirring 450 rpm, shearing 470 rpm) for 5-10 minutes. Add an appropriate amount of 50% ethanol water, and make wet granules at a speed (stirring 450 rpm, shearing 470 rpm) for 3 to 5 minutes. The wet granules are granulated with a swing granulator through a 20-mesh screen.
  • the wet granules are poured into the Glatt boiling fluidized bed machine, at the inlet temperature of 50-60°C, the material temperature is about 50°C, and the drying time is about 8-14 minutes. Controlling moisture ⁇ 3.5% is the end of drying.
  • the materials are granulated with a 20-mesh screen to prepare metformin hydrochloride granules.
  • each tablet contains 2.5mg typagliflozin and 250mg metformin hydrochloride. Measure the quality and get it in packaging.
  • the prescription amount of metformin hydrochloride and hypromellose were passed through an 80-mesh sieve, and then put into the silo of the wet granulator, and dry blended at a speed (mixing 450 rpm, shearing 470 rpm) for 5-10 minutes. Add an appropriate amount of 30% ethanol water, and make wet granules at a speed (stirring 450 rpm, shearing 470 rpm) for 3 to 5 minutes. The wet granules are granulated with a swing granulator through a 20-mesh screen.
  • the wet granules are poured into the Glatt boiling fluidized bed machine, at the inlet temperature of 50-60°C, the material temperature is about 50°C, and the drying time is about 8-14 minutes. Controlling moisture ⁇ 3.5% is the end of drying.
  • the materials are granulated with a 20-mesh screen to prepare metformin hydrochloride granules.
  • each tablet contains 5mg typagliflozin and 250mg metformin hydrochloride. Measure the quality and get it in packaging.
  • the prescription amount of metformin hydrochloride and polyvinylpyrrolidone were passed through an 80-mesh sieve, and then put into the silo of the wet granulator, and dry blended at a speed (agitating 480 rpm, shearing 500 rpm) for 5-10 minutes. Add an appropriate amount of 50% ethanol water, and make wet granules at a speed (stirring 480 rpm, shearing 500 rpm) for 3 to 5 minutes. The wet granules are granulated with a swing granulator through a 20-mesh screen.
  • the wet granules are poured into the Glatt boiling fluidized bed machine, at the inlet temperature of 50-60°C, the material temperature is about 50°C, and the drying time is about 8-14 minutes. Controlling moisture ⁇ 3.5% is the end of drying.
  • the materials are granulated with a 20-mesh screen to prepare metformin hydrochloride granules.
  • the mixing time is 3 to 5 minutes, after the mixing is finished, pour out the material and weigh it, determine the content of tyaggliflozin and metformin hydrochloride in the intermediate particles content. Measure the moisture of the total mixed material ( ⁇ 3.5%).
  • each tablet contains 5mg tyaggliflozin and 500mg metformin hydrochloride. Measure the quality and get it in packaging.
  • the prescription amount of metformin hydrochloride and hydroxypropyl cellulose were passed through an 80-mesh sieve respectively, and then put into the silo of the wet granulator, and dry blended at a speed (mixing 480 rpm, shearing 500 rpm) for 5-10 minutes. Add an appropriate amount of 50% ethanol water, and make wet granules at a speed (stirring 480 rpm, shearing 500 rpm) for 3 to 5 minutes. The wet granules are granulated with a swing granulator through a 20-mesh screen.
  • the wet granules are poured into the Glatt boiling fluidized bed machine, at the inlet temperature of 50-60°C, the material temperature is about 50°C, and the drying time is about 8-14 minutes. Controlling moisture ⁇ 3.5% is the end of drying.
  • the materials are granulated with a 20-mesh screen to prepare metformin hydrochloride granules.
  • tyaggliflozin with particle size (D 10 2.468, D 50 21.51, D 90 57.23), optimized microcrystalline cellulose, croscarmellose sodium, metformin hydrochloride granules, talcum powder, and calcium stearate into the mix
  • the mixing time is 3 to 5 minutes.
  • the material is discharged and weighed to determine the content of tyaggliflozin and metformin hydrochloride in the intermediate particles. Measure the moisture of the total mixed material ( ⁇ 3.5%).
  • each tablet contains 10mg typagliflozin and 500mg metformin hydrochloride. Measure the quality and get it in packaging.
  • the prescription amount of metformin hydrochloride, polyvinylpyrrolidone, and hydroxypropyl cellulose are respectively passed through an 80-mesh sieve, and then put into the silo of the wet granulator, and dry blended at a speed (stirring 550rpm, shearing 600rpm) for 5-10 minutes.
  • the wet granules are granulated with a swing granulator through a 20-mesh screen.
  • the wet granules are poured into the Glatt boiling fluidized bed machine, at the inlet temperature of 50-60°C, the material temperature is about 50°C, and the drying time is about 8-14 minutes. Controlling moisture ⁇ 3.5% is the end of drying.
  • the materials are granulated with a 20-mesh screen to prepare metformin hydrochloride granules.
  • each tablet contains 5mg tyaggliflozin and 850mg metformin hydrochloride. Measure the quality and get it in packaging.
  • the prescription amount of metformin hydrochloride, polyvinylpyrrolidone, and hypromellose were passed through an 80-mesh sieve respectively, and then put into the silo of the wet granulator, and dry blended at a speed (stirring 550rpm, shearing 600rpm) for 5-10 minutes.
  • the wet granules are granulated with a swing granulator through a 20-mesh screen.
  • the wet granules are poured into the Glatt boiling fluidized bed machine, at the inlet temperature of 50-60°C, the material temperature is about 50°C, and the drying time is about 8-14 minutes. Controlling moisture ⁇ 3.5% is the end of drying.
  • the materials are granulated with a 20-mesh screen to prepare metformin hydrochloride granules.
  • each tablet contains 5mg typagliflozin and 1000mg metformin hydrochloride. Measure the quality and get it in packaging.
  • the prescription amount of metformin hydrochloride and hydroxypropyl cellulose were passed through an 80-mesh sieve respectively, and then put into the silo of the wet granulator, and dry blended at a speed (mixing 480 rpm, shearing 500 rpm) for 5-10 minutes. Add an appropriate amount of 30% ethanol water, and make wet granules at a speed (stirring 480 rpm, shearing 500 rpm) for 3 to 5 minutes. The wet granules are granulated with a swing granulator through a 20-mesh screen.
  • the wet granules are poured into the Glatt boiling fluidized bed machine, at the inlet temperature of 50-60°C, the material temperature is about 50°C, and the drying time is about 8-14 minutes. Controlling moisture ⁇ 3.5% is the end of drying.
  • the materials are granulated with a 20-mesh screen to prepare metformin hydrochloride granules.
  • each capsule contains 5mg tyaggliflozin and 250mg metformin hydrochloride.
  • Example 7 similarly prepared capsules.
  • the preparation method of the present invention was used to prepare a 10 mg/250 mg typagliflozin and metformin hydrochloride pharmaceutical composition, which is detailed as follows:
  • the prescription amount of metformin hydrochloride and hydroxypropyl cellulose were passed through an 80-mesh sieve respectively, and then put into the silo of the wet granulator, and dry blended at a speed (mixing 480 rpm, shearing 500 rpm) for 5-10 minutes. Add an appropriate amount of 30% ethanol water, and make wet granules at a speed (stirring 480 rpm, shearing 500 rpm) for 3 to 5 minutes. The wet granules are granulated with a swing granulator through a 20-mesh screen.
  • the wet granules are poured into the Glatt boiling fluidized bed machine, at the inlet temperature of 50-60°C, the material temperature is about 50°C, and the drying time is about 8-14 minutes. Controlling moisture ⁇ 3.5% is the end of drying.
  • the materials are granulated with a 20-mesh screen to prepare metformin hydrochloride granules.
  • each capsule contains 10mg tyaggliflozin and 250mg metformin hydrochloride.
  • Example 3 Except for tyaggliflozin with larger particle size (D 10 6.076, D 50 26.45, D 90 85.23) instead of tyaglide with particle size (D 10 2.405, D 50 16.38, D 90 55.96), and In Example 3, tablets were prepared in the same manner.
  • the powders of Examples 1-10 are basically the same, and are suitable for tableting or capsule filling according to Karl's law.
  • tyagliflozin and metformin compositions prepared in Examples 1-10 were tested for related substances and compared with typagliflozin or metformin hydrochloride alone, as follows:
  • tyagliflozin control solution accurately weigh 25mg of tyagliflozin reference substance into a 50ml volumetric flask, add 42% acetonitrile solution to dissolve and dilute to the mark to make a solution with a concentration of 0.5mg/ml.
  • test solution accurately weigh the tablets of tyaggliflozin metformin tablets prepared in Examples 1-6 and 10 and the appropriate amount of particles in tyagliptin metformin capsules prepared in Examples 7-9 (containing Tyaggliflozin 5mg) was placed in a 10ml volumetric flask, and 42% acetonitrile solution was added to ultrasound for 15 minutes. After standing at room temperature, it was diluted to the mark, shaken, 4000 rpm/centrifuged for 5 minutes, and the supernatant was taken as the test solution.
  • metformin hydrochloride control solution accurately weigh 50 mg of metformin hydrochloride and place it in a 10ml volumetric flask, add the mobile phase to ultrasonic for 5 minutes to dissolve and dilute to the mark, shake well.
  • test solution accurately weigh the tablets of tyaggliflozin metformin tablets prepared in Examples 1-6 and 10 and the appropriate amount of particles in tyagliptin metformin capsules prepared in Examples 7-9 (containing Metformin hydrochloride (125mg) was placed in a 25ml volumetric flask, added mobile phase and sonicated for 15 minutes, placed at room temperature, diluted to the mark, and shaken. Separate the heart at 4000 rpm for 5 minutes, and take the supernatant as the test solution.
  • Mobile phase 1.7% ammonium dihydrogen phosphate solution (adjust the pH to 3.0 with phosphoric acid); flow rate: 1mL/min; wavelength: 218nm; column temperature: 30 ⁇ 35°C; chromatographic column: sulfonic acid group cation exchange bonded silica gel As filler, UltimateXB-SCX C18 4.6mm ⁇ 250mm, 5 ⁇ m.
  • Figures 8-27 show the determination patterns of related substances of tyagliflozin and metformin hydrochloride in the pharmaceutical composition of typagliflozin and metformin hydrochloride in Examples 1-10 of the present invention;
  • Figures 28-30 respectively Liejing related substances determination spectrum, metformin hydrochloride related substances determination spectrum, and dicyandiamide reference substance determination HPLC spectrum.
  • chromatographic conditions According to high performance liquid chromatography, octadecyl bonded silica gel is used as a packed column, methanol-water (80:20) is used as the mobile phase, and the detection wavelength is 222nm. Take the test solution and the reference solution respectively into If the sample is 20 ⁇ l, the number of theoretical plates is not less than 3000 according to tyaggliflozin.
  • volume dissolution medium take another tyaggliflozin reference substance about 14mg, accurately weigh it, put it in a 100ml volumetric flask, add methanol to dissolve and dilute to the mark, shake well, accurately pipette 2ml into a 25ml volumetric flask, add 0.1mol/ Dilute the L hydrochloric acid solution to the mark, shake it up, and use it as a reference solution.
  • high-performance liquid chromatography Choinese Pharmacopoeia 2015 Edition Four General Rules 0512), take 20 ⁇ l each of the test solution and the reference solution into the high-performance liquid chromatograph, record the chromatogram, and calculate according to the external standard method.
  • Figure 4 shows the dissolution test curve of typagliflozin metformin pharmaceutical composition in Examples 1, 2, 3, 4, 5, 6, and 10 of the present invention
  • Figure 5 shows the implementation of the present invention The metformin hydrochloride dissolution test curve of the tyaggliflozin metformin pharmaceutical composition in Examples 1, 2, 3, 4, 5, 6, and 10.
  • the experimental results show that the dissolution of tyagliflozin in compound preparations prepared from different particle sizes of tyagliflozin is different.
  • the dissolution curve of metformin hydrochloride in 0.1mol/L hydrochloric acid solution is faster, and there is no difference in the basic total dissolution.
  • the prescription process of the pharmaceutical composition of tyaggliflozin and metformin hydrochloride is reasonable.
  • chromatographic conditions According to high performance liquid chromatography, octadecyl bonded silica gel is used as a packed column, methanol-water (80:20) is used as the mobile phase, and the detection wavelength is 222nm. Take the test solution and the reference solution respectively into If the sample is 20 ⁇ l, the number of theoretical plates is not less than 3000 according to tyaggliflozin.
  • Figure 6 shows the comparison of the dissolution determination curves of tyaggliflozin and metformin pharmaceutical compositions prepared from tyaggliflozin with different particle sizes in Examples 7, 8, and 9 of the present invention
  • Figure 7 shows Comparison of the metformin hydrochloride dissolution test curves of the tyaggliflozin metformin pharmaceutical composition prepared from tyaggliflozin with different particle diameters in Examples 7, 8, and 9 of the present invention.
  • Example 8 The dissolution rate of tyagliflozin in 60 minutes is less than 90% and cannot be completely dissolved. Therefore, the control particle size of tyagliflozin is D10 ⁇ 5 ⁇ m, D50 ⁇ 25 ⁇ m, D90 ⁇ 70 ⁇ m, preferably D10 ⁇ 3 ⁇ m, D50 ⁇ 20 ⁇ m, D90 ⁇ 55 ⁇ m, so as to ensure the uniformity of the mixing of the two active ingredients and the fluidity of the particles, and ensure that the total dissolution curve is ⁇ 75% in 30 minutes and ⁇ 90% in 60 minutes, thus ensuring better absorption in the body.
  • the particle size of tyaggliflozin is tested with reference to the particle size distribution method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0982 Method 3).
  • Sample preparation Take an appropriate amount of Taipagliflozin API, dilute with water to a suspension with a concentration of 0.5g/100ml, stir to make it evenly dispersed, and wait for testing.
  • Measurement method add distilled water to the detection cell, circulate ultrasonic for 1 minute, correct the background, add an appropriate amount of sample solution to the detection cell, and measure the particle size distribution when the shading rate is about 20%.
  • particle size D10 ⁇ 5 ⁇ m, D50 ⁇ 25 ⁇ m, D90 ⁇ 70 ⁇ m all of which can ensure that the quality of the preparation meets the regulations.
  • the particle size is D10 ⁇ 3 ⁇ m, D50 ⁇ 20 ⁇ m, and D90 ⁇ 55 ⁇ m.
  • the rats were fasted for 16 hours, and the fasting blood glucose was measured.
  • the rats were randomly divided into groups according to the fasting blood glucose, 4 rats in each group, orally administered, tyaggliflozin group, metformin hydrochloride group, group 2, 3, 4, 5, 6, 9 ,
  • the dosages are 5, 250, 5+250, 5+500, 10+500, 5+850, 5+1000, 10+250mg/kg, 0.5 hours after the drug, orally give glucose 4.5g/kg, give sugar After 0.5 hours, the blood glucose values of rats in each group were measured, and the inhibition rate of the rats in each administration group was calculated. Sugar effect.
  • Example 5 Compared with Example 3, Example 4>Example 6>Example 2>Example 9.
  • Example 9 has the same dosage of metformin hydrochloride, and the dosage of typagliflozin is increased from 5mg to 10mg, but the blood sugar suppressing effect is greatly reduced.
  • Example 4 The dosage of tyaggliflozin is the same, the amount of metformin hydrochloride is increased from 250mg to 500mg, and the blood sugar suppression effect is greatly improved.
  • the ratio of typagliflozin and metformin hydrochloride has a greater impact on the blood sugar inhibitory effect.
  • the mass ratio of typagliflozin and metformin hydrochloride is 1:50-200, it has a significant synergistic effect of inhibiting blood sugar; preferably, the mass ratio of tyagliflozin and metformin hydrochloride is 1:50-170.
  • the preferred dosage of typagliflozin is 5mg-10mg, and the preferred dosage of metformin hydrochloride is 500mg-850mg.

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Abstract

本发明涉及一种用于治疗糖尿病的药物组合物，其包含泰格列净和盐酸二甲双胍，其中所述泰格列净与盐酸二甲双胍的质量比为1:50～1:200。本发明还提供了泰格列净与盐酸二甲双胍药物组合物的制备方法和用途。本发明的药物组合物是以特定比例的SGLT2抑制剂泰格列净与盐酸二甲双胍组合而成，可更有效地控制血糖的生率等达到协同治疗糖尿病的作用，还可使患者服药方便，增加依从性。本发明的制备所述药物组合物的方法通过控制盐酸二甲双胍颗粒和泰格列净的粒径，从而保证两种活性成分的混合均一性，以及颗粒的流动性和可压性，并且适合工业化大生产。本发明的药物组合物可用于治疗II型糖尿病。

Description

一种用于治疗糖尿病的药物组合物及其制备方法和用途 技术领域
本发明涉及降糖制剂相关的药物领域，具体而言，涉及一种用于治疗糖尿病的药物组合物及其制备方法和用途。
背景技术
糖尿病的发病率持续上升，已成为全世界发病率和死亡率最高的5种疾病之一，尤以中国、印支次大陆及非洲等发展中国家增加更为显著。糖尿病可分为I型，即胰岛素依赖性糖尿病(IDDM)，以及II型，即非胰岛素依赖性糖尿病(NIDDM)两型。糖尿病随病程进展常发生血管并发症，包括大血管病变和微血管病变，导致心、脑、肾、眼等器官的慢性进行性损害。糖尿病的危害主要来自这些并发症。据中华医学会糖尿病分会的报道，我国糖尿病血管并发症的患病率为：高血压31.9％、脑血管病12.2％、心血管病15.9％、下肢血管病5.0％、肾脏病(肾微血管病变)33.6％、视网膜病变24.3％，总患病率73.2％。在数量上急剧增加的糖尿病患者中，NIDDM至少占患者总数的90％以上。NIDDM治疗药物包括磺酰脲类、双胍类、α-葡萄糖苷酶抑制药、胰岛素增敏药和餐时血糖调节药等。
我国最新指南推荐的II型糖尿病药物治疗的首选药物是二甲双胍。如果没有禁忌症，二甲双胍应一直保留在糖尿病的治疗方案中。不适合二甲双胍治疗者可选择α-葡萄糖苷酶抑制剂或胰岛素促分泌剂。如单独使用二甲双胍治疗而血糖仍未达标，则可加用α-葡萄糖苷酶抑制剂、胰岛素促分泌剂、DPP-4抑制剂或噻唑烷二酮(二线治疗)。不适合二甲双胍者可采用其它口服药间的联合治疗。两种口服药联合治疗而血糖仍不达标者，可加用胰岛素治疗(每日1次基础胰岛素或每日1～2次预混胰岛素)或采用3种口服药间的联合治疗。GLP-1受体激动剂可用于三线治疗。如基础胰岛素或预混胰岛素与口服药联合治疗控制血糖仍不达标，则应将治疗方案调整为多次胰岛素治疗(基础胰岛素加餐时胰岛素或每日3次预混胰岛素类似物)。采用预混胰岛素治疗和多次胰岛素治疗时应停用胰岛素促分泌剂。
上述用药方案是根据药物卫生经济学、疗效和安全性等方面的临床证据以及我国国情等因素权衡考虑后指南推荐的II型糖尿病高血糖治疗路径。
钠葡萄糖共同转运蛋白2(SGLT2)抑制剂包括达格列净(dapagliflozin)、瑞格列净(remogliflozin)、舍格列净(sergliflozin)、坎格列净(canagliflozin)、阿格列净(atigliflozin)等，其中达格列净是第1个获批准并已在欧洲上市的SGLT2抑制剂，其糖尿病治疗效果已得到临床研究的初步证实。
据报道，SGLT2抑制剂具有降低体重、很少引起低血糖、治疗作用不依赖胰岛素的存在等优点。但是，SGLT2抑制剂也存在一些“先天”的不足：与传统降糖药物相比，SGLT2抑制剂在预防或延缓糖尿病并发症方面没有循证医学的证据，它导致长期糖尿状态是否对肾脏产生不利影响(如泌尿系统感染、肾功能损害或肾病加重)，仍有待考察。
SGLT2抑制剂作为一个非胰岛素依赖型药物，可以从血糖、体重、血压等多方面来控制II型糖尿病的进展，用于患者现有单药治疗的附加药物，为临床治疗提供另外一种选择。
2012年至今，共有6个SGLT2抑制剂先后在欧盟、美国和日本上市，这些药物目前在国内尚处于审批阶段。
泰格列净(Tianagliflozin)为新的SGLT2抑制剂，具有5个手性中心立体结构。化学名：(1S)-1,5-脱水-6-脱氧-1-C-[4-氯-3-[(4-乙氧基苯基)甲基]苯基]-D-葡萄糖醇，分子式：C 21H 25ClO 5，分子量：392.87，结构式：
Figure PCTCN2019074405-appb-000001
目前已上市产品有盐酸吡格列酮与盐酸二甲双胍的联合应用，该复方制剂已由日本武田制药开发上市，规格有15/500mg和15/850mg，商品名为ACTOPLUS MET。格列美脲和盐酸二甲双胍的复方制剂原研由美国施贵宝制药开发的，规格为2.5/500mg和5/500mg。
美国食品与药物管理局(FDA)批准了SGLT2抑制剂坎格列净(canagliflozin)与二甲双胍的固定复方制剂用于治疗成人II型糖尿病。该药名为Invokamet，包括50或150mg坎格列净或500或1000mg二甲双胍的片剂，推荐剂量为每日两次，是美国市场上的首个坎格列净与二甲双胍的固定复方制剂。
FDA近日批准阿斯利康(AstraZeneca)旗下糖尿病复方新药Xigduo XR(达格列净/缓释型盐酸二甲双胍)在美国上市，用于治疗II型糖尿病。
Xigduo XR首次将SGLT2抑制剂达格列净(dapagliflozin，商品名Forxiga)和缓释型盐酸二甲双胍相结合；对于需要达格列净联合二甲双胍治疗的II型糖尿病成人患者，该药可作为辅助药物，配合饮食和运动来控制血糖。此前，Xigduo(达格列净/速释盐酸二甲双胍)已于2014年1月获欧盟批准，是欧盟上市的首个SGLT2抑制剂和二甲双胍复方产品。Xigduo XR的用法是，每日1次，在清晨进餐时服用。缓释型制剂逐量释放药物成分可减少二甲双胍带来的胃肠道不良反应。每日最大推荐剂量为达格列净10mg/缓释型盐酸二甲双胍2000mg。
EMEA于2007年11月14日批准诺华(Novartis)的维格列汀/盐酸二甲双胍复方片上市，治疗II型糖尿病，用于治疗使用二甲双胍最大耐受剂量仍不能有效控制血糖的患者或目前已联合使用维格列汀(Galvus)与二甲双胍的患者。该复方片剂的剂量规格为维格列汀/盐酸二甲双胍50mg/850mg或50mg/1000mg。上市产品与盐酸二甲双胍的复方制剂产品表明疗效均优于单方制剂。
现有技术中仍然需要一种稳定的、能有效控制血糖并具有协同作用的治疗糖尿病的药物组合物。
发明内容
因此，本发明的一个目的是提供一种稳定的、能有效控制血糖并具有较好协同作用的治疗糖尿病的药物组合物。
本发明的另一个目的是提供一种制备本发明的药物组合物的方法。
本发明的又一个目的是提供一种本发明的药物组合物的用途。
本发明的再一个目的是提供一种治疗II型糖尿病的方法。
本发明的目的是通过以下技术方案来实现的。
一方面，本发明提供一种用于治疗糖尿病的药物组合物，其包含泰格列净和盐酸二甲双胍，其中所述泰格列净与盐酸二甲双胍的质量比为1:50～200，优选1:50～170。
在本发明的某些实施方案中，每单位制剂中，所述泰格列净的含量为2.5mg～20mg，优选为2.5mg～10mg，最优选为5mg～10mg；所述盐酸二甲双胍含量为250mg～1000mg，优选为500mg～1000mg，最优选为500mg～850mg。
在本发明的某些实施方案中，所述药物组合物为口服制剂，如片剂、胶囊剂等，优选为片剂；优选地，所述口服制剂是通过包括先将盐酸二甲 双胍单独与药学上可接受的辅料一起制粒后得到盐酸二甲双胍颗粒，再将所述盐酸二甲双胍颗粒与泰格列净和另外的药学上可接受的辅料混合的步骤的方法制成。
在本发明的某些实施方案中，所述药学上可接受的辅料选自填充剂、崩解剂、粘合剂和润滑剂中的一种或多种。
在本发明的某些实施方案中，所述填充剂选自微晶纤维素、优化微晶纤维素和磷酸氢钙中的一种或多种；所述崩解剂选自交联聚维酮、交联羧甲基纤维素钠、羧甲基纤维素钙和低取代羟丙基纤维素中的一种或多种；所述粘合剂选自羟丙纤维素、聚维酮和羟丙甲纤维素中的一种或多种；和/或所述润滑剂选自硬脂酸镁、硬脂酸钙、山嵛酸甘油酯、硬脂富马酸钠、二氧化硅、微粉硅胶和滑石粉中的一种或多种。
另一方面，本发明提供一种制备本发明所述的药物组合物的方法，包括以下步骤：
(1)将盐酸二甲双胍与药学上可接受的辅料混合，并通过湿法制粒工艺制备成颗粒，即得到盐酸二甲双胍颗粒；
(2)将步骤(1)中得到的盐酸二甲双胍颗粒与泰格列净和另外的药学上可接受的辅料混合均匀，制得所述药物组合物。
在本发明的某些实施方案中，所述湿法制粒工艺为高剪切湿法制粒工艺和/或流化床工艺，优选高剪切湿法制粒工艺。
在本发明的某些实施方案中，所述盐酸二甲双胍颗粒的粒径为D90≤180μm和/或在混合前所述泰格列净的粒径为D10≤5μm，D50≤25μm，D90≤70μm，优选D10≤3μm，D50≤20μm，D90≤55μm，从而能够保证两种活性成分的混合均一性，以及颗粒的流动性和可压性。
又一方面，本发明提供本发明的药物组合物在制备用于治疗II型糖尿病的药物中的用途。
再一方面，本发明提供一种治疗II型糖尿病的方法，包括给予需要的受试者治疗有效量的本发明所述的药物组合物。
本发明具有以下有益效果：
本发明的药物组合物是以特定比例的SGLT2抑制剂泰格列净与盐酸二甲双胍组合而成，可更有效的控制血糖的生率等达到协同治疗糖尿病的作用。本发明的药物组合物可使患者服药方便，增加依从性，具有较好协同作用。
本发明的制备所述药物组合物的方法通过控制盐酸二甲双胍颗粒和 泰格列净的粒径，从而保证两种活性成分的混合均一性，以及颗粒的流动性和可压性，泰格列净的粒径如D90>70μm，后期溶出度较慢，在60分钟不能溶出完全，影响体内的吸收。本发明的制备方法适合工业化大生产。
附图的简要说明
以下，结合附图来详细说明本发明的实施方案，其中：
图1示出了泰格列净在0.1mol/L盐酸溶液中的紫外吸收光谱图；
图2示出了盐酸二甲双胍在0.1mol/L盐酸溶液中的紫外吸收光谱图；
图3示出了泰格列净与盐酸二甲双胍(1:1)的混合物在0.1mol/L盐酸溶液中的紫外吸收光谱图；
图4示出了本发明实施例1、2、3、4、5、6、10中的泰格列净二甲双胍药物组合物的泰格列净溶出度测定曲线；
图5示出了本发明实施例1、2、3、4、5、6、10中的泰格列净二甲双胍药物组合物的盐酸二甲双胍溶出度测定曲线；
图6示出了本发明实施例7、8、9由不同粒径的泰格列净制备的泰格列净二甲双胍药物组合物的泰格列净溶出度测定曲线比较；
图7示出了本发明实施例7、8、9由不同粒径的泰格列净制备的泰格列净二甲双胍药物组合物的盐酸二甲双胍溶出度测定曲线比较；
图8示出了本发明实施例1中的泰格列净二甲双胍药物组合物的泰格列净有关物质测定图谱；
图9示出了本发明实施例1中的泰格列净二甲双胍药物组合物的盐酸二甲双胍有关物质测定图谱；
图10示出了本发明实施例2中的泰格列净二甲双胍药物组合物的泰格列净有关物质测定图谱；
图11示出了本发明实施例2中的泰格列净二甲双胍药物组合物的盐酸二甲双胍有关物质测定图谱；
图12示出了本发明实施例3中的泰格列净二甲双胍药物组合物的泰格列净有关物质测定图谱；
图13示出了本发明实施例3中的泰格列净二甲双胍药物组合物的盐酸二甲双胍有关物质测定图谱；
图14示出了本发明实施例4中的泰格列净二甲双胍药物组合物的泰格列净有关物质测定图谱；
图15示出了本发明实施例4中的泰格列净二甲双胍药物组合物的盐 酸二甲双胍有关物质测定图谱；
图16示出了本发明实施例5中的泰格列净二甲双胍药物组合物的泰格列净有关物质测定图谱；
图17示出了本发明实施例5中的泰格列净二甲双胍药物组合物的盐酸二甲双胍有关物质测定图谱；
图18示出了本发明实施例6中的泰格列净二甲双胍药物组合物的泰格列净有关物质测定图谱；
图19示出了本发明实施例6中的泰格列净二甲双胍药物组合物的盐酸二甲双胍有关物质测定图谱；
图20示出了本发明实施例7中的泰格列净二甲双胍药物组合物的泰格列净有关物质测定图谱；
图21示出了本发明实施例7中的泰格列净二甲双胍药物组合物的盐酸二甲双胍有关物质测定图谱；
图22示出了本发明实施例8中的泰格列净二甲双胍药物组合物的泰格列净有关物质测定图谱；
图23示出了本发明实施例8中的泰格列净二甲双胍药物组合物的盐酸二甲双胍有关物质测定图谱；
图24示出了本发明实施例9中的泰格列净二甲双胍药物组合物的泰格列净有关物质测定图谱；
图25示出了本发明实施例9中的泰格列净二甲双胍药物组合物的盐酸二甲双胍有关物质测定图谱；
图26示出了本发明实施例10中的泰格列净二甲双胍药物组合物的泰格列净有关物质测定图谱；
图27示出了本发明实施例10中的泰格列净二甲双胍药物组合物的盐酸二甲双胍有关物质测定图谱；
图28示出了泰格列净有关物质测定图谱；
图29示出了盐酸二甲双胍有关物质测定图谱；
图30示出了双氰胺对照品测定HPLC图谱。
实施发明的最佳方式
下面通过具体的实施例进一步说明本发明，但是，应当理解为，这些实施例仅仅是用于更详细具体地说明之用，而不应理解为用于以任何形式限制本发明。
本部分对本发明试验中所使用到的材料以及试验方法进行一般性的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的，但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚，在上下文中，如果未特别说明，本发明所用材料和操作方法是本领域公知的。
除非特别指明，以下实施例中所用的试剂和原料均可商购获得。
试验仪器和设备：
Figure PCTCN2019074405-appb-000002
以下实施例中，如无特别说明，所述盐酸二甲双胍颗粒是通过以下步骤制备的：将处方量的盐酸二甲双胍与粘合剂混合，加入适量的乙醇水，以速度(搅拌450rpm、剪切470rpm)制湿颗粒3～5分钟。湿颗粒用摇摆式制粒机经20目筛网制粒。整粒后湿颗粒倒入Glatt沸腾流化床机，于进风温度50～60℃，物料温度50℃左右，干燥时间约8～14分钟。控制水分≤3.5％即为干燥终点。物料以20目筛网整粒，制得盐酸二甲双胍颗粒。
所述的泰格列净二甲双胍组合物是通过以下步骤制备的：将控制一定粒径的泰格列净与盐酸二甲双胍颗粒以及适量的填充剂、崩解剂、润滑剂加入混合机中，盖好并锁紧盖，开启多向运动混合机，混合时间为3～5分钟，混合结束后倒出料并称重，测定中间体颗粒中泰格列净和盐酸二甲双胍的含量。测总混物料的水分(≤3.5％)。
根据中间体颗粒中泰格列净和盐酸二甲双胍的含量计算片重，使用装有异型冲模的单冲压片机将中间体颗粒压片制成片剂或将中间体颗粒填充到胃溶型1号或0号胶囊壳中制成胶囊。
以下实施例中，如无特别说明，所述比例、份数均为重量比、重量份数。为了描述方便，原料采用克数，也可以采用重量份替换。
图1～图3分别示出了泰格列净、盐酸二甲双胍、泰格列净与盐酸二甲双胍(1:1)的混合物在0.1mol/L盐酸溶液中的紫外吸收光谱图。
实施例1
本实施例用于说明本发明的泰格列净与盐酸二甲双胍药物组合物及其制备方法，具体详述如下：规格2.5mg/250mg
Figure PCTCN2019074405-appb-000003
制备工艺：
将处方量的盐酸二甲双胍与聚乙烯吡咯烷酮分别过80目筛，再投入湿法制粒机料仓中，以速度(搅拌450rpm、剪切470rpm)干混5～10分钟。加入适量的50％乙醇水，以速度(搅拌450rpm、剪切470rpm)制湿颗粒3～5分钟。湿颗粒用摇摆式制粒机经20目筛网制粒。整粒后湿颗粒倒入Glatt沸腾流化床机，于进风温度50～60℃，物料温度50℃左右，干燥时间约8～14分钟。控制水分≤3.5％即为干燥终点。物料以20目筛网整粒，制得盐酸二甲双胍颗粒。
Figure PCTCN2019074405-appb-000004
制备工艺：
将粒径为(D 103.076，D 5020.35，D 9065.13)的泰格列净、微晶纤维素102、交联聚维酮、盐酸二甲双胍颗粒、滑石粉、硬脂酸镁加入混合机中，盖好并锁紧盖，开启多向运动混合机，混合时间为3～5分钟，混合结束后倒出料并称重，测定中间体颗粒中泰格列净和盐酸二甲双胍的含量。测总混物料的水分(≤3.5％)。
根据中间体颗粒中泰格列净和盐酸二甲双胍的含量计算片重，使用装有异型冲模的单冲压片机将中间体颗粒压片。其中，每片中含2.5mg泰格 列净和250mg盐酸二甲双胍。测定质量，包装即得。
实施例2
本实施例用于说明本发明的泰格列净与盐酸二甲双胍药物组合物及其制备方法，具体详述如下：规格5mg/250mg
Figure PCTCN2019074405-appb-000005
制备工艺：
将处方量的盐酸二甲双胍与羟丙甲纤维素分别过80目筛，再投入湿法制粒机料仓中，以速度(搅拌450rpm、剪切470rpm)干混5～10分钟。加入适量的30％乙醇水，以速度(搅拌450rpm、剪切470rpm)制湿颗粒3～5分钟。湿颗粒用摇摆式制粒机经20目筛网制粒。整粒后湿颗粒倒入Glatt沸腾流化床机，于进风温度50～60℃，物料温度50℃左右，干燥时间约8～14分钟。控制水分≤3.5％即为干燥终点。物料以20目筛网整粒，制得盐酸二甲双胍颗粒。
Figure PCTCN2019074405-appb-000006
制备工艺：
将粒径为(D 103.637，D 5021.24，D 9060.83)的泰格列净、微晶纤维素101、交联羧甲纤维素钠、盐酸二甲双胍颗粒、滑石粉、微粉硅胶加入混合机中，盖好并锁紧盖，开启多向运动混合机，混合时间为3～5分钟，混合结束后倒出料并称重，测定中间体颗粒中泰格列净和盐酸二甲双胍的含量。测总混物料的水分(≤3.5％)。
根据中间体颗粒中泰格列净和盐酸二甲双胍的含量计算片重，使用装有异型冲模的单冲压片机将中间体颗粒压片。其中，每片中含5mg泰格列净和250mg盐酸二甲双胍。测定质量，包装即得。
实施例3
本实施例用于说明本发明的泰格列净与盐酸二甲双胍药物组合物及其制备方法，具体详述如下：规格5mg/500mg
Figure PCTCN2019074405-appb-000007
制备工艺：
将处方量的盐酸二甲双胍与聚乙烯吡咯烷酮分别过80目筛，再投入湿法制粒机料仓中，以速度(搅拌480rpm、剪切500rpm)干混5～10分钟。加入适量的50％乙醇水，以速度(搅拌480rpm、剪切500rpm)制湿颗粒3～5分钟。湿颗粒用摇摆式制粒机经20目筛网制粒。整粒后湿颗粒倒入Glatt沸腾流化床机，于进风温度50～60℃，物料温度50℃左右，干燥时间约8～14分钟。控制水分≤3.5％即为干燥终点。物料以20目筛网整粒，制得盐酸二甲双胍颗粒。
Figure PCTCN2019074405-appb-000008
制备工艺：
将粒径为(D 102.405，D 5016.38，D 9055.96)的泰格列净、磷酸氢钙、微晶纤维素102、交联聚维酮、盐酸二甲双胍颗粒、滑石粉、硬脂酸镁加入混合机中，盖好并锁紧盖，开启多向运动混合机，混合时间为3～5分钟，混合结束后倒出料并称重，测定中间体颗粒中泰格列净和盐酸二甲双胍的含量。测总混物料的水分(≤3.5％)。
根据中间体颗粒中泰格列净和盐酸二甲双胍的含量计算片重，使用装有异型冲模的单冲压片机将中间体颗粒压片。其中，每片中含5mg泰格列净和500mg盐酸二甲双胍。测定质量，包装即得。
实施例4
本实施例用于说明本发明的泰格列净与盐酸二甲双胍药物组合物及其制备方法，具体详述如下：规格10mg/500mg
Figure PCTCN2019074405-appb-000009
制备工艺：
将处方量的盐酸二甲双胍与羟丙纤维素分别过80目筛，再投入湿法制粒机料仓中，以速度(搅拌480rpm、剪切500rpm)干混5～10分钟。加入适量的50％乙醇水，以速度(搅拌480rpm、剪切500rpm)制湿颗粒3～5分钟。湿颗粒用摇摆式制粒机经20目筛网制粒。整粒后湿颗粒倒入Glatt沸腾流化床机，于进风温度50～60℃，物料温度50℃左右，干燥时间约8～14分钟。控制水分≤3.5％即为干燥终点。物料以20目筛网整粒，制得盐酸二甲双胍颗粒。
Figure PCTCN2019074405-appb-000010
制备工艺：
将粒径为(D 102.468，D 5021.51，D 9057.23)的泰格列净、优化微晶纤维素、交联羧甲纤维素钠、盐酸二甲双胍颗粒、滑石粉、硬脂酸钙加入混合机中，盖好并锁紧盖，开启多向运动混合机，混合时间为3～5分钟，混合结束后倒出料并称重，测定中间体颗粒中泰格列净和盐酸二甲双胍的含量。测总混物料的水分(≤3.5％)。
根据中间体颗粒中泰格列净和盐酸二甲双胍的含量计算片重，使用装有异型冲模的单冲压片机将中间体颗粒压片。其中，每片中含10mg泰格列净和500mg盐酸二甲双胍。测定质量，包装即得。
实施例5
本实施例用于说明本发明的泰格列净与盐酸二甲双胍药物组合物及其制备方法，具体详述如下：规格5mg/850mg
Figure PCTCN2019074405-appb-000011
制备工艺：
将处方量的盐酸二甲双胍与聚乙烯吡咯烷酮、羟丙纤维素分别过80目筛，再投入湿法制粒机料仓中，以速度(搅拌550rpm、剪切600rpm)干混5～10分钟。加入适量的50％乙醇水，以速度(搅拌550rpm、剪切600rpm)制湿颗粒3～5分钟。湿颗粒用摇摆式制粒机经20目筛网制粒。整粒后湿颗粒倒入Glatt沸腾流化床机，于进风温度50～60℃，物料温度50℃左右，干燥时间约8～14分钟。控制水分≤3.5％即为干燥终点。物料以20目筛网整粒，制得盐酸二甲双胍颗粒。
Figure PCTCN2019074405-appb-000012
制备工艺：
将粒径为(D 102.876，D 5016.67，D 9053.75)的泰格列净、微晶纤维素102、交联聚维酮、盐酸二甲双胍颗粒、滑石粉、二氧化硅、硬脂酸镁加入混合机中，盖好并锁紧盖，开启多向运动混合机，混合时间为3～5分钟，混合结束后倒出料并称重，测定中间体颗粒中泰格列净和盐酸二甲双胍的含量。测总混物料的水分(≤3.5％)。
根据中间体颗粒中泰格列净和盐酸二甲双胍的含量计算片重，使用装有异型冲模的单冲压片机将中间体颗粒压片。其中，每片中含5mg泰格列净和850mg盐酸二甲双胍。测定质量，包装即得。
实施例6
本实施例用于说明本发明的泰格列净与盐酸二甲双胍药物组合物及其制备方法，具体详述如下：规格5mg/1000mg
Figure PCTCN2019074405-appb-000013
制备工艺：
将处方量的盐酸二甲双胍与聚乙烯吡咯烷酮、羟丙甲纤维素分别过80目筛，再投入湿法制粒机料仓中，以速度(搅拌550rpm、剪切600rpm)干混5～10分钟。加入适量的50％乙醇水，以速度(搅拌550rpm、剪切600rpm)制湿颗粒3～5分钟。湿颗粒用摇摆式制粒机经20目筛网制粒。整粒后湿颗粒倒入Glatt沸腾流化床机，于进风温度50～60℃，物料温度50℃左右，干燥时间约8～14分钟。控制水分≤3.5％即为干燥终点。物料以20目筛网整粒，制得盐酸二甲双胍颗粒。
Figure PCTCN2019074405-appb-000014
制备工艺：
将粒径为(D 102.468，D 5021.51，D 9057.23)的泰格列净、微晶纤维素101、交联聚维酮、盐酸二甲双胍颗粒、滑石粉、微粉硅胶、硬脂酸镁加入混合机中，盖好并锁紧盖，开启多向运动混合机，混合时间为3～5分钟，混合结束后倒出料并称重，测定中间体颗粒中泰格列净和盐酸二甲双胍的含量。测总混物料的水分(≤3.5％)。
根据中间体颗粒中泰格列净和盐酸二甲双胍的含量计算片重，使用装有异型冲模的单冲压片机将中间体颗粒压片。其中，每片中含5mg泰格列 净和1000mg盐酸二甲双胍。测定质量，包装即得。
实施例7
本实施例用于说明本发明的泰格列净与盐酸二甲双胍药物组合物及其制备方法，具体详述如下：规格5mg/250mg
Figure PCTCN2019074405-appb-000015
制备工艺：
将处方量的盐酸二甲双胍与羟丙基纤维素分别过80目筛，再投入湿法制粒机料仓中，以速度(搅拌480rpm、剪切500rpm)干混5～10分钟。加入适量的30％乙醇水，以速度(搅拌480rpm、剪切500rpm)制湿颗粒3～5分钟。湿颗粒用摇摆式制粒机经20目筛网制粒。整粒后湿颗粒倒入Glatt沸腾流化床机，于进风温度50～60℃，物料温度50℃左右，干燥时间约8～14分钟。控制水分≤3.5％即为干燥终点。物料以20目筛网整粒，制得盐酸二甲双胍颗粒。
Figure PCTCN2019074405-appb-000016
制备工艺：
将粒径为(D 102.876，D 5016.67，D 9053.75)泰格列净、乳糖、交联羧甲纤维素钠、盐酸二甲双胍颗粒、滑石粉、硬脂酸镁加入混合机中，盖好并锁紧盖，开启多向运动混合机，混合时间为3～5分钟，混合结束后倒出料并称重，测定中间体颗粒中泰格列净和盐酸二甲双胍的含量。测总混物料的水分(≤3.5％)。
将中间体颗粒填充到1号胃溶型胶囊壳中，包装即得。其中，每个胶囊中含5mg泰格列净和250mg盐酸二甲双胍。
实施例8
除了以较大粒径(D 106.076，D 5026.45，D 9085.23)的泰格列净代替粒径为(D 102.876，D 5016.67，D 9053.75)的泰格列净之外，与实施例7同样地制备胶囊。
实施例9
本实施例采用本发明的制备方法制备规格为10mg/250mg的泰格列净与盐酸二甲双胍药物组合物，具体详述如下：
Figure PCTCN2019074405-appb-000017
制备工艺：
将处方量的盐酸二甲双胍与羟丙基纤维素分别过80目筛，再投入湿法制粒机料仓中，以速度(搅拌480rpm、剪切500rpm)干混5～10分钟。加入适量的30％乙醇水，以速度(搅拌480rpm、剪切500rpm)制湿颗粒3～5分钟。湿颗粒用摇摆式制粒机经20目筛网制粒。整粒后湿颗粒倒入Glatt沸腾流化床机，于进风温度50～60℃，物料温度50℃左右，干燥时间约8～14分钟。控制水分≤3.5％即为干燥终点。物料以20目筛网整粒，制得盐酸二甲双胍颗粒。
Figure PCTCN2019074405-appb-000018
制备工艺：
将粒径为(D 103.637，D 5021.24，D 9060.83)的泰格列净、乳糖、交联羧甲纤维素钠、盐酸二甲双胍颗粒、滑石粉、硬脂酸镁加入混合机中，盖好并锁紧盖，开启多向运动混合机，混合时间为3～5分钟，混合结束后倒出料并称重，测定中间体颗粒中泰格列净和盐酸二甲双胍的含量。测总混物料的水分(≤3.5％)。
将中间体颗粒填充到1号胃溶型胶囊壳中，包装即得。其中，每个胶囊中含10mg泰格列净和250mg盐酸二甲双胍。
实施例10
除了以较大粒径(D 106.076，D 5026.45，D 9085.23)的泰格列净代替粒径为(D 102.405，D 5016.38，D 9055.96)的泰格列净之外，与实施例3同样地制备片剂。
实施例11
泰格列净在不同溶液以及不同pH值缓冲液中的溶解性测定结果表明：本品在甲醇、乙腈、乙醇或乙酸乙酯中溶解，在水或0.1mol/L氢氧化钠溶液中几乎不溶，且本品溶解性不存在pH依赖。具体如下：
表1泰格列净在不同溶液中的溶解性(25℃)
溶媒 溶解度(g/100ml) 溶解性
甲醇 8.317 溶解
乙醇 8.350 溶解
乙腈 10.02 溶解
乙酸乙酯 9.990 溶解
水 0.006 几乎不溶
0.1mol/L氢氧化钠 0.005 几乎不溶
表2泰格列净在不同pH值缓冲液中的溶解性(25℃)
Figure PCTCN2019074405-appb-000019
Figure PCTCN2019074405-appb-000020
实施例12
本发明颗粒及片剂的物理性质测定
取上述实施例1-6和10的片剂以及压片前的中间体颗粒，和实施例7-9的装胶囊前的中间体颗粒，进行颗粒水分、休止角、堆密度、振实密度，以及片剂硬度、脆碎度的测定，结果见下表：
Figure PCTCN2019074405-appb-000021
实施例1-10颗粒粉体学基本一致，根据卡尔氏定律适合进行压片或装胶囊。
实施例13
对实施例1-10制备的泰格列净二甲双胍组合物，进行了有关物质测定，与单独泰格列净或盐酸二甲双胍进行比较，具体如下：
1、泰格列净二甲双胍组合物中泰格列净的测定方法
(1)溶液配制：
泰格列净对照溶液配制：精密称取泰格列净对照品25mg置50ml容量瓶中，加42％乙腈溶液溶解并稀释至刻度，制成0.5mg/ml浓度的溶液。
供试品溶液配制：分别精密称取实施例1-6和10制备的泰格列净二甲双胍片剂的片粉以及实施例7-9制备的泰格列净二甲双胍胶囊剂中的颗粒适量(含泰格列净5mg)置10ml容量瓶中，加42％乙腈溶液超声15分钟， 放置室温后稀释至刻度，摇匀，4000转/分离心5分钟，取上清液为供试品溶液。
系统适用性溶液：精密称取已知杂质对照品TY702-BN((1S)-1,5-脱水-6-脱氧-1-C-[3-[(3-苄基-4-乙氧基苯基)甲基]-4-氯-苯基]-6-脱氧-D-葡萄糖醇)约2.5mg置50ml量瓶中，加42％乙腈溶液溶解并稀释至刻度，摇匀。精密量取1ml置10ml量瓶中，另精密量取1ml泰格列净对照溶液1ml置同一10ml容量瓶中，加42％乙腈溶液溶解并稀释至刻度摇匀。
(2)泰格列净的HPLC条件：
用十八烷基硅烷键和硅胶(Waters Symmetry C18，150mm×4.6mm，5μm)为填充剂；流动相A为乙腈-水(42:58)，流动相B为乙腈，流速为每分钟1.0mL，按下表进行线性梯度洗脱；柱温为30～35℃；检测波长为210nm。
时间(分钟) 流动相A(％) 流动相B(％)
0 100 0
11 100 0
40 8.6 91.4
50 8.6 91.4
51 100 0
60 100 0
(3)泰格列净的HPLC测定：
精密量取泰格列净对照溶液、供试品溶液和系统适用性溶液各20μl，注入高效液相色谱仪，记录色谱图。按面积归一化法计算各杂质百分量。
2、泰格列净二甲双胍组合物中盐酸二甲双胍的测定方法
(1)溶液配制
盐酸二甲双胍对照溶液配制：精密称取盐酸二甲双胍50mg置10ml容量瓶中，加流动相超声5分钟溶解并稀释至刻度，摇匀。
双氰胺对照品溶液配制；精密称取双氰胺对照品10mg置100ml量瓶中，加水使溶解并稀释至刻度，摇匀。精密量取1ml置100ml量瓶中，加流动相稀释至刻度。
供试品溶液配制：分别精密称取实施例1-6和10制备的泰格列净二甲双胍片剂的片粉以及实施例7-9制备的泰格列净二甲双胍胶囊剂中的颗粒适量(含盐酸二甲双胍125mg)置25ml容量瓶中，加流动相超声15分钟， 放置室温后稀释至刻度，摇匀。4000转/分离心5分钟，取上清液为供试品溶液。
(2)盐酸二甲双胍的HPLC条件：
流动相：1.7％磷酸二氢铵溶液(用磷酸调节pH值至3.0)；流速：1mL/min；波长：218nm；柱温：30～35℃；色谱柱：用磺酸基阳离子交换键合硅胶为填充剂，UltimateXB-SCX C18 4.6mm×250mm，5μm。
(3)盐酸二甲双胍的HPLC测定：
精密量取盐酸二甲双胍对照溶液、供试品溶液和双氰胺对照品溶液各10μl，注入液相色谱仪，记录色谱图。双氰胺杂质采用对照品外标法计算，其它按面积归一化法计算各杂质百分量。具体参考中国药典2015版二部，盐酸二甲双胍项下测定。检测结果见表3～4。
表3泰格列净二甲双胍药物组合物中泰格列净有关物质测定结果(归一化法)
Figure PCTCN2019074405-appb-000022
表4泰格列净二甲双胍药物组合物中盐酸二甲双胍有关物质测定结果
Figure PCTCN2019074405-appb-000023
Figure PCTCN2019074405-appb-000024
图8～图27分别示出了本发明实施例1～10中的泰格列净二甲双胍药物组合物的泰格列净、盐酸二甲双胍有关物质测定图谱；图28～图30分别示出了泰格列净有关物质测定图谱、盐酸二甲双胍有关物质测定图谱、以及双氰胺对照品测定HPLC图谱。
实验结果表明：制备成复方制剂后各实施例中泰格列净和盐酸二甲双胍与单方的泰格列净或盐酸二甲双胍比较有关物质已知杂质和总杂未见明显增加。
实施例14
取实施例1、2、3、4、5、6、10片剂进行溶出度测定
测定色谱条件：照高效液相色谱法，用十八烷基键合硅胶为填充柱，甲醇-水(80:20)为流动相，检测波长222nm，取供试品溶液和对照品溶液分别进样20μl，理论板数按泰格列净计算不低于3000。
溶出度测定方法：
分别取实施例1、2、3、4、5、6、10的片剂，照溶出度测定法(中国药典2015版四部通则0931第二法)，以900ml的0.1mol/L盐酸溶液为溶出介质，桨法转速为50rpm，依法操作，经5、10、15、30、45、60分钟时，取溶液滤过，取续滤液作为泰格列净供试品溶液，同时补加同温等体积溶出介质；另取泰格列净对照品约14mg，精密称定，置100ml容量瓶中，加甲醇溶解并稀释至刻度，摇匀，精密移取2ml置25ml容量瓶中，加0.1mol/L盐酸溶液稀释至刻度，摇匀，作为对照品溶液。照高效液相色谱法(中国药典2015版四部通则0512)测定，取供试品溶液、对照品溶液各20μl注入高效液相色谱仪，记录色谱图，按照外标法计算。
另精密移取上述泰格列净供试品溶液，加0.1mol/L盐酸溶液稀释配制成每1ml中约含11.2μg盐酸二甲双胍的溶液作为盐酸二甲双胍的供试品溶液，另精密称取盐酸二甲双胍对照品适量，以0.1mol/L盐酸溶液溶解制 成母液，再以0.1mol/L盐酸定量稀释制成每1ml中约含11.2μg盐酸二甲双胍的溶液作为盐酸二甲双胍的对照品溶液。照紫外分光光度法(中国药典2015版四部通则0401)测定，取供试品溶液、对照品溶液分别测定吸收值，按照外标法计算。
表5泰格列净二甲双胍片中泰格列净累积溶出度比较
Figure PCTCN2019074405-appb-000025
表6泰格列净二甲双胍片中盐酸二甲双胍累积溶出度比较
Figure PCTCN2019074405-appb-000026
图4示出了本发明实施例1、2、3、4、5、6、10中的泰格列净二甲双胍药物组合物的泰格列净溶出度测定曲线；图5示出了本发明实施例1、2、3、4、5、6、10中的泰格列净二甲双胍药物组合物的盐酸二甲双胍溶出度测定曲线。
实验结果表明：由不同粒径的泰格列净制备的复方制剂中泰格列净的 溶出度有差异，盐酸二甲双胍在0.1mol/L盐酸溶液中溶出曲线较快，基本全溶出没有差异，表明泰格列净与盐酸二甲双胍的药物组合物处方工艺合理。
实施例15
取实施例7、8、9胶囊比较由不同粒径的泰格列净制备的胶囊的溶出度测定结果。
测定色谱条件：照高效液相色谱法，用十八烷基键合硅胶为填充柱，甲醇-水(80:20)为流动相，检测波长222nm，取供试品溶液和对照品溶液分别进样20μl，理论板数按泰格列净计算不低于3000。
溶出度测定方法：
分别取实施例7、8、9的胶囊，照溶出度测定法(中国药典2015版四部通则0931第一法)，以900ml的0.1mol/L盐酸溶液为溶出介质，篮法转速为50rpm，依法操作，经5、10、15、30、45、60分钟时，取溶液滤过，取续滤液作为泰格列净供试品溶液，同时补加同温等体积溶出介质；另取泰格列净对照品约14mg，精密称定，置100ml容量瓶中，加甲醇溶解并稀释至刻度，摇匀，精密移取2ml置25ml容量瓶中，加0.1mol/L盐酸溶液稀释至刻度，摇匀，作为对照品溶液。照高效液相色谱法(中国药典2015版四部通则0512)测定，取供试品溶液、对照品溶液各20μl注入高效液相色谱仪，记录色谱图，按照外标法计算。
另精密移取上述泰格列净供试品溶液，加0.1mol/L盐酸溶液稀释配制成每1ml中约含11.2μg盐酸二甲双胍的溶液作为盐酸二甲双胍的供试品溶液，另精密称取盐酸二甲双胍对照品适量，以0.1mol/L盐酸溶液溶解制成母液，再以0.1mol/L盐酸定量稀释制成每1ml中约含11.2μg盐酸二甲双胍的溶液作为盐酸二甲双胍的对照品溶液。照紫外分光光度法(中国药典2015版四部通则0401)测定，取供试品溶液、对照品溶液分别测定吸收值，按照外标法计算。
表7泰格列净二甲双胍胶囊中泰格列净累积溶出度比较
Figure PCTCN2019074405-appb-000027
Figure PCTCN2019074405-appb-000028
表8泰格列净二甲双胍胶囊中盐酸二甲双胍累积溶出度比较
Figure PCTCN2019074405-appb-000029
图6示出了本发明实施例7、8、9的由不同粒径的泰格列净制备的泰格列净二甲双胍药物组合物的泰格列净溶出度测定曲线比较；图7示出了本发明实施例7、8、9的由不同粒径的泰格列净制备的泰格列净二甲双胍药物组合物的盐酸二甲双胍溶出度测定曲线比较。
实验结果表明：泰格列净粒径不同，溶出度结果有一定的差异，对二甲双胍溶出度没有影响。实施例8泰格列净在60分钟溶出度小于90％，不能全溶出，故泰格列净控制粒径为D10≤5μm，D50≤25μm，D90≤70μm，优选D10≤3μm，D50≤20μm，D90≤55μm，从而能够保证两种活性成分的混合均一性，以及颗粒的流动性，保证全溶出度曲线在30分钟≥75％，60分钟≥90％，从而可以确保体内吸收较好。
实施例16
泰格列净粒度参照粒度分布测定法(中国药典2015年版四部通则0982第三法)进行检测。
(1)仪器：BT-9300HT型激光粒度分布仪(丹东市百特仪器有限公司)
(2)样品来源：自制样品
(3)试验方法
样品配制：取泰格列净原料药适量，用水稀释至浓度为0.5g/100ml的混悬液，搅拌使之分散均匀，待测。
测定方法：向检测池中加入蒸馏水，超声循环1分钟，校正背景，向检测池中加入适量样品溶液，使遮光率约为20％时，测定粒度分布。
表9泰格列净各批次原料药粒径分布
Figure PCTCN2019074405-appb-000030
Figure PCTCN2019074405-appb-000031
综合考虑原料粒度内控标准为：粒径D10≤5μm，D50≤25μm，D90≤70μm，均可以保证制剂的质量符合规定。优选粒径D10≤3μm，D50≤20μm，D90≤55μm。
实施例17大鼠体内糖耐量的测定
一、实验材料：
1.样品：实施例2、3、4、5、6、9，组合比例分别为5mg/250mg、5mg/500mg、10mg/500mg、5mg/850mg、5mg/1000mg、10mg/250mg
2.动物：大鼠，雄性，体重200-220g
3.试剂：葡萄糖
4.仪器：血糖仪
实验方法：
大鼠禁食16小时，测定空腹血糖，按照空腹血糖随机分组，每组4只，口服给药，泰格列净组、盐酸二甲双胍组、实施例2、3、4、5、6、9组，给药剂量分别为5、250、5+250、5+500、10+500、5+850、5+1000、10+250mg/kg，药后0.5小时口服给予葡萄糖4.5g/kg，给糖后0.5小时测定各组大鼠血糖值，计算各给药组大鼠降低血糖的抑制率，计算各处方组与泰格列净和盐酸二甲双胍组血糖抑制率的比值，判断各处方给药后降糖作用情况。
表10大鼠体内糖耐量的测定结果
Figure PCTCN2019074405-appb-000032
Figure PCTCN2019074405-appb-000033
实验结果表明：各实施例对正常大鼠葡萄糖耐量作用强度排序如下：实施例5﹥实施例3﹥实施例4﹥实施例6﹥实施例2﹥实施例9。出人意料地，实施例9与实施例2相比，盐酸二甲双胍的用量相同，泰格列净的用量由5mg增加到10mg，但血糖抑制效果却大大降低；而实施例4与实施例9相比，泰格列净的用量相同，盐酸二甲双胍的量由250mg增加到500mg，血糖抑制效果则大大提高。由此可见，在该药物组合物中，泰格列净与盐酸二甲双胍的配比对血糖抑制效果影响较大。通过进一步研究发现，当泰格列净与盐酸二甲双胍质量比为1：50～200时，具有明显的抑制血糖的协同效果；优选泰格列净与盐酸二甲双胍的质量比为1：50～170。泰格列净的优选用量为5mg～10mg，盐酸二甲双胍的优选用量为500mg～850mg。

Claims (11)

  1. 一种用于治疗糖尿病的药物组合物，其包含泰格列净和盐酸二甲双胍，其中所述泰格列净与盐酸二甲双胍的质量比为1：50～200。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述泰格列净与盐酸二甲双胍的质量比为1：50～170。
  3. 根据权利要求1或2所述的药物组合物，其特征在于，每单位制剂中，所述泰格列净的含量为2.5mg～20mg，优选为2.5mg～10mg，最优选为5mg～10mg；所述盐酸二甲双胍含量为250mg～1000mg，优选为500mg～1000mg，最优选为500mg～850mg。
  4. 根据权利要求1～3中任一项所述的药物组合物，其特征在于，所述药物组合物为口服制剂；优选地，所述口服制剂为片剂或胶囊剂；优选地，所述口服制剂是通过包括先将盐酸二甲双胍与药学上可接受的辅料一起制粒后得到盐酸二甲双胍颗粒，再将所述盐酸二甲双胍颗粒与泰格列净和另外的药学上可接受的辅料混合的步骤的方法制成。
  5. 根据权利要求4所述的药物组合物，其特征在于，所述药学上可接受的辅料选自填充剂、崩解剂、粘合剂和润滑剂中的一种或多种。
  6. 根据权利要求5所述的药物组合物，其特征在于，所述填充剂选自微晶纤维素、优化微晶纤维素和磷酸氢钙中的一种或多种；所述崩解剂选自交联聚维酮、交联羧甲基纤维素钠、羧甲基纤维素钙和低取代羟丙基纤维素中的一种或多种；所述粘合剂选自羟丙纤维素、聚维酮和羟丙甲纤维素中的一种或多种；和/或所述润滑剂选自硬脂酸镁、硬脂酸钙、山嵛酸甘油酯、硬脂富马酸钠、二氧化硅、微粉硅胶和滑石粉中的一种或多种。
  7. 一种制备根据权利要求1至6中任一项所述的药物组合物的方法，包括以下步骤：
    (1)将盐酸二甲双胍与药学上可接受的辅料混合，并通过湿法制粒工艺制备成颗粒，即得到盐酸二甲双胍颗粒；
    (2)将步骤(1)中得到的盐酸二甲双胍颗粒与泰格列净和另外的药学上可接受的辅料混合均匀，制得所述药物组合物。
  8. 根据权利要求7所述的方法，其特征在于，所述湿法制粒工艺为高剪切湿法制粒工艺和/或流化床工艺。
  9. 根据权利要求7所述的方法，其特征在于，所述盐酸二甲双胍颗粒的粒径为D90≤180μm；和/或在混合前所述泰格列净的粒径为D10≤5μm， D50≤25μm，D90≤70μm，优选D10≤3μm，D50≤20μm，D90≤55μm。
  10. 权利要求1～6中任一项所述的药物组合物在制备用于治疗II型糖尿病的药物中的用途。
  11. 一种治疗II型糖尿病的方法，包括给予需要的受试者治疗有效量的权利要求1至6中任一项所述的药物组合物。
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