WO2022104621A1 - Fixed-dose combination of sglt-2 inhibitor and angiotensin converting enzyme inhibitor, and use thereof - Google Patents

Fixed-dose combination of sglt-2 inhibitor and angiotensin converting enzyme inhibitor, and use thereof Download PDF

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Publication number
WO2022104621A1
WO2022104621A1 PCT/CN2020/129947 CN2020129947W WO2022104621A1 WO 2022104621 A1 WO2022104621 A1 WO 2022104621A1 CN 2020129947 W CN2020129947 W CN 2020129947W WO 2022104621 A1 WO2022104621 A1 WO 2022104621A1
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Prior art keywords
inhibitor
hydrate
solvate
sglt
crystal
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PCT/CN2020/129947
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French (fr)
Chinese (zh)
Inventor
贾慧娟
张加晏
石洪宇
任晓慧
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北京睿创康泰医药研究院有限公司
天津睿创康泰生物技术有限公司
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Priority to CN202080105444.5A priority Critical patent/CN116234545A/en
Priority to PCT/CN2020/129947 priority patent/WO2022104621A1/en
Publication of WO2022104621A1 publication Critical patent/WO2022104621A1/en

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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
    • A61K31/33—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to the technical field of chemical medicines, in particular to a fixed-dose composition and application of a SGLT-2 inhibitor and an angiotensin-converting enzyme inhibitor.
  • CKD Chronic kidney disease
  • CKD chronic kidney disease
  • cardiovascular and cerebrovascular diseases diabetes, and malignant tumors.
  • CKD can also lead to disability and reduced quality of life.
  • Hyperglycemia and hypertension are the main risk factors for CKD, and high fasting blood glucose is the main risk factor for CKD.
  • ACEIs angiotensin-converting enzyme inhibitors
  • Angiotensin-converting enzyme inhibitors have antihypertensive effects, can delay and reverse ventricular remodeling, prevent the further development of myocardial hypertrophy, improve vascular endothelial function and cardiac function, reduce the occurrence of arrhythmias, and improve survival. Improve prognosis.
  • Commonly used ACEIs include captopril, enalapril, benazepril, fosinopril, and ramipril.
  • ACEIs have a good therapeutic effect on hypertension. In patients with mild and moderate hypertension, ACEIs alone can control blood pressure. When the effect of single use is not good, combined diuretics can enhance the effect.
  • Renovascular hypertension is particularly efficacious to treat with ACEIs because of its high renin levels.
  • ACEIs are the first choice.
  • ACEIs can reduce the mortality of heart failure patients, improve the prognosis of congestive heart failure, prolong life, and its effect is better than other vasodilators and cardiotonic drugs.
  • ACEIs can reduce the mortality of myocardial infarction complicated by heart failure and improve hemodynamics and organ perfusion. Increased glomerular pressure can lead to damage to glomerular and renal function, and diabetic patients are often complicated by nephropathy.
  • ACEIs can improve or prevent the deterioration of renal function in both type 1 and 2 diabetes, with or without hypertension.
  • it also has certain curative effects on renal dysfunction caused by other causes, such as hypertension, glomerular nephropathy, and interstitial nephritis, and can reduce proteinuria.
  • SGLT-2 sodium-glucose cotransporter 2
  • SGLT-2 inhibitors have become a focus of attention as a unique potential oral diabetes drug.
  • SGLT-2 is a low-affinity glucose transporter that is specifically expressed in renal proximal tubules and plays an important role in renal glucose reabsorption. Therefore, specific inhibition of SGLT-2 protein can reduce proximal tubule reabsorption of glucose, promote urinary glucose excretion, lower blood glucose levels in diabetic patients, and have a series of potential advantages such as lower risk of hypoglycemia and weight loss.
  • SGLT-2 inhibitors also reduce the absorption of sodium by the kidneys, thereby achieving their blood pressure lowering effect.
  • the technical problem to be solved by the present invention is to provide a kind of SGLT-2 inhibitor of fixed dose and composition and purposes of angiotensin converting enzyme inhibitor, the SGLT-2 inhibitor of fixed dose of preparation and angiotensin
  • the compound composition of the enzyme converting enzyme inhibitor has high stability.
  • the present invention provides a fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor composition, comprising:
  • an SGLT-2 inhibitor or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
  • an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof.
  • the mass ratio of the component a) and the component b) is 800:1-1:150.
  • the mass ratio of the component a) and the component b) is 5:40-10:5.
  • the SGLT-2 inhibitor is Dapagliflozin, Canagliflozin, Empagliflozin, Ipragliflozin, Lupagliflozin ( Luseogliflozin, Tofogliflozin, Ertugliflozin, Janagliflozin, Bexagliflozin, Sotagliflozin, Henagliflozin , Tianagliflozin, Remogliflozin, Alligliflozin, Remogliflozin etabonate or Ringagliflozin ((1R,2S,3S,4R,5S) )-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol ).
  • Lupagliflozin Luseogliflo
  • the SGLT-2 inhibitor is free crystalline form of SGLT-2 inhibitor, SGLT-2 inhibitor ⁇ proline co-crystal, SGLT-2 inhibitor hydrate, SGLT-2 inhibitor ⁇ sarcosine Co-crystal or SGLT-2 inhibitor solvate hydrate.
  • the SGLT-2 inhibitor is dapagliflozin ⁇ proline co-crystal, dapagliflozin free crystalline form, dapagliflozin ⁇ sarcosine co-crystal or dapagliflozin propylene glycol hydrate .
  • the SGLT-2 inhibitor ⁇ sarcosine co-crystal is a sufficient crystal form.
  • the molar ratio of the SGLT-2 inhibitor to sarcosine is preferably 1:(0.5-5); in some specific embodiments of the present invention , the molar ratio of SGLT-2 inhibitor to sarcosine is preferably 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:0.95, 1:1.0, 1:1.05, 1:1.1, 1:1.2, 1: 1.3, 1: 1.4, 1: 1.5, 1: 1.6, 1: 1.7, 1: 1.8, 1: 1.9 or 1: 2.0; or the range value with the above ratio as the upper or lower limit; more preferably, SGLT- 2 Molar ratio of inhibitor to sarcosine 1:0.8, 1:0.9, 1:0.95, 1:1.0, 1:1.05, 1:1.1, 1:1.2 or 1:1.3, 1:1.4 or 1:1.5 .
  • the co-crystal of the SGLT-2 inhibitor and sarcosine of the present invention can be a solvate or hydrate of the co-crystal or a solvate hydrate of the co-crystal, and the co-crystal of SGLT-2 and sarcosine can pass X-rays Characterized by the diffraction angle 2 ⁇ of the characteristic diffraction peak at a specific position in the powder diffraction (XRPD) pattern, the XRPD pattern of the co-crystal of SGLT-2 inhibitor and sarcosine described in the present invention is except for the co-crystal with SGLT-2 inhibitor In addition to some of the characteristic diffraction peaks, there are also characteristic peaks at the following positions: 10.6 ⁇ 0.2°, 19.6 ⁇ 0.2°, 22.1 ⁇ 0.2°, 33.6 ⁇ 0.2°.
  • the XRPD spectrum of the dapagliflozin ⁇ sarcosine co-crystal has characteristic peaks at the following positions: 3.8 ⁇ 0.2°, 10.6 ⁇ 0.2°, 13.7 ⁇ 0.2°, 17.0 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.1 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.1 ⁇ 0.2°, 23.0 ⁇ 0.2°, 25.4 ⁇ 0.2°, 27.6 ⁇ 0.2°, 33.6 ⁇ 0.2°.
  • the dapagliflozin ⁇ sarcosine co-crystal using Cu-K ⁇ radiation and X-ray powder diffraction (XRPD) pattern represented by diffraction angle 2 ⁇ , has characteristic peaks at the following positions: 3.77 ⁇ 0.2°, 10.66 ⁇ 0.2°, 11.21 ⁇ 0.2°, 13.67 ⁇ 0.2°, 14.94 ⁇ 0.2°, 16.96 ⁇ 0.2°, 17.98 ⁇ 0.2°, 18.60 ⁇ 0.2°, 19.59 ⁇ 0.2°, 20.10 ⁇ 0.2°, 20.34 ⁇ 0.2°, and 33.62 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the melting point of the dapagliflozin ⁇ sarcosine co-crystal is about 149.0°C, which is 70°C higher than the melting point of the marketed dapagliflozin (S)-propylene glycol monohydrate.
  • S dapagliflozin
  • the present invention adopts the sarcosine co-crystal form in the preparation process, which is more convenient to simplify the preparation production process and reduce the production cost.
  • the above-mentioned SGLT-2 inhibitor ⁇ sarcosine co-crystal is prepared according to the following method:
  • the source of the SGLT-2 inhibitor is not particularly limited, and can be generally commercially available or prepared according to methods well known to those skilled in the art, and can be pure, crude or intermediate.
  • the solvent in the SGLT-2 inhibitor solution is selected from different single solvents or mixed solvents among C1-C10 alcohols, C3-C10 ketones, ethers, and nitriles.
  • the solvent is one or more of ethanol, acetone, tetrahydrofuran and acetonitrile; more preferably, ethanol.
  • the solvent of the sarcosine solution is preferably water.
  • the molar ratio of the SGLT-2 inhibitor and sarcosine is preferably 1:(0.5-5.0), more preferably 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:0.95, 1:1.0 , 1:1.05, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2.0.
  • the temperature of the standing crystallization or cooling crystallization is preferably -20°C to 40°C.
  • the crystallization temperature is preferably: -15°C to 35°C, -10°C to 30°C °C, -5°C ⁇ 30°C, 0°C ⁇ 30°C, 5°C ⁇ 30°C, 10°C ⁇ 30°C, 15°C ⁇ 30°C or 20°C ⁇ 30°C.
  • the time for standing crystallization or cooling crystallization is preferably 4-48 hours, preferably 4-24 hours, 4-16 hours, 4-12 hours, more preferably 8-12 hours.
  • the drying temperature is preferably 20°C to 80°C, more preferably 30°C to 80°C.
  • the obtained SGLT-2 inhibitor ⁇ sarcosine co-crystal may be a co-crystal solvate, a co-crystal solvate hydrate, or a co-crystal hydrate.
  • the eutectic crystal form prepared by the invention is stable, and is not affected by crystallization conditions, storage conditions and environment, and the phenomenon of crystal transformation or mixed crystal occurs.
  • the SGLT-2 inhibitor ⁇ sarcosine co-crystal prepared by the invention has no single impurity exceeding 0.1%, and the total amount of impurities is less than 0.5%.
  • the angiotensin-converting enzyme inhibitor is Captopril, Lisinopril, Enalapril, Fosinopril, Benazepril Benazepril, Ramipril, Quinapril, Perindopril, Moexipril, or Trandopril and their parent drugs Enalaprilat, Fosinoprilat, Benazeprilat, Ramiprilat, Quinaprilat, Perindopril (Perindoprilat), Moexiprilat or Trandoprilat, more preferably benazeprilat.
  • the angiotensin-converting enzyme inhibitor is benazepril hydrochloride.
  • the combined use of the SGLT-2 inhibitor and the ACEIs in the present invention can exert a synergistic effect, is used for the treatment and prevention of chronic kidney disease, and is an ideal drug for solving the unmet therapeutic needs of the clinical treatment of chronic kidney disease.
  • the current treatment options have the following disadvantages:
  • the present invention provides a fixed-dose compound preparation, comprising:
  • an SGLT-2 inhibitor or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
  • an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
  • the dose of the SGLT-2 inhibitor is 2.5 mg to 20 mg of dapagliflozin, 50 mg to 300 mg of canagliflozin, 2.5 mg to 50 mg of empagliflozin, 5 mg to 150 mg of empagliflozin, 1mg to 20mg of ggliflozin, 5mg to 50mg of topagliflozin, 2.5mg to 50mg of ipagliflozin, 5mg to 100mg of jagliflozin, 5mg to 100mg of bepagliflozin, 50mg to 800mg of soxagliflozin, Ligagliflozin 2.5 mg to 100 mg, tagagliflozin 2.5 mg to 200 mg, repagliflozin 1 mg to 200 mg, empagliflozin 2.5 mg to 200 mg, adoregliflozin 1 mg to 200 mg, or ringagliflozin 1 mg to 200 mg.
  • the dose of the angiotensin-converting enzyme inhibitor is 12.5 mg to 150 mg of captopril, 2.5 mg to 40 mg of lisinopril, 2.5 mg to 40 mg of enalapril, and 5 mg to 40 mg of fosinopril.
  • 40 mg benazepril 5 mg to 80 mg, ramipril 1.25 mg to 10 mg, quinapril 5 mg to 80 mg, perindopril 2 mg to 10 mg, moxipril 3.75 mg to 30 mg, or trandolapril 1 mg to 10 mg 10mg.
  • the mass ratio of the component a) and the component b) is 800:1-1:150.
  • the mass ratio of the component a) and the component b) is 5:40-10:5.
  • the unit dose of the component a) is 2.5-25 mg, more preferably 2.5-20 mg.
  • the unit dose of the component b) is 5-80 mg, more preferably 5-40 mg.
  • the unit dose refers to the amount of the main drug contained in the smallest unit of the drug; for example, the weight of the drug contained in one tablet, one capsule, or one bag of granules.
  • the unit of the unit dose is mg/tablet.
  • the SGLT-2 inhibitor and the angiotensin-converting enzyme inhibitor are the same as above, and will not be repeated here.
  • the adjuvant is selected from one or more of diluents, disintegrants, binders, glidants, lubricants, and flavoring agents.
  • the diluent in the combination formulation of the present invention can be one or more compounds that provide the desired dosage form, eg, tablet, volume.
  • Desirable diluents include, but are not limited to, microcrystalline cellulose, lactose, mannitol, erythritol, maltitol, sorbitol, trehalose, sucrose, white sugar, glucose, fructose, corn starch, cellulose lactose, wheat starch, One or more of dextrin, licorice powder, pregelatinized starch, partially pregelatinized starch, magnesium sulfate, calcium sulfate; further preferably one or more of microcrystalline cellulose, cellulose lactose, and partially pregelatinized starch one or more.
  • the disintegrant in the compound preparation of the present invention can be one or more compounds that can promote the disintegration of the compound preparation when it contacts an aqueous medium.
  • the disintegrants include but are not limited to corn starch, partially alpha starch, hydroxypropyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose
  • the disintegrants include but are not limited to corn starch, partially alpha starch, hydroxypropyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose
  • sodium starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone further preferably one or more of low-substituted hydroxypropyl cellulose and crospovidone one or more.
  • the binder is selected from one or more of hydroxypropyl cellulose, hypromellose, povidone, starch pulp, and sodium carboxymethyl cellulose.
  • the glidant in the compound preparation of the present invention can be one or more compounds that can reduce the friction between particles, improve the fluidity of the powder, and help reduce the weight difference, and the glidant includes but is not limited to talc One or more of powder and silica.
  • the lubricant in the compound preparation of the present invention is one or more compounds that can reduce the friction between the material and the mold wall, and ensure the smooth progress of tablet pressing, capsule filling or granule dispensing.
  • the lubricants include but are not limited to magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, talc One or more of powder and silica.
  • the moisture content in the compound preparation is less than 5%, more preferably less than 3%.
  • the dosage form of the compound preparation is tablet, granule, dry suspension, capsule or film.
  • the tablet is a double-layer tablet, a multi-layer tablet, or a chip-encapsulated tablet.
  • the technology of isolating SGLT-2 inhibitors and ACEIs can be used to avoid close contact between the two, including but not limited to double-layer tablets; multi-layer tablets; One ingredient is in the tablet core and one ingredient is in the coating; two ingredients are separately prepared into granules or one of the ingredients is prepared into granules; one ingredient is coated or two are coated separately.
  • the compound preparation can be a tablet, preferably, including:
  • angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
  • the component c) specifically includes:
  • Partially pregelatinized starch 20wt% ⁇ 50wt%;
  • the component c) specifically includes:
  • Partially pregelatinized starch 20wt% ⁇ 30wt%;
  • the component c) specifically includes:
  • the compound preparation can be a capsule, preferably, including:
  • angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
  • the component c) specifically includes:
  • the component c) specifically includes:
  • the compound preparation can be a bilayer tablet, preferably, including:
  • angiotensin-converting enzyme inhibitor 2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
  • the A layer is a tablet core, and the B layer is a coating
  • the A layer is a coating
  • the B layer is a tablet core
  • the active ingredients SGLT-2 inhibitor and ACEIs are respectively arranged on the tablet core layer and the coating layer, thereby improving the stability of the compound preparation.
  • the diluent is cellulose lactose or microcrystalline cellulose, and the content of the diluent is preferably 40wt% to 80wt%.
  • the disintegrant is crospovidone, and the content of the disintegrant is preferably 5wt% to 15wt%.
  • the glidant and lubricant are selected from silica and talc.
  • the content of the silica is preferably 1wt% to 3wt%.
  • the content of the talc powder is preferably 1wt% to 3wt%.
  • the compound preparation can be a three-layer tablet, preferably, including:
  • angiotensin-converting enzyme inhibitor 2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
  • the A layer is a tablet core, and the B layer is a coating
  • the A layer is a coating
  • the B layer is a tablet core
  • the C layer is an intermediate layer.
  • the invention isolates the active ingredient SGLT-2 inhibitor and ACEIs by adding an intermediate layer, adopts physical isolation measures to reduce the direct contact of the two ingredients, and improves the stability of the compound preparation.
  • the adjuvant of the A layer includes:
  • the adjuvant of the B layer includes:
  • the adjuvant of the C layer includes:
  • the compound preparation can be a tablet, preferably, including:
  • Component B is a compound having Component B:
  • angiotensin-converting enzyme inhibitor 2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
  • the A component is granulated, then mixed with the B component (extra part), and compressed into tablets;
  • the B-part (granular part) is granulated and then mixed with the A-part (extra part) and compressed into tablets.
  • the adjuvants for the particulate fraction preferably include:
  • the adjuvant of the additional part preferably includes:
  • the compound preparation can be a tablet, preferably, including:
  • Component B is a compound having Component B:
  • angiotensin-converting enzyme inhibitor 2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
  • the A component and the B component are separately granulated (granular part), then mixed with the C component (extra part), and compressed into tablets.
  • the adjuvants for the particulate fraction preferably include:
  • the adjuvant of the additional part preferably includes:
  • the present invention improves the stability of the tablet by granulating the two active ingredients separately, or granulating one of the active ingredients and then compressing the tablet.
  • the compound preparation can be a granule or a dry suspension, preferably, including:
  • the component c) comprises:
  • the above-mentioned fixed-dose composition or compound preparation provided by the present invention can be used for the treatment and prevention of chronic kidney disease (whether associated with diabetes or not), the treatment of diabetes with hypertension, the treatment and prevention of diabetes, the treatment of hypertension, and the treatment of hypertension.
  • chronic kidney disease With the treatment and prevention of chronic kidney disease, it can also delay the worsening of renal failure and prevent cardiovascular (CV) and renal death in patients with chronic kidney disease (CKD).
  • CV cardiovascular
  • CKD chronic kidney disease
  • the present invention provides the above-mentioned fixed-dose SGLT-2 inhibitor and angiotensin-converting-enzyme inhibitor composition, or the above-mentioned fixed-dose compound preparation, which is used for the prevention, treatment or alleviation of essential hypertension, hypertension, combined Chronic kidney disease with or without hypertension, chronic kidney disease with or without diabetes, diabetes, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, or diabetes complications and drug application in pulmonary fibrosis.
  • the present invention provides a kind of prevention, treatment or alleviation of essential hypertension, hypertension, chronic kidney disease with or without hypertension, chronic kidney disease with or without diabetes, diabetes, insulin resistance, hyperglycemia, hyperinsulinemia Symptoms, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, or diabetic complications, and pulmonary fibrosis treatment methods, including the above fixed doses of SGLT-2 inhibitors and angiotensin-converting enzyme inhibitors
  • the dosage composition, or the fixed-dose combination formulation described above, is contacted with the biological sample.
  • the present invention provides a fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor composition, comprising: a) SGLT-2 inhibitor, or a pharmaceutically acceptable salt thereof , a co-crystal, a solvate hydrate or a hydrate; b) an angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal or solvate hydrate thereof.
  • SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof
  • an angiotensin-converting enzyme inhibitor or a pharmaceutically acceptable salt, co-crystal or solvate hydrate thereof.
  • composition is convenient to carry or take, the cost of medication is relatively reduced, the risk of missing multiple doses is avoided, and the compliance of patients taking medication is improved;
  • composition has good stability, especially it is not easy to form polymer esterification impurities of carboxylic acid in the structure of ACEI (or degradation product) and hydroxyl group in the structure of SGLT-2 inhibitor;
  • compositions and uses of the fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor provided by the present invention are described in detail below with reference to the examples.
  • the embodiments provide some experiments as illustrative examples, but the content of the present invention is not limited to the embodiments.
  • the materials and reagents used in the examples are common commercially available products, and the main materials include:
  • Lactose Lactose, cellulose lactose, crospovidone, microcrystalline cellulose, silicon dioxide, magnesium stearate, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, talc. Specific embodiments are as follows.
  • Table 1 Formulation composition of unit preparation (mg/tablet, 50 tablets/batch)
  • Example 14 Mix the benazepril granules with the added part uniformly, and press into tablets.
  • Example 15 The dapagliflozin granules were uniformly mixed with the additional part, and tableted.
  • Example 16 Mix dapagliflozin granules and benazepril granules with the added part uniformly, and press into tablets.
  • the raw and auxiliary materials (shown in Table 6) are mixed evenly and bagged.
  • Example 18 benazepril hydrochloride 40 40 Dapagliflozin Propylene Glycol Hydrate 12.3 12.3 Mannitol 125 150 lactose 71.4 44.7 Sodium Stearyl Fumarate 1.3 / Hypromellose / 3 gross weight 250 250
  • Embodiment 19 ⁇ 20 The influence of moisture on preparation
  • Example 19 Example 20 benazepril hydrochloride 40 40 Dapagliflozin Propylene Glycol Hydrate 12.3 / Dapagliflozin sarcosine co-crystal / 12.1 Microcrystalline Cellulose PH102 187.7 187.9 silica 5 5 talcum powder 5 5 gross weight 250 250
  • Example 19 the combined powder was dried under reduced pressure at 45°C and the moisture content was controlled at about 3%.
  • the tablet and the reference preparation were tested for three-month stability under accelerated conditions of 40°C ⁇ 2°C/RH75% ⁇ 5%. The test results are shown in the table below:
  • Example 19 the moisture content of the total mixed powder was controlled not to exceed 3%, and the prepared tablets were placed under accelerated conditions of 40°C/RH75% for 3 months, and the growth rate of each degraded impurity and total impurity did not exceed the reference preparation Luoxin The growth rate of each degraded impurity in tin.
  • ACEI drugs dapagliflozin propylene glycol hydrate, microcrystalline cellulose, crospovidone, silicon dioxide, talc powder according to the recipe quantities (shown in Table 12), mix the materials of each layer for 8min, pass Mix 8 times with a 50-mesh sieve, and use a tablet press to compress double-layer tablets.
  • Examples 26 to 28 respectively weigh the materials according to the recipe quantities (shown in Table 13), mix the materials for each layer for 8 minutes, pass through a 50-mesh sieve and mix for 8 times, and use a tablet machine to press the double-layer tablets.
  • Embodiments 29-30 respectively weigh the materials according to the recipe quantity (shown in Table 13), mix the ACEI layer materials for 8min, pass through a 50-mesh sieve and mix 8 times, and set aside; mix the canagliflozin layer materials for 8min, pass through a 50-mesh sieve Sieve and mix 8 times, dry granulation, and set aside; use a tablet machine to press double-layer tablets.
  • Example 31 Weigh benazepril hydrochloride, dapagliflozin sarcosine co-crystal, microcrystalline cellulose PH102, partially pregelatinized starch, crospovidone, Silica and talc were mixed for 8 minutes, passed through a 50-mesh sieve 8 times, and the powder was directly compressed into tablets.
  • Example 32 Weigh benazepril hydrochloride, dapagliflozin sarcosine co-crystal, microcrystalline cellulose PH102, crospovidone, silicon dioxide, talc powder according to the recipe quantity (shown in Table 14) and mix 8min, pass through a 50-mesh sieve 8 times, and the powder is directly loaded into capsules.
  • Example 33 According to the recipe quantity (shown in Table 14), the materials of layer A and layer B were weighed, and the materials of each layer were mixed for 8 minutes respectively, passed through a 50-mesh sieve and mixed for 8 times, and a tableting machine was used to press the double-layer tablet.

Abstract

Provided are a fixed-dose combination of an SGLT-2 inhibitor and an angiotensin converting enzyme (ACEI) inhibitor, and the use thereof. The combination comprises: a) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, a co-crystal, a solvate hydrate or a hydrate thereof; and b) an angiotensin converting enzyme inhibitor, or a pharmaceutically acceptable salt, a co-crystal or a solvate hydrate thereof. The combination is convenient to carry or take, the medication cost is relatively reduced, the risk of overdose or missed medication is avoided, and the medication compliance of patients is improved; the stability is good, especially in terms of it not being easy for polymeric esterified impurities of carboxylic acid in an ACEI (or a degradation product) structure and hydroxy in an SGLT-2 inhibitor structure to form; the probability and safety risk of drug interaction is reduced; and the synergistic effect can be better exerted.

Description

固定剂量的SGLT-2抑制剂与血管紧张素转化酶抑制剂的组合物及用途Composition and use of fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor 技术领域technical field
本发明涉及化学药物技术领域，尤其涉及一种固定剂量的SGLT-2抑制剂与血管紧张素转化酶抑制剂的组合物及用途。The invention relates to the technical field of chemical medicines, in particular to a fixed-dose composition and application of a SGLT-2 inhibitor and an angiotensin-converting enzyme inhibitor.
背景技术Background technique
慢性肾脏病(CKD)的发病率高、知晓率低、预后差、医疗费用高等特点已经成为继心脑血管疾病、糖尿病、恶性肿瘤后又一严重危害人类健康的疾病。CKD除了导致大量的死亡以外，还会导致患者残疾，生活质量下降。高血糖、高血压是CKD的主要危险因素，而空腹血糖高是CKD的主要危险因素。Chronic kidney disease (CKD) is characterized by high incidence, low awareness, poor prognosis, and high medical costs. It has become another disease that seriously endangers human health after cardiovascular and cerebrovascular diseases, diabetes, and malignant tumors. In addition to causing a large number of deaths, CKD can also lead to disability and reduced quality of life. Hyperglycemia and hypertension are the main risk factors for CKD, and high fasting blood glucose is the main risk factor for CKD.
目前针对慢性肾脏疾病，主要的防治目标为：At present, the main goals of prevention and treatment for chronic kidney disease are:
(1)延缓肾脏损坏的进展速度；(1) Delay the progression of kidney damage;
(2)预防心血管并发症的发生；(2) Prevent the occurrence of cardiovascular complications;
(3)预防其他并发症的发生，如肾性骨病、贫血等；(3) Prevent the occurrence of other complications, such as renal bone disease, anemia, etc.;
(4)提高患者的生存率和生存质量，提高社会复归率。(4) Improve the survival rate and quality of life of patients, and improve the social reversion rate.
基于上述防治目标，高血压和糖尿病肾病进展的重要危险因素，血糖和血压越高，肾病进展的风险越高。保护肾脏、控制血糖、降低血压以及最大限度地减少蛋白尿是CKD患者的主要治疗目标。针对这一目标，血管紧张素转化酶抑制剂(ACEIs)是目前证据最多的治疗药物，其对肾脏的保护作用贯穿于CKD发生、发展的始终。Based on the above prevention and control goals, hypertension and diabetic nephropathy progression are important risk factors, and the higher the blood glucose and blood pressure, the higher the risk of nephropathy progression. Protecting the kidneys, controlling blood sugar, lowering blood pressure, and minimizing proteinuria are the main goals of treatment in patients with CKD. Aiming at this goal, angiotensin-converting enzyme inhibitors (ACEIs) are the therapeutic drugs with the most evidence at present, and their protective effects on the kidneys run through the occurrence and development of CKD.
血管紧张素转化酶抑制剂(ACEIs)具有降压作用，可以延缓和逆转心室重构，阻止心肌肥厚的进一步发展，改善血管内皮功能和心功能，减少心律失常的发生，还能提高生存率，改善预后。临床上常用的ACEIs有卡托普利、依那普利、贝那普利、福辛普利、雷米普利等。ACEIs对高血压的治疗效果好，轻、中度高血压患者单用ACEIs即可控制血压，单用效果不好时，合用利尿药可增强疗效。肾血管性高血压因其肾素水平高，用ACEIs治疗特别有效。对伴有心衰或糖尿病、肾病的高血压患者，ACEIs为首选药。ACEIs能降低心衰患者的死亡率，改善充血性心力衰竭预后，延长寿命，其效果优于其他血管舒张药和强心药。ACEIs能降低心肌梗死并发心衰的病死率，改善血流动力学 和器官灌流。因肾小球囊内压升高可导致肾小球与肾功能损伤，糖尿病患者常并发肾脏病变。ACEIs对1型和2型糖尿病，无论有无高血压均能改善或阻止肾功能的恶化。除多囊肾外，对其他原因引起的肾功能障碍如高血压、肾小球肾病、间质性肾炎等也有一定疗效，且能减轻蛋白尿。Angiotensin-converting enzyme inhibitors (ACEIs) have antihypertensive effects, can delay and reverse ventricular remodeling, prevent the further development of myocardial hypertrophy, improve vascular endothelial function and cardiac function, reduce the occurrence of arrhythmias, and improve survival. Improve prognosis. Commonly used ACEIs include captopril, enalapril, benazepril, fosinopril, and ramipril. ACEIs have a good therapeutic effect on hypertension. In patients with mild and moderate hypertension, ACEIs alone can control blood pressure. When the effect of single use is not good, combined diuretics can enhance the effect. Renovascular hypertension is particularly efficacious to treat with ACEIs because of its high renin levels. For hypertensive patients with heart failure or diabetes and kidney disease, ACEIs are the first choice. ACEIs can reduce the mortality of heart failure patients, improve the prognosis of congestive heart failure, prolong life, and its effect is better than other vasodilators and cardiotonic drugs. ACEIs can reduce the mortality of myocardial infarction complicated by heart failure and improve hemodynamics and organ perfusion. Increased glomerular pressure can lead to damage to glomerular and renal function, and diabetic patients are often complicated by nephropathy. ACEIs can improve or prevent the deterioration of renal function in both type 1 and 2 diabetes, with or without hypertension. In addition to polycystic kidney disease, it also has certain curative effects on renal dysfunction caused by other causes, such as hypertension, glomerular nephropathy, and interstitial nephritis, and can reduce proteinuria.
近年来，钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂作为一种独具潜力的糖尿病口服药已成为关注热点。SGLT-2是一种低亲和力的葡萄糖转运蛋白，其特异性表达于肾脏近端小管，并在肾脏对葡萄糖的重吸收作用中扮演着重要角色。因而，特异性抑制SGLT-2蛋白能够减少近端小管对葡萄糖的重吸收，促进尿葡萄糖排泄，降低糖尿病患者的血糖水平，并具有较低的低血糖风险和减轻体重等一系列潜在优势。SGLT-2抑制剂除减少肾脏对葡萄糖的重吸收外，也减少了肾脏对钠的吸收，从而实现其降血压的作用。In recent years, sodium-glucose cotransporter 2 (SGLT-2) inhibitors have become a focus of attention as a unique potential oral diabetes drug. SGLT-2 is a low-affinity glucose transporter that is specifically expressed in renal proximal tubules and plays an important role in renal glucose reabsorption. Therefore, specific inhibition of SGLT-2 protein can reduce proximal tubule reabsorption of glucose, promote urinary glucose excretion, lower blood glucose levels in diabetic patients, and have a series of potential advantages such as lower risk of hypoglycemia and weight loss. In addition to reducing the reabsorption of glucose by the kidneys, SGLT-2 inhibitors also reduce the absorption of sodium by the kidneys, thereby achieving their blood pressure lowering effect.
发明内容SUMMARY OF THE INVENTION
有鉴于此，本发明要解决的技术问题在于提供一种固定剂量的SGLT-2抑制剂与血管紧张素转化酶抑制剂的组合物及用途，制备的固定剂量的SGLT-2抑制剂和血管紧张素转化酶抑制剂的复方组合物具有较高的稳定性。In view of this, the technical problem to be solved by the present invention is to provide a kind of SGLT-2 inhibitor of fixed dose and composition and purposes of angiotensin converting enzyme inhibitor, the SGLT-2 inhibitor of fixed dose of preparation and angiotensin The compound composition of the enzyme converting enzyme inhibitor has high stability.
为达到上述目的，本发明提供了一种固定剂量的SGLT-2抑制剂和血管紧张素转化酶抑制剂组合物，包括：To achieve the above object, the present invention provides a fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor composition, comprising:
a)SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；a) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
b)血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、水合物或溶剂化物水合物。b) an angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof.
本发明优选的，所述组分a)和组分b)的质量比为800:1-1:150。Preferably, the mass ratio of the component a) and the component b) is 800:1-1:150.
更优选的，所述组分a)和组分b)的质量比为5:40-10:5。More preferably, the mass ratio of the component a) and the component b) is 5:40-10:5.
本发明优选的，所述SGLT-2抑制剂为达格列净(Dapagliflozin)、坎格列净(Canagliflozin)、恩格列净(Empagliflozin)、依格列净(Ipragliflozin)、鲁格列净(Luseogliflozin)、托格列净(Tofogliflozin)、埃格列净(Ertugliflozin)、加格列净(Janagliflozin)、贝格列净(Bexagliflozin)、索格列净(Sotagliflozin)、恒格列净(Henagliflozin)、泰格列净(Tianagliflozin)、瑞格列净(Remogliflozin)、艾格列净(Alligliflozin)、依碳酸瑞格列净(Remogliflozin etabonate)或荣格 列净((1R,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol)。Preferably, the SGLT-2 inhibitor is Dapagliflozin, Canagliflozin, Empagliflozin, Ipragliflozin, Lupagliflozin ( Luseogliflozin, Tofogliflozin, Ertugliflozin, Janagliflozin, Bexagliflozin, Sotagliflozin, Henagliflozin , Tianagliflozin, Remogliflozin, Alligliflozin, Remogliflozin etabonate or Ringagliflozin ((1R,2S,3S,4R,5S) )-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol ).
优选的，所述SGLT-2抑制剂为SGLT-2抑制剂游离体晶型、SGLT-2抑制剂·脯氨酸共晶体、SGLT-2抑制剂水合物、SGLT-2抑制剂·肌氨酸共晶体或SGLT-2抑制剂溶剂化物水合物。Preferably, the SGLT-2 inhibitor is free crystalline form of SGLT-2 inhibitor, SGLT-2 inhibitor·proline co-crystal, SGLT-2 inhibitor hydrate, SGLT-2 inhibitor·sarcosine Co-crystal or SGLT-2 inhibitor solvate hydrate.
更优选的，所述SGLT-2抑制剂为达格列净·脯氨酸共晶体，达格列净游离体晶型、达格列净·肌氨酸共晶体或达格列净丙二醇水合物。More preferably, the SGLT-2 inhibitor is dapagliflozin·proline co-crystal, dapagliflozin free crystalline form, dapagliflozin·sarcosine co-crystal or dapagliflozin propylene glycol hydrate .
本发明中，所述SGLT-2抑制剂·肌氨酸共晶体是一种充分的结晶形态。In the present invention, the SGLT-2 inhibitor·sarcosine co-crystal is a sufficient crystal form.
本发明中，所述SGLT-2抑制剂·肌氨酸共晶体中，SGLT-2抑制剂与肌氨酸的摩尔比优选为1：(0.5～5)；在本发明的一些具体实施例中，SGLT-2抑制剂与肌氨酸摩尔比优选为1：0.6、1：0.7、1：0.8、1：0.9、1：0.95、1：1.0、1：1.05、1：1.1、1：1.2、1：1.3、1：1.4、1：1.5、1：1.6、1：1.7、1：1.8、1：1.9或1：2.0；或者以上述比例为上限或下限的范围值；进一步优选的，SGLT-2抑制剂与肌氨酸的摩尔比为1：0.8、1：0.9、1：0.95、1：1.0、1：1.05、1：1.1、1：1.2或1：1.3、1：1.4或1：1.5。In the present invention, in the SGLT-2 inhibitor-sarcosine co-crystal, the molar ratio of the SGLT-2 inhibitor to sarcosine is preferably 1:(0.5-5); in some specific embodiments of the present invention , the molar ratio of SGLT-2 inhibitor to sarcosine is preferably 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:0.95, 1:1.0, 1:1.05, 1:1.1, 1:1.2, 1: 1.3, 1: 1.4, 1: 1.5, 1: 1.6, 1: 1.7, 1: 1.8, 1: 1.9 or 1: 2.0; or the range value with the above ratio as the upper or lower limit; more preferably, SGLT- 2 Molar ratio of inhibitor to sarcosine 1:0.8, 1:0.9, 1:0.95, 1:1.0, 1:1.05, 1:1.1, 1:1.2 or 1:1.3, 1:1.4 or 1:1.5 .
本发明所述SGLT-2抑制剂与肌氨酸共晶体，可以是共晶体的溶剂化物或水合物或共晶体的溶剂化物水合物，SGLT-2与肌氨酸的共晶体可通过X-射线粉末衍射(XRPD)图谱中在特定位置的特征衍射峰的衍射角2θ来表征，本发明所述SGLT-2抑制剂与肌氨酸共晶体的XRPD谱图中除具有SGLT-2抑制剂共晶部分的特征衍射峰外，还在以下位置有特征峰：10.6±0.2°、19.6±0.2°、22.1±0.2°、33.6±0.2°。The co-crystal of the SGLT-2 inhibitor and sarcosine of the present invention can be a solvate or hydrate of the co-crystal or a solvate hydrate of the co-crystal, and the co-crystal of SGLT-2 and sarcosine can pass X-rays Characterized by the diffraction angle 2θ of the characteristic diffraction peak at a specific position in the powder diffraction (XRPD) pattern, the XRPD pattern of the co-crystal of SGLT-2 inhibitor and sarcosine described in the present invention is except for the co-crystal with SGLT-2 inhibitor In addition to some of the characteristic diffraction peaks, there are also characteristic peaks at the following positions: 10.6±0.2°, 19.6±0.2°, 22.1±0.2°, 33.6±0.2°.
在本发明的一些具体实施例中，所述达格列净·肌氨酸共晶体的XRPD谱图在以下位置具有特征峰：3.8±0.2°、10.6±0.2°、13.7±0.2°、17.0±0.2°、18.0±0.2°、18.6±0.2°、19.6±0.2°、20.1±0.2°、21.4±0.2°、22.1±0.2°、23.0±0.2°、25.4±0.2°、27.6±0.2°、33.6±0.2°。In some specific embodiments of the present invention, the XRPD spectrum of the dapagliflozin·sarcosine co-crystal has characteristic peaks at the following positions: 3.8±0.2°, 10.6±0.2°, 13.7±0.2°, 17.0± 0.2°, 18.0±0.2°, 18.6±0.2°, 19.6±0.2°, 20.1±0.2°, 21.4±0.2°, 22.1±0.2°, 23.0±0.2°, 25.4±0.2°, 27.6±0.2°, 33.6± 0.2°.
进一步优选的，所述达格列净·肌氨酸共晶体，使用Cu-Kɑ辐射以衍射角2θ表示的X-射线粉末衍射(XRPD)图谱，在以下位置具有特征峰：3.77±0.2°、10.66±0.2°、11.21±0.2°、13.67±0.2°、14.94±0.2°、16.96±0.2°、17.98±0.2°、18.60±0.2°、19.59±0.2°、20.10±0.2°、20.34±0.2°、21.40±0.2°、22.10±0.2°、 22.46±0.2°、22.96±0.2°、24.87±0.2°、25.22±0.2°、25.48±0.2°、26.23±0.2°、27.61±0.2°、28.48±0.2°及33.62±0.2°。Further preferably, the dapagliflozin·sarcosine co-crystal, using Cu-Kɑ radiation and X-ray powder diffraction (XRPD) pattern represented by diffraction angle 2θ, has characteristic peaks at the following positions: 3.77±0.2°, 10.66±0.2°, 11.21±0.2°, 13.67±0.2°, 14.94±0.2°, 16.96±0.2°, 17.98±0.2°, 18.60±0.2°, 19.59±0.2°, 20.10±0.2°, 20.34±0.2°, and 33.62±0.2°.
所述达格列净·肌氨酸共晶的熔点大约在149.0℃，高于已上市的达格列净(S)-丙二醇一水合物的熔点70℃，合适的熔点使得制剂在片剂制粒、压片过程中，不易熔融、聚团，导致粘冲或均匀度不合格，本发明在制剂过程中采用肌氨酸共晶体形式，更便于简化制剂生产工艺，降低生产成本。The melting point of the dapagliflozin·sarcosine co-crystal is about 149.0°C, which is 70°C higher than the melting point of the marketed dapagliflozin (S)-propylene glycol monohydrate. In the process of granulation and tabletting, it is not easy to melt and agglomerate, resulting in sticking or unqualified uniformity. The present invention adopts the sarcosine co-crystal form in the preparation process, which is more convenient to simplify the preparation production process and reduce the production cost.
本发明优选的，上述SGLT-2抑制剂·肌氨酸共晶体按照以下方法制备：Preferably in the present invention, the above-mentioned SGLT-2 inhibitor·sarcosine co-crystal is prepared according to the following method:
将SGLT-2抑制剂的溶液和肌氨酸的溶液混合，静置析晶或降温析晶，固液分离，得到SGLT-2抑制剂·肌氨酸共晶体。Mix the solution of SGLT-2 inhibitor and the solution of sarcosine, stand for crystallization or cool down for crystallization, and separate solid and liquid to obtain SGLT-2 inhibitor and sarcosine co-crystal.
本发明中，对所述SGLT-2抑制剂的来源并无特殊限定，可以为一般市售或按照本领域技术人员熟知的方法制备，可以为纯品，也可以为粗品或中间体。In the present invention, the source of the SGLT-2 inhibitor is not particularly limited, and can be generally commercially available or prepared according to methods well known to those skilled in the art, and can be pure, crude or intermediate.
本发明优选的，所述SGLT-2抑制剂溶液中的溶剂选自C1-C10醇类、C3-C10酮类、醚类、腈类中的不同单一溶剂或混合溶剂。进一步优选的，所述溶剂为乙醇、丙酮、四氢呋喃和乙腈中的一种或多种；进一步优选为乙醇。Preferably in the present invention, the solvent in the SGLT-2 inhibitor solution is selected from different single solvents or mixed solvents among C1-C10 alcohols, C3-C10 ketones, ethers, and nitriles. Further preferably, the solvent is one or more of ethanol, acetone, tetrahydrofuran and acetonitrile; more preferably, ethanol.
所述肌氨酸溶液的溶剂优选为水。The solvent of the sarcosine solution is preferably water.
所述SGLT-2抑制剂和肌氨酸的摩尔比优选为1：(0.5～5.0)，进一步优选为1：0.6、1：0.7、1：0.8、1：0.9、1：0.95、1：1.0、1：1.05、1：1.1、1：1.2、1：1.3、1：1.4、1：1.5、1：1.6、1：1.7、1：1.8、1：1.9或1：2.0。The molar ratio of the SGLT-2 inhibitor and sarcosine is preferably 1:(0.5-5.0), more preferably 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:0.95, 1:1.0 , 1:1.05, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2.0.
本发明优选的，所述静置析晶或降温析晶的温度优选为-20℃～40℃，在一些实施例中，析晶温度优选为：-15℃～35℃、-10℃～30℃、-5℃～30℃、0℃～30℃、5℃～30℃、10℃～30℃、15℃～30℃或20℃～30℃。Preferably, the temperature of the standing crystallization or cooling crystallization is preferably -20°C to 40°C. In some embodiments, the crystallization temperature is preferably: -15°C to 35°C, -10°C to 30°C ℃, -5℃～30℃, 0℃～30℃, 5℃～30℃, 10℃～30℃, 15℃～30℃ or 20℃～30℃.
本发明优选的，所述静置析晶或降温析晶的时间优选为4-48小时，优选4-24小时，4-16小时，4-12小时，更优选8-12小时。Preferably in the present invention, the time for standing crystallization or cooling crystallization is preferably 4-48 hours, preferably 4-24 hours, 4-16 hours, 4-12 hours, more preferably 8-12 hours.
本发明中，得到SGLT-2抑制剂·肌氨酸共晶体后，优选对其进行干燥处理，所述干燥的温度优选为20℃～80℃，进一步优选为30℃～80℃。In the present invention, after the SGLT-2 inhibitor-sarcosine co-crystal is obtained, it is preferably subjected to drying treatment, and the drying temperature is preferably 20°C to 80°C, more preferably 30°C to 80°C.
所得到的SGLT-2抑制剂·肌氨酸共晶体可以为共晶体的溶剂化物、共晶体的溶剂化物水合物或共晶体的水合物。The obtained SGLT-2 inhibitor·sarcosine co-crystal may be a co-crystal solvate, a co-crystal solvate hydrate, or a co-crystal hydrate.
本发明所制得的共晶体晶型稳定，不受析晶条件影响或贮藏条件、环境影响而出现转晶或混晶现象。The eutectic crystal form prepared by the invention is stable, and is not affected by crystallization conditions, storage conditions and environment, and the phenomenon of crystal transformation or mixed crystal occurs.
本发明制备得到的SGLT-2抑制剂·肌氨酸共晶体中无超过0.1％的单个杂质，杂质总量小于0.5％。The SGLT-2 inhibitor·sarcosine co-crystal prepared by the invention has no single impurity exceeding 0.1%, and the total amount of impurities is less than 0.5%.
本发明优选的，所述血管紧张素转化酶抑制剂为卡托普利(Captopril)、赖诺普利(Lisinopril)、依那普利(Enalapril)、福辛普利(Fosinopril)、贝那普利(Benazepril)、雷米普利(Ramipril)、喹那普利(Quinapril)、培哚普利(Perindopril)、莫西普利(Moexipril)或群多普利(Trandopril)以及上述药物的母体药物依那普利拉(Enalaprilat)、福辛普利拉(Fosinoprilat)、贝那普利拉(Benazeprilat)、雷米普利拉(Ramiprilat)、喹那普利拉(Quinaprilat)、培哚普利拉(Perindoprilat)、莫西普利拉(Moexiprilat)或群多普利拉(Trandoprilat),更优选为贝那普利。Preferably in the present invention, the angiotensin-converting enzyme inhibitor is Captopril, Lisinopril, Enalapril, Fosinopril, Benazepril Benazepril, Ramipril, Quinapril, Perindopril, Moexipril, or Trandopril and their parent drugs Enalaprilat, Fosinoprilat, Benazeprilat, Ramiprilat, Quinaprilat, Perindopril (Perindoprilat), Moexiprilat or Trandoprilat, more preferably benazeprilat.
在本发明的一些具体实施例中，所述血管紧张素转化酶抑制剂为盐酸贝那普利。In some specific embodiments of the present invention, the angiotensin-converting enzyme inhibitor is benazepril hydrochloride.
本发明将SGLT-2抑制剂与ACEIs联合使用可发挥协同作用，用于慢性肾脏病的治疗和预防，是解决临床上慢性肾病治疗未满足治疗需求的理想药物。但目前的治疗方案存在如下缺点：The combined use of the SGLT-2 inhibitor and the ACEIs in the present invention can exert a synergistic effect, is used for the treatment and prevention of chronic kidney disease, and is an ideal drug for solving the unmet therapeutic needs of the clinical treatment of chronic kidney disease. However, the current treatment options have the following disadvantages:
(1)患者需分别服用ACEIs与SGLT-2抑制剂的单方制剂，顺应性差；(1) Patients need to take single preparations of ACEIs and SGLT-2 inhibitors respectively, and the compliance is poor;
(2)ACEIs产品稳定性不好，同SGLT-2抑制剂做成复方制剂，稳定性更差；(2) The stability of ACEIs products is not good, and they are made into compound preparations with SGLT-2 inhibitors, and the stability is even worse;
(3)很多慢性肾脏疾病患者同时患有其他疾病，多种药物分别服用单方制剂会大大增加药物相互作用的概率和风险，存在很大的安全隐患。(3) Many patients with chronic kidney disease suffer from other diseases at the same time. Taking a single preparation of multiple drugs will greatly increase the probability and risk of drug interaction, and there are great potential safety hazards.
基于此，本发明提供了一种固定剂量复方制剂，包括：Based on this, the present invention provides a fixed-dose compound preparation, comprising:
a)SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；a) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
b)血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、水合物或溶剂化物水合物；b) an angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
c)药学上可接受的辅剂。c) pharmaceutically acceptable adjuvants.
本发明优选的，所述SGLT-2抑制剂的剂量为达格列净2.5mg至20mg、坎格列净50mg至300mg、恩格列净2.5mg至50mg、依格列净5mg至150mg、鲁格列净1mg至20mg、托格列净5mg至50mg、埃格列净2.5mg至50mg、加格列净5mg至100mg、贝格列净5mg至100mg、索格列净50mg至800mg、 恒格列净2.5mg至100mg、泰格列净2.5mg至200mg、瑞格列净1mg至200mg、艾格列净2.5mg至200mg、依碳酸瑞格列净1mg至200mg或者荣格列净1mg至200mg。Preferably in the present invention, the dose of the SGLT-2 inhibitor is 2.5 mg to 20 mg of dapagliflozin, 50 mg to 300 mg of canagliflozin, 2.5 mg to 50 mg of empagliflozin, 5 mg to 150 mg of empagliflozin, 1mg to 20mg of ggliflozin, 5mg to 50mg of topagliflozin, 2.5mg to 50mg of ipagliflozin, 5mg to 100mg of jagliflozin, 5mg to 100mg of bepagliflozin, 50mg to 800mg of soxagliflozin, Ligagliflozin 2.5 mg to 100 mg, tagagliflozin 2.5 mg to 200 mg, repagliflozin 1 mg to 200 mg, empagliflozin 2.5 mg to 200 mg, etapagliflozin 1 mg to 200 mg, or ringagliflozin 1 mg to 200 mg.
本发明优选的，所述血管紧张素转化酶抑制剂的剂量为卡托普利12.5mg至150mg、赖诺普利2.5mg至40mg、依那普利2.5mg至40mg、福辛普利5mg至40mg、贝那普利5mg至80mg、雷米普利1.25mg至10mg、喹那普利5mg至80mg、培哚普利2mg至10mg、莫西普利3.75mg至30mg或者群多普利1mg至10mg。Preferably in the present invention, the dose of the angiotensin-converting enzyme inhibitor is 12.5 mg to 150 mg of captopril, 2.5 mg to 40 mg of lisinopril, 2.5 mg to 40 mg of enalapril, and 5 mg to 40 mg of fosinopril. 40 mg, benazepril 5 mg to 80 mg, ramipril 1.25 mg to 10 mg, quinapril 5 mg to 80 mg, perindopril 2 mg to 10 mg, moxipril 3.75 mg to 30 mg, or trandolapril 1 mg to 10 mg 10mg.
本发明优选的，所述组分a)和组分b)的质量比为800:1-1:150。Preferably, the mass ratio of the component a) and the component b) is 800:1-1:150.
更优选的，所述组分a)和组分b)的质量比为5:40-10:5。More preferably, the mass ratio of the component a) and the component b) is 5:40-10:5.
本发明优选的，所述组分a)的单位剂量为2.5～25mg，更优选为2.5～20mg。Preferably, the unit dose of the component a) is 2.5-25 mg, more preferably 2.5-20 mg.
本发明优选的，所述组分b)的单位剂量为5～80mg，更优选为5～40mg。Preferably in the present invention, the unit dose of the component b) is 5-80 mg, more preferably 5-40 mg.
本发明中，所述单位剂量指药品最小单元所含主药的量；如一片，一颗胶囊，一袋颗粒中所含的药品的重量。例如，当所述复方制剂为片剂时，所述单位剂量的单位是mg/片。In the present invention, the unit dose refers to the amount of the main drug contained in the smallest unit of the drug; for example, the weight of the drug contained in one tablet, one capsule, or one bag of granules. For example, when the combination preparation is a tablet, the unit of the unit dose is mg/tablet.
所述SGLT-2抑制剂、血管紧张素转化酶抑制剂同上，在此不再赘述。The SGLT-2 inhibitor and the angiotensin-converting enzyme inhibitor are the same as above, and will not be repeated here.
本发明优选的，所述辅剂选自稀释剂、崩解剂、粘合剂、助流剂、润滑剂、矫味剂中的一种或多种。Preferably in the present invention, the adjuvant is selected from one or more of diluents, disintegrants, binders, glidants, lubricants, and flavoring agents.
本发明复方制剂中的稀释剂可以是一种或多种能提供获得期望的剂型，(如片剂)体积的化合物。理想的稀释剂包含但不限于微晶纤维素、乳糖、甘露醇、赤藓醇、麦芽糖醇、山梨糖醇、海藻糖、蔗糖、白糖、葡萄糖、果糖、玉米淀粉、纤维素乳糖、小麦淀粉、糊精、甘草粉末、预胶化淀粉、部分预胶化淀粉、硫酸镁、硫酸钙中的一种或多种；进一步优选为微晶纤维素、纤维素乳糖、部分预胶化淀粉中的一种或多种。The diluent in the combination formulation of the present invention can be one or more compounds that provide the desired dosage form, eg, tablet, volume. Desirable diluents include, but are not limited to, microcrystalline cellulose, lactose, mannitol, erythritol, maltitol, sorbitol, trehalose, sucrose, white sugar, glucose, fructose, corn starch, cellulose lactose, wheat starch, One or more of dextrin, licorice powder, pregelatinized starch, partially pregelatinized starch, magnesium sulfate, calcium sulfate; further preferably one or more of microcrystalline cellulose, cellulose lactose, and partially pregelatinized starch one or more.
本发明复方制剂中的崩解剂可以是能促进复方制剂与水介质接触时崩解的一种或多种化合物。The disintegrant in the compound preparation of the present invention can be one or more compounds that can promote the disintegration of the compound preparation when it contacts an aqueous medium.
本发明优选的，所述崩解剂包含但不限于玉米淀粉、部分α化淀粉、羟丙基淀粉、羧甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交聚维酮中的一种或多种；进一 步优选为低取代羟丙基纤维素、交聚维酮中的一种或多种。Preferably in the present invention, the disintegrants include but are not limited to corn starch, partially alpha starch, hydroxypropyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose One or more of sodium starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone; further preferably one or more of low-substituted hydroxypropyl cellulose and crospovidone one or more.
本发明优选的，所述粘合剂选自羟丙纤维素、羟丙甲纤维素、聚维酮、淀粉浆、羧甲纤维素钠中的一种或多种。Preferably in the present invention, the binder is selected from one or more of hydroxypropyl cellulose, hypromellose, povidone, starch pulp, and sodium carboxymethyl cellulose.
本发明复方制剂中的助流剂可以是能降低颗粒之间的摩擦力，改善粉体流动性，有助于减少重量差异的一种或多种化合物，所述助流剂包括但不限于滑石粉、二氧化硅中的一种或多种。The glidant in the compound preparation of the present invention can be one or more compounds that can reduce the friction between particles, improve the fluidity of the powder, and help reduce the weight difference, and the glidant includes but is not limited to talc One or more of powder and silica.
本发明复方制剂中的润滑剂是可以降低物料与模壁之间的摩擦力，保证压片推片、胶囊灌装或颗粒分装顺利进行的一种或多种化合物。所述润滑剂包括但不限于硬脂酸镁、硬脂酸、硬脂酸钙、硬脂富马酸钠、聚乙二醇、氢化植物油、聚乙二醇、十二烷基硫酸钠、滑石粉、二氧化硅中的一种或多种。The lubricant in the compound preparation of the present invention is one or more compounds that can reduce the friction between the material and the mold wall, and ensure the smooth progress of tablet pressing, capsule filling or granule dispensing. The lubricants include but are not limited to magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, talc One or more of powder and silica.
本发明优选的，所述复方制剂中的水分含量低于5％，更优选低于3％。Preferably in the present invention, the moisture content in the compound preparation is less than 5%, more preferably less than 3%.
本发明优选的，所述复方制剂的剂型为片剂、颗粒剂、干混悬剂、胶囊剂或膜剂。Preferably in the present invention, the dosage form of the compound preparation is tablet, granule, dry suspension, capsule or film.
进一步优选的，所述片剂为双层片、多层片、包芯片。Further preferably, the tablet is a double-layer tablet, a multi-layer tablet, or a chip-encapsulated tablet.
为提高所述复方制剂的稳定性，本发明优选的，可以采用隔离SGLT-2抑制剂、ACEIs的技术，避免二者的紧密接触，包括但不限于双层片；多层片；包芯片；一种成分在片芯一种成分在包衣；两种成分分别制备颗粒或其中一种成分制备颗粒；将其一成分包衣或两种分别包衣。In order to improve the stability of the compound preparation, it is preferred in the present invention that the technology of isolating SGLT-2 inhibitors and ACEIs can be used to avoid close contact between the two, including but not limited to double-layer tablets; multi-layer tablets; One ingredient is in the tablet core and one ingredient is in the coating; two ingredients are separately prepared into granules or one of the ingredients is prepared into granules; one ingredient is coated or two are coated separately.
具体的，所述复方制剂可以为片剂，优选的，包括：Specifically, the compound preparation can be a tablet, preferably, including:
a)2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体溶剂化物、、溶剂化物水合物或水合物；a) 2wt% to 60wt% of SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal solvate, solvate hydrate or hydrate thereof;
b)2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；b) 2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
c)10wt％～90wt％的稀释剂；c) 10wt%～90wt% diluent;
0～20wt％的崩解剂；0～20wt% disintegrant;
0～2wt％的助流剂；0～2wt% of glidant;
0～3wt％的润滑剂。0-3wt% lubricant.
在本发明的一些具体实施例中，所述组分c)具体包括：In some specific embodiments of the present invention, the component c) specifically includes:
微晶纤维素PH102 40wt％～60wt％；Microcrystalline cellulose PH102 40wt%～60wt%;
部分预胶化淀粉 20wt％～50wt％；Partially pregelatinized starch 20wt%～50wt%;
二氧化硅 1wt％～2wt％；Silica 1wt%～2wt%;
滑石粉 1wt％～2wt％。Talc 1wt%～2wt%.
在本发明的一些具体实施例中，所述组分c)具体包括：In some specific embodiments of the present invention, the component c) specifically includes:
纤维素乳糖 40wt％～60wt％；Cellulose lactose 40wt%～60wt%;
部分预胶化淀粉 20wt％～30wt％；Partially pregelatinized starch 20wt%～30wt%;
交聚维酮 3wt％～8wt％；Crospovidone 3wt%～8wt%;
二氧化硅 1wt％～2wt％；Silica 1wt%～2wt%;
滑石粉 1wt％～2wt％。Talc 1wt%～2wt%.
在本发明的一些具体实施例中，所述组分c)具体包括：In some specific embodiments of the present invention, the component c) specifically includes:
纤维素乳糖 50wt％～70wt％；Cellulose lactose 50wt%～70wt%;
交聚维酮 5wt％～15wt％；Crospovidone 5wt%～15wt%;
二氧化硅 1wt％～2wt％；Silica 1wt%～2wt%;
滑石粉 1wt％～2wt％。Talc 1wt%～2wt%.
本发明中，所述复方制剂可以为胶囊剂，优选的，包括：In the present invention, the compound preparation can be a capsule, preferably, including:
a)2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；a) 2wt% to 60wt% of SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
b)2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、水合物或溶剂化物水合物；b) 2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
c)10wt％～90wt％的稀释剂；c) 10wt%～90wt% diluent;
0～20wt％的崩解剂；0～20wt% disintegrant;
0～2wt％的助流剂；0～2wt% of glidant;
0～3wt％的润滑剂。0-3wt% lubricant.
在本发明的一些具体实施例中，所述组分c)具体包括：In some specific embodiments of the present invention, the component c) specifically includes:
微晶纤维素PH102 50wt％～70wt％；Microcrystalline cellulose PH102 50wt%～70wt%;
交聚维酮 0～15wt％；Crospovidone 0～15wt%;
二氧化硅 1wt％～2wt％；Silica 1wt%～2wt%;
滑石粉 1wt％～2wt％。Talc 1wt%～2wt%.
在本发明的一些具体实施例中，所述组分c)具体包括：In some specific embodiments of the present invention, the component c) specifically includes:
纤维素乳糖 50wt％～70wt％；Cellulose lactose 50wt%～70wt%;
交聚维酮 0～15wt％；Crospovidone 0～15wt%;
二氧化硅 1wt％～2wt％；Silica 1wt%～2wt%;
滑石粉 1wt％～2wt％。Talc 1wt%～2wt%.
本发明中，所述复方制剂可以为双层片剂，优选的，包括：In the present invention, the compound preparation can be a bilayer tablet, preferably, including:
A层：Floor A:
2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；2wt% to 60wt% of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
50wt％～80wt％的稀释剂50wt%～80wt% diluent
5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
B层：Layer B:
2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、水合物或溶剂化物水合物；2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
50wt％～80wt％的稀释剂50wt%～80wt% diluent
5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
所述A层为片芯，B层为包衣；The A layer is a tablet core, and the B layer is a coating;
或者所述A层为包衣，B层为片芯。Or the A layer is a coating, and the B layer is a tablet core.
本发明将有效成分SGLT-2抑制剂和ACEIs分别设置于片芯层和包衣层，提高了所述复方制剂的稳定性。In the present invention, the active ingredients SGLT-2 inhibitor and ACEIs are respectively arranged on the tablet core layer and the coating layer, thereby improving the stability of the compound preparation.
本发明优选的，所述稀释剂为纤维素乳糖或微晶纤维素，所述稀释剂的含量优选为40wt％～80wt％。Preferably in the present invention, the diluent is cellulose lactose or microcrystalline cellulose, and the content of the diluent is preferably 40wt% to 80wt%.
本发明优选的，所述崩解剂为交聚维酮，所述崩解剂的含量优选为5wt％～15wt％。Preferably in the present invention, the disintegrant is crospovidone, and the content of the disintegrant is preferably 5wt% to 15wt%.
本发明优选的，所述助流剂和润滑剂选自二氧化硅和滑石粉。Preferably in the present invention, the glidant and lubricant are selected from silica and talc.
所述二氧化硅的含量优选为1wt％～3wt％。The content of the silica is preferably 1wt% to 3wt%.
所述滑石粉的含量优选为1wt％～3wt％。The content of the talc powder is preferably 1wt% to 3wt%.
本发明中，所述复方制剂可以为三层片剂，优选的，包括：In the present invention, the compound preparation can be a three-layer tablet, preferably, including:
A层：Floor A:
2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；2wt% to 60wt% of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
50wt％～80wt％的稀释剂50wt%～80wt% diluent
5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
B层：Layer B:
2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、水合物或溶剂化物水合物；2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
50wt％～80wt％的稀释剂50wt%～80wt% diluent
5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
C层：Layer C:
50wt％～80wt％的稀释剂50wt%～80wt% diluent
0～10wt％的崩解剂；0～10wt% disintegrant;
0～3wt％的助流剂；0～3wt% of glidant;
0～3wt％的润滑剂；0～3wt% lubricant;
所述A层为片芯，B层为包衣；The A layer is a tablet core, and the B layer is a coating;
或者所述A层为包衣，B层为片芯；Or the A layer is a coating, and the B layer is a tablet core;
所述C层为中间层。The C layer is an intermediate layer.
本发明通过添加中间层，将有效成分SGLT-2抑制剂和ACEIs进行隔离，采用物理隔离措施减少两种成分的直接接触，提高了复方制剂的稳定性。The invention isolates the active ingredient SGLT-2 inhibitor and ACEIs by adding an intermediate layer, adopts physical isolation measures to reduce the direct contact of the two ingredients, and improves the stability of the compound preparation.
本发明优选的，所述A层的辅剂包括：Preferably in the present invention, the adjuvant of the A layer includes:
纤维素乳糖 40wt％～80wt％；Cellulose lactose 40wt%～80wt%;
交聚维酮 6wt％～9wt％；Crospovidone 6wt%～9wt%;
二氧化硅 1wt％～2wt％；Silica 1wt%～2wt%;
滑石粉 1wt％～2wt％。Talc 1wt%～2wt%.
本发明优选的，所述B层的辅剂包括：Preferably in the present invention, the adjuvant of the B layer includes:
纤维素乳糖 40wt％～80wt％；Cellulose lactose 40wt%～80wt%;
交聚维酮 6wt％～9wt％；Crospovidone 6wt%～9wt%;
二氧化硅 1wt％～2wt％；Silica 1wt%～2wt%;
滑石粉 1wt％～2wt％。Talc 1wt%～2wt%.
本发明优选的，所述C层的辅剂包括：Preferably in the present invention, the adjuvant of the C layer includes:
纤维素乳糖 40wt％～80wt％；Cellulose lactose 40wt%～80wt%;
二氧化硅 1wt％～2wt％；Silica 1wt%～2wt%;
滑石粉 1wt％～2wt％。Talc 1wt%～2wt%.
本发明中，所述复方制剂可以为片剂，优选的，包括：In the present invention, the compound preparation can be a tablet, preferably, including:
A组分：A component:
2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；2wt% to 60wt% of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
50wt％～80wt％的稀释剂50wt%～80wt% diluent
5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
B组分：Component B:
2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、水合物或溶剂化物水合物；2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
50wt％～80wt％的稀释剂50wt%～80wt% diluent
5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
所述A组分(颗粒部分)经制粒，然后与B组分(外加部分)混合，压片；The A component (particulate part) is granulated, then mixed with the B component (extra part), and compressed into tablets;
或者所述B组分(颗粒部分)经制粒，然后与A组分(外加部分)混合， 压片。Alternatively, the B-part (granular part) is granulated and then mixed with the A-part (extra part) and compressed into tablets.
所述颗粒部分的辅剂优选包括：The adjuvants for the particulate fraction preferably include:
微晶纤维素PH101 50wt％～85wt％；Microcrystalline cellulose PH101 50wt%～85wt%;
交聚维酮 5wt％～15wt％；Crospovidone 5wt%～15wt%;
羟丙纤维素 0～4wt％。Hypromellose 0～4wt%.
所述外加部分的辅剂优选包括：The adjuvant of the additional part preferably includes:
微晶纤维素PH102 30wt％～70wt％；Microcrystalline cellulose PH102 30wt%～70wt%;
交聚维酮 5wt％～15wt％；Crospovidone 5wt%～15wt%;
二氧化硅 3wt％～10wt％；Silica 3wt%～10wt%;
滑石粉 3wt％～10wt％。Talc powder 3wt%～10wt%.
本发明中，所述复方制剂可以为片剂，优选的，包括：In the present invention, the compound preparation can be a tablet, preferably, including:
A组分：A component:
2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；2wt% to 60wt% of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
50wt％～80wt％的稀释剂50wt%～80wt% diluent
5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
B组分：Component B:
2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、水合物或溶剂化物水合物；2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
50wt％～80wt％的稀释剂50wt%～80wt% diluent
5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
C组分：Component C:
50wt％～80wt％的稀释剂50wt%～80wt% diluent
0～10wt％的崩解剂；0～10wt% disintegrant;
0～3wt％的助流剂；0～3wt% of glidant;
0～3wt％的润滑剂；0～3wt% lubricant;
所述A组分、B组分分别制粒(颗粒部分)，然后与C组分(外加部分)混合，压片。The A component and the B component are separately granulated (granular part), then mixed with the C component (extra part), and compressed into tablets.
所述颗粒部分的辅剂优选包括：The adjuvants for the particulate fraction preferably include:
微晶纤维素PH101 50wt％～85wt％；Microcrystalline cellulose PH101 50wt%～85wt%;
交聚维酮 5wt％～15wt％；Crospovidone 5wt%～15wt%;
羟丙纤维素 0～4wt％。Hypromellose 0～4wt%.
所述外加部分的辅剂优选包括：The adjuvant of the additional part preferably includes:
微晶纤维素PH102 30wt％～70wt％；Microcrystalline cellulose PH102 30wt%～70wt%;
交聚维酮 5wt％～15wt％；Crospovidone 5wt%～15wt%;
二氧化硅 3wt％～10wt％；Silica 3wt%～10wt%;
滑石粉 3wt％～10wt％。Talc powder 3wt%～10wt%.
本发明通过将两种有效成分分别制粒，或将其中一种有效成分制粒，然后压片，提高了片剂的稳定性。The present invention improves the stability of the tablet by granulating the two active ingredients separately, or granulating one of the active ingredients and then compressing the tablet.
本发明中，所述复方制剂可以为颗粒剂或干混悬剂，优选的，包括：In the present invention, the compound preparation can be a granule or a dry suspension, preferably, including:
a)2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物水合物或水合物；a) 2wt% to 60wt% of SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate hydrate or hydrate thereof;
b)2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体或溶剂化物水合物；b) 2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal or solvate hydrate thereof;
c)10wt％～90wt％的稀释剂；c) 10wt%～90wt% diluent;
0～20wt％的崩解剂；0～20wt% disintegrant;
0～2wt％的助流剂；0～2wt% of glidant;
0～3wt％的润滑剂。0-3wt% lubricant.
本发明优选的，所述组分c)包括：Preferably in the present invention, the component c) comprises:
甘露醇 40wt％～70wt％；Mannitol 40wt%～70wt%;
乳糖 10wt％～30wt％；Lactose 10wt%～30wt%;
硬脂富马酸钠或羟丙纤维素 0.3wt％～1.5wt％。Sodium stearyl fumarate or hydroxypropyl cellulose 0.3wt%～1.5wt%.
本发明提供的上述固定剂量的组合物或复方制剂，可用于慢性肾脏疾病(无论是否伴有糖尿病)的治疗及预防、糖尿病伴高血压治疗、糖尿病的治疗 及预防、高血压的治疗、高血压伴慢性肾病的治疗及预防、还可延缓慢性肾脏病(CKD)患者肾功能衰竭恶化以及预防心血管(CV)和肾脏死亡。The above-mentioned fixed-dose composition or compound preparation provided by the present invention can be used for the treatment and prevention of chronic kidney disease (whether associated with diabetes or not), the treatment of diabetes with hypertension, the treatment and prevention of diabetes, the treatment of hypertension, and the treatment of hypertension. With the treatment and prevention of chronic kidney disease, it can also delay the worsening of renal failure and prevent cardiovascular (CV) and renal death in patients with chronic kidney disease (CKD).
本发明提供了上述固定剂量的SGLT-2抑制剂和血管紧张素转化酶抑制剂组合物，或上述固定剂量复方制剂，在制备用于预防、治疗或减轻原发性高血压、高血压、合并或不合并高血压的慢性肾病、合并或不合并糖尿病的慢性肾病、糖尿病、胰岛素抵抗、高血糖、高胰岛素血症、脂肪酸或甘油的升高的血含量、高脂血、血脂障碍、肥胖、或糖尿病并发症以及肺纤维化的药物中的应用。The present invention provides the above-mentioned fixed-dose SGLT-2 inhibitor and angiotensin-converting-enzyme inhibitor composition, or the above-mentioned fixed-dose compound preparation, which is used for the prevention, treatment or alleviation of essential hypertension, hypertension, combined Chronic kidney disease with or without hypertension, chronic kidney disease with or without diabetes, diabetes, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, or diabetes complications and drug application in pulmonary fibrosis.
本发明提供了一种预防、治疗或减轻原发性高血压、高血压、合并或不合并高血压的慢性肾病、合并或不合并糖尿病的慢性肾病、糖尿病、胰岛素抵抗、高血糖、高胰岛素血症、脂肪酸或甘油的升高的血含量、高脂血、血脂障碍、肥胖、或糖尿病并发症及肺纤维化治疗方法，包括将上述固定剂量的SGLT-2抑制剂和血管紧张素转化酶抑制剂组合物，或上述固定剂量复方制剂，与生物样本接触。The present invention provides a kind of prevention, treatment or alleviation of essential hypertension, hypertension, chronic kidney disease with or without hypertension, chronic kidney disease with or without diabetes, diabetes, insulin resistance, hyperglycemia, hyperinsulinemia Symptoms, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, or diabetic complications, and pulmonary fibrosis treatment methods, including the above fixed doses of SGLT-2 inhibitors and angiotensin-converting enzyme inhibitors The dosage composition, or the fixed-dose combination formulation described above, is contacted with the biological sample.
与现有技术相比，本发明提供了一种固定剂量的SGLT-2抑制剂和血管紧张素转化酶抑制剂组合物，包括：a)SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物水合物或水合物；b)血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体或溶剂化物水合物。本发明提供的上述组合物具有以下有益效果：Compared with the prior art, the present invention provides a fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor composition, comprising: a) SGLT-2 inhibitor, or a pharmaceutically acceptable salt thereof , a co-crystal, a solvate hydrate or a hydrate; b) an angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal or solvate hydrate thereof. The above-mentioned composition provided by the present invention has the following beneficial effects:
1、所述组合物携带或服用方便，用药成本相对降低，避免了多服漏服的风险，改善了患者服药的顺应性；1. The composition is convenient to carry or take, the cost of medication is relatively reduced, the risk of missing multiple doses is avoided, and the compliance of patients taking medication is improved;
2、所述组合物稳定性好，特别是不易形成ACEI(或降解物)结构中羧酸与SGLT-2抑制剂结构中羟基的聚合酯化杂质；2. The composition has good stability, especially it is not easy to form polymer esterification impurities of carboxylic acid in the structure of ACEI (or degradation product) and hydroxyl group in the structure of SGLT-2 inhibitor;
3、很多慢性肾脏疾病患者同时患有其他疾病，多种药物分别服用单方制剂会大大增加药物相互作用的概率和风险，存在很大的安全隐患，本发明降低了药物相互作用发生的概率和安全风险；3. Many patients with chronic kidney disease suffer from other diseases at the same time. Taking a single preparation of multiple drugs will greatly increase the probability and risk of drug interaction, and there is a great potential safety hazard. The present invention reduces the probability and safety of drug interaction. risk;
4、ACEIs和SGLT-2做成固定剂量复方制剂后，便于更好地发挥其协同作用。4. After ACEIs and SGLT-2 are made into a fixed-dose compound preparation, it is convenient to exert their synergistic effect better.
具体实施方式Detailed ways
为了进一步说明本发明，下面结合实施例对本发明提供的固定剂量的SGLT-2抑制剂与血管紧张素转化酶抑制剂的组合物及用途进行详细描述。In order to further illustrate the present invention, the compositions and uses of the fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor provided by the present invention are described in detail below with reference to the examples.
申请人在研究过程中通过大量试验、筛选和验证确定本发明的技术方案。为了说明本发明的特点和优点，实施例提供了部分试验作为说明示例，但本发明内容并不局限于实施例。实施例中使用的材料和试剂均为普通市售产品，主要材料包括：In the research process, the applicant has determined the technical solution of the present invention through a large number of tests, screening and verification. In order to illustrate the features and advantages of the present invention, the embodiments provide some experiments as illustrative examples, but the content of the present invention is not limited to the embodiments. The materials and reagents used in the examples are common commercially available products, and the main materials include:
乳糖、纤维素乳糖、交聚维酮、微晶纤维素、二氧化硅、硬脂酸镁、低取代羟丙纤维素、部分预胶化淀粉、滑石粉。具体实施方案如下。Lactose, cellulose lactose, crospovidone, microcrystalline cellulose, silicon dioxide, magnesium stearate, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, talc. Specific embodiments are as follows.
以上实施例除非特殊注明，否则用前均采用50℃减压干燥至水分低于3.0％。Unless otherwise specified, the above examples were all dried under reduced pressure at 50° C. to a moisture content of less than 3.0% before use.
实施例1～5 单层片剂Examples 1-5 Monolayer Tablets
制备工艺：Preparation Process:
按处方量(表1所示)称取盐酸贝那普利、达格列净丙二醇水合物/肌氨酸共晶、微晶纤维素PH102、部分预胶化淀粉、纤维素乳糖、交联聚维酮、二氧化硅、滑石粉混合8min，过50目筛8次，粉末直接压片。Weigh benazepril hydrochloride, dapagliflozin propylene glycol hydrate/sarcosine co-crystal, microcrystalline cellulose PH102, partially pregelatinized starch, cellulose lactose, cross-linked polymer Vidone, silicon dioxide, and talc were mixed for 8 minutes, passed through a 50-mesh sieve for 8 times, and the powder was directly compressed into tablets.
溶出试验Dissolution test
pH 1.0盐酸溶液500ml，桨法，温度：37℃，转速：60rpm。实施例1-5样品中盐酸贝那普利、达格列净在15min溶出度均＞85％，同各自单方制剂的参比制剂洛汀新、安达唐溶出行为一致。具体溶出度结果如表5所示。pH 1.0 hydrochloric acid solution 500ml, paddle method, temperature: 37°C, rotating speed: 60rpm. The dissolution rates of benazepril hydrochloride and dapagliflozin in the samples of Examples 1-5 were all >85% in 15 minutes, which were consistent with the dissolution behaviors of the reference preparations Lotingxin and Andatang of their respective single preparations. The specific dissolution results are shown in Table 5.
表1 单位制剂处方组成(mg/片，50片/批)Table 1 Formulation composition of unit preparation (mg/tablet, 50 tablets/batch)
Figure PCTCN2020129947-appb-000001
Figure PCTCN2020129947-appb-000001
Figure PCTCN2020129947-appb-000002
Figure PCTCN2020129947-appb-000002
实施例6～实施例9 胶囊剂Example 6 to Example 9 Capsules
制备工艺：Preparation Process:
按处方量(表2所示)称取盐酸贝那普利、达格列净丙二醇水合物/肌氨酸共晶、微晶纤维素PH102、纤维素乳糖、交联聚维酮、二氧化硅、滑石粉混合8min，过50目筛8次，粉末直接装胶囊。Weigh benazepril hydrochloride, dapagliflozin propylene glycol hydrate/sarcosine co-crystal, microcrystalline cellulose PH102, cellulose lactose, crospovidone, silicon dioxide according to the prescription amount (shown in Table 2). , Mix talcum powder for 8 minutes, pass through a 50-mesh sieve 8 times, and directly pack the powder into capsules.
溶出结果：Dissolution Results:
pH 1.0盐酸溶液500ml，桨法，温度：37℃，转速：60rpm。实施例6-9样品中盐酸贝那普利、达格列净在15min溶出度均＞85％，同各自单方制剂的参比制剂洛汀新、安达唐溶出行为一致。具体溶出度结果如表5所示。pH 1.0 hydrochloric acid solution 500ml, paddle method, temperature: 37°C, rotating speed: 60rpm. The dissolution rates of benazepril hydrochloride and dapagliflozin in the samples of Examples 6-9 were all >85% in 15 minutes, which were consistent with the dissolution behaviors of the reference preparations Luotingxin and Andatang of their respective single preparations. The specific dissolution results are shown in Table 5.
表2 单位制剂处方组成(mg/粒，50粒/批)Table 2 Formulation composition of unit preparation (mg/grain, 50 grains/batch)
Figure PCTCN2020129947-appb-000003
Figure PCTCN2020129947-appb-000003
Figure PCTCN2020129947-appb-000004
Figure PCTCN2020129947-appb-000004
实施例10Example 10
按处方量(表3所示)分别称取A层和B层物料，将各层物料分别混合8min，过50目筛混合8次，采用压片机压制双层片。Weigh the materials of layer A and layer B respectively according to the recipe quantity (shown in Table 3), mix the materials of each layer for 8 minutes, pass through a 50-mesh sieve and mix 8 times, and press the double-layer tablet by a tablet machine.
实施例11Example 11
按处方量(表3所示)分别称取A层和B层物料，将各层物料分别混合8min，过50目筛混合8次，将B层物料干法制粒，所得颗粒与A层混粉，采用压片机压制双层片。Weigh the materials of layer A and layer B respectively according to the recipe quantity (shown in Table 3), mix the materials of each layer for 8 minutes, pass through a 50-mesh sieve and mix 8 times, dry granulate the materials of layer B, and mix the obtained granules with the powder of layer A. , using a tablet press to press double-layer tablets.
实施例12Example 12
按处方量(表3所示)分别称取A层和B层物料，将各层物料分别混合8min，过50目筛混合8次，采用压片机压制双层片。Weigh the materials of layer A and layer B respectively according to the recipe quantity (shown in Table 3), mix the materials of each layer for 8 minutes, pass through a 50-mesh sieve and mix 8 times, and press the double-layer tablet by a tablet machine.
实施例13Example 13
按处方量(表3所示)分别称取A层、B层、C层物料，将各层物料分别混合8min，过50目筛混合8次，采用压片机压制三层片(C层为中间层)。Weigh the materials of layer A, layer B, and layer C respectively according to the recipe quantity (shown in Table 3), mix the materials of each layer for 8 minutes, pass through a 50-mesh sieve and mix 8 times, and use a tablet machine to press the three-layer tablet (layer C is middle layer).
溶出结果：Dissolution Results:
pH1.0盐酸溶液500ml，桨法，温度：37℃，转速：60rpm。实施例10-13样品中盐酸贝那普利、达格列净在15min溶出度均＞85％，同各自单方制剂的参比制剂洛汀新、安达唐溶出行为一致。具体溶出度结果如表5所示。pH1.0 hydrochloric acid solution 500ml, paddle method, temperature: 37°C, rotation speed: 60rpm. The dissolution rates of benazepril hydrochloride and dapagliflozin in the samples of Examples 10-13 were all >85% in 15 minutes, which were consistent with the dissolution behaviors of the reference preparations Lotingxin and Andatang of their respective single preparations. The specific dissolution results are shown in Table 5.
表3 单位制剂处方组成(mg/片，50片/批)Table 3 Formulation composition of unit preparation (mg/tablet, 50 tablets/batch)
Figure PCTCN2020129947-appb-000005
Figure PCTCN2020129947-appb-000005
Figure PCTCN2020129947-appb-000006
Figure PCTCN2020129947-appb-000006
实施例14～16 单层片Examples 14-16 Monolayer sheet
制备工艺：Preparation Process:
按处方量(表4所示)分别称取原辅料，将羟丙纤维素加水溶解作为粘合剂，将含盐酸贝那普利的颗粒部分的除羟丙纤维素外的物料混合，加入羟丙纤维素溶液制颗粒，过30目筛制粒，50℃下干燥至水分≤2.0％，取出，过24目 筛整粒，得贝那普利颗粒，备用。将含达格列净丙二醇水合物的颗粒部分物料混合均匀，干法制粒，得达格列净颗粒，备用。Weigh the raw and auxiliary materials according to the recipe quantity (shown in Table 4), dissolve the hydroxypropyl cellulose in water as a binder, mix the materials except the hydroxypropyl cellulose in the granular part containing benazepril hydrochloride, add the hydroxypropyl cellulose The propyl cellulose solution was granulated, passed through a 30-mesh sieve to granulate, dried at 50° C. to a moisture content of ≤2.0%, taken out, and granulated through a 24-mesh sieve to obtain benazepril granules for use. Mix the granular material containing dapagliflozin propylene glycol hydrate evenly, and dry granulate to obtain dapagliflozin granules for use.
实施例14：将贝那普利颗粒同外加部分混合均匀，压片。Example 14: Mix the benazepril granules with the added part uniformly, and press into tablets.
实施例15：将达格列净颗粒同外加部分混合均匀，压片。Example 15: The dapagliflozin granules were uniformly mixed with the additional part, and tableted.
实施例16：将达格列净颗粒、贝那普利颗粒同外加部分混合均匀，压片。Example 16: Mix dapagliflozin granules and benazepril granules with the added part uniformly, and press into tablets.
溶出结果：Dissolution Results:
pH 1.0盐酸溶液500ml，桨法，温度：37℃，转速：60rpm。实施例14-16样品中盐酸贝那普利、达格列净在15min溶出度均＞85％，同各自单方制剂的参比制剂洛汀新、安达唐溶出行为一致。具体溶出度结果如表5所示。pH 1.0 hydrochloric acid solution 500ml, paddle method, temperature: 37°C, rotating speed: 60rpm. In the samples of Examples 14-16, the dissolution rates of benazepril hydrochloride and dapagliflozin in 15 minutes were all >85%, which were consistent with the dissolution behaviors of the reference preparations Luotingxin and Andatang of their respective single preparations. The specific dissolution results are shown in Table 5.
表4 单位制剂处方组成(mg/片，50片/批)Table 4 Formulation composition of unit preparation (mg/tablet, 50 tablets/batch)
Figure PCTCN2020129947-appb-000007
Figure PCTCN2020129947-appb-000007
Figure PCTCN2020129947-appb-000008
Figure PCTCN2020129947-appb-000008
表5 实施例1-16及参比制剂洛汀新和安达唐15min溶出度结果Table 5 Example 1-16 and reference preparations Lottin and Ada Tang 15min dissolution results
Figure PCTCN2020129947-appb-000009
Figure PCTCN2020129947-appb-000009
由表5可以看出，以上各实施例的15分钟的溶出均大于85％，与参比制剂溶出一致。It can be seen from Table 5 that the dissolution in 15 minutes of each of the above examples is greater than 85%, which is consistent with the dissolution of the reference preparation.
实施例17 颗粒剂Example 17 Granules
将原辅料(表6所示)混合均匀，装袋，即得。The raw and auxiliary materials (shown in Table 6) are mixed evenly and bagged.
实施例18 干混悬剂Example 18 Dry Suspension
按处方量分别称取原辅料(表6所示)，将羟丙纤维素加水溶解作为粘合剂，将其余物料混合，加入羟丙纤维素溶液制颗粒，过14目筛制粒，50℃下干燥至水分≤2.0％，取出，过12目筛和50目筛整粒，得颗粒。Weigh the raw and auxiliary materials (shown in Table 6) according to the recipe, dissolve the hydroxypropyl cellulose in water as a binder, mix the remaining materials, add the hydroxypropyl cellulose solution to make granules, pass through a 14-mesh sieve and granulate at 50°C It is dried to a moisture content of ≤2.0%, taken out, sieved through a 12-mesh sieve and a 50-mesh sieve and granulated to obtain granules.
表6 单位制剂处方组成(mg/袋，50袋/批)Table 6 Formulation composition of unit preparation (mg/bag, 50 bags/batch)
组分component 实施例17Example 17 实施例18Example 18
盐酸贝那普利benazepril hydrochloride 4040 4040
达格列净丙二醇水合物Dapagliflozin Propylene Glycol Hydrate 12.312.3 12.312.3
甘露醇Mannitol 125125 150150
乳糖lactose 71.471.4 44.744.7
硬脂富马酸钠Sodium Stearyl Fumarate 1.31.3 //
羟丙纤维素Hypromellose // 33
总重gross weight 250250 250250
稳定性考察Stability investigation
将实施例1-18和参比制剂放50℃考察10天，采用HPLC法分别检测盐酸贝那普利和达格列净有关物质，结果如下表7所示。The examples 1-18 and the reference preparation were placed at 50°C for 10 days, and the HPLC method was used to detect the related substances of benazepril hydrochloride and dapagliflozin respectively. The results are shown in Table 7 below.
表7 实施例1-18有关物质测定结果(50℃，％)Table 7 Measurement results of related substances in Examples 1-18 (50°C, %)
Figure PCTCN2020129947-appb-000010
Figure PCTCN2020129947-appb-000010
Figure PCTCN2020129947-appb-000011
Figure PCTCN2020129947-appb-000011
Figure PCTCN2020129947-appb-000012
Figure PCTCN2020129947-appb-000012
Figure PCTCN2020129947-appb-000013
Figure PCTCN2020129947-appb-000013
根据表7的有关物质结果可以看出，本发明提供的复方制剂稳定性较好，特别是将二主药隔离更有助于稳定性提高。According to the related substance results in Table 7, it can be seen that the compound preparation provided by the present invention has better stability, and especially the isolation of the two main drugs is more conducive to improving the stability.
实施例19～20 水分对制剂的影响Embodiment 19～20 The influence of moisture on preparation
制备工艺：Preparation Process:
采用未干燥处理的原辅料，按处方量(表8所示)称取盐酸贝那普利、达格列净丙二醇水合物/肌氨酸共晶、微晶纤维素PH102、二氧化硅、滑石粉混合8min，过50目筛8次，将以上混粉采用45℃减压干燥不同时间，以获得不同水分的混粉，混粉含水量如表9所示，将混粉压片。Using undried raw and auxiliary materials, weigh benazepril hydrochloride, dapagliflozin propylene glycol hydrate/sarcosine co-crystal, microcrystalline cellulose PH102, silicon dioxide, talc according to the recipe quantity (shown in Table 8). The powder was mixed for 8 minutes, passed through a 50-mesh sieve for 8 times, and the above mixed powder was dried under reduced pressure at 45°C for different times to obtain mixed powder with different moisture.
溶出试验：Dissolution Test:
pH1.0盐酸溶液500ml，桨法，温度：37℃，转速：60rpm。实施例19、20样品中盐酸贝那普利、达格列净在15min溶出度结果见下表9所示。pH1.0 hydrochloric acid solution 500ml, paddle method, temperature: 37°C, rotation speed: 60rpm. The dissolution results of benazepril hydrochloride and dapagliflozin in the samples of Examples 19 and 20 at 15 min are shown in Table 9 below.
表8 单位制剂处方组成(mg/片，20片/批)Table 8 Composition of unit preparation formulation (mg/tablet, 20 tablets/batch)
组分component 实施例19Example 19 实施例20Example 20
盐酸贝那普利benazepril hydrochloride 4040 4040
达格列净丙二醇水合物Dapagliflozin Propylene Glycol Hydrate 12.312.3 //
达格列净肌氨酸共晶Dapagliflozin sarcosine co-crystal // 12.112.1
微晶纤维素PH102Microcrystalline Cellulose PH102 187.7187.7 187.9187.9
二氧化硅silica 55 55
滑石粉talcum powder 55 55
总重gross weight 250250 250250
表9 单位制剂处方组成(mg/片，20片/批)Table 9 Formulation composition of unit preparation (mg/tablet, 20 tablets/batch)
Figure PCTCN2020129947-appb-000014
Figure PCTCN2020129947-appb-000014
Figure PCTCN2020129947-appb-000015
Figure PCTCN2020129947-appb-000015
由以上表9所示结果可知，水分对制剂中盐酸贝那普利和达格列净的溶出影响不大。From the results shown in Table 9 above, it can be seen that moisture has little effect on the dissolution of benazepril hydrochloride and dapagliflozin in the preparation.
将实施例19、20制备的片剂置于50℃条件下考察10天，采用HPLC法分别检测盐酸贝那普利和达格列净有关物质，结果如下表10所示。The tablets prepared in Examples 19 and 20 were placed under the condition of 50°C for 10 days, and the related substances of benazepril hydrochloride and dapagliflozin were detected by HPLC method respectively. The results are shown in Table 10 below.
表10 单位制剂处方组成(mg/片，20片/批)Table 10 Formulation composition of unit preparation (mg/tablet, 20 tablets/batch)
Figure PCTCN2020129947-appb-000016
Figure PCTCN2020129947-appb-000016
Figure PCTCN2020129947-appb-000017
Figure PCTCN2020129947-appb-000017
由表10的数据可以看出，水分对制剂稳定性影响较大，制剂的水分含量需控制在5％以内，最优在3％以内。It can be seen from the data in Table 10 that moisture has a great influence on the stability of the formulation, and the moisture content of the formulation needs to be controlled within 5%, and the optimum is within 3%.
实施例19、20中总混粉经45℃减压干燥将水分控制在3％左右压制的片剂与参比制剂经加速条件40℃±2℃/RH75％±5％考察三个月的稳定性实验结果见下表：In Examples 19 and 20, the combined powder was dried under reduced pressure at 45°C and the moisture content was controlled at about 3%. The tablet and the reference preparation were tested for three-month stability under accelerated conditions of 40°C±2°C/RH75%±5%. The test results are shown in the table below:
表11 加速试验条件(40℃/RH75％)放置3个月的稳定性结果Table 11 The stability results of the accelerated test conditions (40℃/RH75%) for 3 months
Figure PCTCN2020129947-appb-000018
Figure PCTCN2020129947-appb-000018
实施例19、20控制总混粉水分不超过3％，制备的片剂经加速条件40℃ /RH75％条件放置3个月，各降解杂质及总杂的增长幅度均未超过参比制剂洛新汀中各降解杂质的增长幅度。In Examples 19 and 20, the moisture content of the total mixed powder was controlled not to exceed 3%, and the prepared tablets were placed under accelerated conditions of 40°C/RH75% for 3 months, and the growth rate of each degraded impurity and total impurity did not exceed the reference preparation Luoxin The growth rate of each degraded impurity in tin.
实施例21～25 双层片Embodiment 21～25 Double layer sheet
制备工艺：Preparation Process:
按处方量(表12所示)分别称取ACEI类药物、达格列净丙二醇水合物、微晶纤维素、交联聚维酮、二氧化硅、滑石粉，将各层物料混合8min，过50目筛混合8次，采用压片机压制双层片。Weigh ACEI drugs, dapagliflozin propylene glycol hydrate, microcrystalline cellulose, crospovidone, silicon dioxide, talc powder according to the recipe quantities (shown in Table 12), mix the materials of each layer for 8min, pass Mix 8 times with a 50-mesh sieve, and use a tablet press to compress double-layer tablets.
溶出结果：Dissolution Results:
pH 1.0盐酸溶液900ml，桨法，温度：37℃，转速：60rpm。实施例21～25样品中ACEI类药物、达格列净在15min溶出度均＞85％。pH 1.0 hydrochloric acid solution 900ml, paddle method, temperature: 37°C, rotating speed: 60rpm. In the samples of Examples 21-25, the dissolution rates of ACEI drugs and dapagliflozin in 15 minutes were all >85%.
表12 单位制剂处方组成(mg/片，50片/批)Table 12 Formulation composition of unit preparation (mg/tablet, 50 tablets/batch)
Figure PCTCN2020129947-appb-000019
Figure PCTCN2020129947-appb-000019
Figure PCTCN2020129947-appb-000020
Figure PCTCN2020129947-appb-000020
实施例26～28 双层片Embodiment 26～28 Double layer sheet
制备工艺：Preparation Process:
实施例26～28：按处方量(表13所示)分别称取物料，将各层物料混合8min，过50目筛混合8次，采用压片机压制双层片。Examples 26 to 28: respectively weigh the materials according to the recipe quantities (shown in Table 13), mix the materials for each layer for 8 minutes, pass through a 50-mesh sieve and mix for 8 times, and use a tablet machine to press the double-layer tablets.
实施例29～30：按处方量(表13所示)分别称取物料，将ACEI层物料混合8min，过50目筛混合8次，备用；将卡格列净层物料混合8min，过50目筛混合8次，干法制粒，备用；采用压片机压制双层片。Embodiments 29-30: respectively weigh the materials according to the recipe quantity (shown in Table 13), mix the ACEI layer materials for 8min, pass through a 50-mesh sieve and mix 8 times, and set aside; mix the canagliflozin layer materials for 8min, pass through a 50-mesh sieve Sieve and mix 8 times, dry granulation, and set aside; use a tablet machine to press double-layer tablets.
溶出结果：Dissolution Results:
pH 1.0盐酸溶液900ml，桨法，温度：37℃，转速：60rpm。实施例26-30样品中ACEI类药物、SGLT-2抑制剂在15min溶出度均＞85％。pH 1.0 hydrochloric acid solution 900ml, paddle method, temperature: 37°C, rotating speed: 60rpm. The dissolution rates of ACEI drugs and SGLT-2 inhibitors in the samples of Examples 26-30 were all >85% in 15 minutes.
表13 单位制剂处方组成(mg/片，50片/批)Table 13 Formulation composition of unit preparation (mg/tablet, 50 tablets/batch)
Figure PCTCN2020129947-appb-000021
Figure PCTCN2020129947-appb-000021
Figure PCTCN2020129947-appb-000022
Figure PCTCN2020129947-appb-000022
实施例31：按处方量(表14所示)称取盐酸贝那普利、达格列净肌氨酸共晶、微晶纤维素PH102、部分预胶化淀粉、交联聚维酮、二氧化硅、滑石粉混合8min，过50目筛8次，粉末直接压片。Example 31: Weigh benazepril hydrochloride, dapagliflozin sarcosine co-crystal, microcrystalline cellulose PH102, partially pregelatinized starch, crospovidone, Silica and talc were mixed for 8 minutes, passed through a 50-mesh sieve 8 times, and the powder was directly compressed into tablets.
实施例32：按处方量(表14所示)称取盐酸贝那普利、达格列净肌氨酸共晶、微晶纤维素PH102、交联聚维酮、二氧化硅、滑石粉混合8min，过50目筛8次，粉末直接装胶囊。Example 32: Weigh benazepril hydrochloride, dapagliflozin sarcosine co-crystal, microcrystalline cellulose PH102, crospovidone, silicon dioxide, talc powder according to the recipe quantity (shown in Table 14) and mix 8min, pass through a 50-mesh sieve 8 times, and the powder is directly loaded into capsules.
实施例33：按处方量(表14所示)分别称取A层和B层物料，将各层物料分别混合8min，过50目筛混合8次，采用压片机压制双层片。Example 33: According to the recipe quantity (shown in Table 14), the materials of layer A and layer B were weighed, and the materials of each layer were mixed for 8 minutes respectively, passed through a 50-mesh sieve and mixed for 8 times, and a tableting machine was used to press the double-layer tablet.
表14 单位制剂处方组成(mg/粒，50粒/批)Table 14 Formulation composition of unit preparation (mg/grain, 50 grains/batch)
Figure PCTCN2020129947-appb-000023
Figure PCTCN2020129947-appb-000023
Figure PCTCN2020129947-appb-000024
Figure PCTCN2020129947-appb-000024
溶出试验Dissolution test
pH 1.0盐酸溶液500ml，桨法，温度：37℃，转速：60rpm。实施例31-33样品中盐酸贝那普利、达格列净在15min溶出度均大于85％。pH 1.0 hydrochloric acid solution 500ml, paddle method, temperature: 37°C, rotating speed: 60rpm. In the samples of Examples 31-33, the dissolution rates of benazepril hydrochloride and dapagliflozin in 15 minutes were all greater than 85%.
药代动力学研究Pharmacokinetic Studies
将实施例4和9的自制制剂和参比制剂进行比格犬的PK研究。使用3只比格犬(11.6–14.8kg)进行3周期3交叉研究，其中单方参比制剂洛汀新和参比制剂安达唐同时给药。给药后分别于0.25、0.5、0.75、1、1.5、2、2.5、3、4、6、8、12和24h取血，采用LC-MS进行检测。采用WinNonlin非房室模型计算药代动力学，结果如下：The home-made formulations and reference formulations of Examples 4 and 9 were subjected to a PK study in beagle dogs. A 3-cycle 3-crossover study was conducted using 3 beagle dogs (11.6–14.8 kg), in which the single reference formulation Lotine and the reference formulation Andatang were administered simultaneously. Blood was collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours after administration, and detected by LC-MS. Pharmacokinetics were calculated using the WinNonlin non-compartmental model and the results are as follows:
表15 达格列净结果Table 15 Dapagliflozin results
Figure PCTCN2020129947-appb-000025
Figure PCTCN2020129947-appb-000025
表16 贝那普利结果Table 16 Benazepril results
Figure PCTCN2020129947-appb-000026
Figure PCTCN2020129947-appb-000026
表17 活性代谢物贝那普利拉结果Table 17 Results of the active metabolite benazeprilat
Figure PCTCN2020129947-appb-000027
Figure PCTCN2020129947-appb-000027
结论：由上述结果可知，自制制剂与参比制剂在比格犬体内Cmax Ratio和AUC0-24Ratio均在80％-125％范围内，说明自制制剂与参比制剂在比格犬体内生物等效。Conclusion: From the above results, it can be seen that the Cmax Ratio and AUC0-24Ratio of the homemade preparation and the reference preparation in beagle dogs are in the range of 80%-125%, indicating that the homemade preparation and the reference preparation are bioequivalent in beagle dogs.
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指 出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。The descriptions of the above embodiments are only used to help understand the method and the core idea of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can also be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (24)

  1. 一种固定剂量的SGLT-2抑制剂和血管紧张素转化酶抑制剂组合物，包括：A fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor combination comprising:
    a)SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；a) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
    b)血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物水合物、溶剂化物或水合物。b) An angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate hydrate, solvate or hydrate thereof.
  2. 根据权利要求1所述的固定剂量的SGLT-2抑制剂和血管紧张素转化酶抑制剂组合物，其特征在于，所述组分a)和组分b)的质量比为800:1-1:150。The fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor composition according to claim 1, wherein the mass ratio of the component a) and the component b) is 800:1-1 : 150.
  3. 根据权利要求1所述的固定剂量的SGLT-2抑制剂和血管紧张素转化酶抑制剂组合物，其特征在于，所述SGLT-2抑制剂为达格列净、坎格列净、恩格列净、依格列净、鲁格列净、托格列净、埃格列净、加格列净、贝格列净、索格列净、恒格列净、泰格列净、瑞格列净、艾格列净、依碳酸瑞格列净或荣格列净。The fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor composition according to claim 1, wherein the SGLT-2 inhibitor is dapagliflozin, canagliflozin, Engel Ligagliflozin, ipagliflozin, lupagliflozin, topagliflozin, ipagliflozin, japagliflozin, bepagliflozin, soxagliflozin, constantagliflozin, tagagliflozin, regpa Ligagliflozin, icogliflozin, ethanogliflozin, or Ringagliflozin.
  4. 根据权利要求1所述的固定剂量的SGLT-2抑制剂和血管紧张素转化酶抑制剂组合物，其特征在于，所述SGLT-2抑制剂为SGLT-2抑制剂·肌氨酸共晶体、游离体、SGLT-2抑制剂·脯氨酸共晶体、SGLT-2抑制剂水合物或SGLT-2抑制剂溶剂化物水合物；优选为达格列净·肌氨酸共晶体或达格列净丙二醇水合物。The fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor composition according to claim 1, wherein the SGLT-2 inhibitor is an SGLT-2 inhibitor-sarcosine co-crystal, Free form, SGLT-2 inhibitor·proline co-crystal, SGLT-2 inhibitor hydrate or SGLT-2 inhibitor solvate hydrate; preferably dapagliflozin·sarcosine co-crystal or dapagliflozin Propylene Glycol Hydrate.
  5. 根据权利要求1所述的固定剂量的SGLT-2抑制剂和血管紧张素转化酶抑制剂组合物，其特征在于，所述血管紧张素转化酶抑制剂为卡托普利、赖诺普利、依那普利、依那普利拉、福辛普利、福辛普利拉、贝那普利、贝那普利拉、雷米普利、雷米普利拉、喹那普利、喹那普利拉、培哚普利、培哚普利拉、莫西普利、莫西普利拉或群多普利及群多普利拉。The fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor composition according to claim 1, wherein the angiotensin-converting enzyme inhibitor is captopril, lisinopril, Enalapril, Enalapril, Fosinopril, Fosinopril, Benazepril, Benazeprilat, Ramipril, Ramipril, Quinapril, Quinapril Naprilat, perindopril, perindopril, moxipril, moxipril, or trandoprilat and trandoprilat.
  6. 一种固定剂量复方制剂，包括：A fixed-dose combination preparation comprising:
    a)SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；a) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
    b)血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化 物、溶剂化物水合物或水合物；b) an angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
    c)药学上可接受的辅剂。c) pharmaceutically acceptable adjuvants.
  7. 根据权利要求6所述的复方制剂，其特征在于，所述组分a)的单位剂量为2.5～25mg；The compound preparation according to claim 6, wherein the unit dose of the component a) is 2.5-25 mg;
    所述组分b)的单位剂量为5～80mg。The unit dose of the component b) is 5-80 mg.
  8. 根据权利要求6所述的复方制剂，其特征在于，所述组分a)和组分b)的质量比为5:40-10:5。The compound preparation according to claim 6, wherein the mass ratio of the component a) and the component b) is 5:40-10:5.
  9. 根据权利要求6所述的复方制剂，其特征在于，所述SGLT-2抑制剂为达格列净、坎格列净、恩格列净、依格列净、鲁格列净、托格列净、埃格列净、加格列净、贝格列净、索格列净、恒格列净、泰格列净、瑞格列净、艾格列净、依碳酸瑞格列净或荣格列净。The compound preparation according to claim 6, wherein the SGLT-2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, ipagliflozin, lupagliflozin, topagliflozin Net, Epagliflozin, Japagliflozin, Bepagliflozin, Soxagliflozin, Hengliflozin, Tagagliflozin, Repagliflozin, Iogliflozin, Repagliflozin, or Jung List the net.
  10. 根据权利要求6所述的复方制剂，其特征在于，所述SGLT-2抑制剂为SGLT-2抑制剂游离体药用晶型、SGLT-2抑制剂·肌氨酸共晶体、SGLT-2抑制剂·脯氨酸共晶体；优选为达格列净·肌氨酸共晶体或达格列净丙二醇水合物。The compound preparation according to claim 6, wherein the SGLT-2 inhibitor is a free pharmaceutical crystal form of the SGLT-2 inhibitor, an SGLT-2 inhibitor·sarcosine co-crystal, and a SGLT-2 inhibitor Agent·proline co-crystal; preferably dapagliflozin·sarcosine co-crystal or dapagliflozin propylene glycol hydrate.
  11. 根据权利要求6所述的复方制剂，其特征在于，所述血管紧张素转化酶抑制剂为卡托普利、赖诺普利、依那普利、福辛普利、贝那普利、雷米普利、喹那普利、培哚普利、莫西普利或群多普利以及上述药物的母体药物依那普利拉、福辛普利拉、贝那普利拉、雷米普利拉、喹那普利拉、培哚普利拉、莫西普利拉或群多普利拉。The compound preparation according to claim 6, wherein the angiotensin-converting enzyme inhibitor is captopril, lisinopril, enalapril, fosinopril, benazepril, miapril, quinapril, perindopril, moxipril, or trandolapril and the parent drug enalapril, fosinapril, benazeprilat, ramipril Lira, quinaprilat, perindopril, moxipril, or trandoprilat.
  12. 根据权利要求6所述的复方制剂，其特征在于，所述辅剂选自稀释剂、崩解剂、粘合剂、助流剂、润滑剂、矫味剂中的一种或多种。The compound preparation according to claim 6, wherein the adjuvant is selected from one or more of diluents, disintegrating agents, binders, glidants, lubricants, and flavoring agents.
  13. 根据权利要求12所述的复方制剂，其特征在于，所述稀释剂选自微晶纤维素、乳糖、甘露醇、赤藓醇、麦芽糖醇、山梨糖醇、海藻糖、蔗糖、白糖、葡萄糖、果糖、玉米淀粉、纤维素乳糖、小麦淀粉、糊精、甘草粉末、预胶化淀粉、部分预胶化淀粉、硫酸镁、硫酸钙中的一种或多种；The compound preparation according to claim 12, wherein the diluent is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, erythritol, maltitol, sorbitol, trehalose, sucrose, white sugar, glucose, One or more of fructose, corn starch, cellulose lactose, wheat starch, dextrin, licorice powder, pregelatinized starch, partially pregelatinized starch, magnesium sulfate, calcium sulfate;
    所述崩解剂选自玉米淀粉、部分α化淀粉、羟丙基淀粉、羧甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交聚维酮中的一种或多种；Described disintegrant is selected from corn starch, partial alpha starch, hydroxypropyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl One or more of base cellulose, croscarmellose sodium, and crospovidone;
    所述粘合剂选自羟丙纤维素、羟丙甲纤维素、聚维酮、淀粉浆、羧甲纤维素钠中的一种或多种；Described binder is selected from one or more in hypromellose, hypromellose, povidone, starch pulp, sodium carboxymethyl cellulose;
    所述助流剂选自滑石粉、二氧化硅中的一种或多种；Described glidant is selected from one or more in talc, silicon dioxide;
    所述润滑剂选自硬脂酸镁、硬脂酸、硬脂酸钙、硬脂富马酸钠、聚乙二醇、氢化植物油、聚乙二醇、十二烷基硫酸钠、滑石粉、二氧化硅中的一种或多种。Described lubricant is selected from magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, talc, One or more of silica.
  14. 根据权利要求6所述的复方制剂，其特征在于，所述复方制剂的剂型为片剂、颗粒剂、干混悬剂、胶囊剂或膜剂。The compound preparation according to claim 6, wherein the dosage form of the compound preparation is tablet, granule, dry suspension, capsule or film.
  15. 根据权利要求14所述的复方制剂，其特征在于，所述片剂为双层片、多层片、包芯片。The compound preparation according to claim 14, wherein the tablet is a double-layered tablet, a multi-layered tablet, or a core-encapsulated tablet.
  16. 根据权利要求6所述的复方制剂，其特征在于，所述复方制剂为片剂，包括：compound preparation according to claim 6, is characterized in that, described compound preparation is tablet, comprises:
    a)2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；a) 2wt% to 60wt% of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
    b)2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体或溶剂化物、溶剂化物水合物或水合物；b) 2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal or solvate, solvate hydrate or hydrate thereof;
    c)10wt％～90wt％的稀释剂；c) 10wt%～90wt% diluent;
    0～20wt％的崩解剂；0～20wt% disintegrant;
    0～2wt％的助流剂；0～2wt% of glidant;
    0～3wt％的润滑剂。0-3wt% lubricant.
  17. 根据权利要求6所述的复方制剂，其特征在于，所述复方制剂为胶囊剂，包括：compound preparation according to claim 6, is characterized in that, described compound preparation is capsule, comprises:
    a)2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；a) 2wt% to 60wt% of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
    b)2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、水合物或溶剂化物水合物；b) 2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
    c)10wt％～90wt％的稀释剂；c) 10wt%～90wt% diluent;
    0～20wt％的崩解剂；0～20wt% disintegrant;
    0～2wt％的助流剂；0～2wt% of glidant;
    0～3wt％的润滑剂。0-3wt% lubricant.
  18. 根据权利要求6所述的复方制剂，其特征在于，所述复方制剂为双层片剂，包括：The compound preparation according to claim 6, wherein the compound preparation is a bilayer tablet, comprising:
    A层：Floor A:
    2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；2wt% to 60wt% of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
    50wt％～80wt％的稀释剂50wt%～80wt% diluent
    5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
    1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
    1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
    B层：Layer B:
    2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、水合物或溶剂化物水合物；2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
    50wt％～80wt％的稀释剂50wt%～80wt% diluent
    5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
    1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
    1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
    所述A层为片芯，B层为包衣；The A layer is a tablet core, and the B layer is a coating;
    或者所述A层为包衣，B层为片芯。Alternatively, the A layer is a coating, and the B layer is a tablet core.
  19. 根据权利要求6所述的复方制剂，其特征在于，所述复方制剂为三层片剂，包括：The compound preparation according to claim 6, wherein the compound preparation is a three-layer tablet, comprising:
    A层：Floor A:
    2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；2wt% to 60wt% of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
    50wt％～80wt％的稀释剂50wt%～80wt% diluent
    5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
    1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
    1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
    B层：Layer B:
    2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶 体、溶剂化物、水合物或溶剂化物水合物；2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
    50wt％～80wt％的稀释剂50wt%～80wt% diluent
    5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
    1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
    1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
    C层：Layer C:
    50wt％～80wt％的稀释剂50wt%～80wt% diluent
    0～10wt％的崩解剂；0～10wt% disintegrant;
    0～3wt％的助流剂；0～3wt% of glidant;
    0～3wt％的润滑剂；0～3wt% lubricant;
    所述A层为片芯，B层为包衣；The A layer is a tablet core, and the B layer is a coating;
    或者所述A层为包衣，B层为片芯；Or the A layer is a coating, and the B layer is a tablet core;
    所述C层为中间层。The C layer is an intermediate layer.
  20. 根据权利要求6所述的复方制剂，其特征在于，所述复方制剂为片剂，包括：compound preparation according to claim 6, is characterized in that, described compound preparation is tablet, comprises:
    A组分：A component:
    2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；2wt% to 60wt% of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
    50wt％～80wt％的稀释剂50wt%～80wt% diluent
    5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
    1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
    1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
    B组分：Component B:
    2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、水合物或溶剂化物水合物；2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
    50wt％～80wt％的稀释剂50wt%～80wt% diluent
    5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
    1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
    1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
    所述A组分经制粒，然后与B组分混合，压片；The A component is granulated, then mixed with the B component, and compressed into a tablet;
    或者所述B组分经制粒，然后与A组分混合，压片。Alternatively, the B component is granulated and then mixed with the A component and compressed into a tablet.
  21. 根据权利要求6所述的复方制剂，其特征在于，所述复方制剂为片剂，包括：compound preparation according to claim 6, is characterized in that, described compound preparation is tablet, comprises:
    A组分：A component:
    2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；2wt% to 60wt% of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
    50wt％～80wt％的稀释剂50wt%～80wt% diluent
    5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
    1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
    1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
    B组分：Component B:
    2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、水合物或溶剂化物水合物；2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
    50wt％～80wt％的稀释剂50wt%～80wt% diluent
    5wt％～10wt％的崩解剂；5wt%～10wt% disintegrant;
    1wt％～3wt％的助流剂；1wt% to 3wt% of glidant;
    1wt％～3wt％的润滑剂；1wt% to 3wt% of lubricant;
    C组分：Component C:
    50wt％～80wt％的稀释剂50wt%～80wt% diluent
    0～10wt％的崩解剂；0～10wt% disintegrant;
    0～3wt％的助流剂；0～3wt% of glidant;
    0～3wt％的润滑剂；0～3wt% lubricant;
    所述A组分、B组分分别制粒，然后与C组分混合，压片。The A component and the B component are separately granulated, then mixed with the C component, and compressed into a tablet.
  22. 根据权利要求6所述的复方制剂，其特征在于，所述复方制剂为颗粒剂或干混悬剂，包括：compound preparation according to claim 6, is characterized in that, described compound preparation is granule or dry suspension, comprises:
    a)2wt％～60wt％的SGLT-2抑制剂，或其药学上可接受的盐、共晶体、溶剂化物、溶剂化物水合物或水合物；a) 2wt% to 60wt% of SGLT-2 inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, solvate hydrate or hydrate thereof;
    b)2wt％～40wt％的血管紧张素转化酶抑制剂，或其药学上可接受的盐、 共晶体、溶剂化物、水合物或溶剂化物水合物；b) 2wt% to 40wt% of angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, co-crystal, solvate, hydrate or solvate hydrate thereof;
    c)10wt％～90wt％的稀释剂；c) 10wt%～90wt% diluent;
    0～20wt％的崩解剂；0～20wt% disintegrant;
    0～2wt％的助流剂；0～2wt% of glidant;
    0～3wt％的润滑剂。0-3wt% lubricant.
  23. 根据权利要求6所述的复方制剂，其特征在于，所述复方制剂中的水分含量低于5％，更优选低于3％。The compound preparation according to claim 6, wherein the moisture content in the compound preparation is lower than 5%, more preferably lower than 3%.
  24. 权利要求1～5任一项所述的固定剂量的SGLT-2抑制剂和血管紧张素转化酶抑制剂组合物，或权利要求6～23任一项所述的固定剂量复方制剂，在制备用于预防、治疗或减轻原发性高血压、高血压、合并或不合并高血压的慢性肾病、合并或不合并糖尿病的慢性肾病、糖尿病、胰岛素抵抗、高血糖、高胰岛素血症、脂肪酸或甘油的升高的血含量、高脂血、血脂障碍、肥胖、或糖尿病并发症以及肺纤维化的药物中的应用。The fixed-dose SGLT-2 inhibitor and angiotensin-converting enzyme inhibitor composition according to any one of claims 1 to 5, or the fixed-dose compound preparation according to any one of claims 6 to 23, used in preparation For the prevention, treatment or alleviation of essential hypertension, hypertension, chronic kidney disease with or without hypertension, chronic kidney disease with or without diabetes, diabetes, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acid or glycerol The use of drugs for elevated blood levels, hyperlipidemia, dyslipidemia, obesity, or complications of diabetes and pulmonary fibrosis.
PCT/CN2020/129947 2020-11-19 2020-11-19 Fixed-dose combination of sglt-2 inhibitor and angiotensin converting enzyme inhibitor, and use thereof WO2022104621A1 (en)

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