WO2022104621A1 - Combinaison à dose fixe d'inhibiteur de sglt-2 et d'inhibiteur d'enzyme de conversion de l'angiotensine et utilisation associée - Google Patents

Combinaison à dose fixe d'inhibiteur de sglt-2 et d'inhibiteur d'enzyme de conversion de l'angiotensine et utilisation associée Download PDF

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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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inhibitor
hydrate
solvate
sglt
crystal
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PCT/CN2020/129947
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English (en)
Chinese (zh)
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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/zh
Priority to PCT/CN2020/129947 priority patent/WO2022104621A1/fr
Publication of WO2022104621A1 publication Critical patent/WO2022104621A1/fr

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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

L'invention concerne une combinaison à dose fixe d'un inhibiteur de SGLT-2 et d'un inhibiteur d'enzyme de conversion de l'angiotensine (IECA), ainsi qu'une utilisation associée. La combinaison comprend : a) un inhibiteur de SGLT-2 ou un sel pharmaceutiquement acceptable, un co-cristal, un hydrate de solvate ou un hydrate correspondant ; et b) un inhibiteur d'enzyme de conversion de l'angiotensine ou un sel pharmaceutiquement acceptable, un co-cristal ou un hydrate de solvate correspondant. La combinaison est pratique à porter ou à prendre, le coût de médication est relativement réduit, le risque de surdose ou de médicament oublié est évité et l'observance des traitements des patients est améliorée ; la stabilité est bonne, en particulier en ce qui concerne l'absence d'impuretés estérifiées polymères d'acide carboxylique dans une structure d'IECA (ou d'un produit de dégradation) et l'absence d'hydroxy dans une structure d'inhibiteur de SGLT-2 devant être formée ; la probabilité et le risque de sécurité de l'interaction médicamenteuse sont réduits ; et l'effet synergique peut être mieux exercé.
PCT/CN2020/129947 2020-11-19 2020-11-19 Combinaison à dose fixe d'inhibiteur de sglt-2 et d'inhibiteur d'enzyme de conversion de l'angiotensine et utilisation associée WO2022104621A1 (fr)

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PCT/CN2020/129947 WO2022104621A1 (fr) 2020-11-19 2020-11-19 Combinaison à dose fixe d'inhibiteur de sglt-2 et d'inhibiteur d'enzyme de conversion de l'angiotensine et utilisation associée

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