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WO2018198102A1 - Préparations pharmaceutiques orales de rémogliflozine - Google Patents

Préparations pharmaceutiques orales de rémogliflozine Download PDF

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Publication number
WO2018198102A1
WO2018198102A1 PCT/IB2018/054091 IB2018054091W WO2018198102A1 WO 2018198102 A1 WO2018198102 A1 WO 2018198102A1 IB 2018054091 W IB2018054091 W IB 2018054091W WO 2018198102 A1 WO2018198102 A1 WO 2018198102A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
remogliflozin
dosage form
metformin
oral dosage
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2018/054091
Other languages
English (en)
Inventor
Ulhas Dhuppad
Nitin Deshmukh
Krishna SADAPHAL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glenmark Pharmaceuticals Ltd
Original Assignee
Glenmark Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Pharmaceuticals Ltd filed Critical Glenmark Pharmaceuticals Ltd
Priority to MX2019014687A priority Critical patent/MX2019014687A/es
Priority to CN201880038198.9A priority patent/CN110753540A/zh
Priority to BR112019026029-3A priority patent/BR112019026029A2/pt
Priority to PH1/2019/502767A priority patent/PH12019502767A1/en
Priority to KR1020197038666A priority patent/KR20200013719A/ko
Publication of WO2018198102A1 publication Critical patent/WO2018198102A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present disclosure relates to technical field of pharmaceutical formulations.
  • the present disclosure relates to immediate release formulation of remogliflozin for oral administration.
  • the present disclosure further relates to pharmaceutical formulation that includes a synergistic combination of remogliflozin and metformin.
  • Type II diabetes is characterized by insulin resistance and impaired glucose- stimulated insulin secretion by the pancreatic-cells, and it has increased in incidence with changes in lifestyles that lead to weight gain and obesity.
  • chronic hyperglycemia leads to progressive impairment of insulin secretion and to insulin resistance of peripheral tissues, a phenomenon often referred to as glucose toxicity, which further worsens the blood glucose level.
  • type II diabetes usually begins with dietary changes and exercise, followed by oral antidiabetic therapy.
  • the goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications associated with elevated glucose in blood.
  • Oral therapeutic options for the treatment of type II diabetes mellitus include agents known as: biguanides (metformin), sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors. These agents are all indicated as monotherapy and some are indicated for use in combination therapy, generally, after monotherapy has been found to be inadequate.
  • metformin is regarded as the first-line drug of choice for the treatment of type II diabetes in overweight and obese people.
  • Metformin is usually administered orally, and it improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose.
  • the United Kingdom Prospective Diabetes Study demonstrated that intensive treatment of type II diabetes with metformin resulted in only a limited improvement of glycemic control.
  • the use of conventional combination therapies e.g. combination of metformin with sulfonylurea may show an increased risk for side effects, such as hypoglycemia or weight gain, which may limit their safety and efficacy.
  • Remogliflozin is another class of antidiabetic agent useful for the treatment of type
  • Remogliflozin is a highly selective sodium glucose co-transporter 2 (SGLT2) inhibitor.
  • the low-affinity sodium glucose cotransporter (SGLT2) plays an important role in renal glucose reabsorption and is a remarkable transporter as a molecular target for the treatment of diabetes.
  • Remogliflozin works by inhibiting the sodium-glucose transport (SGLT) proteins which are responsible for glucose reabsorption in the kidney (Fujimori et al., Journal of Pharmacology and Experimental Therapeutics 2008, 327, 268-276).
  • Remogliflozin etabonate is a prodrug of remogliflozin.
  • Remogliflozin etabonate is chemically known as 5 -methyl-4-[4-(l -methylethoxy)benzyl]-l-(l -methyl ethyl)- 1H- pyrazol-3-yl 6-0-(ethoxycarbonyl)- -D-glucopyranoside. Remogliflozin etabonate is also known as GSK 189075 or KGT-1681. Upon administration and absorption, the prodrug is converted to its active form remogliflozin and acts selectively on the SGLT2.
  • Remogliflozin etabonate has the potential to be used as monotherapy for the treatment of type II diabetes in human subjects suffering from diabetes. Efforts have been made to develop oral formulations of remogliflozin for the treatment of type II diabetes.
  • WO2001016147 relates to remogliflozin base
  • WO02053573_ relates to remogliflozin etabonate
  • WO2012006398 A2_ relates to biphasic formulation comprising remogliflozin etabonate in immediate and controlled release phases
  • US8951976 relates to method of treatment for NAFL, NASH, hypernutritive fatty liver, alcoholic fatty liver disease, diabetic fatty liver and acute fatty liver using remogliflozin etabonate
  • WO2010092125 relates to composition comprising (a) an SGLT2 inhibitor, and (b) a DPPIV inhibitor, and (c) a third anti-diabetic agent
  • the present disclosure satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.
  • a solid oral pharmaceutical formulation that includes remogliflozin in combination with one or more pharmaceutically acceptable excipients.
  • the disclosed formulation of remogliflozin can provide immediate release of the drug, and can effectively control plasma glucose level in a mammalian subject having abnormal levels of plasma glucose.
  • the immediate release formulation of remogliflozin can include an intragranular portion and an extragranular portion.
  • the intragranular portion can include a quantity of remogliflozin in combination with at least one disintegrant and at least one binder.
  • the extragranular portion can include at least one disintegrant and at least one lubricant.
  • the immediate release formulation of remogliflozin can further include a coating, preferably film coating.
  • the formulation of remogliflozin is in the form of an immediate-release tablet for oral administration.
  • a combination formulation that includes a synergistic combination of remogliflozin and metformin.
  • the combination formulation can exhibit a synergist effect on glycemic control in subjects with diabetes, thereby enhancing the treatment effectiveness.
  • the combination formulation disclosed herein can be in the form of a solid dosage form which can include (a) a first layer including metformin or a pharmaceutically acceptable salt thereof in an extended release formulation; and (b) a second layer including remogliflozin in an immediate release formulation.
  • the combination formulation can include remogliflozin in the form of remogliflozin etabonate, and metformin in the form of metformin hydrochloride.
  • the combination formulation disclosed herein can be in the form of a fixed dose bilayer tablet for oral administration.
  • the present invention relates to the use of fixed dose solid oral dosage form comprising remogliflozin etabonate and metformin hydrochloride for the treatment of diabetes mellitus wherein remogliflozin etabonate is present in an immediate release form and metformin hydrochloride is present in an extended release form.
  • the present invention relates to method of treating diabetes mellitus by administering a patient in need thereof, a fixed dose solid oral dosage form comprising remogliflozin etabonate in an immediate release form and metformin hydrochloride in an extended release form.
  • the present invention relates to a bilayer tablet comprising an immediate release layer and an extended release layer wherein the immediate release layer comprises remogliflozin or pharmaceutically acceptable salts thereof and the extended release layer comprises metformin or pharmaceutically acceptable salts thereof wherein the tablet may comprise one or more pharmaceutically acceptable excipients.
  • the immediate release layer comprises remogliflozin etabonate in an amount of about lOOmg or 250mg and the extended release layer comprises metformin hydrochloride in an amount of about 500mg or 850mg or 1000 mg with one or more pharmaceutically acceptable excipients.
  • the present invention relates to bilayer tablet comprising an immediate release layer and an extended release layer wherein the immediate release layer comprises remogliflozin or pharmaceutically acceptable salts thereof and the extended release layer comprises metformin or pharmaceutically acceptable salts thereof wherein the total daily dose of remogliflozin or pharmaceutically acceptable salts does not exceed 500mg and total daily dose of metformin or pharmaceutically acceptable salts does not exceed 2000mg.
  • the pharmaceutical formulations disclosed herein can be administered to mammalian subjects, preferably humans, for the treatment of type II diabetes, impaired glucose tolerance, insulin resistance, and diabetic complications such as hyperglycemia, hyperinsulinemia, and obesity.
  • FIG.l is a flow chart showing an exemplary process for producing remogliflozin etabonate immediate release tablets.
  • FIG.2 is a flow chart showing an exemplary process for producing bilayer tablets comprising a fixed dose combination of remogliflozin etabonate and metformin hydrochloride.
  • an excipient includes a single excipient as well as two or more different excipients, and the like.
  • the numbers expressing quantities of ingredients, properties such as concentration, process conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term "about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
  • the term "about” is used synonymously with the term “approximately.”
  • the use of the term “about” with regard to a certain therapeutically effective pharmaceutical dose indicates that values slightly outside the cited values, e.g., plus or minus 0.1% to 10%, which are also effective and safe.
  • treating and its grammatical variants (e.g. “to treat,” “treating,” and
  • treatment refers to administration of remogliflozin etabonate to a patient with the purpose of ameliorating or reducing the incidence of one or more symptoms of a condition or disease state in the patient. Such symptoms may be chronic or acute; and such amelioration may be partial or complete.
  • the present invention relates to immediate release oral formulation of remogliflozin for the treatment of type II diabetes, impaired glucose tolerance, insulin resistance, and diabetic complications such as hyperglycemia, hyperinsulinemia, and obesity.
  • the invention also relates to synergistic combination of remogliflozin and other anti diabetic agent wherein remogliflozin is available in immediate release dosage form.
  • the disclosed immediate release formulation of remogliflozin can exhibit desired drug dissolution profile, and can effectively control plasma glucose level in a mammalian subject having abnormal levels of plasma glucose.
  • remogliflozin refers to remogliflozin, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complex, cocrystals, cogeners and prodrugs thereof.
  • Remogliflozin etabonate or a pharmaceutically acceptable salt thereof such as the hydrochloride, all of which are collectively referred to as remogliflozin etabonate.
  • metformin refers to metformin, its salts, hydroxylated forms, hydrates, solvates, polymorphic forms, analogs, derivatives, esters, complex, cocrystals, cogeners and prodrugs thereof.
  • combination includes administration of one or more active pharmaceutical ingredients either in a single dosage form or in separate dosage forms; in fixed dose combination or administered separately as adjuvant therapy.
  • immediate release refers to a feature of a pharmaceutical formulation wherein the pharmaceutically active agent in the formulation is made bioavailable without substantial delay.
  • the immediate release formulation of remogliflozin can include an intragranular portion and an extragranular portion.
  • the intragranular portion can include a quantity of remogliflozin in combination with at least one disintegrant and at least one binder.
  • the extragranular portion can include at least one disintegrant and at least one lubricant.
  • the immediate release formulation of remogliflozin can further include a coating, preferably film coating.
  • the immediate release formulation of remogliflozin can be in the form of a solid dosage form for oral administration.
  • the disclosed formulation of remogliflozin can be in the form of an immediate -release tablet for oral administration.
  • Immediate release tablets may further comprise one or more pharmaceutically acceptable excipients.
  • suitable pharmaceutically acceptable excipients include, but are not limited to one or more of diluents, disintegrant, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, opacifiers, colorants, gelling agents / viscosity modifying agents, antioxidants, solvents, co-solvents, and combinations thereof.
  • Formulations may comprise polymeric excipients for extended release of the drug.
  • Non-limiting examples of diluents include one or more of microcrystalline cellulose, silicified microcrystalline cellulose (e.g., Prosolv®), microfine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, sugars such as dextrose, mannitol, sorbitol, or sucrose and combinations thereof.
  • the diluents according to current invention are present in an amount 5-30% w/w.
  • Non limiting examples of disintegrants suitable for use herein include, povidone, crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, pregelatinised starch, micro crystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants.
  • disintegrants suitable for use herein include, povidone, crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, pregelatinised starch, micro crystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants.
  • disintegrant suitable for use in the formulations described herein.
  • any grade of crospovidone can be used, including for example crospovidone XL- 10, and includes members selected from the group consisting of Kollidon CL.RTM., Polyplasdone XL.RTM., Kollidon CL-M.RTM., Polyplasdone XL-10.RTM., and Polyplasdone INF-10.RTM.
  • the disintegrant, if present, of the stock granulation is sodium starch glycolate, croscarmellose sodium and/or crospovidone. These materials are also referred to as insoluble polyvidone, insoluble PVP, crosslinked PVP, and PVPP.
  • the crospovidone can be substituted with croscarmellose sodium, sodium starch glycolate.
  • the disintegrant according to current invention are present in an amount 1-30% w/w.
  • Non-limiting examples of glidants and lubricants include one or more of stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate.
  • the glidant according to current invention are present in an amount 0.1-5% w/w.
  • Non limiting examples of binder include starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols.
  • the binder according to current invention are present in an amount 0.5-10% w/w.
  • Non-limiting examples of preservatives include one or more of phenoxyethanol, parabens such as methyl paraben and propyl paraben and their sodium salts, propylene glycols, sorbates, urea derivatives such as diazolindinyl urea, and mixtures thereof.
  • Non-limiting examples of buffering agents include sodium hydroxide, potassium hydroxide, ammonium hydroxide and mixtures thereof.
  • Non-limiting examples of chelating agents include ethylene diamine tetraacetic acid (“EDTA”), and disodium edetate and EDTA derivatives.
  • the binder according to current invention are present in an amount 0.1-2% w/w.
  • Non-limiting examples of polymers include one or more of gum arabic, guar gum, sodium based lignosulfonate, polyethylene oxide, methyl methacrylate, methacrylate copolymers, isobutyl methacrylate, ethylene glycol dimethacrylate and cellulosic polymers including hydroxyl propyl cellulose, carboxy methyl cellulose, hydroxyl propyl methyl cellulose,.
  • Solvents include one or more of aqueous or non-aqueous solvents including alcoholic solvents and oils.
  • Non-limiting examples include water, tetrahydrofuran, methanol, ethanol, isopropyl alcohol and higher alcohols; hydrogenated castor oil, alkanes, e.g., pentane, hexane and heptane; ketones, e.g., acetone and methyl ethyl ketone; chlorinated hydrocarbons, e.g., chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride acetates, e.g., ethyl acetate.
  • the immediate release tablet according to present invention comprises combination of remogliflozin etabonate and metformin further comprising crosscarmellose sodium, microcrystalline cellulose, magnesium stearate and povidone.
  • the remogliflozin immediate release formulation disclosed herein can include (a) an intragranular portion including remogliflozin, at least one disintegrant and at least one binder; (b) an extragranular portion including at least one disintegrant and at least one lubricant; and (c) a coating.
  • the intragranular portion of the immediate release formulation can include (by weight): 31.25% remogliflozin etabonate, 1.5% croscarmellose sodium, 6.46% microcrystalline cellulose, and 2.08% K 29/32.
  • the extragranular portion can include (by weight): 2.1% croscarmellose sodium, 55.71% microcrystalline cellulose, and 0.90% magnesium stearate.
  • the coating can include 2.0-3.0% by weight of opadry white.
  • the present disclosure provides a method for treating type II diabetes in a mammalian subject suffering from diabetes.
  • the method can include administering to the mammalian subject a therapeutically effective amount of the immediate release formulation of remogliflozin disclosed herein.
  • the present invention relates to the use of fixed dose solid oral dosage form comprising remogliflozin etabonate and metformin hydrochloride for the treatment of diabetes mellitus wherein remogliflozin etabonate is present in an immediate release form and metformin hydrochloride is present in an extended release form.
  • the present invention relates to method of treating diabetes mellitus by administering a patient in need thereof, a fixed dose solid oral dosage form comprising remogliflozin etabonate in an immediate release form and metformin hydrochloride in an extended release form.
  • the present invention relates to a bilayer tablet comprising an immediate release layer and an extended release layer wherein the immediate release layer comprises remogliflozin or pharmaceutically acceptable salts thereof and the extended release layer comprises metformin or pharmaceutically acceptable salts thereof wherein the tablet may comprise one or more pharmaceutically acceptable excipients.
  • the immediate release layer comprises remogliflozin etabonate in an amount of about lOOmg or 250mg and the extended release layer comprises metformin hydrochloride in an amount of about 500mg or 850mg or 1000 mg with one or more pharmaceutically acceptable excipients.
  • the present invention relates to bilayer tablet comprising an immediate release layer and an extended release layer wherein the immediate release layer comprises remogliflozin or pharmaceutically acceptable salts thereof and the extended release layer comprises metformin or pharmaceutically acceptable salts thereof wherein the total daily dose of remogliflozin or pharmaceutically acceptable salts does not exceed 500mg and total daily dose of metformin or pharmaceutically acceptable salts does not exceed 2000mg.
  • the present disclosure provides a combination formulation that includes remogliflozin in combination with metformin or a pharmaceutically acceptable salt thereof.
  • the combination formulation disclosed herein can be in the form of a solid dosage form which can include (a) a first layer including metformin or a pharmaceutically acceptable salt thereof in an extended release formulation; and (b) a second layer including remogliflozin in an immediate release formulation.
  • extended release means a pharmaceutical formulation designed to gradually and continually release amounts of metformin or its pharmaceutically acceptable salt to maintain a level of therapeutic or prophylactic effect over an extended period of time.
  • the combination formulation disclosed herein can be in the form of a fixed dose bilayer tablet for oral administration.
  • the bilayer tablet can include metformin hydrochloride extended release formulation as the first layer, and remogliflozin etabonate immediate release formulation as the second layer.
  • the amount of metformin in the present combination formulation can range from 30% to 90% by weight based on the total weight of the combination formulation, and the amount of remogliflozin can range from 5% to 60% by weight based on the total weight of the combination formulation.
  • the present invention relates to remogliflozin etabonate in daily dose of lOOmg, 200mg, 250mg and 500mg in single or divided doses and is administered to patients who have inadequate glycemic control.
  • the total daily dose of remogliflozin etabonate does not exceed 500mg.
  • the current formulation can be administered once or twice daily.
  • the present invention relates to metformin hydrochloride in daily dose of 500mg, 750, 800mg and lOOOmg in single or divided doses and is administered to patients who have inadequate glycemic control.
  • the total daily dose of metformin hydrochloride does not exceed 2000mg.
  • the current formulation relates to the synergistic combination of remogliflozin etabonate and metformin hydrochloride which can be administered once or twice daily.
  • the first layer of the combination formulation can contain 500 mg of metformin hydrochloride in an extended release formulation
  • the second layer of the combination formulation can contain 100 mg of remogliflozin etabonate in an immediate release formulation.
  • the first layer can contain 500 mg of metformin hydrochloride in an extended release formulation, and the second layer can contain 250 mg of remogliflozin etabonate in an immediate release formulation.
  • the first layer can contain 1000 mg of metformin hydrochloride in an extended release formulation, and the second layer can contain 100 mg of remogliflozin etabonate in an immediate release formulation.
  • the first layer can contain 1000 mg of metformin hydrochloride in an extended release formulation
  • the second layer can contain 250 mg of remogliflozin etabonate in an immediate release formulation.
  • both the extended release metformin layer and the immediate release remogliflozin layer can include one or more pharmaceutically acceptable excipients.
  • Present invention relates to a stable bilayer tablet composition
  • a stable bilayer tablet composition comprising immediate release remogliflozin etabonate layer and extended release layer comprising metformin or pharmaceutically acceptable salt, solvate, prodrugs, esters thereof, wherein the composition exhibits dissolution of not less than 75% remogliflozin etabonate in 45min, not less than 20% metformin or salts thereof in 60min and not less than 80% metformin or salts thereof in lOhrs.
  • the present invention also relates to a stable composition of remogliflozin etabomate wherein remogliflozin etabonate is present in immediate release form.
  • the present invention relates to a stable bilayer composition of remogliflozin etabonate and metformin hydrochloride wherein, remogliflozin etabonate is present in immediate release layer whereas metformin hydrochloride is present in an extended release layer.
  • Remogliflozin tablet formulation as well as bilayer formulation of remogliflozin and metformin are stable at 25°C ⁇ 20C & 60% RH ⁇ 5 % RH. Further formulations are also stable at 30°C ⁇ 20C & 75% RH ⁇ 5 % RH and at 40°C ⁇ 20C & 75% RH ⁇ 5 % RH
  • the present disclosure provides a method for treating type II diabetes in a mammalian subject suffering from diabetes.
  • the method can include administering to the mammalian subject a therapeutically effective amount of a combination formulation in the form of a solid dosage form which includes (a) a first layer including metformin or a pharmaceutically acceptable salt thereof in an extended release formulation; and (b) a second layer including remogliflozin in an immediate release formulation.
  • the immediate release formulation of remogliflozin and the combination formulation of remogliflozin and metformin can be administered to mammalian subjects, preferably humans, for the treatment of type II diabetes, impaired glucose tolerance, insulin resistance, and diabetic complications such as hyperglycemia, hyperinsulinemia, and obesity.
  • EXAMPLE 1 Table- 1 below lists the ingredients and amount for the formulation of remogliflozin 100 mg immediate -release tablets.
  • EXAMPLE 3 Table-3 below lists the ingredients and amount for the preparation of bilayer tablets containing metformin HC1 (500 mg) extended release formulation and remogliflozin etabonate (100 mg) immediate release formulation.
  • Bilayer tablets were manufactured according to the process as shown in the flow chart of FIG. 2.
  • EXAMPLE 4 Table-4 below lists the ingredients and amount for the preparation of bilayer tablets containing metformin HC1 (500 mg) extended release formulation and remoglifiozin etabonate (250 mg) immediate release formulation.
  • EXAMPLE 5 Table-5 below lists the ingredients and amount for the preparation of bilayer tablets containing metformin HCl (1000 mg) extended release formulation and remogliflozin etabonate (100 mg) immediate release formulation.
  • Bilayer tablets were manufactured according to the process as shown in the flow chart of FIG. 2.
  • EXAMPLE 6 Table-6 below lists the ingredients and amount for the preparation of bilayer tablets containing metformin HC1 (1000 mg) extended release formulation and remogliflozin etabonate (250 mg) immediate release formulation.
  • Bilayer tablets were manufactured according to the process as shown in the flow chart of FIG. 2.

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Abstract

La présente invention concerne une préparation orale de rémogliflozine à libération immédiate ou des sels de qualité pharmaceutique de celle-ci, administré(s) à des patients en ayant besoin, pour le traitement du diabète sucré. La présente invention porte également sur une préparation pharmaceutique comprenant une combinaison synergique d'étabonate de rémogliflozine et d'hydrochlorure de metformine. Dans un mode de réalisation préféré, l'invention porte sur un comprimé bicouche comprenant un couche à libération immédiate et une couche à libération prolongée, la couche à libération immédiate comprenant de l'étabonate de rémogliflozine ou des sels de qualité pharmaceutique de celui-ci et la couche à libération prolongée comprenant de la metformine ou un sel de qualité pharmaceutique de celle-ci.
PCT/IB2018/054091 2017-06-08 2018-06-07 Préparations pharmaceutiques orales de rémogliflozine Ceased WO2018198102A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
MX2019014687A MX2019014687A (es) 2017-06-08 2018-06-07 Formulaciones farmaceuticas orales de remogliflozina.
CN201880038198.9A CN110753540A (zh) 2017-06-08 2018-06-07 瑞格列净的口服药物制剂
BR112019026029-3A BR112019026029A2 (pt) 2017-06-08 2018-06-07 Formulações farmacêuticas orais de remogliflozina
PH1/2019/502767A PH12019502767A1 (en) 2017-06-08 2018-06-07 Oral pharmaceutical formulations of remogliflozin
KR1020197038666A KR20200013719A (ko) 2017-06-08 2018-06-07 레모글리플로진의 경구 약학적 제제

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WO2019162841A1 (fr) * 2018-02-21 2019-08-29 Glenmark Pharmaceuticals Limited Composition pharmaceutique comprenant de la rémogliflozine pour le traitement du diabète sucré
CN111246917A (zh) * 2018-02-21 2020-06-05 格兰马克药品有限公司 包含瑞格列净和抗糖尿病药物的药物组合物
WO2020182792A1 (fr) 2019-03-12 2020-09-17 Dsm Ip Assets B.V. Capsules de coacervat enrobées

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019162841A1 (fr) * 2018-02-21 2019-08-29 Glenmark Pharmaceuticals Limited Composition pharmaceutique comprenant de la rémogliflozine pour le traitement du diabète sucré
CN111246917A (zh) * 2018-02-21 2020-06-05 格兰马克药品有限公司 包含瑞格列净和抗糖尿病药物的药物组合物
WO2020182792A1 (fr) 2019-03-12 2020-09-17 Dsm Ip Assets B.V. Capsules de coacervat enrobées

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CN110753540A (zh) 2020-02-04
BR112019026029A2 (pt) 2020-06-23

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