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WO2018185669A1 - Compositions effervescentes comprenant de la saxagliptine ou un sel de celle-ci - Google Patents

Compositions effervescentes comprenant de la saxagliptine ou un sel de celle-ci Download PDF

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Publication number
WO2018185669A1
WO2018185669A1 PCT/IB2018/052313 IB2018052313W WO2018185669A1 WO 2018185669 A1 WO2018185669 A1 WO 2018185669A1 IB 2018052313 W IB2018052313 W IB 2018052313W WO 2018185669 A1 WO2018185669 A1 WO 2018185669A1
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WIPO (PCT)
Prior art keywords
saxagliptin
agent
drugs
effervescent
salt
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Ceased
Application number
PCT/IB2018/052313
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English (en)
Inventor
Sivakumar Venkata BOBBA
Bhimrao Jadhav
Dhananjay Shinde
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Zenvision Pharma LLP
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Zenvision Pharma LLP
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Publication of WO2018185669A1 publication Critical patent/WO2018185669A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds

Definitions

  • the present application has been made combining two Indian Application Nos. 201721012521 dated April 7, 2017 and 201721012522 dated April 7, 2017.
  • the present invention relates to effervescent compositions comprising Saxagliptin or salt thereof optionally in combination with metformin for the treatment of type 2 diabetes.
  • Diabetes mellitus type 2 (also known as type 2 diabetes) is a long-term metabolic disorder that is characterized by high blood sugar level. Common symptoms include increased thirst, frequent urination, increased hunger, feeling tired and sores that do not heal.
  • Type 2 diabetes primarily occurs as a result of obesity and lack of exercise. Some people are more genetically at risk than others. Type 2 diabetes makes up about 90% of cases of diabetes, with the other 10% due primarily to diabetes mellitus type 1 and gestational diabetes. Type 2 diabetes is typically a chronic disease associated with a ten-year-shorter life expectancy.
  • Blood sugars levels in Type 2 diabetes can be controlled by proper exercise and nutrition. If blood sugar level not controlled on exercise and nutrition, there are several anti-diabetic medications available.
  • the anti-diabetic agent includes dipeptidyl peptidase 4 inhibitors, non-sulfonylureas, alpha-glucosidase inhibitors, amylin analogs, incretin mimetics, insulin, meglitinides, SGLT-2 inhibitors and thiazolidinediones.
  • the dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of oral drugs for the treatment of type 2 diabetes. They inhibit the breakdown of glucagon-like peptide- 1 (GLP- 1) and increase the incretin effect in patients with type 2 diabetes. In clinical practice they are associated with significant reductions in HbAi c (glycated haemoglobin), no weight gain and a low risk of hypoglycemia.
  • the different dipeptidyl peptidase-4 (DPP-4) inhibitors are saxagliptin, sitagliptin, linagliptin, alogliptin and like.
  • Saxagliptin is anti-diabetic drug of dipeptidyl peptidase-4 inhibitor class. Chemically Saxagliptin is (l S,3S,5S)-2- ((2S)-2-Amino-2-(3-hydroxyadamantan- l-yl) acetyl)-2- azabicyclo [3.1.0] hexane-3-carbonitrile and its molecular weight is 315.41. Its empirical formula is C18H25 3O2. Saxagli tin is represented by compound of structural formula I
  • Saxagliptin monohydrate is a white to light yellow or light brown, non-hygroscopic, crystalline powder. It is sparingly soluble in water at 24°C ⁇ 3°C, slightly soluble in ethyl acetate, and soluble in ethanol, acetonitrile, isopropyl alcohol, methanol, acetone and polyethylene glycol 400.
  • the non-sulfonylureas are anti-hyperglycemic agent used in the treatment of type 2 diabetes. Different biguanides include metformin, phenformin and buformin. Buformin and Phenformin both are withdrawn from the market due to toxic effects. Metformin is widely used in the treatment of diabetes mellitus type 2.
  • Metformin hydrochloride is a biguanide anti-hyperglycemic agent used for treating non- insulin-dependent diabetes mellitus. Chemically Metformin hydrochloride is N, N- dimethylimidodicarbonimidic diamide hydrochloride and its molecular weight is 165.63. Its empirical formula is C4H11N5 ⁇ HC1. Metformin hydrochloride is represented by compound of structural formula II
  • Metformin hydrochloride is a white to off-white crystalline powder. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol and is practically insoluble in ether, acetone and chloroform.
  • Saxagliptin hydrochloride tablets has been approved in USA as on July 31 , 2009 under the trade name Onglyza ® and is available in the strength of 2.5mg and 5mg. The product is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.
  • CN102379869A discloses novel oral formulation of Saxagliptin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein said oral formulation is a tablet, capsule, dispersible tablets, chewable tablets, pills, granules, dry suspension, orally disintegrating tablets, soft capsules, buccal tablets, effervescent tablets, oral solutions, oral suspensions, drops, sustained release formulations or controlled release formulations, for the treatment of diabetes or related diseases.
  • the invention of this Chinese Patent Publication CN102379869A was particularly directed towards dispersible composition of Saxagliptin or salt thereof.
  • This patent publication generically discloses wide variety of dosage forms including effervescent tablets; however, it does not teach about technology, composition, method of manufacturing or need of developing the effervescent composition of Saxagliptin or salt thereof.
  • WO2015040460 discloses stable effervescent tablet, granule or powder composition free from sodium introduced by the effervescing couple, comprising an effective amount of antidiabetic compound metformin.
  • the PCT Publication No. WO2014191806 discloses delayed-release pharmaceutical composition, comprising: an effervescent tablet, granule, or powder and effective amount of metformin as active ingredient.
  • the PCT Publication No. WO20131 15745 discloses effervescent composition comprising Voglibose and metformin hydrochloride.
  • the commercially marketed product of Saxagliptin for the treatment of type 2 diabetes is available in the form of conventional immediate release tablet.
  • the commercially marketed product of Saxagliptin or salt thereof as well as products known in the prior art suffer from several drawbacks in terms of bioavailability and in terms of release of active ingredient from the dosage form. Also, they have several adverse effects such as upper respiratory tract infection, urinary tract infection, headache, hypersensitivity reactions including anaphylaxis, angioedema and exfoliative skin conditions, acute pancreatitis, Severe and disabling arthralgia.
  • Saxagliptin is classified as BCS Class 3 drug which is high soluble and low permeable.
  • the intrinsic membrane permeability of Saxagliptin is very low; therefore, absorption is limited by the permeation rate. Due to its low permeability 75% of Saxagliptin is absorbed and the oral systemic bioavailability is only 50% compared to intravenous administration.
  • compositions comprising Saxagliptin or salt thereof which allow more permeation of Saxagliptin through gastrointestinal membrane and efficient release of Saxagliptin or salt thereof through the dosage form.
  • a first aspect of the present invention is to provide effervescent compositions comprising Saxagliptin or salt thereof.
  • compositions comprising Saxagliptin or salt thereof along with one or more pharmaceutically acceptable excipient.
  • In another aspect of the present invention is to provide effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet of Saxagliptin or salt thereof.
  • In another aspect of the present invention is to provide effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet of Saxagliptin or salt thereof comprising one or more pharmaceutically acceptable excipient.
  • the present invention is to provide process of manufacturing the effervescent compositions comprising Saxagliptin or salt thereof. In another aspect of the present invention is to provide effervescent compositions comprising Saxagliptin or salt thereof optionally in combination with metformin or salt thereof. In another aspect of the present invention is to provide method of treating type 2 diabetes by administering effervescent composition comprising Saxagliptin or salt thereof. In another aspect of the present invention is to provide method of treating type 2 diabetes by administering effervescent composition comprising Saxagliptin or salt thereof optionally in combination with metformin or salt thereof.
  • the present invention relates to effervescent compositions comprising Saxagliptin or salt thereof.
  • the effervescent compositions of the present invention may be in the form of composition which is meant to be administered directly in to the gastrointestinal tract via oral route.
  • the effervescent compositions of the present invention may float in the gastrointestinal tract.
  • compositions of the present invention may be in the form of composition which is meant to be added into the glass of water just before administration and the drug solution or dispersion is to be consumed immediately.
  • effervescent composition means the composition of Saxagliptin or salt thereof which upon contact with aqueous media produces carbon dioxide.
  • effervescent composition also means the composition of Saxagliptin or salt thereof which comprises acidic agent and basic agent.
  • the effervescent compositions of the present invention offer enhanced dissolution and absorption of saxagliptin or salt thereof resulting in increased bioavailability. According to present invention Saxagliptin or salt thereof are absorbed better from effervescent formulations as compared to dry, solid tablet formulations.
  • the effervescent compositions of the present invention provide quick dissolution upon contact with aqueous media, clear aqueous composition after dissolution, pleasant taste and enhanced absorption.
  • the effervescent compositions comprising Saxagliptin or salt thereof of the present invention may be in the form of effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet.
  • the effervescent compositions comprising Saxagliptin or salt thereof may contain one or more pharmaceutically acceptable excipient selected from the group consisting of diluents, acidic agent, basic agent, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavor, pH regulating agent, stabilizing agent, lubricant, glidant and coloring agents.
  • diluents include but not limited to mannitol, sorbitol, xylitol, cellulose derivatives, starch, maltodextrin, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide or mixture thereof.
  • the examples of acidic agents include but not limited to citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, anhydrides and salts of acid or mixture thereof.
  • the acid agent is present in the effervescent composition in an amount of about 3% to about 75% based on the total weight of the composition; preferably in an amount of about 5% to about 40%; more preferably in an amount of about 5% to about 15%.
  • the examples of basic agents include but not limited to sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, arginine carbonate or mixture thereof.
  • the basic agent is present in the effervescent composition in an amount of about 5% to about 80% based on the total weight of the composition; preferably in an amount of about 20% to about 50%.
  • binders include but not limited to, ethyl cellulose, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch or mixture thereof.
  • the binder is present in the effervescent composition in an amount of about 0.5% to about 30% based on the total weight of the composition; preferably in an amount of about 1% to about 10%
  • disintegrants include but not limited to croscarmellose sodium, carboxymethyl cellulose, chitosan, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, starch, sodium starch glycolate or mixture thereof.
  • the disintegrant is present in the effervescent composition in an amount of about 1% to about 20% based on the weight of the composition.
  • solubilizing agent or surfactant examples include but not limited to polyethylene glycol, polyvinylpyrrolidone, dextran, polysorbate, sodium lauryl sulphate, polyoxyethylene, polyoxypropylene glycol or mixture thereof.
  • the solubilizing agent is present in the effervescent composition in an amount of about 0.1% to about 20% based on the total weight of the composition.
  • sweeteners include but not limited to acesulfame potassium, sodium saccharin, cyclamates, sucralose or mixture thereof.
  • sweetener is present in the effervescent composition in an amount of about 0.1% to about 6% based on the total weight of the composition; preferably in an amount of about 0.1% to about 2%
  • flavor include but not limited to fruit flavor, peppermint flavor or mixture thereof.
  • the flavor is present in the effervescent composition in an amount of about 0% to about 10% based on the total weight of the composition; preferably in an amount of about 2% to about 6%
  • pH regulating agent examples include but not limited to fumarate, citrate, phosphate, carbonate, tartrate, acetate, amino acid salts or mixture thereof.
  • stabilizing agent examples include but not limited to tocopherol, cyclodextrin, tetrasodium edetate, nicotinamide or mixture thereof.
  • lubricant examples include but not limited to calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or mixture thereof.
  • the lubricant is present in the effervescent composition in an amount of about 0.1% to about 6% based on the total weight of the composition; preferably in an amount of about 0.2 to about 4%
  • glidant examples include but not limited to silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate or mixture thereof.
  • the glidant is present in the effervescent composition in an amount of about 0.1% to about 20% based on the total weight of the composition.
  • coloring agents include but not limited to titanium dioxide and dye suitable for food such as those known as F.D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika or mixture thereof.
  • the coloring agent is present in the effervescent composition in an amount of about 0.1% to about 3.5% based on the total weight of the composition.
  • the present invention is to provide process of manufacturing the effervescent compositions comprising Saxagliptin or salt thereof.
  • the effervescent compositions comprising Saxagliptin or salt thereof of the present invention can be manufactured by process such as direct compression, dry granulation (slugging), wet granulation, heat fusion, roller compaction and hot melt extrusion.
  • the process of manufacturing effervescent composition comprising admixture of Saxagliptin or salt thereof, acidic agent, basic agent optionally along with one or more pharmaceutically acceptable excipient; wherein said admixture can be either filled in to the capsule, sachet; or compressed in to the unit dosage form.
  • the compressed unit dosage form may be tablet, caplet and like.
  • the effervescent composition can comprise any suitable amount of the Saxagliptin or salt thereof in order to produce an effective blood level of the Saxagliptin in the type 2 diabetic patient.
  • the weight percentage of Saxagliptin or salt thereof can be 0.05% to 90%, preferably 0.5 to 70% based on the total weight of composition.
  • the amount of Saxagliptin or salt thereof may ranges from 0.5mg to 50mg, preferably 0.5 to 20mg, more preferably 1.25mg, 2.5mg, 5mg, 7.5mg and lOmg.
  • the effervescent composition of the present invention may comprise Saxagliptin base or its salt like hydrochloride, bromide, nitrate, fumarate, sulfate, maleate, citrate, trifluoroacetic acid salt, benzoate, methanesulfonate, benzene sulfonate, butenedioate, P- toluenesulfonate, phosphate, aspartate, glycinates, malonates, succinate, acetate, hemifumarate, perchlorates, arginine.
  • the effervescent composition of the present invention preferably contains hydrochloride salt of saxagliptin.
  • the ratio of acidic to basic agent may ranges between 1 :3 to 3: 1.
  • the acidic agents may be like citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, anhydrides and salts of acid or mixture thereof; more preferably acidic agents. More preferably acidic agents may be citric acid.
  • the basic agents may be like sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, arginine carbonate. More preferably basic agent may be sodium bicarbonate.
  • Acidic agent and basic agent present in the effervescent composition reacts with aqueous media; wherein acid neutralizes base with the liberation of carbon dioxide and formation of acid salt and water
  • the effervescent compositions comprising Saxagliptin or salt thereof of the present invention reacts with aqueous media and produces carbon dioxide by effervescent reaction.
  • the carbon dioxide produced by effervescent reaction allows enhanced permeability of Saxagliptin or salt thereof due to an alteration of the paracellular as well as transcellular pathway.
  • the paracellular pathway is the primary route of absorption for active ingredients in which solutes diffuse into the intercellular space between epithelial cells.
  • the carbon dioxide produced by effervescent alters (widens) the intercellular space between cells, which leads to greater absorption of active ingredients.
  • the effervescent compositions comprising Saxagliptin or salt thereof of the present invention also promote transcellular absorption by inducing a change in the cell membrane structure.
  • the effervescent compositions comprising Saxagliptin or salt thereof of the present invention shows quick disintegration and dissolution upon contact with water.
  • the effervescent composition of the present invention when formulated as tablet has a disintegration time of about 300 seconds or less.
  • the disintegration time of the effervescent tablet is about 180 seconds or less and more preferably about 90 seconds or less.
  • the disintegration time is measured in 200 ml of water at room temperature of about 25°C ⁇ 5°C.
  • the effervescent compositions comprising Saxagliptin or salt thereof of the present invention upon dissolution has pH ranges from 3 to 6.5.
  • the pH is measured in 200 ml of water at room temperature of about 25°C ⁇ 5°C.
  • the effervescent compositions comprising Saxagliptin or salt thereof of the present invention has pleasant taste which allows patient acceptability and better compliance in the treatment of type 2 diabetes.
  • the effervescent compositions comprising Saxagliptin or salt thereof of the present invention can be made up of any weight with suitable quantities of Saxagliptin or salt thereof and pharmaceutically acceptable excipient.
  • compositions of present invention like appearance, thickness, weight variation, hardness, friability, smell, taste, after taste were found to be satisfactory.
  • the effervescent compositions comprising Saxagliptin or salt thereof of the present invention may contain optionally one or more therapeutic agent selected from the group consisting of analgesics, antipyretics, antihistamines, anorexics, antiasthmatics, antiflatulents, antimigraine agents, antispasmodics, decongestants, antiallergic agents, anxiolytic, hypnotics, stimulants, antibiotics, antidiabetic agents, oncolytic agents, expectorants, electrolyte preparations, laxatives, vitamins, phytopharmaceuticals, pulmonary drugs, antihypertensives, antiemetics, anti-inflammatory drugs, renal drugs, steroids, drugs for neurological disorders, anti-psychotic drugs, drugs for treating endocrine disorders, drugs for promoting immunology, drugs for treating osteoarthritis, drugs for treating glaucoma, drugs for treating allergic rhinitis, drugs for treating anemias and other hematological disorders, drugs for treating infectious diseases, drugs
  • one or more therapeutic agent selected from the group consisting of antidiabetic agent wherein anti-diabetic agent is selected from the group consisting of like biguanides, insulin, long and short acting insulin analogues, sulfonylureas, DPP-IV inhibitors, SGLT2 inhibitors, 1 lbeta-hydroxysteroid dehydrogenase inhibitors, glucokinase activators, AMPK activators, alpha-glucosidase inhibitors, Glp- 1 receptor agonists, G1P receptor agonists, a glycogen phosphorylase inhibitor, an inhibitor of fatty acid binding protein, DGAT inhibitors, PPAR gamma agonists, PPAR delta agonists, and other antidiabetics derived from thiazolidinediones.
  • anti-diabetic agent is selected from the group consisting of like biguanides, insulin, long and short acting insulin analogues, sulfonylureas
  • the antidiabetic agent is biguanide wherein the biguanide is a metformin or salt thereof.
  • compositions comprising Saxagliptin or salt thereof, optionally in combination with metformin in the treatment of type 2 diabetes patient.
  • compositions comprising Saxagliptin or salt thereof in combination with metformin provides better patient compliance for patients whose diabetes is not controlled on Saxagliptin monotherapy.
  • the effervescent composition can comprise any suitable amount of the Saxagliptin or salt thereof or metformin or salt thereof in order to produce an effective blood level of the Saxagliptin in the type 2 diabetic patient with less adverse effect such as upper respiratory tract infection, urinary tract infection, headache, hypersensitivity reactions including anaphylaxis, angioedema and exfoliative skin conditions, acute pancreatitis, severe and disabling arthralgia.
  • the effervescent composition can comprise any suitable amount of the Saxagliptin or salt thereof or metformin or salt thereof; the amount of metformin or salt thereof ranges from 200mg to 2gm; preferably 250mg to 1.5gm.
  • the amount of Saxagliptin or salt thereof ranges from 0.5mg to 50mg, preferably 0.5 to 20mg, more preferably 1.25mg, 2.5mg, 5mg, 7.5mg and lOmg.
  • compositions comprising Saxagliptin or salt thereof optionally in combination with metformin or salt thereof of the present invention can be packaged in suitable air tight containers and moisture proof packs.
  • Magnesium stearate was sifted through ASTM #40.
  • step 1 was lubricated with magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Example 2 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Magnesium stearate was sifted through ASTM #40.
  • step 1 was lubricated with part quantity magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablets at lower hardness using tablet compression machine.
  • Milled granules of step-5 were lubricated by mixing with remaining quantity of magnesium stearate of step -2.
  • step 6 The blend of step 6 was compressed using suitable tooling fitted to compression machine.
  • Saxagliptin hydrochloride and mannitol were sifted through ASTM #40 and mixed in a granulator.
  • Step -1 Materials from Step -1 were granulated using binder of step -2 and obtained granules were dried and milled.
  • Milled granules were mixed with citric acid, sodium citrate, sodium bicarbonate, sucralose, cherry flavor and colloidal silicon dioxide.
  • Magnesium stearate was sifted through ASTM #60.
  • step 4 was lubricated with magnesium stearate of step 5.
  • step 6 The blend of step 6 was compressed into tablet using tablet compression machine.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.
  • Metformin Hydrochloride, Saxagliptin hydrochloride, Sodium bicarbonate, Mannitol, Sucralose, Polyvinyl Pyrrolidone, Forest Fruit Flavor and colloidal silicon dioxide were sifted through ASTM #40. Citric acid and Sodium citrate were sifted through 20 # and mixed in blender.
  • Magnesium stearate was sifted through ASTM #40.
  • step 1 was lubricated with part quantity magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablets at lower hardness using tablet compression machine.
  • Milled granules of step-5 were lubricated by mixing with remaining quantity of magnesium stearate of step -2.
  • step 6 The blend of step 6 was compressed using suitable tooling fitted to compression machine.
  • Metformin Hydrochloride, Saxagliptin hydrochloride and mannitol were sifted through ASTM #40 and mixed in a granulator.
  • Step - 1 Materials from Step - 1 were granulated using binder of step -2 and obtained granules were dried and milled.
  • Milled granules were mixed with sifted citric acid, sodium citrate, sodium bicarbonate, sucralose, forest fruit flavour and colloidal silicon dioxide.
  • Magnesium stearate was sifted through ASTM #60.
  • step 4 was lubricated with magnesium stearate of step 5.
  • step 6 The blend of step 6 was compressed into tablet using tablet compression machine.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablets using tablet compression machine.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with magnesium stearate of step 2.
  • Metformin Hydrochloride, Saxagliptin hydrochloride, sodium bicarbonate, mannitol, sucralose, polyvinyl pyrrolidone, Forest fruit flavor and colloidal silicon dioxide were sifted through ASTM #40.
  • Citric acid and Sodium citrate were sifted through 20 # and mixed in blender.
  • step 1 The blend of step 1 was lubricated with sodium benzoate of step 2.
  • step 3 was compressed into tablet using tablet compression machine
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with magnesium stearate of step 2.
  • Colloidal silicon dioxide were sifted through ASTM #40, Tartaric acid was sifted through #20 and mixed.
  • Magnesium stearate was sifted through ASTM #60.
  • step 1 was lubricated with magnesium stearate of step 2.
  • step 3 The blend of step 3 was compressed into tablets using tablet compression machine.
  • Colloidal silicon dioxide were sifted through ASTM #40. Citric acid and Sodium citrate were sifted through #20 and mixed.
  • step 3 The blend of step 1 was lubricated with Sodium benzoate of step 2.
  • step 3 The blend of step 3 was compressed into tablet using tablet compression machine.

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Abstract

La présente invention concerne des compositions effervescentes comprenant de la saxagliptine ou un sel de celle-ci et un procédé de fabrication de ces compositions. Les compositions effervescentes comprennent un agent acide, un agent basique facultativement avec un ou plusieurs excipients pharmaceutiquement acceptables. Les compositions effervescentes permettent une dissolution rapide, un goût agréable et une absorption améliorée dans le traitement du diabète de type 2. Les compositions effervescentes contiennent éventuellement de la metformine dans le traitement du diabète de type 2 dont le diabète n'est pas contrôlé sur la monothérapie de saxagliptine.
PCT/IB2018/052313 2017-04-07 2018-04-04 Compositions effervescentes comprenant de la saxagliptine ou un sel de celle-ci Ceased WO2018185669A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN201721012521 2017-04-07
IN201721012521 2017-04-07
IN201721012522 2017-04-07
IN201721012522 2017-04-07

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WO2018185669A1 true WO2018185669A1 (fr) 2018-10-11

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CN112494485A (zh) * 2020-11-26 2021-03-16 北京福元医药股份有限公司 一种沙格列汀和盐酸二甲双胍缓释片
WO2021054912A1 (fr) 2019-09-16 2021-03-25 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulations de comprimés effervescents comprenant de la dapagliflozine et de la metformine

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US20110206766A1 (en) * 2008-04-03 2011-08-25 Boehringer Ingelheim International Gmbh Dpp-iv inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
WO2013077824A1 (fr) * 2011-11-23 2013-05-30 Mahmut Bilgic Procédé de fabrication d'une préparation comprenant de la metformine
WO2013095316A1 (fr) * 2011-12-19 2013-06-27 Mahmut Bilgic Combinaison synergique comprenant un agent anti-diabétique
WO2013179307A2 (fr) * 2012-05-29 2013-12-05 Mylan Laboratories Limited Compositions pharmaceutiques stabilisées de saxagliptine
WO2017098481A1 (fr) * 2015-12-12 2017-06-15 Steerlife India Private Limited Compositions effervescentes de metformine et leurs procédés de préparation

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US20110206766A1 (en) * 2008-04-03 2011-08-25 Boehringer Ingelheim International Gmbh Dpp-iv inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
WO2013077824A1 (fr) * 2011-11-23 2013-05-30 Mahmut Bilgic Procédé de fabrication d'une préparation comprenant de la metformine
WO2013095316A1 (fr) * 2011-12-19 2013-06-27 Mahmut Bilgic Combinaison synergique comprenant un agent anti-diabétique
WO2013179307A2 (fr) * 2012-05-29 2013-12-05 Mylan Laboratories Limited Compositions pharmaceutiques stabilisées de saxagliptine
WO2017098481A1 (fr) * 2015-12-12 2017-06-15 Steerlife India Private Limited Compositions effervescentes de metformine et leurs procédés de préparation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021054912A1 (fr) 2019-09-16 2021-03-25 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulations de comprimés effervescents comprenant de la dapagliflozine et de la metformine
EP4031122A4 (fr) * 2019-09-16 2023-08-30 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulations de comprimés effervescents comprenant de la dapagliflozine et de la metformine
CN112494485A (zh) * 2020-11-26 2021-03-16 北京福元医药股份有限公司 一种沙格列汀和盐酸二甲双胍缓释片
CN112494485B (zh) * 2020-11-26 2022-04-01 北京福元医药股份有限公司 一种沙格列汀和盐酸二甲双胍缓释片

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