WO2019244171A1 - Composition pharmaceutique orale stable d'empagliflozine amorphe et son procédé de préparation - Google Patents

Composition pharmaceutique orale stable d'empagliflozine amorphe et son procédé de préparation Download PDF

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Publication number
WO2019244171A1
WO2019244171A1 PCT/IN2019/050464 IN2019050464W WO2019244171A1 WO 2019244171 A1 WO2019244171 A1 WO 2019244171A1 IN 2019050464 W IN2019050464 W IN 2019050464W WO 2019244171 A1 WO2019244171 A1 WO 2019244171A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
empagliflozin
composition
present
amorphous
Prior art date
Application number
PCT/IN2019/050464
Other languages
English (en)
Inventor
Arum Kumar PANDEY
Dr. Roshan Lal SANDAL
Chinmaya Nayak
Original Assignee
Alkem Laboratories 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 Alkem Laboratories Ltd. filed Critical Alkem Laboratories Ltd.
Publication of WO2019244171A1 publication Critical patent/WO2019244171A1/fr

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Classifications

    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin

Definitions

  • the Invention relates to a stable oral pharmaceutical composition of Amorphous Empagliflozin and process for preparing thereof
  • Empagliflozin is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2).
  • Empagliflozin is known chemically as (1S)-1, 5-anhydro-l-(4-chloro-3- ⁇ 4-[(3S) - tetrahydrofuran-3-yloxy) benzyl ⁇ phenyl)-D-glucitol / also known as D-Glucitol, 1, 5-anhydro-l-C-.
  • SGLT-2 sodium glucose co-transporter-2
  • SGLT2 co-transporters are responsible for reabsorption of glucose from the glomerular filtrate in the kidney.
  • the glucuretic effect resulting from SGLT2 inhibition reduces renal absorption and lowers the renal threshold for glucose, therefore resulting in increased glucose excretion. Additionally, it contributes to reduced hyperglycaemia and also assists weight loss and blood pressure reduction.
  • empaglifozin was 41.2% eliminated in feces and 54.4% eliminated in urine. Apparent oral clearance was found to be 10.6 L/h based on population pharmacokinetic analysis.
  • empaglifozin is primarily metabolized by glucuronidation by 5'-diphospho-glucuronosyltransferases UG2B7, UGT1A3, UGT1A8, and UGT1A9.
  • the most abundant metabolites are three glucuronide metabolites: 2-0-, 3-0-, and 6-0- glucuronide.
  • Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms.
  • SGLT-2 sodium glucose co-transporter-2
  • SGLT2 co-transporters are responsible for reabsorption of glucose from the glomerular filtrate in the kidney.
  • the glucuretic effect resulting from SGLT2 inhibition reduces renal absorption and lowers the renal threshold for glucose, resulting in increased glucose excretion. Additionally, it contributes to reduced hyperglycaemia, assists weight loss, and reduces blood pressure.
  • Empagliflozin is available in the United States of America as JARDIANCE* (empagliflozin) oral tablets and indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus and to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease. It is available in various strengths i.e. 10 and 25 mg strengths for oral administration.
  • US 7,579,449 B2 discloses glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture.
  • US 7713938 B2 discloses crystalline form of l-chloro-4-$-D-glucopyranos-l-yl)-2-[4-((S)- tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments.
  • US 8551957 B2 discloses a pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative in combination with a DPP IV inhibitor which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia.
  • US 20110014284 A1 discloses pharmaceutical compositions comprising a SGLT-2 inhibitor, pharmaceutical dosage forms, their preparation, their use and methods for treating metabolic disorders.
  • US 20140256624 A1 discloses a pharmaceutical composition comprising an SGLT2 inhibitor and an insulin which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia.
  • US 7723309 B2 discloses crystalline forms of l-chloro-4- ⁇ -D-glucopyranos-l-yl)-2-[4-((R)- tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for the preparation thereof, as well as, the use thereof for preparing medicaments.
  • WO 2016169534 A1 discloses novel forms of amorphous empagliflozin, processes for preparing the same and the use thereof in dosage forms. These solid forms of amorphous empagliflozin can be advantageously used to increase the chemical and polymorphic stability of amorphous empagliflozin.
  • WO 2016051368 A1 discloses a solid dispersion of a complex of amorphous empagliflozin and a cyclodextrin.
  • An amorphous form generally provides better solubility and bioavailability than the crystalline form and may be useful for formulations which can have better stability, solubility and compressibility etc. which are important for formulation and product manufacturing.
  • amorphous form of drug with high purity to meet the needs of regulatory agencies and highly reproducible processes for its preparation. in view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of oral solid dosage form of amorphous form of empagliflozin.
  • the amorphous form provided herein in the composition of the present invention is stable under ordinary stability conditions with respect to purity and storage.
  • a coating wherein the percentage by weight is relative to the total weight of the composition and wherein about 95 to 98% of Empagliflozin is released from the composition in about 20 minutes in an aqueous buffer solution of about pH 6.8 with a paddle speed of 75 rpm.
  • It is another object of the present invention to provide a stable oral pharmaceutical composition comprising;
  • the present invention relates to a stable oral pharmaceutical composition of Amorphous Empagliflozin and process for preparing thereof
  • A) A stable oral pharmaceutical composition comprising:
  • a stable oral pharmaceutical composition comprising;
  • a process of preparing the stable oral pharmaceutical composition as B above comprises: a) Dissolving empagliflozin in a mixture of Isopropyl alcohol and methylene chloride and adding hydroxypropyl methylcellulose to the above solution. b) Spraying the solution of a) into mixture of microcrystalline cellulose, maize starch and croscarmellose sodium, then adding required amount of colloidal silicon dioxide & Magnesium stearate c) Compressing the lubricated blend of b) into tablets, followed by film coating of the tablets. d) The pharmaceutical compositions as in A & B above, wherein the said pharmaceutical composition is as physically stable as the commercially available compositions in the United States of America i.e. JARDIANCE ⁇ oral tablets. e) The pharmaceutical compositions as in A & B above, wherein the said pharmaceutical composition is bioequivalent to the commercially available compositions in the United States of America i.e. JARDIANCE ® oral tablets.
  • the present invention relates to a stable oral pharmaceutical composition of amorphous empagliflozin comprising higher percentage of disintegrant which surprisingly shows better dissolution rate as compared to the composition having conventional amount of disintegrant.
  • stable refers to chemical stability of amorphous form of Empagliflozin in solid dosage forms wherein there is no change in assay values and dissolution and/or the total impurity remains less than 1%, when the dosage form is kept at 40 e C/75% RH for 6 months.
  • composition as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant that the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof
  • polymorph refers to polymorph form of Empagliflozin which, when present as a solid, exists as different crystalline forms.
  • polymorph includes solid forms of a compound such as crystals, microcrystals, foams, and powders, among others.
  • Polymorphs typically differ in their physical properties due to the order of the molecules in the lattice of the polymorph, in addition, the physical properties of the polymorph can differ due to the presence of solvates or other molecules incorporated into the lattice of the polymorph.
  • polymorphs are readily distinguished using techniques such as melting point, rate of dissolution, Infrared (IR) and Raman spectroscopy, and X-ray diffraction such as crystal and powder techniques.
  • amorphous refers to a compound having no definite crystal structure or form, in the present application, the term amorphous refers to amorphous Empagliflozin that can be present in the amorphous form as a solid or in a solution.
  • the dosage form can be formulated as oral formulation by any suitable granulation process, dry or wet in the form of tablet, coated tablet or multi-particulate formulation known to those skilled in the art.
  • the dosage form can be formulated as oral tablets formulation and dissolution of formulated oral tablets is evaluated by Drug Dissolution Apparatus II USP (Paddle), known to those skilled in the art.
  • the pharmaceutical composition of the present invention may further comprise conventional pharmaceutically acceptable excipients.
  • Conventional pharmaceutical excipients include those which function in a dosage form, for example, as fillers or diluents, binders, disintegrants, lubricants, glidants, and film forming material.
  • Disintegrants include, but are not limited to crospovidone, croscarmellose sodium, sodium starch glycolate, combinations thereof and the like.
  • disintegrant can be present in an amount ranging from about 45% to about 55%, preferably from about 48% to about 53%, or from about 50% to about 52% by weight relative to the total weight of the composition.
  • Fillers or diluents for use in the formulations of the present invention include fillers or diluents typically used in the formulation of pharmaceuticals.
  • Examples of fillers or diluents for use in accordance with the present invention include but are not limited to lactose, dextrose, glucose, sucrose, microcrystalline cellulose, maize starch, pregelatinized starch, modified corn starch, cellulose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium carbonates, magnesium carbonates, combinations thereof, and the like.
  • lactose selected from the group consisting of anhydrous lactose, lactose monohydrate, directly compressible anhydrous lactose, and modified lactose monohydrate
  • one or more diluents can be present in an amount ranging from about 10% to about 40%, preferably from about 15% to about 35%, or from about 20% to about 30% by weight relative to the total weight of the composition.
  • Binders for use in the formulations of the present invention include binders commonly used in the formulation of pharmaceuticals.
  • binders for use in accordance with the present invention include but are not limited to hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, glycol, sucrose, dextrose, corn syrup, acacia, targacanth, guar, alginates, maize starch, corn starch, pregelatinized starch, modified corn starch, polyvinylpyrrolidone, polyethylene, polyethylene glycol, combinations thereof and the like.
  • binder can be present in an amount ranging from about 5% to about 15%, for example, from about 8% to about 13%, or from about 10% to about 12% by weight relative to the total weight of the composition
  • Lubricants for use in the formulations of the present invention include lubricants commonly used in the formulation of pharmaceuticals.
  • examples of lubricants for use in accordance with the present invention include but are not limited to magnesium carbonate, magnesium lauryl sulphate, calcium silicate, talc, fumed silicon dioxide, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium acetate, sodium chloride, combinations thereof.
  • one or more lubricants can be present in an amount ranging from about 0.5% to about 2%, preferably from about 0.75% to about 1.5, or from about 1% to about 1.2% by weight relative to the total weight of the composition.
  • Coats include, but are not limited to Opadry. In one embodiment, the coat is Opadry yellow. In another embodiment, the coat is Opadry II. In the present invention coat can be present in an amount ranging from about 1% to about 3%, preferably from about 0.7% to about 0.9 % by weight relative to the total weight of the composition
  • compositions of the present invention may be prepared by the conventional processes such as wet granulation, dry granulation or direct compression as known to those skilled in the art.
  • composition of the present invention was prepared as given in table 1.
  • Prelubricatlon was carried out with Colloidal silicon dioxide and mixed for 15 minutes in blender & Lubrication was carried out with Magnesium stearate for S minutes. Compressed the lubricated Blend In to tablets with suitable punch size and shape. Finally film coating of compressed tablets carried out with suitable coating material.
  • composition of the present invention was prepared as given in table 2.
  • Prelubrication was carried out with Croscarmellose sodium, Colloidal silicon dioxide & Microcrystalline Cellulose and mixed for 15 minutes in blender. Lubrication was carried out with Magnesium stearate for 5 minutes. Compressed the lubricated blend in to tablets with suitable punch size and shape. Finally film coating of compressed tablets carried out with suitable coating material.
  • composition of the comparative Batch was prepared as given in table 3.
  • Example 1 & Example 2 of the present invention The comparative dissolution study between Example 1 & Example 2 of the present invention with example 3 (the comparative batch) are shown in table-6. From the given data, it can be see that about 95 to 98 % of Empagliflozin is released in about 20 minutes in an aqueous buffer solution of about pH 6.8 with a paddle speed of 75 rpm wherein the an aqueous buffer solution is 0.05 M Phosphate Buffer in Dissolution Apparatus II USP (Paddle) of Example 1 & Example 2 (in both cases from about 45%-55% disintegrant is used) of the present invention.
  • an aqueous buffer solution is 0.05 M Phosphate Buffer in Dissolution Apparatus II USP (Paddle) of Example 1 & Example 2 (in both cases from about 45%-55% disintegrant is used) of the present invention.
  • composition comprising higher percentage of disintegrant has shown better dissolution rate contrast to the composition having conventional amount of disintegrant.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique orale stable comprenant (a) de l'empagliflozine ou un sel pharmaceutiquement acceptable de celle-ci, (b) au moins un délitant, et (c) un ou plusieurs excipients pharmaceutiquement acceptables.
PCT/IN2019/050464 2018-06-20 2019-06-20 Composition pharmaceutique orale stable d'empagliflozine amorphe et son procédé de préparation WO2019244171A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201821022675 2018-06-20
IN201821022675 2018-06-20

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WO2019244171A1 true WO2019244171A1 (fr) 2019-12-26

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140303097A1 (en) * 2013-04-05 2014-10-09 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
CN104586803A (zh) * 2015-02-12 2015-05-06 浙江华海药业股份有限公司 一种恩格列净微晶纤维素组合物的制备方法
CN106692069A (zh) * 2017-02-14 2017-05-24 佛山市腾瑞医药科技有限公司 一种恩格列净固体分散体制剂及其制备方法
US20170333465A1 (en) * 2013-04-18 2017-11-23 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140303097A1 (en) * 2013-04-05 2014-10-09 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US20170333465A1 (en) * 2013-04-18 2017-11-23 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
CN104586803A (zh) * 2015-02-12 2015-05-06 浙江华海药业股份有限公司 一种恩格列净微晶纤维素组合物的制备方法
CN106692069A (zh) * 2017-02-14 2017-05-24 佛山市腾瑞医药科技有限公司 一种恩格列净固体分散体制剂及其制备方法

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