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WO2025080212A1 - Composition pharmaceutique d'empagliflozine et de metformine à profil de dissolution amélioré - Google Patents

Composition pharmaceutique d'empagliflozine et de metformine à profil de dissolution amélioré Download PDF

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Publication number
WO2025080212A1
WO2025080212A1 PCT/TR2023/051105 TR2023051105W WO2025080212A1 WO 2025080212 A1 WO2025080212 A1 WO 2025080212A1 TR 2023051105 W TR2023051105 W TR 2023051105W WO 2025080212 A1 WO2025080212 A1 WO 2025080212A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
glidant
granular phase
metformin
empagliflozin
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.)
Pending
Application number
PCT/TR2023/051105
Other languages
English (en)
Inventor
Abdulhaluk SANCAK
Yunus SANCAK
Elif Zehra ATUKEREN
Hakan Gürpinar
Akif ERDOĞAN
Şeyhmus EMEN
Koray YILMAZ
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.)
Humanis Saglik AS
Original Assignee
Humanis Saglik AS
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 Humanis Saglik AS filed Critical Humanis Saglik AS
Priority to PCT/TR2023/051105 priority Critical patent/WO2025080212A1/fr
Publication of WO2025080212A1 publication Critical patent/WO2025080212A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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

Definitions

  • the present invention relates to a wet granulation process for preparing a pharmaceutical composition comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, its use in the treatment of high blood sugar levels caused by type 2 diabetes.
  • the pharmaceutical composition comprises at least a glidant as pharmaceutical acceptable excipient, wherein the glidant is present both in an intra-granular and an extra-granular phase with a specific weight ratio and wherein an improved dissolution profile has been obtained.
  • Empagliflozin and Metformin combination is used with proper diet and exercise to treat high blood sugar levels caused by type 2 diabetes.
  • the brand name of the medicine for this combination is Synjardy. It is also used to lower the risk of cardiovascular death in patients with type 2 diabetes and heart or blood vessel disease.
  • Synjardy As an antidiabetic medication, there is a requirement to develop a simple, reproducible and cost-effective manufacturing process and a stable pharmaceutical composition comprising Empagliflozin and Metformin with an improved flowability, content uniformity and processability, while at the same time ensuring that the desired properties such as dissolution, stability, bioavailability are maintained and are comparable with respect to the Reference Product Synjardy.
  • An aim of the present invention to solve the problems of the prior art and is to provide an improved pharmaceutical composition comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, obtaining concurrently comparable and satisfactory dissolution rates.
  • wet granulation method involves addition of a liquid solution (with or without binder) to powders, to form a wet mass or it forms granules by adding the powder together with an adhesive, instead of by compaction. Then, drying process starts and then sized to obtained granules with desired mesh. The granulate may then be tabletted /compressed, or other excipients may be added prior to tableting with suitable excipients.
  • % by total weight is used herein to mean the percentage by weight of each ingredient in an uncoated pharmaceutical composition, based on the total weight of the uncoated pharmaceutical composition.
  • the pharmaceutical composition is preferably in a form of a tablet, either uncoated or coated tablet.
  • the present invention relates to a wet granulation process for preparing a pharmaceutical composition comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and also relevant excipients, for use in the treatment of high blood sugar levels caused by type 2 diabetes.
  • Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected.
  • the present invention relates to the pharmaceutical composition
  • the pharmaceutical composition comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and also relevant excipients, wherein the excipients are selected from the group including, but are not limited to solvents, diluents, lubricants, fdlers, disintegrants, binders, surfactants, and other materials known to one of ordinary skill in the art and the mixtures thereof.
  • Lubricants can also be used in the process. Lubricants are used for preventing adhesion of the tablet material to the surfaces of the die and punches. This helps to reduce the wear and tear on the tableting equipment and to prevent the formation of tablet defects, such as cracks or chips.
  • Solvents can also be used in the process. Solvents are excipients used to enhance solubility, taste, anti-microbial effectiveness or stability, to reduce dose volume (such as oral, injections). Conversely, solvents can be used to optimize insolubility (if taste of an active pharmaceutical ingredient is an issue).
  • compositions of the present invention comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, are prepared by a wet granulation process.
  • the present invention relates to the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein the composition has an intra-granular phase and an extra-granular phase.
  • the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein Empagliflozin and Metformin as active ingredients, a certain amount of glidant, binder and solvent are in the intra-granular phase.
  • the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein remaining amount of glidant and lubricant are in the extra-granular phase.
  • the present invention relates to the pharmaceutical compositions comprising Empagliflozin and Metformin or pharmaceutically acceptable salts thereof, wherein the ratio of magnesium stearate as lubricant present in the extra-granular phase is from 0,2 to 0,8% by total weight, preferably from 0,35 to 0,65% by total weight.
  • Process flow for Preparing of Example 2 is summarized as below: a) Mixing povidone with a sufficient amount of purified water and preparing a homogenous solution, b) Sieving Empagliflozin, Metformin HC1 and a certain amount of colloidal anhydrous silica, c) Loading the substances from step b into high shear granulator and mixing at a certain speed, d) Adding the granulation solution on to the mix from step c and keeping on mixing for preparing a homogenous solution, e) Sieving the wet granules obtained after step d, f) Drying the granules from step e, g) Sieving the dried granules from step f, h) Sieving the colloidal anhydrous silica and mixing it with granules from step g homogenously, i) Sieving the magnesium stearate and adding it to the mix from step h homogenously, j) Tablet compressing, k
  • Dissolution test values for pharmaceutical compositions are one of the essential parameters for process development and solid dosage manufacturing. General properties of relevant batches are shown in Table 3.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Inorganic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de granulation par voie humide pour préparer une composition pharmaceutique comprenant de l'empagliflozine et de la metformine ou des sels pharmaceutiquement acceptables de celles-ci, ainsi que son utilisation dans le traitement des taux de glycémie élevés causés par le diabète de type 2. La composition pharmaceutique comprend au moins un agent de glissement comme excipient pharmaceutiquement acceptable, l'agent de glissement étant présent à la fois dans une phase intra-granulaire et extra-granulaire avec un rapport pondéral spécifique, un profil de dissolution amélioré ayant été obtenu.
PCT/TR2023/051105 2023-10-09 2023-10-09 Composition pharmaceutique d'empagliflozine et de metformine à profil de dissolution amélioré Pending WO2025080212A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2023/051105 WO2025080212A1 (fr) 2023-10-09 2023-10-09 Composition pharmaceutique d'empagliflozine et de metformine à profil de dissolution amélioré

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2023/051105 WO2025080212A1 (fr) 2023-10-09 2023-10-09 Composition pharmaceutique d'empagliflozine et de metformine à profil de dissolution amélioré

Publications (1)

Publication Number Publication Date
WO2025080212A1 true WO2025080212A1 (fr) 2025-04-17

Family

ID=95396143

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2023/051105 Pending WO2025080212A1 (fr) 2023-10-09 2023-10-09 Composition pharmaceutique d'empagliflozine et de metformine à profil de dissolution amélioré

Country Status (1)

Country Link
WO (1) WO2025080212A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104586834A (zh) * 2014-12-12 2015-05-06 周连才 一种艾帕列净和二甲双胍的药物组合物及其制备方法
WO2021123165A1 (fr) * 2019-12-19 2021-06-24 Krka, D.D., Novo Mesto Forme posologique comprenant une solution solide amorphe d'empagliflozine avec un polymère
CN114404436A (zh) * 2022-02-24 2022-04-29 北京百奥药业有限责任公司 一种二甲双胍恩格列净组合物及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104586834A (zh) * 2014-12-12 2015-05-06 周连才 一种艾帕列净和二甲双胍的药物组合物及其制备方法
WO2021123165A1 (fr) * 2019-12-19 2021-06-24 Krka, D.D., Novo Mesto Forme posologique comprenant une solution solide amorphe d'empagliflozine avec un polymère
CN114404436A (zh) * 2022-02-24 2022-04-29 北京百奥药业有限责任公司 一种二甲双胍恩格列净组合物及其制备方法

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