WO2023234901A1 - Formulation comprenant de l'empagliflozine et du chlorhydrate de metformine - Google Patents

Formulation comprenant de l'empagliflozine et du chlorhydrate de metformine Download PDF

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Publication number
WO2023234901A1
WO2023234901A1 PCT/TR2023/050471 TR2023050471W WO2023234901A1 WO 2023234901 A1 WO2023234901 A1 WO 2023234901A1 TR 2023050471 W TR2023050471 W TR 2023050471W WO 2023234901 A1 WO2023234901 A1 WO 2023234901A1
Authority
WO
WIPO (PCT)
Prior art keywords
film coated
coated tablet
empagliflozin
lactose
tablet according
Prior art date
Application number
PCT/TR2023/050471
Other languages
English (en)
Inventor
Fatih Sunel
Nur PEHLIVAN AKALIN
Merve ARMUT
Tolga GULER
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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
Priority claimed from TR2022/008868 external-priority patent/TR2022008868A1/tr
Application filed by Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Publication of WO2023234901A1 publication Critical patent/WO2023234901A1/fr

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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
    • A61K31/13—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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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

Definitions

  • the present invention relates to a film coated tablet comprising empagliflozin and metformin hydrochloride, wherein comprising at least two fillers and the amount of fillers is 10.0% to 60.0% by weight in the total composition, the tablet provides the desired stability and pharmacotechnical properties and the desired dissolution profile.
  • the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the tablet.
  • Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors.
  • Type 1 and Type 2 There are two main types of diabetes; Type 1 and Type 2:
  • Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged. In Type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot get into the body's cells for use as energy. People with Type 1 diabetes must use insulin injections to control their blood glucose.
  • Type 2 diabetes the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly. This diabetes occurs most often in people who are over 40 years old and overweighed. Type 2 diabetes may sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.
  • Metformin is antidiabetics having an orally-administrated biguanide structure.
  • Metformin hydrochloride is a white to off-white crystalline compound and it is freely soluble in water and practically insoluble in acetone, ether and chloroform.
  • Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 500 to 850 mg. It is used singly or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin.
  • metformin hydrochloride is 1,1-dimethylbiguanide hydrochloride, has the following chemical structure of Formula I.
  • Empagliflozin is a known SGLT2 inhibitor that is described for the treatment or improvement in glycemic control in patients with type 2 diabetes mellitus.
  • the chemical name of empagliflozin is 1 - chloro-4-(3-D-glucopyranos-l -yl)- 2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and its chemical structure is shown in the Formula II.
  • Combination product of empagliflozin and metformin hydrochloride is marketed under the trademark Synjardy®.
  • the combination is to help control blood glucose in people with T2D.
  • Empagliflozin a sodium glucose co-transporter-2 (SGLT2) inhibitor, removes excess glucose through the urine by blocking glucose re-absorption in the kidney.
  • SGLT2 sodium glucose co-transporter-2
  • Active ingredients have some disadvantages in the formulation and process.
  • the main problem encountered when preparing formulations comprising empagliflozin is low solubility, leading to difficulties with disintegration and dissolution times.
  • metformin is a very poorly compressible active substance and metformin presents in high amounts in a composition. This causes some problems for examples; homogeneity, flowability and dissolution profile.
  • WO2011039337 (Al) application discloses pharmaceutical compositions comprising fixed dose combinations of a SGLT-2 inhibitor drug and a partner drug, processes for the preparation thereof, and their use to treat certain diseases.
  • CN104586834 (A) application discloses a pharmaceutical composition of empagliflozin and metformin, a preparation method and application thereof.
  • the composition comprises the following components: i.) empagliflozin; ii.) metformin hydrochloride; and one or more fillers; one or more adhesives; one or more flow aids and one or more lubricants.
  • the main object of the present invention is to provide a film coated tablet comprising empagliflozin and metformin hydrochloride with having the desired level of dissolution rate and excellent physicochemical properties, such as flowability, compressibility, homogeneity, and content uniformity which overcomes the above-described problems in the prior art and have additive advantages over them.
  • Another object of the present invention is to provide a film coated tablet comprising empagliflozin and metformin hydrochloride with having high stability.
  • Another object of the present invention is to provide a process for preparing a film coated tablet comprising empagliflozin and metformin hydrochloride.
  • the process is a simple, rapid, cost effective, time-saving, and industrially convenient method.
  • a film coated tablet comprises metformin hydrochloride and empagliflozin wherein comprising at least two fillers and the amount of fillers is 10.0% to 60.0% by weight in the total composition.
  • the film coated tablet is obtained which shows the desired dissolution profile, and physicochemical properties, such as flowability, compressibility, homogeneity, and content uniformity.
  • Suitable fillers are selected from the group comprising microcrystalline cellulose, lactose, anhydrous lactose, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, neutral pellets, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof.
  • the fillers are microcrystalline cellulose and lactose.
  • the fillers provide flowability and compressibility of metformin HCI.
  • the amount of fillers is 30.0% to 50.0% by weight in the total composition.
  • the amount of microcrystalline cellulose is 5.0% to 30.0% by weight in the total composition.
  • the amount of lactose is 5.0% to 30.0% by weight in the total composition.
  • the film coated tablet comprises metformin hydrochloride and empagliflozin wherein comprising microcrystalline cellulose and lactose as filler and the amount of fillers is 10.0% to 60.0% by weight in the total composition.
  • the film coated tablet further comprises at least one glidant/lubricant.
  • Suitable glidants/lubricants are selected from the group comprising anhydrous colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, magnesium oxide, starch, silicone dioxide, talc, polyethylene glycol, stearic acid, aluminum silicate, magnesium silicate, colloidal silica or mixtures thereof.
  • the glidant/lubricant is anhydrous colloidal silicon dioxide or magnesium stearate or mixtures thereof. These excipients provide the flowability of the powder mixture.
  • the amount of glidants/lubricants is 0.2% to 10.0% by weight in the total composition, the amount of glidants/lubricants used helps to provide the desired flowability and compressibility of tablet.
  • the amount of anhydrous colloidal silicon dioxide used helps to provide the desired flowability and compressibility of tablet, the amount of anhydrous colloidal silicon dioxide is 0.1% to 5.0% by weight in each layer composition.
  • the film coated tablet is coated with at least one film coating agent.
  • Suitable film coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, talc, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), glycerin, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), iron oxide yellow, iron oxides, all kinds of Opadry®, pigments, dyes, titanium dioxide, coloring agent or mixtures thereof.
  • the film coated tablet comprises; a) Metformin HCI b) Empagliflozin c) Microcrystalline cellulose d) Lactose e) Anhydrous colloidal silicon dioxide f) Magnesium stearate
  • the film coated tablet of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression or dry granulation or wet granulation.
  • a process for the preparation of the film coated tablet comprises the following steps: a) Mixing Metformin HCI, empagliflozin, microcrystalline cellulose, lactose and anhydrous colloidal silicon dioxide, b) Sieving the mixture and then mixing, c) Adding magnesium stearate and then mixing, d) Compressing the mixture into the tablet, e) Coating the tablets with film coating agent.
  • a process for the preparation of the film coated tablet comprises the following steps: a) Mixing Metformin HCI, empagliflozin, microcrystalline cellulose and lactose, b) Granulating the mixture at step (b) with a solvent (preferably water), c) Sieving the wet granule, d) Drying the wet granules and sieving, e) Adding anhydrous colloidal silicon dioxide and magnesium stearate and then mixing, f) Compressing the mixture into the tablet, g) Coating the tablets with film coating agent.
  • a solvent is used at wet granulation.
  • Suitable solvents are selected from the group comprising pure water, dichloromethane, 0.1N HCI, methanol, ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, cyclomethicone or mixtures thereof.
  • the solvent is water.
  • Example 1 The tablet formulation
  • a process for example 1 a) Sieving metformin HCI through 2 mm, b) Mixing Metformin HCI, empagliflozin, microcrystalline cellulose, lactose and colloidal silicon dioxide, c) Sieving the mixture through 630 p and then mixing, d) Adding magnesium stearate and then mixing, e) Compressing the mixture into the tablet, f) Coating the tablets with film coating agent.
  • a process for example 1 a) Sieving metformin HCI through 2 mm, b) Mixing Metformin HCI, empagliflozin, microcrystalline cellulose and lactose, c) Granulating the mixture at step (b) with a solvent (preferably water), d) Sieving the wet granule through 8 mm, e) Drying the wet granules at 50 °C and sieving through 1.5 mm, f) Adding anhydrous colloidal silicon dioxide and magnesium stearate and then mixing, g) Compressing the mixture into the tablet, h) Coating the tablets with film coating agent.
  • a solvent preferably water

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un comprimé pelliculé comprenant de l'empagliflozine et du chlorhydrate de metformine, ledit comprimé comprenant au moins deux charges et la quantité de charges étant de 10,0 % à 60,0 % en poids par rapport à la composition totale, le comprimé offrant la stabilité et les propriétés pharmacotechniques souhaitées ainsi que le profil de dissolution souhaité. La présente invention concerne également un procédé simple, rapide, économique, offrant un gain de temps et pratique au plan industriel pour la préparation dudit comprimé.
PCT/TR2023/050471 2022-05-31 2023-05-25 Formulation comprenant de l'empagliflozine et du chlorhydrate de metformine WO2023234901A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2022/008868 TR2022008868A1 (tr) 2022-05-31 Empagli̇flozi̇n ve metformi̇n hi̇droklorür i̇çeren bi̇r formülasyon
TR2022008868 2022-05-31

Publications (1)

Publication Number Publication Date
WO2023234901A1 true WO2023234901A1 (fr) 2023-12-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2023/050471 WO2023234901A1 (fr) 2022-05-31 2023-05-25 Formulation comprenant de l'empagliflozine et du chlorhydrate de metformine

Country Status (1)

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WO (1) WO2023234901A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017093419A1 (fr) * 2015-12-04 2017-06-08 Boehringer Ingelheim International Gmbh Composition pharmaceutique, méthodes de traitement et leurs utilisations
CN113616624A (zh) * 2021-09-16 2021-11-09 南京康川济医药科技有限公司 一种恩格列净二甲双胍缓释制剂及其制备方法
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
WO2017093419A1 (fr) * 2015-12-04 2017-06-08 Boehringer Ingelheim International Gmbh Composition pharmaceutique, méthodes de traitement et leurs utilisations
CN113616624A (zh) * 2021-09-16 2021-11-09 南京康川济医药科技有限公司 一种恩格列净二甲双胍缓释制剂及其制备方法
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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