[go: up one dir, main page]

WO2023234899A1 - Formulation de comprimé bicouche comprenant de l'empagliflozine et de la metformine - Google Patents

Formulation de comprimé bicouche comprenant de l'empagliflozine et de la metformine Download PDF

Info

Publication number
WO2023234899A1
WO2023234899A1 PCT/TR2023/050469 TR2023050469W WO2023234899A1 WO 2023234899 A1 WO2023234899 A1 WO 2023234899A1 TR 2023050469 W TR2023050469 W TR 2023050469W WO 2023234899 A1 WO2023234899 A1 WO 2023234899A1
Authority
WO
WIPO (PCT)
Prior art keywords
bilayer tablet
layer
tablet according
pharmaceutical
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.)
Ceased
Application number
PCT/TR2023/050469
Other languages
English (en)
Inventor
Fatih Sunel
Nur PEHLIVAN AKALIN
Merve ARMUT
Tolga GULER
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.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret 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
Priority claimed from TR2022/008870 external-priority patent/TR2022008870A1/tr
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Priority to EP23816494.1A priority Critical patent/EP4531828A1/fr
Publication of WO2023234899A1 publication Critical patent/WO2023234899A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/2072—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
    • 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
    • A61K9/2022—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 bilayer tablet comprising empagliflozin and metformin, 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 bilayer 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. In 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 bilayer 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 bilayer tablet comprising empagliflozin and metformin hydrochloride with having high stability.
  • Another object of the present invention is to provide a process for preparing a bilayer tablet comprising empagliflozin and metformin hydrochloride.
  • the process is a simple, rapid, cost effective, time-saving, and industrially convenient method.
  • bilayer tablet refers to a layered tablet consisting of two layers of granulate compressed together to form a single tablet. This dosage form has the advantage of separating two incompatible substances. Each layer is fed from distinct feed frame with individual weight control.
  • layer and “layer composition” have the same meaning.
  • the bilayer tablet comprising empagliflozin and metformin hydrochloride offers advantages like: increased efficacy of the active components due to their additive or synergistic effect, improved adherence to treatment regimens by patients, convenience of use, and also the desired dissolution profile.
  • a pharmaceutical bilayer tablet comprises; a. first layer comprising metformin hydrochloride b. second layer comprising empagliflozin wherein each layer comprising at least one disintegrant.
  • the bilayer tablet is obtained which shows good efficacy and an appropriate dissolution profile, and physicochemical properties, such as flowability, compressibility, homogeneity, and content uniformity. Empagliflozin is low solubility, leading to difficulties with disintegration and dissolution times. Using at least one disintegrant at the second layer provides the desired dissolution profile.
  • using the disintegrant at first layer helps to provide the desired dissolution profile and disintegration rate.
  • Suitable disintegrants are selected from the group comprising croscarmellose sodium, crospovidone, sodium starch glycollate, sodium alginate, gums, starch, magnesium aluminum silicate or a mixture thereof.
  • the disintegrant is croscarmellose sodium.
  • the disintegrant is used both the first layer and the second layer.
  • the amount of disintegrants is 0.1% to 15.0% by weight, preferably 0.1% to 10.0% by weight in the first layer composition.
  • the amount of disintegrants is 3.0% to 10.0% by weight, preferably 3.0% to 5.0% in the second layer composition.
  • the bilayer tablet further comprises at least one pharmaceutically acceptable excipient which is selected from fillers, glidants/lubricants or mixtures thereof.
  • Another problem, at the first layer, encountered while developing formulations is the flowabilityproblem and compressibility of metformin HCI, which makes the production difficult. It has been observed that this problem is overcome by using at least one filler.
  • 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 filler is microcrystalline cellulose or lactose or mixtures thereof.
  • the fillers provide flowability and compressibility of metformin HCI.
  • the filler is microcrystalline cellulose in the first layer, the filler is lactose in the second layer. According to an embodiment of the present invention, the amount of fillers is 5.0% to 50.0% by weight in the first layer composition.
  • the amount of fillers is 70.0% to 85.0% by weight in the second layer composition.
  • Suitable glidants/lubricants are selected from the group comprising colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, magnesium oxide, starch, silica colloidal anhydrous, talc, polyethylene glycol, stearic acid, aluminum silicate, magnesium silicate, colloidal silica or mixtures thereof.
  • the glidant/lubricant is colloidal silicon dioxide or magnesium stearate or mixtures thereof.
  • the amount of glidants/lubricants is 0.2% to 10.0% by weight in each layer composition.
  • the amount of glidants/lubricants used helps to provide the desired flowability and compressibility of tablet.
  • the amount of colloidal silicon dioxide used helps to provide the desired flowability and compressibility of tablet, the amount of colloidal silicon dioxide is 0.1% to 5.0% by weight in each layer composition.
  • the bilayer 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 bilayer tablet comprises; a) First layer comprising metformin HCI and microcrystalline cellulose, b) Second layer comprising empagliflozin and lactose.
  • the bilayer tablet comprises; a) Metformin HCI b) Empagliflozin c) Microcrystalline cellulose d) Croscarmellose sodium e) Colloidal silicon dioxide f) Magnesium stearate g) Lactose
  • excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability, stability of an active agent. For this reason, the excipients which accompany an active agents have to be selected in a careful and conscious manner while a formulation (especially the mixture) is developed.
  • the described formulation should have no physicochemical incompatibility between the active agents and the excipients.
  • the bilayer 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.
  • the first layer is obtained by using dry granulation
  • the second layer is obtained by using wet granulation.
  • 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.
  • a process for the preparation of the bilayer tablet comprises the following steps:
  • First layer a) Sieving metformin HCI through 2 mm, b) Mixing Metformin HCI, microcrystalline cellulose and croscarmellose sodium, c) Sieving the mixture through 630 p and then mixing, d) Adding colloidal silicon dioxide and magnesium stearate and then mixing, and obtained a mixture for the first layer.
  • a solvent for example; pure water
  • Tablet compression The first layer and second layer are compressed to form a bilayer tablet.
  • Film coating Film coating with moisture-barrier coating.
  • a desired compressibility and a desired content uniformity of the bilayer tablet is obtained and it has a simple and low-cost preparation process, in favor of industrial production.
  • Example 1 The bilayer tablet formulation
  • First layer a) Sieving metformin HCI through 2 mm, b) Mixing Metformin HCI, microcrystalline cellulose and croscarmellose sodium, c) Sieving the mixture through 630 p and then mixing, d) Adding colloidal silicon dioxide and magnesium stearate and then mixing, and obtained a mixture for the first layer.
  • a solvent for example; pure water
  • Tablet compression The first layer and second layer are compressed to form a bilayer tablet.
  • Film coating Film coating with moisture-barrier coating.

Landscapes

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

Abstract

La présente invention concerne un comprimé bicouche comprenant de l'empagliflozine et de la metformine, le comprimé assurant la stabilité et les propriétés pharmacotechniques souhaitées et le profil de dissolution souhaité. La présente invention concerne également un procédé simple, rapide, économique, économe en temps et industriellement pratique de préparation du comprimé bicouche.
PCT/TR2023/050469 2022-05-31 2023-05-25 Formulation de comprimé bicouche comprenant de l'empagliflozine et de la metformine Ceased WO2023234899A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP23816494.1A EP4531828A1 (fr) 2022-05-31 2023-05-25 Formulation de comprimé bicouche comprenant de l'empagliflozine et de la metformine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2022008870 2022-05-31
TR2022/008870 TR2022008870A1 (tr) 2022-05-31 Empagli̇flozi̇n ve metformi̇n i̇çeren çi̇ft katmanli bi̇r tablet formülasyonu

Publications (1)

Publication Number Publication Date
WO2023234899A1 true WO2023234899A1 (fr) 2023-12-07

Family

ID=89025395

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2023/050469 Ceased WO2023234899A1 (fr) 2022-05-31 2023-05-25 Formulation de comprimé bicouche comprenant de l'empagliflozine et de la metformine

Country Status (1)

Country Link
WO (1) WO2023234899A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117686671A (zh) * 2023-12-11 2024-03-12 国药集团容生制药有限公司 一种优化恩格列净片剂溶出曲线及体内生物等效性的方法

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
CN107432869A (zh) * 2016-05-27 2017-12-05 天津药物研究院有限公司 包含盐酸二甲双胍和恩格列净的双层片及其制备方法
KR20210084053A (ko) * 2019-12-27 2021-07-07 (주)휴온스 엠파글리플로진 및 메트포르민을 포함하는 약제학적 복합제제 및 이의 제조방법

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
CN107432869A (zh) * 2016-05-27 2017-12-05 天津药物研究院有限公司 包含盐酸二甲双胍和恩格列净的双层片及其制备方法
KR20210084053A (ko) * 2019-12-27 2021-07-07 (주)휴온스 엠파글리플로진 및 메트포르민을 포함하는 약제학적 복합제제 및 이의 제조방법

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117686671A (zh) * 2023-12-11 2024-03-12 国药集团容生制药有限公司 一种优化恩格列净片剂溶出曲线及体内生物等效性的方法

Similar Documents

Publication Publication Date Title
EP4161525A1 (fr) Procédé de préparation d'un comprimé pelliculé comprenant de la linagliptine et de la metformine
EP3976014A1 (fr) Combinaison comprenant de l'alogliptine et de la metformine
WO2023234899A1 (fr) Formulation de comprimé bicouche comprenant de l'empagliflozine et de la metformine
EP4079296A1 (fr) Formulation de comprimé bicouche comprenant de la dapagliflozine amorphe et de la metformine
EP4008317A1 (fr) Formulations pharmaceutiques solides de dapagliflozine amorphe
EP4285893A1 (fr) Combinaison comprenant de l'empagliflozine et de l'hydrochlorure de metformine
EP4285894A1 (fr) Formulation d'empagliflozine et de chlorhydrate de metformine
WO2021254409A1 (fr) Composition pharmaceutique de complexe et son procédé de préparation
EP4620522A2 (fr) Combinaison comprenant de la vildagliptine et de la metformine
EP4531828A1 (fr) Formulation de comprimé bicouche comprenant de l'empagliflozine et de la metformine
EP4008316A1 (fr) Formulation de comprimé revêtu de film comprenant de la dapagliflozine et du chlorhydrate de metformine
WO2023136797A2 (fr) Composition de comprimé bicouche comprenant de la metformine et de la dapagliflozine amorphe
WO2022119540A2 (fr) Procédé pour formulations de dapagliflozine et de chlorhydrate de metformine
EP4531830A1 (fr) Formulation comprenant de l'empagliflozine et du chlorhydrate de metformine
WO2023234901A1 (fr) Formulation comprenant de l'empagliflozine et du chlorhydrate de metformine
EP4008318A1 (fr) Procédé de formulations de comprimés comprenant de la dapagliflozine et du chlorhydrate de metformine
EP4531829A1 (fr) Comprimé comprenant de l'empagliflozine et du chlorhydrate de metformine
WO2023234900A1 (fr) Comprimé comprenant de l'empagliflozine et du chlorhydrate de metformine
EP2468267B1 (fr) Composition de combinaison bicouche de vildagliptine et de gliclazide
WO2024162930A1 (fr) Comprimés pelliculés d'empagliflozine et de chlorhydrate de metformine
EP4410280A1 (fr) Comprimés d'enrobage de film d'empagliflozine et de chlorhydrate de metformine
WO2018185669A1 (fr) Compositions effervescentes comprenant de la saxagliptine ou un sel de celle-ci
TR2022008870A1 (tr) Empagli̇flozi̇n ve metformi̇n i̇çeren çi̇ft katmanli bi̇r tablet formülasyonu
TR2023001202A1 (tr) Fi̇lm kapli empagliflozin ve metformin hi̇droklorür tabletleri̇
TR2022008868A1 (tr) Empagli̇flozi̇n ve metformi̇n hi̇droklorür i̇çeren bi̇r formülasyon

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23816494

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2023816494

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2023816494

Country of ref document: EP

Effective date: 20250102

WWP Wipo information: published in national office

Ref document number: 2023816494

Country of ref document: EP