EP4161525A1 - Verfahren zur herstellung einer filmbeschichteten tablette mit linagliptin und metformin - Google Patents

Verfahren zur herstellung einer filmbeschichteten tablette mit linagliptin und metformin

Info

Publication number
EP4161525A1
EP4161525A1 EP21818094.1A EP21818094A EP4161525A1 EP 4161525 A1 EP4161525 A1 EP 4161525A1 EP 21818094 A EP21818094 A EP 21818094A EP 4161525 A1 EP4161525 A1 EP 4161525A1
Authority
EP
European Patent Office
Prior art keywords
mixture
preparation
film coated
coated tablet
linagliptin
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
EP21818094.1A
Other languages
English (en)
French (fr)
Other versions
EP4161525A4 (de
Inventor
Selda SARI
Nur PEHLIVAN AKALIN
Fatih Sunel
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
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of EP4161525A1 publication Critical patent/EP4161525A1/de
Publication of EP4161525A4 publication Critical patent/EP4161525A4/de
Pending 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
    • A61K9/2004—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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • 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
    • 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
    • A61K9/2893—Tablet coating processes

Definitions

  • the present invention relates to a process for the preparation of a film coated tablet comprising linagliptin and metformin HCI, so the process provides the desired stability and dissolution profile of the tablet.
  • the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.
  • 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 overweight. 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.
  • Linagliptin is used for type 2 or non-insulin dependent diabetes. It is a selective, orally administered, xanthine based dipeptidyl peptidase-4 (DPP-4) inhibitor used as an adjunct to diet and exercise to improve glycemic control. DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
  • DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
  • DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic peptide
  • Linagliptin works by binding to DPP-4 and preventing it from breaking down the GLP-1 and GIP. This increases the levels of these hormones in the body and so increases their effect on controlling blood sugar.
  • linagliptin 8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-yn-1-yl)-3-methyl-1- [(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1 H-purine-2,6-dione and its chemical structure is shown in the Formula I.
  • 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 II.
  • a combination therapy of linagliptin with metformin HCI provides an even more effective treatment of type II diabetes.
  • Linagliptin in combination with Metformin is marketed in the United States under the brand name Jentadueto ® by Boehringer Ingelheim.
  • U.S. Patent Application No. US 20130122089 discloses a pharmaceutical composition comprising linagliptin with mannitol, pregelatinized starch, copovidone, cornstarch, and magnesium stearate.
  • linagliptin with a primary or secondary amino group are unstable and shows incompatibilities, degradation problems, or extraction problems.
  • US patent number 201 1206766 discloses pharmaceutical composition comprising linagliptin and metformin HCI and one or more pharmaceutical excipients, and a nucleophilic and/or basic agents for stabilizing said linagliptin against degradation. Furthermore, the patent discloses use of a basic amino acid L-arginine, which may be suitable for stabilizer.
  • stabilizer does not only provide the desired stability but also isolates Linagliptin from the destabilizing matters which can be occurred during the preparation of the formulation.
  • the present invention is aimed to ensure a process for a film tablet comprising linagliptin and metformin HCI having good content uniformity and desired physically and chemically stability.
  • the process is a simple, rapid, cost effective, time-saving and industrially convenient method.
  • Another object of the present invention is to eliminate problems and bringing additional advantages to the relevant prior art.
  • Another object of this present invention is to provide a process for a film tablet comprising linagliptin and metformin HCI having desired dissolution profiles.
  • linagliptin refers to not only linagliptin, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
  • Linagliptin is present as amorphous linagliptin, crystalline linagliptin having polymorphic form A, crystalline linagliptin having polymorphic form B and crystalline linagliptin having polymorphic form C, anhydrous form A, anhydrous form B or mixtures of thereof.
  • linagliptin is present as anhydrous form A and anhydrous form B.
  • These forms of linagliptin are quite stable and stable compared to the amorphous form.
  • the process of preparing the formulation is important due to the very different regarding the amount of active ingredients in the formulation and the stability problems of linagliptin.
  • a process for the preparation of a film coated tablet comprising linagliptin and metformin wherein the process comprises steps of: a) Preparing a mixture called first mixture comprising metformin HCI and at least one pharmaceutically acceptable excipient, b) Preparing a mixture called second mixture comprising linagliptin and meglumine, c) Preparing a granulation solution.
  • Meglumine belongs to the class of organic compounds known as hexoses. These are monosaccharides in which the sugar unit is a six-carbon containing moiety. Meglumine is soluble (in water) and is an organic base used as a pH-adjusting agent and solubilizing agent.
  • linagliptin is not very stable when used with metformin HCI.
  • metformin HCI increases the acidic level of the medium, so linagliptin loses its stability.
  • amine group containing linagliptin may react with many excipients or impurities of excipients.
  • second mixture comprising linagliptin is preparing, it has been surprisingly found that using meglumine provides high stability of linagliptin in a film coated tablet and thus desired level of dissolution rate is provided in the tablet.
  • the second mixture does not comprise any excipient.
  • first mixture comprises at least one pharmaceutically acceptable excipient which is a binder and a disintegrant.
  • the granulation solution comprises a binder.
  • Suitable binder is selected from the group comprising copovidone, povidone, hydroxylpropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, alginate, sodium alginate, glycyrrhizin, polymetacrylates, poloxamer, polyacrylamide, aluminum hydroxide, benthonite, laponite, cetostearyl alcohol, polyoxyethylene-alkyl ethers, polydextrose, polyethylene oxide, xylitol, sucrose stearate or mixtures thereof.
  • a binder is copovidone.
  • Metformin HCI is used big proportion that can lead to considerable problems during the preparation of formulation with regard to the uniformity of the content of active agent in the individual composition units. Because of problems uniformity of the content, the active substance may interact with several excipients. It reflects that content uniformity play important role in the dissolution of the drug. Using the right disintegrant helps to provide uniformity of the content and therefore it provides the desired dissolution profile
  • a disintegrant is selected from the group comprising corn starch, sodium starch glycolate, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydroxypropyl cellulose, methyl cellulose, chitosan, starch, pregelatinized starch or mixtures thereof.
  • a disintegrant is corn starch.
  • the process for the preparation of a film coated tablet comprising linagliptin and metformin comprises steps of: a) Preparing a mixture called first mixture comprising metformin HCI, copovidone and corn starch, b) Preparing a mixture called second mixture comprising linagliptin and meglumine, c) Preparing a granulation solution which comprising dissolving copovidone in water.
  • the process for the preparation of a film coated tablet comprising linagliptin and metformin further comprises steps of: d) Geometric dilution first mixture, second mixture with the granulation solution and obtained wet granule, e) Wet sieving of the granule, f) Drying and then sieving,
  • geometric dilution and wet granulation prosses were used the content uniformity is provided with geometric dilution and wet granulation.
  • Improved content uniformity efficiently contributes to a marked increase in bioavailability.
  • Improved content uniformity also favors to avoid toxicity in the otherwise possible event that the amount of drug substance would be too high.
  • Geometric dilution is a pharmaceutical process that thoroughly mixes a small amount of a drug with an appropriate amount of a diluent, an inert substance that thins or binds the drug it ensures equal distribution of the drug throughout the resulting compound.
  • the process for the preparation of a film coated tablet comprising linagliptin and metformin further comprises steps of: g) Adding a disintegrant at step (f) the mixture and mixing, h) Sieving a glidant and adding at step (g) the mixture, i) Adding a lubricant and mixing, j) Pressing the mixture to form of tablet, k) Coating tablets with coating agents.
  • step (g,h,i) the problem of homogeneity, powder flowability and compressibility is even more likely to occur when two active substances are incorporated in one final dosage form, especially when two actives are used very different regarding the amount.
  • Suitable glidant is selected from the group comprising colloidal silicon dioxide, talc or mixtures thereof.
  • the glidant is colloidal silicon dioxide.
  • Suitable lubricant is selected from the group comprising magnesium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, stearic acid, polyethylene glycol, paraffin or mixtures thereof.
  • the lubricant is magnesium stearate.
  • the disintegrant is corn starch
  • glidant is colloidal silicon dioxide
  • lubricant is magnesium stearate.
  • the process for the preparation of a film coated tablet comprising linagliptin and metformin further comprises steps of: g) Adding corn starch at step (f) the mixture and mixing, h) Sieving colloidal silicon dioxide and adding at step (g) the mixture, i) Adding magnesium stearate and mixing, j) Pressing the mixture to form of tablet, k) Coating tablets with coating agents.
  • the half of used corn starch as disintegrant is added step (a) and the remaining half is added in step (g). It helps to provide the desired dissolution profile.
  • Suitable coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, triacetin, glycerol triacetin, talc, red iron dioxide, yellow iron dioxide, propylene glycol, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, macrogol, coloring agent or mixtures thereof.
  • the coating agents are hydroxypropyl methylcellulose, talc, red iron dioxide, yellow iron dioxide, titanium dioxide, propylene glycol or mixtures thereof.
  • the hardness of a film coated tablet is important for mechanical stability of the formulation.
  • the film coated tablet has a hardness of more than 150 N, preferably between 150 N - 400 N, more preferably between 200 N - 350 N, more preferably 300 N - 350 N.
  • Said process for preparing a film coated tablet comprising linagliptin and metformin HCI in this invention are stable.
  • the combination does not show incompatibilities, degradation problems, or extraction problems with certain excipients such as meglumine, copovidone, corn starch, magnesium stearate, colloidal silicon dioxide.
  • the film coated tablet obtained by the process described in the invention comprises;
  • colloidal silicon dioxide • 0.1 - 3.0% by weight of colloidal silicon dioxide
  • magnesium stearate • 0.1 - 3.0% by weight of magnesium stearate
  • the film coated tablet obtained by the process described in the invention comprises;
  • magnesium stearate • 0.2 - 1 .0% by weight of magnesium stearate
  • Example 1 The film coated tablet formulation comprising linagliptin and metformin
  • Example 2 The film coated tablet formulation comprising linagliptin and metformin
  • Process for example 1 or 2 a) Preparing a mixture called first mixture comprising metformin HCI, the half of copovidone and the half of corn starch, b) Preparing a mixture called second mixture comprising linagliptin and meglumine, c) Preparing a granulation solution which comprising dissolving the remaining half of copovidone in water.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
EP21818094.1A 2020-06-03 2021-05-07 Verfahren zur herstellung einer filmbeschichteten tablette mit linagliptin und metformin Pending EP4161525A4 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2020/08542A TR202008542A2 (tr) 2020-06-03 2020-06-03 Li̇nagli̇pti̇n ve metformi̇n i̇çeren fi̇lm kapli tablet hazirlama prosesi̇
PCT/TR2021/050438 WO2021246985A1 (en) 2020-06-03 2021-05-07 The process for the preparation of a film coated tablet comprising linagliptin and metformin

Publications (2)

Publication Number Publication Date
EP4161525A1 true EP4161525A1 (de) 2023-04-12
EP4161525A4 EP4161525A4 (de) 2024-06-26

Family

ID=78831356

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21818094.1A Pending EP4161525A4 (de) 2020-06-03 2021-05-07 Verfahren zur herstellung einer filmbeschichteten tablette mit linagliptin und metformin

Country Status (4)

Country Link
EP (1) EP4161525A4 (de)
CA (1) CA3185535A1 (de)
TR (1) TR202008542A2 (de)
WO (1) WO2021246985A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116919911A (zh) * 2023-07-20 2023-10-24 北京诺和德美医药技术有限公司 一种糖尿病治疗药物及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014080383A1 (en) * 2012-11-26 2014-05-30 Ranbaxy Laboratories Limited Pharmaceutical composition of dipeptidyl peptidase-iv (dpp-iv) inhibitors in combination with other antidiabetics
WO2015110962A1 (en) * 2014-01-21 2015-07-30 Wockhardt Limited Solid oral pharmaceutical compositions comprising fixed dose combination of metformin and linagliptin or salts thereof
CN104840960A (zh) * 2014-02-14 2015-08-19 广东东阳光药业有限公司 抗糖尿病的药物组合物及其制备方法
KR20190040765A (ko) * 2017-10-11 2019-04-19 (주)휴온스 Dpp-4 억제제를 포함하는 당뇨병 예방 또는 치료용 약제학적 조성물 및 이의 제조 방법

Also Published As

Publication number Publication date
WO2021246985A1 (en) 2021-12-09
TR202008542A2 (tr) 2021-12-21
CA3185535A1 (en) 2021-12-09
EP4161525A4 (de) 2024-06-26

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