WO2021246985A1 - Procédé de préparation d'un comprimé pelliculé comprenant de la linagliptine et de la metformine - Google Patents
Procédé de préparation d'un comprimé pelliculé comprenant de la linagliptine et de la metformine Download PDFInfo
- Publication number
- WO2021246985A1 WO2021246985A1 PCT/TR2021/050438 TR2021050438W WO2021246985A1 WO 2021246985 A1 WO2021246985 A1 WO 2021246985A1 TR 2021050438 W TR2021050438 W TR 2021050438W WO 2021246985 A1 WO2021246985 A1 WO 2021246985A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mixture
- preparation
- film coated
- coated tablet
- linagliptin
- Prior art date
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- 229960002397 linagliptin Drugs 0.000 title claims abstract description 49
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- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
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- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100040918 Pro-glucagon Human genes 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 150000004283 biguanides Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
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- 239000002552 dosage form Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
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- 230000010030 glucose lowering effect Effects 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940103430 jentadueto Drugs 0.000 description 1
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- 210000004185 liver Anatomy 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000003979 response to food Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000037221 weight management Effects 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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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- 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)
Abstract
La présente invention concerne un procédé de préparation d'un comprimé pelliculé comprenant de la linagliptine et de la metformine HCl, le procédé permettant d'obtenir la stabilité et le profil de dissolution souhaités du comprimé. La présente invention concerne également un procédé simple, rapide, économique, économe en temps et pratique du point de vue industriel.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP21818094.1A EP4161525A4 (fr) | 2020-06-03 | 2021-05-07 | Procédé de préparation d'un comprimé pelliculé comprenant de la linagliptine et de la metformine |
CA3185535A CA3185535A1 (fr) | 2020-06-03 | 2021-05-07 | Procede de preparation d'un comprime pellicule comprenant de la linagliptine et de la metformine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TR2020/08542 | 2020-06-03 | ||
TR2020/08542A TR202008542A2 (tr) | 2020-06-03 | 2020-06-03 | Li̇nagli̇pti̇n ve metformi̇n i̇çeren fi̇lm kapli tablet hazirlama prosesi̇ |
Publications (1)
Publication Number | Publication Date |
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WO2021246985A1 true WO2021246985A1 (fr) | 2021-12-09 |
Family
ID=78831356
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/TR2021/050438 WO2021246985A1 (fr) | 2020-06-03 | 2021-05-07 | Procédé de préparation d'un comprimé pelliculé comprenant de la linagliptine et de la metformine |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP4161525A4 (fr) |
CA (1) | CA3185535A1 (fr) |
TR (1) | TR202008542A2 (fr) |
WO (1) | WO2021246985A1 (fr) |
Cited By (1)
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 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014080383A1 (fr) * | 2012-11-26 | 2014-05-30 | Ranbaxy Laboratories Limited | Composition pharmaceutique d'inhibiteurs de la dipeptidyl-peptidase-iv (dpp-iv) en association avec d'autres antidiabétiques |
WO2015110962A1 (fr) * | 2014-01-21 | 2015-07-30 | Wockhardt Limited | Compositions pharmaceutiques orales solides comprenant une combinaison de doses fixes de metformine et de linagliptine ou de leurs sels |
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 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20190040765A (ko) * | 2017-10-11 | 2019-04-19 | (주)휴온스 | Dpp-4 억제제를 포함하는 당뇨병 예방 또는 치료용 약제학적 조성물 및 이의 제조 방법 |
-
2020
- 2020-06-03 TR TR2020/08542A patent/TR202008542A2/tr unknown
-
2021
- 2021-05-07 CA CA3185535A patent/CA3185535A1/fr active Pending
- 2021-05-07 WO PCT/TR2021/050438 patent/WO2021246985A1/fr unknown
- 2021-05-07 EP EP21818094.1A patent/EP4161525A4/fr active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014080383A1 (fr) * | 2012-11-26 | 2014-05-30 | Ranbaxy Laboratories Limited | Composition pharmaceutique d'inhibiteurs de la dipeptidyl-peptidase-iv (dpp-iv) en association avec d'autres antidiabétiques |
WO2015110962A1 (fr) * | 2014-01-21 | 2015-07-30 | Wockhardt Limited | Compositions pharmaceutiques orales solides comprenant une combinaison de doses fixes de metformine et de linagliptine ou de leurs sels |
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 |
Non-Patent Citations (1)
Title |
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See also references of EP4161525A4 * |
Cited By (1)
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 |
Also Published As
Publication number | Publication date |
---|---|
EP4161525A1 (fr) | 2023-04-12 |
CA3185535A1 (fr) | 2021-12-09 |
EP4161525A4 (fr) | 2024-06-26 |
TR202008542A2 (tr) | 2021-12-21 |
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