WO2024117998A1 - Immediate release oral pharmaceutical composition comprising linagliptin - Google Patents
Immediate release oral pharmaceutical composition comprising linagliptin Download PDFInfo
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- WO2024117998A1 WO2024117998A1 PCT/TR2022/051390 TR2022051390W WO2024117998A1 WO 2024117998 A1 WO2024117998 A1 WO 2024117998A1 TR 2022051390 W TR2022051390 W TR 2022051390W WO 2024117998 A1 WO2024117998 A1 WO 2024117998A1
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- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- immediate release
- release pharmaceutical
- composition according
- linagliptin
- Prior art date
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- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 title claims abstract description 53
- 229960002397 linagliptin Drugs 0.000 title claims abstract description 50
- 239000012729 immediate-release (IR) formulation Substances 0.000 title claims abstract description 30
- 239000008203 oral pharmaceutical composition Substances 0.000 title description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 50
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000007907 direct compression Methods 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims description 62
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 19
- 239000000314 lubricant Substances 0.000 claims description 18
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 16
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 16
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 16
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 16
- 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 claims description 14
- 229930195725 Mannitol Natural products 0.000 claims description 14
- 239000011230 binding agent Substances 0.000 claims description 14
- 239000000594 mannitol Substances 0.000 claims description 14
- 235000010355 mannitol Nutrition 0.000 claims description 14
- 239000000843 powder Substances 0.000 claims description 14
- 239000007884 disintegrant Substances 0.000 claims description 13
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 229920000881 Modified starch Polymers 0.000 claims description 7
- 239000001913 cellulose Chemical class 0.000 claims description 6
- 239000000454 talc Substances 0.000 claims description 6
- 229910052623 talc Inorganic materials 0.000 claims description 6
- 235000012222 talc Nutrition 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical class [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 229920002678 cellulose Chemical class 0.000 claims description 4
- 235000010980 cellulose Nutrition 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- -1 glidants Substances 0.000 claims description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 229940069328 povidone Drugs 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000005434 MCC/mannitol excipient Substances 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
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- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229920003124 powdered cellulose Polymers 0.000 claims description 2
- 235000019814 powdered cellulose Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 2
- 239000007787 solid Substances 0.000 abstract description 11
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- 238000013379 physicochemical characterization Methods 0.000 abstract description 2
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- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 4
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- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 3
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- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 2
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- 239000003112 inhibitor Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229940075420 xanthine Drugs 0.000 description 2
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
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- 229940125396 insulin Drugs 0.000 description 1
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
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- 229960005095 pioglitazone Drugs 0.000 description 1
- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical group NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 description 1
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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
- A61K9/2013—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
- 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
- A61K9/2004—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
Definitions
- the present invention relates to an oral immediate -release pharmaceutical composition comprising therapeutically effective amount of linagliptin or pharmaceutically acceptable forms or derivatives thereof. More specifically, the present invention relates to a solid oral dosage form manufactured by direct compression method presenting improved physicochemical characterizations along with release and impurity profiles.
- Type 2 diabetes mellitus is a chronic metabolic disorder characterizes by multiple metabolic abnormalities involving insulin resistance, impaired insulin secretion, and increased glucose production wherein morbidity and mortality associated with type 2 diabetes mellitus is leaded to the risk of microvascular and macro- vascular complications, in addition to diet and exercise, there are many medications to lower blood sugar with having some limitations related with safety and tolerability issues or inconvenience in dosing. Hypoglycaemia, weight gain, and gastrointestinal intolerance are some of the most common adverse events are occurred with currently used agents.
- Linagliptin is a selective, orally administered, xanthine-based DPP-4 inhibitor used as an adjunct to diet and exercise to improve glycemic control. Its chemical name is 8-[(3R)-3- aminopiperidin- 1 -yl] -7-(but-2-yn- 1 -yl)-3 -methyl- 1 - [(4-methylquinazolin-2-yl)methyl] -3,7- dihydro-lH-purine-2, 6-dione, is a member of a class of antihyperglycemic agents called dipeptidyl peptidase 4 (DPP-IV) inhibitors that is known with having well tolerated towards potent adverse effect.
- DPP-IV dipeptidyl peptidase 4
- dapagliflozin The empirical formula of dapagliflozin is C25H28N8O2 and its relative molecular mass is 408.87 mg/mole as a free base.
- the structural formula of dapagliflozin is shown in the Formula I.
- Formula I It is a white to yellowish crystalline solid substance. Besides that, it is slightly hygroscopic, but water uptake does not change the crystal modification.
- Linagliptin has one chiral centre at the 3 -aminopiperidine moiety.
- the active substance corresponds to the R-enantiomer. Besides that, it substance simultaneously exists in two polymorphic forms, which are enantiotropic ally related and which reversibly convert into each other approximately at room temperature. The two polymorphic forms do not differ with regard to biopharmaceutical properties.
- Linagliptin base and its pharmaceutically acceptable salts with the process for the preparation first have been described in EP1532149 numbered patent document by Boehringer Ingelheim Pharma for the treatment of diseases, such as, for example, type 1 diabetes, type 2 diabetes, adipositas, arthritis, and calcitonin-caused osteoporosis.
- Linagliptin was first commercially authorized in U.S . Food&Drug Administration in May 2011.
- the medicinal product is currently marketed in the form of immediate release film coated tablets under the trade name of TRAJENTA® in the strength of 5 mg per tablet. It can be used as monotherapy or in combination with other common antidiabetic medications including metformin, sulfonylurea, pioglitazone or insulin.
- EP2023902 relates to pharmaceutical compositions of linagliptin and its preparations for the treatment of diabetes mellitus.
- the patent document is specifically disclosed to qualitative properties of the prepared pharmaceutical composition comprising mannitol and pregelatinized starch are used as diluent, copovidone is used as binder, corn starch is used as disintegrant and magnesium stearat is used as lubricant. It also disclosed the process for the preparation of a pharmaceutical composition in which wet granulation is used. Further, it specifies that excipients like microcrystalline cellulose and lactose were observed as being incompatible with DPP-IV inhibitors.
- EP2023902 has divisional applications such as EP2277509, EP2283819 and EP2910241. These divisional applications are also disclosed to a pharmaceutical composition comprising linagliptin, a first diluent mannitol, a second diluent pregelatinized starch, a binder copovidone, a disintegrant corn starch, and a lubricant magnesium stearate. It is also emphasized that should be avoided from microcrystalline cellulose use which causes oxidation and negative impacts on impurity profile.
- EP1852108 relates to a pharmaceutical composition
- a pharmaceutical composition comprising linagliptin as an active substance and at least one pharmaceutical composition in which mannitol and pregelatinized starch are used as diluent, copovidone is used as binder, corn starch and crospovidone are used as disintegrant, colloidal silicon dioxide is used as glidant and magnesium stearate is used as lubricant.
- EP2882424 relates to a stable pharmaceutical composition
- a stable pharmaceutical composition comprising linagliptin or a pharmaceutically acceptable salt thereof as active ingredient, mannitol, copovidone, and magnesium stearate, wherein the mannitol is present in an amount of 90 to 95 % by weight, based on the pharmaceutical composition, and the pharmaceutical composition is prepared by direct compression.
- EP3311803 relates to a pharmaceutical composition
- a pharmaceutical composition comprising linagliptin, mannitol, copovidone, and magnesium stearate, wherein the pharmaceutical composition is prepared by direct compression.
- W02014080384 relates to a pharmaceutical composition
- a pharmaceutical composition comprising linagliptin and one or more pharmaceutically acceptable excipients, wherein said composition is free of one or more of mannitol, corn starch, copovidone and magnesium stearate.
- W02014009970 relates to an amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, wherein said acceptable carrier comprises one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.
- EP3801539 relates to a solid oral pharmaceutical formulation comprising linagliptin or a pharmaceutically acceptable salt thereof, wherein the composition is free of microcrystalline cellulose, croscarmellose sodium and stearates.
- EP3723761 relates to a pharmaceutical solid oral dosage form comprising linagliptin as an active agent and at least one binder in which the weight ratio of linagliptin to povidone used as binder is between 0.1 and 6.0, preferably is between 0.5 and 2.0.
- EP2853257 relates to a pharmaceutical formulation comprising linagliptin or pharmaceutically acceptable salt thereof, croscarmellose sodium and at least one other pharmaceutically acceptable excipient.
- Linagliptin is a highly soluble active substance in aqueous media (> 1 mg/ml) over the entire physiological pH range. Hence, after oral administration of a 5 mg dose or multiple dosing to healthy volunteers or patients, linagliptin is rapidly absorbed, with peak plasma concentrations (median T m ax) occurring 1.5 hours post-dose and reaches steady-state concentrations within 4 days. However, its absolute bioavailability after oral administration of 10 mg dose is approximately 30%.
- the present invention relates to an oral immediate -release pharmaceutical composition
- an oral immediate -release pharmaceutical composition comprising linagliptin or a pharmaceutically acceptable salt thereof with a powder blend presenting optimized characteristics of powder flowability and compressibility to obtain a solid pharmaceutical composition manufactured by direct compression method.
- improved impurity and release profiles are achieved although the pharmaceutical composition contains hydrophilic excipients and does not contain a disintegrant.
- the object of this invention is to develop an immediate-release pharmaceutical composition
- a therapeutically effective amount of linagliptin which is selective, orally administered, a xanthine-based DPP-4 inhibitor.
- It is an object of the present invention is to develop an immediate-release pharmaceutical composition
- linagliptin which is used for the treatment of diseases such as, for example, type I diabetes, type II diabetes, adipositas, arthritis, and calcitonin-caused osteoporosis.
- the object of the present invention is to provide an immediate-release pharmaceutical composition comprising linagliptin in crystalline form.
- the crystalline form is present as a mixture of two polymorphic forms A and B.
- linagliptin in crystalline form has a D90 particle size less than 20 microns.
- Another object of the present invention is related to an immediate-release pharmaceutical composition
- an immediate-release pharmaceutical composition comprising the active ingredient, at least two diluents, binder, lubricant, and at least one glidant(s) selected as to be the most suitable ones with respect to the intended form of administration, and wherein said composition does not contain any disintegrant.
- Linagliptin is known to cause difficulty in preparing free flowing, compressible solid dosage forms when substantial quantities of linagliptin (either in solid or liquid form) is incorporated in the formulation.
- the difficulty can be a lack of sufficient cohesion in the compact for compression, particularly for direct compression tableting, such that the tablet will withstand the rigors of further processing. Further, it can be difficult to assure that linagliptin is uniformly distributed throughout the solid formulation and expeditiously dispersed upon administration.
- Another object of the present invention is to provide compositions and processes that permit substantial quantities of linagliptin to be incorporated into solid tablet formulations and manufactured by various compression and other manufacturing processes.
- Linagliptin is also known to have a primary or secondary amino group that show incompatibilities, degradation problems, or extraction problems with a number of customary excipients including microcrystalline cellulose from the prior art patent document of EP2023902.
- the amino group appears to react with other reactive carbonyl groups and with carboxylic acid functional groups formed for example at the surface of microcrystalline cellulose by oxidation.
- the present invention is to provide an immediate-release pharmaceutical composition
- an immediate-release pharmaceutical composition comprising a mixture of linagliptin and at least one pharmaceutically acceptable excipient manufactured by using direct compression method, wherein the composition is free of disintegrant, the composition comprises at least two hydrophilic excipients one of the at least two hydrophilic excipients used in the composition is microcrystalline cellulose.
- the present invention provides an immediate -release pharmaceutical composition
- a therapeutically effective amount of linagliptin in crystalline form and at least one pharmaceutically acceptable excipient is manufactured by using direct compression method to get improved properties without using any disintegrant and comprising microcrystalline cellulose as diluent which presents hydrophilic properties.
- Polymorphism is the phenomenon related to the occurrence of different crystal forms, wherein crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice. Those differences can have a direct effect on the ability to process and/or manufacture the drug product, as well as on drug product stability, dissolution, and bioavailability due to having different chemical and physical properties.
- linagliptin is in the mixture of two polymorphic form (“Form A” and “Form B”) which are enantiotropically related and which reversibly convert into each other approximately at room temperature.
- Form A polymorphic form
- Form B polymorphic form
- Linagliptin is an active substance with being highly soluble in aqueous media (> 1 mg/ml) over the entire physiological pH range. Although, it has high solubility and half-life of 12 hours, its oral systemic bioavailability is only about 30% compared to intravenous administration, due to its poor permeability property. Thus, the particle size becomes an important issue to get the completed and desired dissolution profile.
- linagliptin particles have a D90 value less than 20 microns, preferably D90 is less than 15 microns, more preferably D90 is less than 10 microns.
- D90 is defined as 90% of the volume of particles having a diameter less than a specified diameter.
- the value of D90 refers to the particle size distribution of linagliptin particles.
- linagliptin is present as a low-dose drug that is constituted less than 4% weight by the total weight of the composition.
- In another preferred embodiment of the present invention is to provide a pharmaceutical composition comprising linagliptin by using direct compression method wherein provided for the manufacture of tablets containing the active ingredient, diluents, binder, lubricant(s) and glidant(s) selected as to be the most suitable ones with respect to the intended form of administration.
- the pharmaceutical composition comprises at least one diluent can be selected from the group consisting of dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof.
- the diluent is mannitol and microcrystalline cellulose or a mixture thereof, more preferably is a mixture thereof.
- the pharmaceutical composition comprises binder can be selected from the group consisting of hypromellose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, pregelatinized starch, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof.
- the binder is pregelatinized starch.
- the pharmaceutical composition comprises at least one lubricant can be selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid, hydrogenated castor oil and mixtures thereof.
- the lubricant is magnesium stearate.
- the pharmaceutical composition comprises at least one glidant can be selected from the group consisting of colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof.
- the glidants are colloidal silicon dioxide and talc or a mixture thereof.
- Disintegrant(s) is one of the main excipients used in pharmaceutical compositions to ensure the rapid breakdown into their primary particles when they contact with the gastrointestinal tract. Thus, it is highly related to the dissolution or release of active substances. However, in the present invention, the inventors have surprisingly found that a developed pharmaceutical composition comprising linagliptin is obtained with a suitable dissolution profile with free of disintegrant.
- the embodiment in accordance with the present invention was designed with an adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using the direct compression method.
- Linagliptin active substance itself has very poor flowability and compressibility based on the Carr Index value of 28.54 and Hausner ratio value of 1.40.
- Example 1 Considering the above-mentioned information, the foreseen problems were aimed to be overcome by the embodiment named Example 1 is given in below.
- the proposed embodiment based on the invention provides an immediate release solid oral pharmaceutical composition wherein the amounts in w/w% of the total composition are as stated below.
- the diluent 1 used in the composition is mannitol, and diluent 2 used in the composition is microcrystalline cellulose.
- the process for the preparation of a pharmaceutical composition manufactured by using direct compression including the steps of: a) Linagliptin, glidant(s), mannitol and the specified amount of microcrystalline cellulose were screened through a proper sieve and stirred, b) The rest of the microcrystalline cellulose and binder were screened through a proper sieve, added to the powder blend prepared in Step (b) and stirred. c) Lubricant was screened through a proper sieve, added to the powder blend prepared in Step (c) and stirred to obtain a uniform final blend. After getting the final blend, it was observed that the final blend was not suitable for compression due to poor flowability and sticking problem during tablet compression.
- the flowability of the powder blend was targeted to be improved, further the sticking problem during tablet compression was planned to be overcome as well by using specified amounts and different types of lubricants and glidants in the formulation also by keeping the manufacturing process same as in Example 1.
- Table 2 Examples comprising different types and amount ranges of glidants and lubricants
- the Carr compressibility index and Hausner ratio are used that correspond to the percentage of tapped density to bulk density.
- the results of the Carr compressibility index and Hausner ratio of each powder blend are in Table 3.
- Example 4 and Example 5 tablet compression failed for Example 2 and Example 3. Then, the obtained tablets with the compositions of Example 4 and Example 5 were subjected to analytical tests like disintegration, friability and in vitro dissolution determination that are directly connected with the problems of sticking.
- composition proposed should meet the requirements of disintegration, dissolution and dose uniformity tests. Since the compositions comprise multiple types of lubricants and glidants which are known in the art to be hydrophobic, wetting of the tablet will be problematic which leads the tablet to disintegrate. In this case, both examples do not comprise any disintegrant which is beyond the routine development approach.
- Disintegration test plays an important role in tablet dissolution for the active drug substance to release into the absorption site.
- the studies were performed in accordance with USP ⁇ 701 > Disintegration monograph within the acceptance criteria of disintegration time of maximum 15 minutes for core tablet.
- in-vitro dissolution study The conditions of in- vitro dissolution study are defined by US&FDA, based on the information available dissolution medium is 0.1 N HC1. Other conditions are; volume of dissolution medium is 900 ml, temperature of study is 37°C ⁇ 0.5, rotation speed is 50 rpm, apparatus is paddle and the duration of dissolution study is 60 minute-duration.
- Example 5 In the composition of Example 5 is the embodiment indicating most promising physicochemical and release profile results without comprising any disintegrant furtherly analyzed to detect the impurity profile. Since microcrystalline cellulose and mannitol are present in the formulation and very well known with their hydrophilic nature, Example-5 should be analyzed to determine the impurity profile of the composition that comprises an oxidation intensive active substance linagliptin.
- Example 5 The impurity profile of Example 5 is well below the internationally determined specifications.
- an immediate-release pharmaceutical composition comprising linagliptin and at least one pharmaceutically acceptable excipient is manufactured method by using direct compression, wherein the composition: is free of disintegrant, comprises at least two hydrophilic excipients, o one of the at least two hydrophilic excipients is microcrystalline cellulose o one of the at least two hydrophilic excipients is mannitol
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Abstract
The present invention relates to an oral immediate-release pharmaceutical composition comprising therapeutically effective amount of linagliptin or pharmaceutically acceptable forms or derivatives thereof. More specifically, the present invention relates to a solid oral dosage form manufactured by direct compression method presenting improved physicochemical characterizations along with release and impurity profiles.
Description
IMMEDIATE RELEASE ORAL PHARMACEUTICAL COMPOSITION COMPRISING LINAGLIPTIN
FIELD OF INVENTION
The present invention relates to an oral immediate -release pharmaceutical composition comprising therapeutically effective amount of linagliptin or pharmaceutically acceptable forms or derivatives thereof. More specifically, the present invention relates to a solid oral dosage form manufactured by direct compression method presenting improved physicochemical characterizations along with release and impurity profiles.
BACKGROUND OF THE INVENTION
Type 2 diabetes mellitus (non-insulin dependent diabetes mellitus) is a chronic metabolic disorder characterizes by multiple metabolic abnormalities involving insulin resistance, impaired insulin secretion, and increased glucose production wherein morbidity and mortality associated with type 2 diabetes mellitus is leaded to the risk of microvascular and macro- vascular complications, in addition to diet and exercise, there are many medications to lower blood sugar with having some limitations related with safety and tolerability issues or inconvenience in dosing. Hypoglycaemia, weight gain, and gastrointestinal intolerance are some of the most common adverse events are occurred with currently used agents.
Linagliptin is a selective, orally administered, xanthine-based DPP-4 inhibitor used as an adjunct to diet and exercise to improve glycemic control. Its chemical name is 8-[(3R)-3- aminopiperidin- 1 -yl] -7-(but-2-yn- 1 -yl)-3 -methyl- 1 - [(4-methylquinazolin-2-yl)methyl] -3,7- dihydro-lH-purine-2, 6-dione, is a member of a class of antihyperglycemic agents called dipeptidyl peptidase 4 (DPP-IV) inhibitors that is known with having well tolerated towards potent adverse effect.
The empirical formula of dapagliflozin is C25H28N8O2 and its relative molecular mass is 408.87 mg/mole as a free base. The structural formula of dapagliflozin is shown in the Formula I.
Formula I
It is a white to yellowish crystalline solid substance. Besides that, it is slightly hygroscopic, but water uptake does not change the crystal modification.
Linagliptin has one chiral centre at the 3 -aminopiperidine moiety. The active substance corresponds to the R-enantiomer. Besides that, it substance simultaneously exists in two polymorphic forms, which are enantiotropic ally related and which reversibly convert into each other approximately at room temperature. The two polymorphic forms do not differ with regard to biopharmaceutical properties.
Linagliptin base and its pharmaceutically acceptable salts with the process for the preparation first have been described in EP1532149 numbered patent document by Boehringer Ingelheim Pharma for the treatment of diseases, such as, for example, type 1 diabetes, type 2 diabetes, adipositas, arthritis, and calcitonin-caused osteoporosis.
Linagliptin was first commercially authorized in U.S . Food&Drug Administration in May 2011. The medicinal product is currently marketed in the form of immediate release film coated tablets under the trade name of TRAJENTA® in the strength of 5 mg per tablet. It can be used as monotherapy or in combination with other common antidiabetic medications including metformin, sulfonylurea, pioglitazone or insulin.
In the state of art there are many patents/patent applications which are summarized below.
EP2023902 relates to pharmaceutical compositions of linagliptin and its preparations for the treatment of diabetes mellitus. The patent document is specifically disclosed to qualitative properties of the prepared pharmaceutical composition comprising mannitol and pregelatinized starch are used as diluent, copovidone is used as binder, corn starch is used as disintegrant and magnesium stearat is used as lubricant. It also disclosed the process for the preparation of a pharmaceutical composition in which wet granulation is used. Further, it specifies that excipients like microcrystalline cellulose and lactose were observed as being incompatible with DPP-IV inhibitors.
EP2023902 has divisional applications such as EP2277509, EP2283819 and EP2910241. These divisional applications are also disclosed to a pharmaceutical composition comprising linagliptin, a first diluent mannitol, a second diluent pregelatinized starch, a binder copovidone, a disintegrant corn starch, and a lubricant magnesium stearate. It is also emphasized that should be avoided from microcrystalline cellulose use which causes oxidation and negative impacts on impurity profile.
EP1852108 relates to a pharmaceutical composition comprising linagliptin as an active substance and at least one pharmaceutical composition in which mannitol and pregelatinized starch are used as diluent, copovidone is used as binder, corn starch and crospovidone are used as disintegrant, colloidal silicon dioxide is used as glidant and magnesium stearate is used as lubricant.
EP2882424 relates to a stable pharmaceutical composition comprising linagliptin or a pharmaceutically acceptable salt thereof as active ingredient, mannitol, copovidone, and magnesium stearate, wherein the mannitol is present in an amount of 90 to 95 % by weight, based on the pharmaceutical composition, and the pharmaceutical composition is prepared by direct compression.
EP3311803 relates to a pharmaceutical composition comprising linagliptin, mannitol, copovidone, and magnesium stearate, wherein the pharmaceutical composition is prepared by direct compression.
W02014080384 relates to a pharmaceutical composition comprising linagliptin and one or more pharmaceutically acceptable excipients, wherein said composition is free of one or more of mannitol, corn starch, copovidone and magnesium stearate.
W02014009970 relates to an amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, wherein said acceptable carrier comprises one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.
EP3801539 relates to a solid oral pharmaceutical formulation comprising linagliptin or a pharmaceutically acceptable salt thereof, wherein the composition is free of microcrystalline cellulose, croscarmellose sodium and stearates.
EP3723761 relates to a pharmaceutical solid oral dosage form comprising linagliptin as an active agent and at least one binder in which the weight ratio of linagliptin to povidone used as binder is between 0.1 and 6.0, preferably is between 0.5 and 2.0.
EP2853257 relates to a pharmaceutical formulation comprising linagliptin or pharmaceutically acceptable salt thereof, croscarmellose sodium and at least one other pharmaceutically acceptable excipient.
Linagliptin is a highly soluble active substance in aqueous media (> 1 mg/ml) over the entire physiological pH range. Hence, after oral administration of a 5 mg dose or multiple dosing to healthy volunteers or patients, linagliptin is rapidly absorbed, with peak plasma concentrations
(median Tmax) occurring 1.5 hours post-dose and reaches steady-state concentrations within 4 days. However, its absolute bioavailability after oral administration of 10 mg dose is approximately 30%.
Although there are patent applications given in the above, there is still a requirement to develop an oral immediate release pharmaceutical composition that would address the issue relating to the incomplete bioavailability problem of linagliptin or a pharmaceutically acceptable salt thereof with suitable dissolution properties.
Thus, the present invention relates to an oral immediate -release pharmaceutical composition comprising linagliptin or a pharmaceutically acceptable salt thereof with a powder blend presenting optimized characteristics of powder flowability and compressibility to obtain a solid pharmaceutical composition manufactured by direct compression method. Moreover, improved impurity and release profiles are achieved although the pharmaceutical composition contains hydrophilic excipients and does not contain a disintegrant.
SUMMARY OF THE INVENTION
The object of this invention is to develop an immediate-release pharmaceutical composition comprising a therapeutically effective amount of linagliptin, which is selective, orally administered, a xanthine-based DPP-4 inhibitor.
It is an object of the present invention is to develop an immediate-release pharmaceutical composition comprising linagliptin, which is used for the treatment of diseases such as, for example, type I diabetes, type II diabetes, adipositas, arthritis, and calcitonin-caused osteoporosis.
The object of the present invention is to provide an immediate-release pharmaceutical composition comprising linagliptin in crystalline form. Preferably, the crystalline form is present as a mixture of two polymorphic forms A and B.
Another object of the present invention, linagliptin in crystalline form has a D90 particle size less than 20 microns.
Another object of the present invention is to provide an immediate-release pharmaceutical composition comprising linagliptin and one or more pharmaceutically acceptable excipients manufactured by using direct compression method.
Another object of the present invention is to provide an immediate-release pharmaceutical composition comprising linagliptin that can be available to manufacture in solid oral dosage forms, such as film coated-tablet with improved physicochemical characteristics of powder blend, release profile and impurity profile.
Another object of the present invention is related to an immediate-release pharmaceutical composition comprising the active ingredient, at least two diluents, binder, lubricant, and at least one glidant(s) selected as to be the most suitable ones with respect to the intended form of administration, and wherein said composition does not contain any disintegrant.
Linagliptin is known to cause difficulty in preparing free flowing, compressible solid dosage forms when substantial quantities of linagliptin (either in solid or liquid form) is incorporated in the formulation. The difficulty can be a lack of sufficient cohesion in the compact for compression, particularly for direct compression tableting, such that the tablet will withstand the rigors of further processing. Further, it can be difficult to assure that linagliptin is uniformly distributed throughout the solid formulation and expeditiously dispersed upon administration.
Another object of the present invention, therefore, is to provide compositions and processes that permit substantial quantities of linagliptin to be incorporated into solid tablet formulations and manufactured by various compression and other manufacturing processes.
Linagliptin is also known to have a primary or secondary amino group that show incompatibilities, degradation problems, or extraction problems with a number of customary excipients including microcrystalline cellulose from the prior art patent document of EP2023902. The amino group appears to react with other reactive carbonyl groups and with carboxylic acid functional groups formed for example at the surface of microcrystalline cellulose by oxidation.
In a preferred embodiment, the present invention is to provide an immediate-release pharmaceutical composition comprising a mixture of linagliptin and at least one pharmaceutically acceptable excipient manufactured by using direct compression method, wherein the composition is free of disintegrant, the composition comprises at least two hydrophilic excipients one of the at least two hydrophilic excipients used in the composition is microcrystalline cellulose.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an immediate -release pharmaceutical composition comprising a therapeutically effective amount of linagliptin in crystalline form and at least one pharmaceutically acceptable excipient is manufactured by using direct compression method to get improved properties without using any disintegrant and comprising microcrystalline cellulose as diluent which presents hydrophilic properties.
Polymorphism is the phenomenon related to the occurrence of different crystal forms, wherein crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice. Those differences can have a direct effect on the ability to process and/or manufacture the drug product, as well as on drug product stability, dissolution, and bioavailability due to having different chemical and physical properties.
Thus, the selection of proper polymorph of drug substance for therapeutic use is very important to obtain the appropriate drug product with bioavailability and bioequivalence.
In the preferred embodiment, linagliptin is in the mixture of two polymorphic form (“Form A” and “Form B”) which are enantiotropically related and which reversibly convert into each other approximately at room temperature. However, even if there is a conversion, any crystal modification is not observed during the uptaking of the water. Thus, these polymorphic forms make no difference in physicochemical properties (stability, solubility and intrinsic dissolution properties) and have no impact on bioavailability.
Linagliptin is an active substance with being highly soluble in aqueous media (> 1 mg/ml) over the entire physiological pH range. Although, it has high solubility and half-life of 12 hours, its oral systemic bioavailability is only about 30% compared to intravenous administration, due to its poor permeability property. Thus, the particle size becomes an important issue to get the completed and desired dissolution profile.
In the preferred embodiment, linagliptin particles have a D90 value less than 20 microns, preferably D90 is less than 15 microns, more preferably D90 is less than 10 microns.
The term “D90” is defined as 90% of the volume of particles having a diameter less than a specified diameter. The value of D90 refers to the particle size distribution of linagliptin particles.
In the present invention, linagliptin is present as a low-dose drug that is constituted less than 4% weight by the total weight of the composition.
In another preferred embodiment of the present invention is to provide a pharmaceutical composition comprising linagliptin by using direct compression method wherein provided for the manufacture of tablets containing the active ingredient, diluents, binder, lubricant(s) and glidant(s) selected as to be the most suitable ones with respect to the intended form of administration.
In a preferred embodiment, the pharmaceutical composition comprises at least one diluent can be selected from the group consisting of dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. Preferably, the diluent is mannitol and microcrystalline cellulose or a mixture thereof, more preferably is a mixture thereof.
In a preferred embodiment, the pharmaceutical composition comprises binder can be selected from the group consisting of hypromellose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, pregelatinized starch, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is pregelatinized starch.
In a preferred embodiment, the pharmaceutical composition comprises at least one lubricant can be selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid, hydrogenated castor oil and mixtures thereof. Preferably, the lubricant is magnesium stearate.
In a preferred embodiment, the pharmaceutical composition comprises at least one glidant can be selected from the group consisting of colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof. Preferably, the glidants are colloidal silicon dioxide and talc or a mixture thereof.
Disintegrant(s) is one of the main excipients used in pharmaceutical compositions to ensure the rapid breakdown into their primary particles when they contact with the gastrointestinal tract. Thus, it is highly related to the dissolution or release of active substances.
However, in the present invention, the inventors have surprisingly found that a developed pharmaceutical composition comprising linagliptin is obtained with a suitable dissolution profile with free of disintegrant.
The embodiment in accordance with the present invention was designed with an adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using the direct compression method. Linagliptin active substance itself has very poor flowability and compressibility based on the Carr Index value of 28.54 and Hausner ratio value of 1.40.
Considering the above-mentioned information, the foreseen problems were aimed to be overcome by the embodiment named Example 1 is given in below.
The proposed embodiment based on the invention provides an immediate release solid oral pharmaceutical composition wherein the amounts in w/w% of the total composition are as stated below.
Table 1: Unit Formula of Example 1
The diluent 1 used in the composition is mannitol, and diluent 2 used in the composition is microcrystalline cellulose.
Further in a preferred embodiment, the process for the preparation of a pharmaceutical composition manufactured by using direct compression, including the steps of: a) Linagliptin, glidant(s), mannitol and the specified amount of microcrystalline cellulose were screened through a proper sieve and stirred, b) The rest of the microcrystalline cellulose and binder were screened through a proper sieve, added to the powder blend prepared in Step (b) and stirred. c) Lubricant was screened through a proper sieve, added to the powder blend prepared in Step (c) and stirred to obtain a uniform final blend.
After getting the final blend, it was observed that the final blend was not suitable for compression due to poor flowability and sticking problem during tablet compression.
Poor flowability property of the powder blend and the sticking problem during tablet compression are arisen by the use of the inadequate amounts of lubricant and glidant.
Thus, in the present embodiment, the flowability of the powder blend was targeted to be improved, further the sticking problem during tablet compression was planned to be overcome as well by using specified amounts and different types of lubricants and glidants in the formulation also by keeping the manufacturing process same as in Example 1.
Besides, another problem can generate sourced from the use of multiple types and high amounts of glidants and lubricants related to disintegration and dissolution because of their hydrophobic nature.
Thus, multiple examples proposed in parallel to obtain the final blend with suitable flowability and compressibility were prepared as given in Table 2.
Table 2: Examples comprising different types and amount ranges of glidants and lubricants
Before performing the tablet compression, the flowabilities of the final blends were investigated by performing the analytical method in accordance with USP < 1174> and evaluating the effects of specified types and amounts of glidant(s) and lubricants on flowability and compressibility.
The table of classification for the powder flow presented in USP <1174> monograph is as below. This table leads the skilled person in the art about how to evaluate the physicochemical properties of the powder blend.
Scale of flowability;
Thus, to measure the prediction of the propensity of a powder blend to be compressed, the Carr compressibility index and Hausner ratio are used that correspond to the percentage of tapped density to bulk density. The results of the Carr compressibility index and Hausner ratio of each powder blend are in Table 3.
Table 3: Physicochemical properties of proposed Examples
After consideration of the above results for each powder blend, following the tablet compression process activated. However, the problems came across listed below: - Example 2, sticking problem
Example 3, sticking problem
Example 4, no problem
Example 5, no problem
According to the observations above, tablet compression failed for Example 2 and Example 3. Then, the obtained tablets with the compositions of Example 4 and Example 5 were subjected to analytical tests like disintegration, friability and in vitro dissolution determination that are directly connected with the problems of sticking.
After overcoming the flowability and compressibility problems, the composition proposed should meet the requirements of disintegration, dissolution and dose uniformity tests.
Since the compositions comprise multiple types of lubricants and glidants which are known in the art to be hydrophobic, wetting of the tablet will be problematic which leads the tablet to disintegrate. In this case, both examples do not comprise any disintegrant which is beyond the routine development approach.
Disintegration test plays an important role in tablet dissolution for the active drug substance to release into the absorption site. Thus, the studies were performed in accordance with USP <701 > Disintegration monograph within the acceptance criteria of disintegration time of maximum 15 minutes for core tablet.
Thus, the studies were performed in accordance with USP <1216> Friability monograph within the acceptance criteria of friability of maximum 1.0%.
In vitro dissolution and dosage uniformity tests were performed to analyze the embodiments regarding dispersing the active substance in the tablet composition accurately and compare the release profiles with the reference product.
The disintegration time results were found under the acceptance criteria of a maximum of 15 minutes and the comparative results with reference drug product were presented in Table 4 below.
Table 4. Comparative physicochemical results of reference drug product with Examples
Lastly, the obtained tablets were subjected to in-vitro dissolution study. The conditions of in- vitro dissolution study are defined by US&FDA, based on the information available dissolution medium is 0.1 N HC1. Other conditions are; volume of dissolution medium is 900 ml, temperature of study is 37°C±0.5, rotation speed is 50 rpm, apparatus is paddle and the duration of dissolution study is 60 minute-duration.
Table 5: Comparison of dissolution profiles of Examples with reference drug product in 0.1N HC1
Based on the results presented in Table 5 above, dissolution profiles of the reference product and Example 5 were quite similar based on the release profiles particularly accounting 5th minute time point.
In the composition of Example 5 is the embodiment indicating most promising physicochemical and release profile results without comprising any disintegrant furtherly analyzed to detect the impurity profile. Since microcrystalline cellulose and mannitol are present in the formulation and very well known with their hydrophilic nature, Example-5 should be analyzed to determine the impurity profile of the composition that comprises an oxidation intensive active substance linagliptin.
The results of analysis and the specifications are presented in the table below. Thus, an evaluation could be done according to the specification values identified through guidance of ICH (International Council for Harmonization) guidelines.
Table 6: Impurity profile of Example 5
The impurity profile of Example 5 is well below the internationally determined specifications.
According to all results, in embodiments of the present invention, an immediate-release pharmaceutical composition comprising linagliptin and at least one pharmaceutically acceptable excipient is manufactured method by using direct compression, wherein the composition: is free of disintegrant, comprises at least two hydrophilic excipients, o one of the at least two hydrophilic excipients is microcrystalline cellulose
o one of the at least two hydrophilic excipients is mannitol
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.
Claims
1. An oral immediate release pharmaceutical composition manufactured by using direct compression method comprising linagliptin and at least one pharmaceutically acceptable excipient, wherein the composition comprises at least two hydrophilic excipients and is free of disintegrant.
2. An oral immediate release pharmaceutical composition according to Claim 1, wherein one of at least two the hydrophilic excipients is microcrystalline cellulose.
3. An oral immediate release pharmaceutical composition according to any one of the preceding claims, wherein one of at least two hydrophilic excipients is mannitol.
4. An oral immediate release pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises microcrystalline cellulose and mannitol as at least two hydrophilic excipients.
5. An oral immediate release pharmaceutical composition according to any one of the preceding claims, wherein, D90 value of Linagliptin is 20 microns or less.
6. An oral immediate release pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises at least one pharmaceutically acceptable excipient selected from binders, glidants, lubricants, and mixtures thereof.
7. An oral immediate release pharmaceutical composition according to claim 6, wherein the composition comprises binder selected from hypromellose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, pregelatinized starch, povidone, starch, sucrose, polyethylene glycol, and mixtures thereof.
8. An oral immediate release pharmaceutical composition according to claim 7, wherein the binder is pregelatinized starch.
9. An oral immediate release pharmaceutical composition according to any one of the claims 6-8, wherein the composition comprises glidant selected from colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate, and mixtures thereof.
10. An oral immediate release pharmaceutical composition according to Claim 9, wherein the glidant is a mixture of talc and colloidal silicondioxide.
11. An oral immediate release pharmaceutical composition according to any one of the claims 6-10, wherein the composition comprises lubricant selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid, hydrogenated castor oil, and mixtures thereof.
12. An oral immediate release pharmaceutical composition according to Claim 11, wherein the lubricant is magnesium stearate.
13. A direct compression method for the preparation of a pharmaceutical composition according to any one of the preceding claims, wherein the process comprising the steps of; a. Linagliptin, glidant(s), mannitol and the specified amount of microcrystalline cellulose were screened through a proper sieve and stirred, b. The rest of the microcrystalline cellulose and binder were screened through a proper sieve, added to the powder blend prepared in Step (b) and stirred. c. Lubricant was screened through a proper sieve, added to the powder blend prepared in Step (c) and stirred to obtain a uniform final blend.
14. An oral immediate release pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2022/051390 WO2024117998A1 (en) | 2022-11-30 | 2022-11-30 | Immediate release oral pharmaceutical composition comprising linagliptin |
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| Application Number | Priority Date | Filing Date | Title |
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| PCT/TR2022/051390 WO2024117998A1 (en) | 2022-11-30 | 2022-11-30 | Immediate release oral pharmaceutical composition comprising linagliptin |
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| WO2024117998A1 true WO2024117998A1 (en) | 2024-06-06 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/TR2022/051390 WO2024117998A1 (en) | 2022-11-30 | 2022-11-30 | Immediate release oral pharmaceutical composition comprising linagliptin |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3156048A1 (en) * | 2015-10-13 | 2017-04-19 | Galenicum Health S.L. | Stable pharmaceutical composition of linagliptin in the form of immediate release tablets |
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- 2022-11-30 WO PCT/TR2022/051390 patent/WO2024117998A1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3156048A1 (en) * | 2015-10-13 | 2017-04-19 | Galenicum Health S.L. | Stable pharmaceutical composition of linagliptin in the form of immediate release tablets |
Non-Patent Citations (2)
| Title |
|---|
| "Basic Fundamentals of Drug Delivery", 1 January 2019, ELSEVIER, ISBN: 978-0-12-817909-3, article KAR MOUSUMI, CHOURASIYA YASHU, MAHESHWARI RAHUL, TEKADE RAKESH K.: "Current Developments in Excipient Science", pages: 29 - 83, XP055936584, DOI: 10.1016/B978-0-12-817909-3.00002-9 * |
| STEFFENS KRISTINA E.; WAGNER KARL G.: "Immediate-Release Formulations Produced via Twin-Screw Melt Granulation: Systematic Evaluation of the Addition of Disintegrants", AAPS PHARMSCITECH, SPRINGER INTERNATIONAL PUBLISHING, CHAM, vol. 22, no. 5, 16 June 2021 (2021-06-16), Cham , XP037482476, DOI: 10.1208/s12249-021-02056-0 * |
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