CA3085455C - A solid oral dosage form comprising linagliptin - Google Patents
A solid oral dosage form comprising linagliptin Download PDFInfo
- Publication number
- CA3085455C CA3085455C CA3085455A CA3085455A CA3085455C CA 3085455 C CA3085455 C CA 3085455C CA 3085455 A CA3085455 A CA 3085455A CA 3085455 A CA3085455 A CA 3085455A CA 3085455 C CA3085455 C CA 3085455C
- Authority
- CA
- Canada
- Prior art keywords
- dosage form
- oral dosage
- solid oral
- weight
- linagliptin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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 52
- 229960002397 linagliptin Drugs 0.000 title claims abstract description 51
- 239000007787 solid Substances 0.000 title claims abstract description 32
- 239000006186 oral dosage form Substances 0.000 title claims abstract description 30
- 239000011230 binding agent Substances 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims description 42
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 22
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 21
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 20
- 229940069328 povidone Drugs 0.000 claims description 19
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 16
- 239000008109 sodium starch glycolate Substances 0.000 claims description 16
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 16
- 239000011248 coating agent Substances 0.000 claims description 14
- 239000007884 disintegrant Substances 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000945 filler Substances 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 9
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 9
- 239000013543 active substance Substances 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 4
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 4
- 238000000576 coating method Methods 0.000 claims description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000007888 film coating Substances 0.000 claims description 3
- 238000009501 film coating Methods 0.000 claims description 3
- 238000003825 pressing Methods 0.000 claims description 3
- 238000007873 sieving Methods 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 235000001465 calcium Nutrition 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 229940099112 cornstarch Drugs 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 claims description 2
- RRPFCKLVOUENJB-UHFFFAOYSA-L disodium;2-aminoacetic acid;carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O.NCC(O)=O RRPFCKLVOUENJB-UHFFFAOYSA-L 0.000 claims description 2
- 229960000878 docusate sodium Drugs 0.000 claims description 2
- 239000000665 guar gum Substances 0.000 claims description 2
- 235000010417 guar gum Nutrition 0.000 claims description 2
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- 238000004519 manufacturing process Methods 0.000 claims description 2
- 235000010603 pastilles Nutrition 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229960003975 potassium Drugs 0.000 claims description 2
- 235000007686 potassium 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
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 235000015424 sodium Nutrition 0.000 claims 1
- 229910021653 sulphate ion Inorganic materials 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 21
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 239000008185 minitablet Substances 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- 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 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 229940088597 hormone Drugs 0.000 description 4
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
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- 150000003839 salts Chemical class 0.000 description 4
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007941 film coated tablet Substances 0.000 description 3
- 239000004179 indigotine Substances 0.000 description 3
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- -1 iron oxide red Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- YSVBPNGJESBVRM-ZPZFBZIMSA-L Carmoisine Chemical compound [Na+].[Na+].C1=CC=C2C(/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)O)=CC=C(S([O-])(=O)=O)C2=C1 YSVBPNGJESBVRM-ZPZFBZIMSA-L 0.000 description 2
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- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- JFVXEJADITYJHK-UHFFFAOYSA-L disodium 2-(3-hydroxy-5-sulfonato-1H-indol-2-yl)-3-oxoindole-5-sulfonate Chemical compound [Na+].[Na+].Oc1c([nH]c2ccc(cc12)S([O-])(=O)=O)C1=Nc2ccc(cc2C1=O)S([O-])(=O)=O JFVXEJADITYJHK-UHFFFAOYSA-L 0.000 description 2
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- 239000000859 incretin Substances 0.000 description 2
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)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=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The present invention relates to a solid oral dosage form comprising linagliptin and at least one binder.
Description
A SOLID ORAL DOSAGE FORM COMPRISING LINAGLIPTIN
Field of the Invention The present invention relates to a solid oral dosage form comprising linagliptin and at least one binder.
Background of the Invention 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. There are two types of incretin hormones found in the body, called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones are naturally produced by the body in response to food intake. Their function is to help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed. 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.
The chemical name of linagliptin is 8-[(3R)-3-aminopiperidin-1-y1]-7-but-2-yn-1-y1)-3-methyl-1-[(4-methylquinazolin-2-Amethyl]-3,7-dihydro-1H-purine-2,6-dione and its chemical structure is shown in the Formula I.
11110) N
N \
Formula I
W02014/026939 patent application discloses a pharmaceutical composition comprising linagliptin or salts thereof with mannitol, copovidone, and magnesium stearate, a process for the preparation of the pharmaceutical composition.
Field of the Invention The present invention relates to a solid oral dosage form comprising linagliptin and at least one binder.
Background of the Invention 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. There are two types of incretin hormones found in the body, called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones are naturally produced by the body in response to food intake. Their function is to help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed. 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.
The chemical name of linagliptin is 8-[(3R)-3-aminopiperidin-1-y1]-7-but-2-yn-1-y1)-3-methyl-1-[(4-methylquinazolin-2-Amethyl]-3,7-dihydro-1H-purine-2,6-dione and its chemical structure is shown in the Formula I.
11110) N
N \
Formula I
W02014/026939 patent application discloses a pharmaceutical composition comprising linagliptin or salts thereof with mannitol, copovidone, and magnesium stearate, a process for the preparation of the pharmaceutical composition.
2 There still remains a need in the art to provide an improved pharmaceutical composition of linagliptin. At this invention provides having high stability of linagliptin, dissolution rate, and therefore a high bioavailability and a long-term stability.
Detailed Description of the Invention The main object of the present invention is to provide high stability of linagliptin and a long shelf life by the help of selection of excipients in a certain ratio.
Another aim of the present invention is to provide a pharmaceutical dosage form comprising linagliptin which has a long shelf life, a short disintegration time, desired dissolution properties and enables a high bioavailability of linaglitpin in a patient.
The term "linagliptin" as used throughout the specification 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 and pharmaceutically acceptable prodrugs thereof.
The linagliptin is present as amorphous linagliptin, crystalline linagliptin having polymorphic form A, crystalline linagliptin having polymorphic form B and/or crystalline linagliptin having polymorphic form C or mixtures thereof.
In one embodiment of the invention, the linagliptin is present as a mixture of crystalline linagliptin having polymorphic form A and crystalline linagliptin having polymorphic form B.
In one embodiment of the invention, the pharmaceutical solid oral dosage form comprises linagliptin as an active agent and at least one binder in which the weight ratio of linagliptin to binder is between 0.1 and 6Ø This ratio is important in order to providing high stability of linagliptin and improved flow properties.
In one embodiment of the invention, the weight ratio of linagliptin to binder is between 0.3 and 3.0 or between 0.5 and 2Ø
In one embodiment of the invention, the amount of linagliptin in the composition is between 1.0% and 10.0% by weight, preferably it is between 2.0% and 7.0%, more preferably it is between 2.5% and 6.0%.
Detailed Description of the Invention The main object of the present invention is to provide high stability of linagliptin and a long shelf life by the help of selection of excipients in a certain ratio.
Another aim of the present invention is to provide a pharmaceutical dosage form comprising linagliptin which has a long shelf life, a short disintegration time, desired dissolution properties and enables a high bioavailability of linaglitpin in a patient.
The term "linagliptin" as used throughout the specification 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 and pharmaceutically acceptable prodrugs thereof.
The linagliptin is present as amorphous linagliptin, crystalline linagliptin having polymorphic form A, crystalline linagliptin having polymorphic form B and/or crystalline linagliptin having polymorphic form C or mixtures thereof.
In one embodiment of the invention, the linagliptin is present as a mixture of crystalline linagliptin having polymorphic form A and crystalline linagliptin having polymorphic form B.
In one embodiment of the invention, the pharmaceutical solid oral dosage form comprises linagliptin as an active agent and at least one binder in which the weight ratio of linagliptin to binder is between 0.1 and 6Ø This ratio is important in order to providing high stability of linagliptin and improved flow properties.
In one embodiment of the invention, the weight ratio of linagliptin to binder is between 0.3 and 3.0 or between 0.5 and 2Ø
In one embodiment of the invention, the amount of linagliptin in the composition is between 1.0% and 10.0% by weight, preferably it is between 2.0% and 7.0%, more preferably it is between 2.5% and 6.0%.
3 As used here in, 'particle size' means the cumulative volume size distrubition as tested by any conventionally accepted method such as the laser diffraction method (i.e.
Malvern Mastersizer 2000 analysis). The term d (0.9) means the size at which %90 by volume of the particles are finer.
In one embodiment of the invention, linagliptin has ad (0.9) particle size less than 100 pm, preferably linagliptin has a d (0.9) particle size less than 50 pm. This property provides improved flow properties.
Suitable binders are selected from the group comprising povidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, mannitol, gelatin, pullulan, sodium alginate or mixtures thereof.
The present invention comprises one or more binders in an amount of from about 1% to about 20% by weight of the composition.
In general, DPP-4 inhibitors are not very stable compounds. Especially, in solid dosage forms, amine group containing DPP-4 inhibitors like linagliptin may react with many excipients or impurities of excipients. In this invention, it has been surprisingly found that using binder ensures high stability of linagliptin in a solid oral dosage composition. Especially povidone is used as binder in the present invention. Povidone has also disintegration property and it is used to enhance dissolution of poorly soluble drugs from solid-dosage forms.
In one embodiment of the invention, binder is povidone and the amount of povidone in the composition is 1.0% and 5.0% by weight.
In another embodiment, the pharmaceutical acceptable excipients used in the present invention are selected from the group consisting of fillers, disintegrants, lubricants, and film coating agents.
Suitable fillers are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
Malvern Mastersizer 2000 analysis). The term d (0.9) means the size at which %90 by volume of the particles are finer.
In one embodiment of the invention, linagliptin has ad (0.9) particle size less than 100 pm, preferably linagliptin has a d (0.9) particle size less than 50 pm. This property provides improved flow properties.
Suitable binders are selected from the group comprising povidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, mannitol, gelatin, pullulan, sodium alginate or mixtures thereof.
The present invention comprises one or more binders in an amount of from about 1% to about 20% by weight of the composition.
In general, DPP-4 inhibitors are not very stable compounds. Especially, in solid dosage forms, amine group containing DPP-4 inhibitors like linagliptin may react with many excipients or impurities of excipients. In this invention, it has been surprisingly found that using binder ensures high stability of linagliptin in a solid oral dosage composition. Especially povidone is used as binder in the present invention. Povidone has also disintegration property and it is used to enhance dissolution of poorly soluble drugs from solid-dosage forms.
In one embodiment of the invention, binder is povidone and the amount of povidone in the composition is 1.0% and 5.0% by weight.
In another embodiment, the pharmaceutical acceptable excipients used in the present invention are selected from the group consisting of fillers, disintegrants, lubricants, and film coating agents.
Suitable fillers are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
4 According to one embodiment, microcrystalline cellulose is a filler which has the best flowability properties among the other fillers. In this invention, it further improves the disintegration of compositon as well as being a filler. In addition, it further enhances the compressibility by increasing the hardness of the tablet.
In this embodiment, the amount of microcrystalline cellulose is in the range of 70.0 to 90 `)/0, preferably 76.0 to 88.0 `)/0, more preferably it is 80.0 to 85.0 `)/0 by weight of total composition.
Suitable disintegrants are selected from the group comprising sodium starch glycolate, cross-linked polyvinil pyrrolidone (crospovidone), povidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, alginic acid, alginates, sodium dodecyl sulphate, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
A sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredient should be used to form solid oral dosage forms provided herein. However, disintegrants can be mixed with other excipient to increase effective disintegration of the tablet into smaller fragments.
In one embodiment of the invention, disintegrant is sodium starch glycolate, is also known as superdisinteg rant, and the amount of sodium starch glycolate is in the range of 3.0% to 8.0%
and thus desired level of dissolution rate is provided.
Furthermore, the combination of povidone and sodium starch glycolate provides desired short disintegration time and desired dissolution properties in composition.
According to an embodiment of the present invention, the weight ratio of sodium starch glycolate to povidone is between 0.2 and 10.0 or 0.6 and 8Ø
According to another embodiment, the lubricant is selected from the group comprising sodium stearyl fumarate, magnesium stearate, polyethylene glycol (PEG), sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, paraffin or mixtures thereof, preferably sodium stearyl fumarate.
In this embodiment, the amount of microcrystalline cellulose is in the range of 70.0 to 90 `)/0, preferably 76.0 to 88.0 `)/0, more preferably it is 80.0 to 85.0 `)/0 by weight of total composition.
Suitable disintegrants are selected from the group comprising sodium starch glycolate, cross-linked polyvinil pyrrolidone (crospovidone), povidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, alginic acid, alginates, sodium dodecyl sulphate, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
A sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredient should be used to form solid oral dosage forms provided herein. However, disintegrants can be mixed with other excipient to increase effective disintegration of the tablet into smaller fragments.
In one embodiment of the invention, disintegrant is sodium starch glycolate, is also known as superdisinteg rant, and the amount of sodium starch glycolate is in the range of 3.0% to 8.0%
and thus desired level of dissolution rate is provided.
Furthermore, the combination of povidone and sodium starch glycolate provides desired short disintegration time and desired dissolution properties in composition.
According to an embodiment of the present invention, the weight ratio of sodium starch glycolate to povidone is between 0.2 and 10.0 or 0.6 and 8Ø
According to another embodiment, the lubricant is selected from the group comprising sodium stearyl fumarate, magnesium stearate, polyethylene glycol (PEG), sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, paraffin or mixtures thereof, preferably sodium stearyl fumarate.
5 Coating may also preferably be used for moisture protection. Suitable coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, glycerine, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat IR), 5 ethylcellulose dispersions (Sureleasee), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry , pigments, dyes, titanium dioxide, macrogol, coloring agent or mixtures thereof.
Suitable coloring agents are selected from the group comprising ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), ponceau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C
blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
Preferably, the pharmaceutical composition of the present invention comprises linagliptin or a pharmaceutically acceptable salt thereof, povidone, sodium stearyl fumarate, sodium starch glycolate, microcrystalline cellulose.
Solid oral dosage is used for having effective stability and bioavailability.
Another embodiment of the present invention is a pharmaceutical composition in the form of a solid oral dosage form.
In this present invention, the solid oral dosage form is tablet or capsule or pastilles or strip.
.. In this present invention, the solid oral dosage form is tablet. Tablet may be consisted of separated compartments or layer.
An embodiment of this present invention, the pharmaceutical combination is formulated as tablets comprising film-coated tablets, compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, pellet in tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, core-in-tablet, modified release tablets, tablet-in-tablet, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges.
Preferably, the pharmaceutical combination is formulated as film coated tablet.
Suitable coloring agents are selected from the group comprising ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), ponceau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C
blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
Preferably, the pharmaceutical composition of the present invention comprises linagliptin or a pharmaceutically acceptable salt thereof, povidone, sodium stearyl fumarate, sodium starch glycolate, microcrystalline cellulose.
Solid oral dosage is used for having effective stability and bioavailability.
Another embodiment of the present invention is a pharmaceutical composition in the form of a solid oral dosage form.
In this present invention, the solid oral dosage form is tablet or capsule or pastilles or strip.
.. In this present invention, the solid oral dosage form is tablet. Tablet may be consisted of separated compartments or layer.
An embodiment of this present invention, the pharmaceutical combination is formulated as tablets comprising film-coated tablets, compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, pellet in tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, core-in-tablet, modified release tablets, tablet-in-tablet, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges.
Preferably, the pharmaceutical combination is formulated as film coated tablet.
6 In this present invention, the pharmaceutical combination can be prepared in tablet form.
Tablet comprises at least one type of particle, for example; mini-tablets, pellets, agglomerates, granules, powders, liposomes, sphericles or mixtures thereof.
An embodiment of this present invention, each type of particle comprises at least one active agent.
In this present invention, pharmaceutical combination may comprise a film coating if necessary.
In this present invention, pharmaceutical combination can be prepared in capsule form.
Capsule comprises of at least one type of particle, for example; mini-capsules, mini-tablets, pellets, agglomerates, granules, powders, liposomes, sphericles or mixtures thereof.
An embodiment of this present invention, the dosage unit form of composition is mini-capsules in capsule wherein the mini-capsules comprise at least one active agent.
An embodiment of this present invention, the dosage unit form of composition is mini-tablets in capsule wherein a mini-tablets comprise at least one active agent.
An embodiment of this present invention, the dosage unit form of composition is pellets in capsule wherein pellets comprise at least one active agent.
In one embodiment of the present invention, the composition comprises;
a) 2.0 - 10.0% by weight of linagliptin b) 80.0 - 85.0% by weight of filler c) 1.5 - 4.0% by weight of binder d) 3.5 - 6.0% by weight of disintegrant e) 0.1 - 3.0% by weight of lubricant f) 1.0 - 5.0% by weight of coating agents
Tablet comprises at least one type of particle, for example; mini-tablets, pellets, agglomerates, granules, powders, liposomes, sphericles or mixtures thereof.
An embodiment of this present invention, each type of particle comprises at least one active agent.
In this present invention, pharmaceutical combination may comprise a film coating if necessary.
In this present invention, pharmaceutical combination can be prepared in capsule form.
Capsule comprises of at least one type of particle, for example; mini-capsules, mini-tablets, pellets, agglomerates, granules, powders, liposomes, sphericles or mixtures thereof.
An embodiment of this present invention, the dosage unit form of composition is mini-capsules in capsule wherein the mini-capsules comprise at least one active agent.
An embodiment of this present invention, the dosage unit form of composition is mini-tablets in capsule wherein a mini-tablets comprise at least one active agent.
An embodiment of this present invention, the dosage unit form of composition is pellets in capsule wherein pellets comprise at least one active agent.
In one embodiment of the present invention, the composition comprises;
a) 2.0 - 10.0% by weight of linagliptin b) 80.0 - 85.0% by weight of filler c) 1.5 - 4.0% by weight of binder d) 3.5 - 6.0% by weight of disintegrant e) 0.1 - 3.0% by weight of lubricant f) 1.0 - 5.0% by weight of coating agents
7 In one embodiment of the present invention, the composition comprises;
a) 1.0 - 10.0% by weight of linagliptin b) 70.0 - 90.0% by weight of microcrystalline cellulose c) 1.0 - 5.0% by weight of povidone d) 3.0 - 8.0% by weight of sodium starch glycolate e) 0.1 - 5.0% by weight of sodium stearyl fumarate f) 0.5 - 8.0% by weight of coating agents The pharmaceutical composition of the present invention can be prepared, using standard .. techniques and manufacturing processes well known in the art, such as direct compression, wet and dry granulation.
According to one embodiment of the present invention, it has been found that when the formulation is prepared with wet granulation, the formulation has desired stability and desired dissolution rate.
Suitable granulation solutions are selected from a group comprising pure water, ethyl alcohol, glycerin, sorbitol, polyethylene glycol, propylene glycol, isopropyl alcohol or mixtures thereof, preferably the granulation solution is pure water.
An embodiment of the present invention, the process for preparation of the pharmaceutical composition comprises the following steps:
a) Mixing linagliptin, microcrystalline cellulose and sodium starch glycolate b) Granulating povidone with pure water on a separate tank c) Mixing step (a) mixture and step (b) mixture d) Drying the mixture, then sieving the mixture e) Adding sodium stearyl fumarate and then mixing f) Then, pressing to form tablet g) Coating tablets with coating agents.
a) 1.0 - 10.0% by weight of linagliptin b) 70.0 - 90.0% by weight of microcrystalline cellulose c) 1.0 - 5.0% by weight of povidone d) 3.0 - 8.0% by weight of sodium starch glycolate e) 0.1 - 5.0% by weight of sodium stearyl fumarate f) 0.5 - 8.0% by weight of coating agents The pharmaceutical composition of the present invention can be prepared, using standard .. techniques and manufacturing processes well known in the art, such as direct compression, wet and dry granulation.
According to one embodiment of the present invention, it has been found that when the formulation is prepared with wet granulation, the formulation has desired stability and desired dissolution rate.
Suitable granulation solutions are selected from a group comprising pure water, ethyl alcohol, glycerin, sorbitol, polyethylene glycol, propylene glycol, isopropyl alcohol or mixtures thereof, preferably the granulation solution is pure water.
An embodiment of the present invention, the process for preparation of the pharmaceutical composition comprises the following steps:
a) Mixing linagliptin, microcrystalline cellulose and sodium starch glycolate b) Granulating povidone with pure water on a separate tank c) Mixing step (a) mixture and step (b) mixture d) Drying the mixture, then sieving the mixture e) Adding sodium stearyl fumarate and then mixing f) Then, pressing to form tablet g) Coating tablets with coating agents.
8 Example 1: Film coated tablet comprising linagliptin ( /0) amount (w/w) Linagliptin 2.0% - 10.0%
Filler 80.0% - 85.0%
Binder 1.5% - 4.0%
Disinteg rant 3.5% - 6.0%
Lubricant 0.1% - 3.0%
Coating agents 1.0% - 5.0%
Total 100 Example 2: Solid oral dosage form comprising linagliptin ( /0) amount (w/w) Linagliptin 1.0% - 10.0%
Microcrystalline cellulose 70.0% - 90.0%
Povidone 1.0% - 5.0%
Sodium starch glycolate 3.0% - 8.0%
Sodium stearyl fumarate 0.1% - 5.0%
Coating agents 0.5% - 8.0%
Total 100 Process for example 1 or 2:
The process for preparation of the pharmaceutical composition comprises the following steps:
a) Mixing linagliptin, microcrystalline cellulose and sodium starch glycolate b) Granulating povidone with pure water on a separate tank c) Mixing step (a) mixture and step (b) mixture d) drying the mixture, then sieving the mixture e) Adding sodium stearyl fumarate and then mixing f) Then, pressing to form tablet g) Coating tablets with coating agents.
Filler 80.0% - 85.0%
Binder 1.5% - 4.0%
Disinteg rant 3.5% - 6.0%
Lubricant 0.1% - 3.0%
Coating agents 1.0% - 5.0%
Total 100 Example 2: Solid oral dosage form comprising linagliptin ( /0) amount (w/w) Linagliptin 1.0% - 10.0%
Microcrystalline cellulose 70.0% - 90.0%
Povidone 1.0% - 5.0%
Sodium starch glycolate 3.0% - 8.0%
Sodium stearyl fumarate 0.1% - 5.0%
Coating agents 0.5% - 8.0%
Total 100 Process for example 1 or 2:
The process for preparation of the pharmaceutical composition comprises the following steps:
a) Mixing linagliptin, microcrystalline cellulose and sodium starch glycolate b) Granulating povidone with pure water on a separate tank c) Mixing step (a) mixture and step (b) mixture d) drying the mixture, then sieving the mixture e) Adding sodium stearyl fumarate and then mixing f) Then, pressing to form tablet g) Coating tablets with coating agents.
Claims (18)
1. A pharmaceutical solid oral dosage form comprising linagliptin as the active agent and at least one binder in which the weight ratio of linagliptin to binder is between 0.1 and 6.0; wherein the binder is povidone.
2. The pharmaceutical solid oral dosage form according to claim 1, wherein the weight ratio of linagliptin to binder is between 0.3 and 3Ø
3. The pharmaceutical solid oral dosage form according to claim 2, wherein the weight ratio of linagliptin to binder is between 0.5 and 2Ø
4. The pharmaceutical solid oral dosage form according to claim 3, wherein the amount of linagliptin in the composition is between 1.0% and 10.0% by weight.
5. The pharmaceutical solid oral dosage form according to claim 4, wherein the amount of linagliptin in the composition is between 2.0% and 7.0% by weight.
6. The pharmaceutical solid oral dosage form according to claim 4, wherein linagliptin has a d (0.9) particle size less than 100 pm.
7. The pharmaceutical solid oral dosage form according to claim 5, wherein linagliptin has a d (0.9) particle size less than 50 pm.
8. The pharmaceutical solid oral dosage form according to any one of claims 1-7, wherein the amount of povidone in the composition is 1.0% and 5.0%
by weight.
by weight.
9. The pharmaceutical solid oral dosage form according to any one of claims 1-8, further comprising pharmaceutical acceptable excipients which are selected from the group consisting of fillers, disintegrants, lubricants and film coating agents.
10.The pharmaceutical solid oral dosage form according to claim 9, wherein disintegrant is selected from the group consisting of sodium starch glycolate, cross-linked polyvinyl pyrrolidone (crospovidone), povidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, alginic acid, alginates, sodium dodesyl sulphate, sodium glycine carbonate and sodium lauryl sulphate .
11.The pharmaceutical solid oral dosage form according to claim 10, wherein disintegrant is sodium starch glycolate.
12.The pharmaceutical solid oral dosage form according to claim 11, wherein the amount of sodium starch glycolate is in the range of 3.0% to 8.0%.
13.The pharmaceutical solid oral dosage form according to claim 8 or 12, wherein the weight ratio of sodium starch glycolate to povidone is between 0.2 and 10Ø
14.The pharmaceutical solid oral dosage form according to any one of claims 1-13, wherein the solid oral dosage form is tablet or capsule or pastilles or strip.
15.The pharmaceutical solid oral dosage form according to claim 14, wherein the solid oral dosage form is tablet.
16.The pharmaceutical solid oral dosage form according to claim 15, the composition comprising;
a) 2.0 - 10.0% by weight of linagliptin b) 80.0 - 85.0% by weight of filler c) 1.5 - 4.0% by weight of binder d) 3.5 - 6.0% by weight of disintegrant e) 0.1 - 3.0% by weight of lubricant f) 1.0 - 5.0% by weight of coating agents.
a) 2.0 - 10.0% by weight of linagliptin b) 80.0 - 85.0% by weight of filler c) 1.5 - 4.0% by weight of binder d) 3.5 - 6.0% by weight of disintegrant e) 0.1 - 3.0% by weight of lubricant f) 1.0 - 5.0% by weight of coating agents.
17.The pharmaceutical solid oral dosage form according to claim 15, the composition comprising;
a) 1.0 - 10.0% by weight of linagliptin b) 70.0 - 90.0% by weight of microcrystalline cellulose c) 1.0 - 5.0% by weight of povidone d) 3.0 - 8.0% by weight of sodium starch glycolate e) 0.1 - 5.0% by weight of sodium stearyl fumarate f) 0.5 - 8.0% by weight of coating agents.
a) 1.0 - 10.0% by weight of linagliptin b) 70.0 - 90.0% by weight of microcrystalline cellulose c) 1.0 - 5.0% by weight of povidone d) 3.0 - 8.0% by weight of sodium starch glycolate e) 0.1 - 5.0% by weight of sodium stearyl fumarate f) 0.5 - 8.0% by weight of coating agents.
18.Process for preparing the pharmaceutical solid oral dosage form as defined in claim 17, comprising the following steps;
a) Mixing linagliptin, microcrystalline cellulose and sodium starch glycolate b) Granulating povidone with pure water on a separate tank c) Mixing step (a) mixture and step (b) mixture d) Drying the mixture, then sieving the mixture e) Adding sodium stearyl fumarate and then mixing f) Then, pressing to form tablet g) Coating tablets with coating agents.
a) Mixing linagliptin, microcrystalline cellulose and sodium starch glycolate b) Granulating povidone with pure water on a separate tank c) Mixing step (a) mixture and step (b) mixture d) Drying the mixture, then sieving the mixture e) Adding sodium stearyl fumarate and then mixing f) Then, pressing to form tablet g) Coating tablets with coating agents.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2017/20515A TR201720515A2 (en) | 2017-12-15 | 2017-12-15 | A SOLID ORAL DOSAGE FORM CONTAINING LINAGLIPTIN |
| TR2017/20515 | 2017-12-15 | ||
| PCT/TR2018/050812 WO2019203755A2 (en) | 2017-12-15 | 2018-12-14 | A solid oral dosage form comprising linagliptin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA3085455A1 CA3085455A1 (en) | 2019-10-24 |
| CA3085455C true CA3085455C (en) | 2022-08-16 |
Family
ID=67900883
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3085455A Active CA3085455C (en) | 2017-12-15 | 2018-12-14 | A solid oral dosage form comprising linagliptin |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP3723761A4 (en) |
| CA (1) | CA3085455C (en) |
| TR (1) | TR201720515A2 (en) |
| WO (1) | WO2019203755A2 (en) |
Families Citing this family (1)
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| WO2022173406A1 (en) * | 2021-02-15 | 2022-08-18 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A process for formulations of linagliptin or a pharmaceutically acceptable salt thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UY32427A (en) * | 2009-02-13 | 2010-09-30 | Boheringer Ingelheim Internat Gmbh | PHARMACEUTICAL COMPOSITION, PHARMACEUTICAL FORM, PROCEDURE FOR PREPARATION, METHODS OF TREATMENT AND USES OF THE SAME |
| WO2013128379A2 (en) | 2012-02-27 | 2013-09-06 | Dr. Reddy's Laboratories Limited | Crystalline polymorphic forms of linagliptin |
| EP2908806A1 (en) * | 2012-10-09 | 2015-08-26 | Boehringer Ingelheim International GmbH | Use of selectively moisture-adjusted tabletting material in the production of mechanically stable tablets which contain at least one hydrate-forming active substance and/or adjuvant relevant to the mechanical stability of the tablets, particularly arginine-containing tablets |
| WO2014080384A1 (en) | 2012-11-26 | 2014-05-30 | Ranbaxy Laboratories Limited | Pharmaceutical composition of linagliptin |
| WO2014080383A1 (en) * | 2012-11-26 | 2014-05-30 | Ranbaxy Laboratories Limited | Pharmaceutical composition of dipeptidyl peptidase-iv (dpp-iv) inhibitors in combination with other antidiabetics |
| CN106138059A (en) * | 2015-03-27 | 2016-11-23 | 天津汉瑞药业有限公司 | A kind of stable Li Gelieting pharmaceutical composition |
| EP3156048A1 (en) * | 2015-10-13 | 2017-04-19 | Galenicum Health S.L. | Stable pharmaceutical composition of linagliptin in the form of immediate release tablets |
-
2017
- 2017-12-15 TR TR2017/20515A patent/TR201720515A2/en unknown
-
2018
- 2018-12-14 WO PCT/TR2018/050812 patent/WO2019203755A2/en unknown
- 2018-12-14 CA CA3085455A patent/CA3085455C/en active Active
- 2018-12-14 EP EP18914956.0A patent/EP3723761A4/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| TR201720515A2 (en) | 2019-07-22 |
| CA3085455A1 (en) | 2019-10-24 |
| EP3723761A2 (en) | 2020-10-21 |
| WO2019203755A3 (en) | 2020-01-16 |
| EP3723761A4 (en) | 2021-06-30 |
| WO2019203755A2 (en) | 2019-10-24 |
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