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
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • 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
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

• This present invention relates to pharmaceutical composition
• pharmaceutical composition comprising fixed dose combination of liiiagliptin and metformin HCI wherein the composition is devoid of any basic amino acids. Further this invention also relates to process for the preparation of said composition & use of the said composition in treatment of certain diseases.
• Linagliptin is a DPP-IV inhibitor, having antidiabetic activity.
• linagliptin is I -[(4-methyl-quinazol in-2-yl)inethyl]-3-methyl-7-(2-butyn- 1 -yl)-8-(3-(R)-amino- piperidin- 1 -yl)-xanthine. Its
• Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water, soluble in methanol, sparingly soluble in ethanol, very slightly soluble in Isopropanol, and very slightly soluble in acetone. It has a molecular weight of 472.54.
• Metformin, chem ical name of which is N, N-dimethyl imidodicarbonimidic diamide, is a molecule belonging to biguanide class. Its structure is as follows:
• Metformin was first disclosed in the appl ication numbered US3 1 74901. It is known that metformin is especially effective in the treatment of type-2 diabetic patients who are overweight and obese but have healthy kidney functions. On the market, metform in can be found in metformin hydrochloride (HCl) form of 500 mg, 750 mg and 1000 mg film tablet and prolonged-release tablets. Linagliptin is commercially available as a Tradjenta® brand name in 5 mg tablet.
• Jentadueto® which is contains 2.5+500 mg, 2.5+850 mg and 2.5+1000 mg linagliptin & metform in HCl respectively as active ingredients and fol lowing inactive ingredients: arginine, corn starch, copovidone, col loidal silicon dioxide, magnesium stearate, titanium dioxide, propylene glycol, hypromellose, talc, yellow ferric oxide and/or red ferric oxide.
• US patent no 7407955 discloses linagliptin as a product. Further this patent also discloses a pharmaceutical composition of l inagliptin comprising one or more inert carriers or diluents.
• US patent no 81 19648 disclose method of use of linagliptin in treatment of type II diabetes mellitus or obesity.
• US patent no 81 78541 describe the pharmaceutical composition of linagliptin with metformin HCl. Further this patent also discloses the use of linagliptin and metformin HCl combination in treatment in type II diabetes mellitus.
• US201 1206766 discloses pharmaceutical composition comprising or made from DPP- 4 inh ibitor, a partner drug, and one or more pharmaceutical excipients, and a nucleophilic and/or basic agents for stabilizing said DPP-4 inhibitor against degradation.
• the DPP-4 inhibitor is linagliptin and partner drug is metformin HCl.
• US201 1206766 discloses use of a basic amino acid L-arginine, which may be suitable for stabilizing, such as e.g. a suitable buffering agent as stabilizer, to overcome the problems of incompatibility and poor stability, especially decomposition and/or "assay decrease" which may be caused e.g.
• the inventors of the present invention surprisingly found a chemically stable pharmaceutical composition comprising fixed dose combination of linagl iptin and metformin HCI that overcomes the above mentioned problem even without the use of basic amino acid.
• the object of the present invention is to provide a chemical ly stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCI and one or more pharmaceutical acceptable excipients.
• Another object of the present invention is to provide a chemically stable pharmaceutical composition comprising fixed dose combination of l inagl iptin and metformin HCI and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid.
• Another object of the present invention is to provide a chemical ly stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of colloidal silicon dioxide.
• Another object of the present invention is to provide a chemically stable pharmaceutical composition
• a chemically stable pharmaceutical composition comprising fixed dose combination of l inagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid and/or colloidal silicon dioxide.
• Another object of the present invention is to provide a chemically stable pharmaceutical composition
• a chemically stable pharmaceutical composition comprising fixed dose combination of linagl iptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the pharmaceutically acceptable excipients selected form one or more fillers or diluents, one or more binders, one or more disintegrants, one or more lubricants, one or more film coating agents, one or more pigments or plasticizers, and the like, wherein the composition is devoid of basic amino acid and/or col loidal si licon dioxide.
• Another object of the present invention is to provide a process for the preparation of chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid and/or colloidal silicon dioxide.
• Another object of the present invention is to provide a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCl, which is intended for the treatment of diabetes and/or to achieve glycemic control in a type 1 or type 2 diabetes mellitus patients.
• the present invention relates to pharmaceutical composition
• pharmaceutical composition comprising fixed dose combination of linagl iptin and metform in HCI wherein the composition is devoid of any basic amino acids.
• Said composition provides a stable composition to overcome the problem of chemical degradation of free base of linagliptin when combined with metformin HCI. Further the present invention also provides a method for the preparation of said composition. DETAILED DESCRIPTION
• Inventors of this invention surprisingly developed chemically stable pharmaceutical fixed dose combination of linagliptin free base and metformin HCI to overcome the above mentioned problem even without the use of basic amino acid.
• the inventors of the present invention provides a chemically stable pharmaceutical composition comprising fixed dose combination of linagl iptin and metformin HCI wherein the composition is devoid of any basic amino acids and/or colloidal silicon dioxide.
• the "chemically stable pharmaceutical composition” may be defined as a pharmaceutical composition wherein the linagliptin related impurities A, B, C and D are individually not more than 0.5% w/w, 0.5% w/w, 0.5% w/w and 0.4% w/w respectively and total impurity is not more than 2% w/w, when stored at 3 month at 40°C / 75% Relative Humidity (RH).
• impurity A of linagliptin is chemical ly N-acetyl impurity
• impurity B of l inagl iptin is chem ical ly Boc impurity
• impurity C of linagliptin is chemically dimer impurity
• impurity D of linagl iptin is maximum unknown impurity.
• Basic amino acid may be defined as amino acids having an intra-molecular amino group & have basic side chain at neutral pH, such as e.g. L-arginine, L-lysine or L- histigine. Further the said amino acids have alkal ine characteristics.
• the present invention provides a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HC1 and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic am ino acid.
• the present invention is directed to a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HC1 and one or more pharmaceutical acceptable excipients, particularly stable against chem ical degradation.
• One of the preferred embodiments of the present invention is to provide a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HC1 and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of colloidal silicon dioxide.
• a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCI and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid and/or col loidal silicon dioxide.
• the present invention provides a chemically stable pharmaceutical composition
• a chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HCI and one or more pharmaceutical acceptable excipients, wherein the pharmaceutical ly acceptable excipients selected form one or more fi llers or di luents. 10 one or more binders, one or more disintegrants, one or more lubricants, .one or more film coating agents, one or more pigments or plasticizers, and the like, wherein the composition is devoid of basic amino acid and/or colloidal silicon dioxide.
• compositions for the present invention is selected from one or more 1 5 fi llers, one or more binders, one or more di luents, one or more disintegrants, one or more lubricants, one or more film coating agents, one or more pigments or plasticizers, and the like.
• fillers or diluent may include but not limited to mannitol, starch, corn 20 starch, potato starch, pregelatinized starch, si licified m icrocrystalline cellulose, dicalcium phosphate and mixtures thereof. Of these, corn starch and mannitol are preferably used.
• binders may include but not limited to copovidone, 25 hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, methyl cellulose, ethyl cellulose, polyethylene oxide, povidone, starch, pregelatinized starch and mixtures thereof.
• copovidone is preferably used.
• disintegrant may include but not limited to crospovidone, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch and mixtures thereof.
• lubricant may include but not limited to calcium stearate, glyceryl behenate, magnesium stearate, starch, stearic acid, talc, hydrogenated vegetable oil, zinc stearate and mixtures thereof. Of these, magnesium stearate is preferably used.
• the dose & dosing ratio of linagliptin free base and metformin HCl can be changed depending on various factors such as symptoms, age & body weight of the patients.
• the dosage of the l inagliptin free base is typically from 0.1 to 100 mg, in particular 0.5 to 10 mg.
• particular dosage strengths of linagliptin free base are 0.5 mg. 1 mg, 2.5 mg, 5 tng and 10 mg. More particular unit dosage strength of linagliptin free base for inclusion into fixed dose combination pharmaceutical compositions of the present invention is 2.5 mg.
• the unit dosage strengths of the metformin HCl for use in the present invention may be from 100 mg to 2000, preferably from 250 mg to 1000 mg. More particular unit dosage strengths of metformin HCl for incorporation into the fixed dose combination pharmaceutical compositions of the present invention are 500mg, 850mg and 1000 mg of metformin HCl.
• the particular fixed dose combination of linagliptin and metformin HCl may be administred once or twice daily to the patient, in particular twice daily.
• the present invention provides a process for the preparation of chemically stable pharmaceutical composition
• chemically stable pharmaceutical composition comprising fixed dose combination of linagliptin and metformin HC1 and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of basic amino acid and/or colloidal silicon dioxide.
• Excipients are those described herein before.
• the pharmaceutical composition described herein may be prepared by conventional technology well known to those skilled in the art such as wet granulation, dry granulation and direct compression and the like.
• the dosage form of the present invention is solid dosage form such as tablets, capsules, powders, sachets, preferably oral tablets; more preferably mono layer tablet, bilayer tablet, drug layered tablet.
• a typical mono-layer tablet of this invention comprises a linagliptin free base, metformin HCI, one or more fi l lers (such as e.g. corn starch and/or mannitol), one or more binders (such as e.g. copovidone), one or more lubricants (such as e.g. magnesium stearate) and an optional film coat.
• fi l lers such as e.g. corn starch and/or mannitol
• binders such as e.g. copovidone
• lubricants such as e.g. magnesium stearate
• a typical bi-layer tablet of this invention comprises a linagliptin portion comprising linagliptin free base, one or more fillers (such as e.g. corn starch), one or more binders (such as e.g. copovidone) and one or more lubricants (such as e.g. magnesium stearate), and a metformin portion comprising metformin HCI, one or more fillers (such as e.g. corn starch), one of more binders (such as e.g. copovidone) and one or more lubricants (such as e.g. magnesium stearate).
• a drug layered tablet (linagl iptin coating on metformin core, i .e.
• drug layering of linagliptin on metformin core of this invention comprises a metformin core portion comprising metformin HCI, one or more fillers (such as e.g. corn starch), one or more binders (such as e.g. Gopovidone) and one or more lubricants (such as e.g. magnesium stearate), wherein said core portion is seal-coated with a film coat comprising one or more film-coating agents (such as e.g. hypromellose and/or polyvinyl alcohol), one or more plasticizers (such as e.g.
• propylene glycol one or more pigments
• a linagliptin layer comprising a linagliptin free base, one or more film-coating agents (such as e.g. hypromellose) and one or more plasticizers (such as e.g. propylene glycol).
• chemically stable pharmaceutical composition is intended for the treatment of diabetes and/or to achieve glycemic control in a type 1 or type 2 diabetes mellitus patients.
• step 3 Dry mix the material of step 1 and granulate the dry mixed material with binder solution of step 2 using rapid mixer granulator.
• step 7 Lubricate the granules of step 5 with magnesium stearate in a suitable blender.
• step 1 Dissolve Copovidone in purified water to prepare binding solution.
• step 2 Dry mix the material of step 1 and granulate the dry mixed material with binder solution of step 2 using rapid mixer granulator.
• step 7 Lubricate the granules of step 5 with magnesium stearate in suitable blender.
• step II Dissolve Copovidone in purified water to prepare binding solution. 3. Dry mix the material of step I and granulate the dry mixed material with binder solution of step 2 using rapid mixer granulator.
• step 7 Lubricate the granules of step 5 with magnesium stearate in suitable blender.
• step 6 Dry mix the material of step 4 and granulate the dry mixed material with binder solution of step 5 using rapid mixer granulator.
• step 12 Dry mix the material of step 10 and granulate the dry mixed material with binder solution of step 1 1 using rapid mixer granulator.
• impurity C of linagliptin is chemically Dimer impurity
• impurity D of linagl iptin is max unknown impurity (at retention lime when measured through HPLC)
• Acceptable limits of the above said impurities A, B, C and D are individually not more than 0.5% w/w, . 0.5% w/w, 0.5% w/w and 0.4% w/w respectively wherein the impurity level is express by weight of linagliptin. Further, the total impurity of linagliptin related substances is not more than 2% w/w when determined after 3 month kept on 40 C/ 75% RH.
• the assay of Linagliptin and metformin HCl performed at initial and at 3 month at 40°C and 75% RH are within the acceptable limits of 95% - 105%. It can be observed that, at initial and upon storage for 3 month at 40°C and 75% RH, the compositions of present invention are meets the acceptance criteria of individual and total impurity of linagliptin as disclosed herein above.

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• 2014
  • 2014-12-05 WO PCT/IN2014/000751 patent/WO2015107536A2/en active Application Filing
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