WO2014080383A1 - Pharmaceutical composition of dipeptidyl peptidase-iv (dpp-iv) inhibitors in combination with other antidiabetics - Google Patents

Pharmaceutical composition of dipeptidyl peptidase-iv (dpp-iv) inhibitors in combination with other antidiabetics Download PDF

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Publication number
WO2014080383A1
WO2014080383A1 PCT/IB2013/060422 IB2013060422W WO2014080383A1 WO 2014080383 A1 WO2014080383 A1 WO 2014080383A1 IB 2013060422 W IB2013060422 W IB 2013060422W WO 2014080383 A1 WO2014080383 A1 WO 2014080383A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
alkalizing agent
dpp
inhibitor
pharmaceutically acceptable
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PCT/IB2013/060422
Other languages
French (fr)
Inventor
Ajay Kumar Singla
Nidhi Singh
Dillip Kumar JENA
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Ranbaxy Laboratories Limited
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Publication of WO2014080383A1 publication Critical patent/WO2014080383A1/en

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • 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

  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises an alkalizing agent other than the basic amino acids. It further provides processes for the preparation of the pharmaceutical composition and a method of treating diabetes by administering the pharmaceutical composition.
  • DPP-IV is an enzyme that degrades the incretin hormones like GLP- 1 (glucagon- like peptide 1) and GIP (glucose dependent insulinotropic polypeptide). DPP-IV inhibitors block DPP-IV enzyme, and thus inhibit the degradation of GLP- 1 and GIP, which in turn increases insulin secretion and decreases blood glucose levels.
  • U.S. Publication No. 201 1/0206766 discloses pharmaceutical formulation comprising a DPP-IV inhibitor, a partner drug, and a basic agent selected from the group consisting of L-arginine, L-lysine, and L-histidine which provides a stabilizing effect on the formulation by suppressing degradation of the DPP-IV inhibitor in the presence of the partner drug, e.g., biguanides, thiazolidinones, statins, or ARBs.
  • the partner drug e.g., biguanides, thiazolidinones, statins, or ARBs.
  • Methods for suppressing the degradation of a DPP-IV inhibitor include optimization of pH, optimization of the type of alkalizing agent, and optimization of the concentration of the alkalizing agent.
  • the aim of the present invention is to provide an alternative pharmaceutical composition comprising (i) a DPP-IV inhibitor; (ii) at least one additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids.
  • the alkalizing agent is selected from the group comprising meglumine, triethanolamine, diethanolamine, monoethanolamine, alkaline hydroxides, alkaline carbonates, alkaline bicarbonates, alkaline phosphates, alkaline sulfates, alkaline borates, alkaline citrates, ammonia, tris(hydroxymethyl)aminomethane, or mixtures thereof. It further provides processes for the preparation of said pharmaceutical composition, and its use for treating diabetes.
  • a first aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids.
  • the DPP-IV inhibitor is selected from one or more of linagliptin, sitagliptin, vildagliptin, saxagliptin, alogliptin, anagliptin, carmegliptin, teneligliptin, melogliptin, gemigliptin, dutogliptin, and denagliptin, or a salt or polymorph thereof.
  • the DPP-IV inhibitor is linagliptin or a salt or polymorph thereof.
  • the additional antidiabetic drug is selected from one or more of biguanides, thiazolidinediones, sulfonylureas, insulin, or mixtures thereof.
  • the additional antidiabetic drug is metformin or a salt or polymorph thereof.
  • the alkalizing agent (separately or combined) is present in an amount of from about 0.25% to about 10% by weight of the composition.
  • the pharmaceutical composition of the present invention is in the form of a mono-layer, bi-layer, or tri-layer tablet.
  • step (b) blending the granules obtained in step (a) with one or more pharmaceutically acceptable excipients;
  • step (c) compressing the granules obtained in step (b) to obtain tablets;
  • a third aspect of the present invention provides a process for the preparation of the pharmaceutical composition comprising (i) DPP-IV inhibitor; (ii) additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids, and wherein said process comprises the steps of:
  • step (c) blending the granules obtained in step (a), the granules obtained in step (b), an alkalizing agent, and one or more pharmaceutically acceptable excipients;
  • step (d) compressing the granules obtained in step (c) to obtain tablets;
  • a process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
  • step (a) mixing an additional antidiabetic drug, a DPP-IV inhibitor, and one or more pharmaceutically acceptable excipients to form a premix; (b) granulating the premix obtained in step (a) using a granulation fluid comprising an alkalizing agent and a binder dispersed in a solvent;
  • step (c) drying, sieving, and blending the granules obtained in step (b) with one or more pharmaceutically acceptable excipients;
  • step (d) lubricating the granules obtained in step (c) and then compressing them to form mono-layer tablets;
  • step (e) optionally film coating the tablets obtained in step (d).
  • a process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
  • step (b) adding a DPP-IV inhibitor into the pre-warmed blend of step (a);
  • step (c) granulating the pre-warmed blend of step (b) using a granulation fluid
  • step (d) drying, sieving, and blending the granules obtained in step (c) with one or more pharmaceutically acceptable excipients;
  • step (e) lubricating the granules obtained in step (d) and then compressing them to form mono-layer tablets;
  • a process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
  • step (c) lubricating the granules obtained in step (b) and then compressing them into mono-layer tablets.
  • a process for the preparation of the pharmaceutical composition of the present invention comprising the steps of: (a) mixing a DPP-IV inhibitor and one or more pharmaceutically acceptable excipients to yield a premix;
  • step (c) granulating the premix obtained in step (a) using the granulation fluid
  • step (d) drying, sieving, and blending the granules of step (c) with one or more pharmaceutically acceptable excipients, and lubricating to yield blend "A";
  • step (f) granulating the pre-warmed blend obtained in step (e) using the granulation fluid obtained in step (b);
  • step (g) drying, sieving, and blending the granules obtained in step (f) with one or more pharmaceutically acceptable excipients, then lubricating to yield blend "B";
  • a tri-layer tablet is prepared by compressing blends "A" and "B” with the intermediate layer of blend "C” which comprises one or more pharmaceutically acceptable excipients.
  • a fourth aspect of the present invention provides a method of treating diabetes by administering to a patient in need thereof the pharmaceutical composition comprising: (i) DPP-IV inhibitor; (ii) additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids.
  • DPP-IV inhibitor refers to DPP-IV inhibitors which include, but are not limited to, linagliptin, sitagliptin, vildagliptin, saxagliptin, alogliptin, anagliptin, carmegliptin, teneligliptin, melogliptin, gemigliptin, dutogliptin, and denagliptin, or pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline or amorphous forms thereof.
  • the preferred DPP-IV inhibitor is linagliptin (BI- 1356, trade names Tradjenta ® and Trajenta ® ) which is indicated for the treatment of type II diabetes.
  • U.S. Patent No. 7,407,955 discloses linagliptin specifically.
  • additional antidiabetic drug refers to biguanides, thiazolidinediones, sulfonylureas, insulin, or mixtures thereof.
  • metformin is the most preferred.
  • thiazolidinediones pioglitazone is the most preferred.
  • metalformin and "pioglitazone”, are also intended to comprise any pharmaceutically acceptable salt, crystal, hydrate, solvate, diastereomer, or enantiomer thereof.
  • Sulfonylureas include e.g., glipizide, gliclazide, glibenclamide/glyburide, and glimepiride.
  • alkalizing agent refers to substances that provide alkaline characteristics to the pharmaceutical composition for the stability of the product.
  • basic amino acids refers to amino acids, e.g., arginine, lysine, or histidine.
  • a suitable alkalizing agent is selected from the group comprising meglumine, triethanolamine, diethanolamine, monoethanolamine, alkaline hydroxides, alkaline carbonates, alkaline bicarbonates, alkaline phosphates, alkaline sulfates, alkaline borates, alkaline citrates, ammonia, tris(hydroxymethyl)aminomethane, or mixtures thereof.
  • the alkalizing agent is present in an amount of about 0.25% to about 10% by weight of the composition.
  • a preferred alkalizing agent for use in the pharmaceutical composition of the present invention is meglumine. Chemically, meglumine is N-methylglucamine, a derivative of sorbitol in which the hydroxyl group in position 1 is replaced by a methylamino group.
  • meglumine used herein, includes derivatives and salts of meglumine.
  • the derivatives and salts of meglumine include, but are not limited to, meglumine amidodrizoate, meglumine sodium amidodrizoate, meglumine cadopentetate, meglumine gadoterate, meglumine iotalamate, meglumine iotroxate, meglumine gadobenate, meglumine iodoxamate, meglumine fiunixin, and gastrografin (meglumine sulfate).
  • Suitable diluents or fillers are selected from the group comprising microcrystalline cellulose, powdered cellulose, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium carbonate, lactose monohydrate, lactose anhydrous, sucrose, sorbitol, xylitol, mannitol, erythritol, kaolin, calcium silicate, maltodextrin, starch, modified starch e.g., prege latinized starch, maize starch, corn starch, or mixtures thereof.
  • the present invention comprises a diluent in an amount of from about 10% to about 50% by total weight of the pharmaceutical composition.
  • Suitable binders are selected from the group comprising povidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, xanthan gum, gum acacia, gum arabic, tragacanth, sorbitol, dextrose, sucrose, mannitol, gelatin, pullulan, sodium alginate, propylene glycol, polyvinyl alcohol, corn syrup, methacrylates, carboxyvinyl polymers e.g., carbomers, or mixtures thereof.
  • the present invention comprises a binder in an amount of from about 3% to about 15% by weight of the composition.
  • Suitable disintegrants are selected from the group comprising hydroxypropyl cellulose (L-HPC), crospovidone, croscarmellose sodium, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, sodium starch glycolate, gums, alginic acid or alginates, starch, corn starch, modified starch, carboxymethyl starch, polyacrylates, or mixtures thereof.
  • L-HPC hydroxypropyl cellulose
  • crospovidone crospovidone
  • croscarmellose sodium carboxymethyl cellulose sodium
  • carboxymethyl cellulose calcium sodium starch glycolate
  • gums alginic acid or alginates
  • starch corn starch
  • modified starch carboxymethyl starch
  • polyacrylates or mixtures thereof.
  • the present invention comprises a disintegrant in an amount of from about 2% to about 10% by weight of the composition.
  • the pharmaceutical composition of the present invention can be obtained by using known, conventional methods i.e., granulation or direct compression.
  • the process to obtain granulate includes, but is not limited to, wet granulation, fluid bed granulation, spray drying, or dry granulation.
  • solvents used for preparing the granulation fluid or coating solution are selected from the group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.
  • the pharmaceutical composition of the present invention is intended for oral use, and can be in the form of tablets, capsules, minitablets, granules, or pellets, wherein the composition can be further film coated.
  • composition prepared by any of the above described processes may further be coated with a film- forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique.
  • the film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients.
  • a suitable film-forming polymer is selected from the group comprising hydroxypropylmethyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropylmethyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit ® , polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol, or mixtures thereof.
  • a preferred film- forming polymer is hydroxypropylmethyl cellulose.
  • Other suitable film- forming polymers which are known in the art may also be used.
  • Metformin and a diluent are mixed, and linagliptin is added to form a premix.
  • An alkalizing agent and binder are dispersed in water to produce a granulation fluid.
  • step 3 The granulation fluid obtained in step 2 is sprayed onto the premix obtained in step 1 in a fluid bed granulator.
  • step 3 The granules obtained in step 3 are dried, sifted, blended with disintegrant and/or diluents and/or antiadherents, and then lubricated.
  • step 4 The lubricated granules obtained in step 4 are compressed to form a tablet.
  • Linagliptin, a diluent, and a disintegrant are mixed to yield a premix.
  • step 3 The granulation fluid obtained in step 2 is added to the premix obtained in step 1 to yield granules.
  • a binder is dissolved in purified water to produce a granulation fluid.
  • Metformin hydrochloride and a diluent are added to a fluid bed granulator to obtain a blend.
  • step 6 The blend obtained in step 6 is pre-warmed.
  • step 8 The granulation fluid prepared in step 5 is sprayed on the pre-warmed blend obtained in step 7 to form granules.
  • step 8 The granules obtained in step 8 are dried, sieved, blended with
  • Blends "A” and “B” are compressed using a bi-layer tablet press.
  • Linagliptin, a diluent, and a disintegrant are mixed to yield a premix.
  • An alkalizing agent and a binder are dispersed in water to produce a
  • step 3 The granulation fluid obtained in step 2 is added to the premix obtained in step 1 to yield granules.
  • step 3 The granules obtained in step 3 are dried, sieved, blended with a disintegrant and/or diluents, then lubricated to yield blend "A.”
  • a binder is dissolved in purified water to produce a granulation fluid.
  • Metformin hydrochloride and a diluent are added to a fluid bed granulator to obtain a blend.
  • step 6 The blend obtained in step 6 is pre-warmed.
  • step 8 The granulation fluid prepared in step 5 is sprayed on the pre-warmed blend obtained in step 7 to form granules.
  • step 8 The granules obtained in step 8 are dried, sieved, blended with a disintegrant and/or diluents and/or antiadherents, then lubricated to yield blend "B.”
  • a diluent and a disintegrant, alone or in combination, are sifted using a suitable screen, and then lubricated to yield blend "C.”
  • Blends "A” and “B” are compressed with the intermediate layer of blend “C” using a tri-layer tablet press to form a tri-layer tablet.
  • Example 4
  • Copovidone, linagliptin, and meglumine were dissolved in purified water to form a granulation fluid.
  • step 2 obtained in step 2 to obtain a wet mass.
  • step 4 The wet mass obtained in step 3 was dried and then milled to obtain granules.
  • step 4 The granules obtained in step 4 were blended with colloidal anhydrous silica.
  • step 5 The granules obtained in step 5 were lubricated using magnesium stearate.
  • step 6 The lubricated blend obtained in step 6 was compressed into a mono-layer tablet.
  • step 7 The tablet obtained in step 7 was further coated with an Opadry ® dispersion.
  • Table 1 provides stability data of the composition prepared according to Example 4.
  • step 4 The wet mass obtained in step 3 was dried and then milled to obtain granules.
  • step 4 The granules obtained in step 4 were blended with colloidal silicon dioxide.
  • step 7 The tablet obtained in step 7 was further coated with an Opadry ® dispersion.
  • step 3 The blend obtained in step 1 was granulated using the granulation fluid
  • step 2 obtained in step 2 to obtain a wet mass.
  • step 4 The wet mass obtained in step 3 was dried and then milled to obtain granules.
  • Copovidone was dissolved in purified water to form a granulation fluid.
  • step 6 obtained in step 6 to obtain a wet mass.
  • the tablet obtained in step 1 1 was further film-coated using an Opadry dispersion.

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Abstract

The present invention relates to a pharmaceutical composition comprising (i) a DPP- IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients. The pharmaceutical composition comprises an alkalizing agent other than the basic amino acids. It further relates to processes for the preparation of the pharmaceutical composition and a method of treating diabetes by administering the pharmaceutical composition.

Description

PHARMACEUTICAL COMPOSITION OF DIPEPTIDYL PEPTIDASE-IV (DPP- IV) INHIBITORS IN COMBINATION WITH OTHER ANTIDIABETICS
Field of the Invention
The present invention provides a pharmaceutical composition comprising (i) a DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients. The pharmaceutical composition comprises an alkalizing agent other than the basic amino acids. It further provides processes for the preparation of the pharmaceutical composition and a method of treating diabetes by administering the pharmaceutical composition.
Background of the Invention
DPP-IV is an enzyme that degrades the incretin hormones like GLP- 1 (glucagon- like peptide 1) and GIP (glucose dependent insulinotropic polypeptide). DPP-IV inhibitors block DPP-IV enzyme, and thus inhibit the degradation of GLP- 1 and GIP, which in turn increases insulin secretion and decreases blood glucose levels.
U.S. Publication No. 201 1/0206766 discloses pharmaceutical formulation comprising a DPP-IV inhibitor, a partner drug, and a basic agent selected from the group consisting of L-arginine, L-lysine, and L-histidine which provides a stabilizing effect on the formulation by suppressing degradation of the DPP-IV inhibitor in the presence of the partner drug, e.g., biguanides, thiazolidinones, statins, or ARBs.
Methods for suppressing the degradation of a DPP-IV inhibitor include optimization of pH, optimization of the type of alkalizing agent, and optimization of the concentration of the alkalizing agent. The aim of the present invention is to provide an alternative pharmaceutical composition comprising (i) a DPP-IV inhibitor; (ii) at least one additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids.
Summary of the Invention
The present invention provides a pharmaceutical composition comprising (i) a DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids. The alkalizing agent is selected from the group comprising meglumine, triethanolamine, diethanolamine, monoethanolamine, alkaline hydroxides, alkaline carbonates, alkaline bicarbonates, alkaline phosphates, alkaline sulfates, alkaline borates, alkaline citrates, ammonia, tris(hydroxymethyl)aminomethane, or mixtures thereof. It further provides processes for the preparation of said pharmaceutical composition, and its use for treating diabetes.
Detailed Description of the Invention
A first aspect of the present invention provides a pharmaceutical composition comprising (i) DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids.
According to one embodiment, the DPP-IV inhibitor is selected from one or more of linagliptin, sitagliptin, vildagliptin, saxagliptin, alogliptin, anagliptin, carmegliptin, teneligliptin, melogliptin, gemigliptin, dutogliptin, and denagliptin, or a salt or polymorph thereof.
According to another embodiment, the DPP-IV inhibitor is linagliptin or a salt or polymorph thereof.
According to another embodiment, the additional antidiabetic drug is selected from one or more of biguanides, thiazolidinediones, sulfonylureas, insulin, or mixtures thereof.
According to another embodiment, the additional antidiabetic drug is metformin or a salt or polymorph thereof.
According to another embodiment, the alkalizing agent is selected from one or more of meglumine, triethanolamine, diethanolamine, monoethanolamine, alkaline hydroxides, alkaline carbonates, alkaline bicarbonates, alkaline phosphates, alkaline sulfates, alkaline borates, alkaline citrates, ammonia, tris(hydroxymethyl)aminomethane, or mixtures thereof. Preferably, the alkalizing agent is meglumine and
tris(hy droxymethyl) aminomethane .
According to another embodiment, the alkalizing agent (separately or combined) is present in an amount of from about 0.25% to about 10% by weight of the composition. According to yet another embodiment, the pharmaceutical composition of the present invention is in the form of a mono-layer, bi-layer, or tri-layer tablet.
A second aspect of the present invention provides a process for the preparation of the pharmaceutical composition comprising (i) DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids, and wherein said process comprises the steps of:
(a) granulating an additional antidiabetic drug and one or more pharmaceutically acceptable excipients with a granulation fluid comprising a binder, an alkalizing agent, and a DPP-IV inhibitor to obtain granules;
(b) blending the granules obtained in step (a) with one or more pharmaceutically acceptable excipients;
(c) compressing the granules obtained in step (b) to obtain tablets; and
(d) coating the tablets obtained in step (c).
A third aspect of the present invention provides a process for the preparation of the pharmaceutical composition comprising (i) DPP-IV inhibitor; (ii) additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids, and wherein said process comprises the steps of:
(a) granulating a DPP-IV inhibitor and one or more pharmaceutically acceptable excipients with a granulation fluid comprising a binder to obtain granules;
(b) granulating an additional antidiabetic drug and one or more pharmaceutically acceptable excipients with a granulation fluid comprising a binder to obtain granules;
(c) blending the granules obtained in step (a), the granules obtained in step (b), an alkalizing agent, and one or more pharmaceutically acceptable excipients;
(d) compressing the granules obtained in step (c) to obtain tablets; and
(e) coating the tablets obtained in step (d).
A process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
(a) mixing an additional antidiabetic drug, a DPP-IV inhibitor, and one or more pharmaceutically acceptable excipients to form a premix; (b) granulating the premix obtained in step (a) using a granulation fluid comprising an alkalizing agent and a binder dispersed in a solvent;
(c) drying, sieving, and blending the granules obtained in step (b) with one or more pharmaceutically acceptable excipients;
(d) lubricating the granules obtained in step (c) and then compressing them to form mono-layer tablets; and
(e) optionally film coating the tablets obtained in step (d).
A process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
(a) pre -warming an additional antidiabetic drug and one or more
pharmaceutically acceptable excipients;
(b) adding a DPP-IV inhibitor into the pre-warmed blend of step (a);
(c) granulating the pre-warmed blend of step (b) using a granulation fluid
comprising an alkalizing agent and a binder dispersed in a solvent to obtain granules;
(d) drying, sieving, and blending the granules obtained in step (c) with one or more pharmaceutically acceptable excipients;
(e) lubricating the granules obtained in step (d) and then compressing them to form mono-layer tablets; and
(f) optionally, film coating the tablets obtained in step (e).
A process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
(a) preparing granules of an additional antidiabetic drug and one or more
pharmaceutically acceptable excipients;
(b) adding a DPP-IV inhibitor, an alkalizing agent, and one or more
pharmaceutically acceptable excipients extragranularly to the granules of step (a); and
(c) lubricating the granules obtained in step (b) and then compressing them into mono-layer tablets.
A process for the preparation of the pharmaceutical composition of the present invention comprising the steps of: (a) mixing a DPP-IV inhibitor and one or more pharmaceutically acceptable excipients to yield a premix;
(b) dispersing an alkalizing agent and a binder in a solvent to produce a
granulation fluid;
(c) granulating the premix obtained in step (a) using the granulation fluid
obtained in step (b);
(d) drying, sieving, and blending the granules of step (c) with one or more pharmaceutically acceptable excipients, and lubricating to yield blend "A";
(e) blending an additional antidiabetic drug and one or more pharmaceutically acceptable excipients, then pre-warming the blend;
(f) granulating the pre-warmed blend obtained in step (e) using the granulation fluid obtained in step (b);
(g) drying, sieving, and blending the granules obtained in step (f) with one or more pharmaceutically acceptable excipients, then lubricating to yield blend "B"; and
(h) compressing blends "A" and "B" using a bi-layer tablet press to form a bi- layer tablet.
Alternatively, a tri-layer tablet is prepared by compressing blends "A" and "B" with the intermediate layer of blend "C" which comprises one or more pharmaceutically acceptable excipients.
A fourth aspect of the present invention provides a method of treating diabetes by administering to a patient in need thereof the pharmaceutical composition comprising: (i) DPP-IV inhibitor; (ii) additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids.
The term "DPP-IV inhibitor", as used herein, refers to DPP-IV inhibitors which include, but are not limited to, linagliptin, sitagliptin, vildagliptin, saxagliptin, alogliptin, anagliptin, carmegliptin, teneligliptin, melogliptin, gemigliptin, dutogliptin, and denagliptin, or pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline or amorphous forms thereof. The preferred DPP-IV inhibitor is linagliptin (BI- 1356, trade names Tradjenta® and Trajenta®) which is indicated for the treatment of type II diabetes. U.S. Patent No. 7,407,955 discloses linagliptin specifically. The term "additional antidiabetic drug", as used herein, refers to biguanides, thiazolidinediones, sulfonylureas, insulin, or mixtures thereof. Among the biguanides, metformin is the most preferred. Among the thiazolidinediones, pioglitazone is the most preferred. In the present context, the terms "metformin" and "pioglitazone", are also intended to comprise any pharmaceutically acceptable salt, crystal, hydrate, solvate, diastereomer, or enantiomer thereof. Sulfonylureas include e.g., glipizide, gliclazide, glibenclamide/glyburide, and glimepiride.
The term "alkalizing agent", as used herein, refers to substances that provide alkaline characteristics to the pharmaceutical composition for the stability of the product.
The term "basic amino acids", as used herein, refers to amino acids, e.g., arginine, lysine, or histidine.
A suitable alkalizing agent is selected from the group comprising meglumine, triethanolamine, diethanolamine, monoethanolamine, alkaline hydroxides, alkaline carbonates, alkaline bicarbonates, alkaline phosphates, alkaline sulfates, alkaline borates, alkaline citrates, ammonia, tris(hydroxymethyl)aminomethane, or mixtures thereof. The alkalizing agent is present in an amount of about 0.25% to about 10% by weight of the composition. A preferred alkalizing agent for use in the pharmaceutical composition of the present invention is meglumine. Chemically, meglumine is N-methylglucamine, a derivative of sorbitol in which the hydroxyl group in position 1 is replaced by a methylamino group.
The term "meglumine", used herein, includes derivatives and salts of meglumine. The derivatives and salts of meglumine include, but are not limited to, meglumine amidodrizoate, meglumine sodium amidodrizoate, meglumine cadopentetate, meglumine gadoterate, meglumine iotalamate, meglumine iotroxate, meglumine gadobenate, meglumine iodoxamate, meglumine fiunixin, and gastrografin (meglumine sulfate).
Products resulting from chemical modification of the hydroxyl group, amino group, or others of the above-listed meglumines are also included in the meglumine of the present invention.
The term "about", as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
Other pharmaceutically acceptable excipients include, but are not limited to, binders, diluents, disintegrants, and lubricants/glidants/antiadherents. Suitable diluents or fillers are selected from the group comprising microcrystalline cellulose, powdered cellulose, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium carbonate, lactose monohydrate, lactose anhydrous, sucrose, sorbitol, xylitol, mannitol, erythritol, kaolin, calcium silicate, maltodextrin, starch, modified starch e.g., prege latinized starch, maize starch, corn starch, or mixtures thereof. The present invention comprises a diluent in an amount of from about 10% to about 50% by total weight of the pharmaceutical composition.
Suitable binders are selected from the group comprising povidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, xanthan gum, gum acacia, gum arabic, tragacanth, sorbitol, dextrose, sucrose, mannitol, gelatin, pullulan, sodium alginate, propylene glycol, polyvinyl alcohol, corn syrup, methacrylates, carboxyvinyl polymers e.g., carbomers, or mixtures thereof. The present invention comprises a binder in an amount of from about 3% to about 15% by weight of the composition.
Suitable disintegrants are selected from the group comprising hydroxypropyl cellulose (L-HPC), crospovidone, croscarmellose sodium, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, sodium starch glycolate, gums, alginic acid or alginates, starch, corn starch, modified starch, carboxymethyl starch, polyacrylates, or mixtures thereof. The present invention comprises a disintegrant in an amount of from about 2% to about 10% by weight of the composition.
Suitable lubricants/glidants/antiadherents are selected from the group comprising hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, stearic acid, sodium stearyl fumarate, sodium starch fumarate, magnesium stearate, calcium stearate, zinc stearate, aluminum silicate, talc, colloidal silicon dioxide, sucrose esters of fatty acid, waxes, silica gel, or mixtures thereof. The present invention comprises a lubricant in an amount of from about 0.25% to about 5% by weight of the composition.
The pharmaceutical composition of the present invention can be obtained by using known, conventional methods i.e., granulation or direct compression. The process to obtain granulate includes, but is not limited to, wet granulation, fluid bed granulation, spray drying, or dry granulation.
Examples of the solvents used for preparing the granulation fluid or coating solution are selected from the group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.
The pharmaceutical composition of the present invention is intended for oral use, and can be in the form of tablets, capsules, minitablets, granules, or pellets, wherein the composition can be further film coated.
The pharmaceutical composition prepared by any of the above described processes may further be coated with a film- forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique.
The film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients. A suitable film-forming polymer is selected from the group comprising hydroxypropylmethyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropylmethyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol, or mixtures thereof. A preferred film- forming polymer is hydroxypropylmethyl cellulose. Other suitable film- forming polymers which are known in the art may also be used.
The invention is further illustrated by the following examples, which are for illustrative purposes only, and should not be construed as limiting the scope of the invention in any way.
Examples
Example 1 : Preparation of Mono-layer Tablet
Figure imgf000010_0001
Procedure:
1. Metformin and a diluent are mixed, and linagliptin is added to form a premix.
2. An alkalizing agent and binder are dispersed in water to produce a granulation fluid.
3. The granulation fluid obtained in step 2 is sprayed onto the premix obtained in step 1 in a fluid bed granulator.
4. The granules obtained in step 3 are dried, sifted, blended with disintegrant and/or diluents and/or antiadherents, and then lubricated.
5. The lubricated granules obtained in step 4 are compressed to form a tablet.
Example 2: Preparation of Bi-layer Tablet
Figure imgf000011_0001
Procedure:
A. Linagliptin layer
1. Linagliptin, a diluent, and a disintegrant are mixed to yield a premix.
2. An alkalizing agent and a binder are dispersed in water to produce a
granulation fluid.
3. The granulation fluid obtained in step 2 is added to the premix obtained in step 1 to yield granules.
4. The granules obtained in step 3 are dried, sieved, blended with a disintegrant and/or diluents, and lubricated to yield blend "A."
B. Metformin layer
5. A binder is dissolved in purified water to produce a granulation fluid.
6. Metformin hydrochloride and a diluent are added to a fluid bed granulator to obtain a blend.
7. The blend obtained in step 6 is pre-warmed.
8. The granulation fluid prepared in step 5 is sprayed on the pre-warmed blend obtained in step 7 to form granules.
9. The granules obtained in step 8 are dried, sieved, blended with
disintegrant/diluent, and lubricated using suitable lubricants to yield blend "B."
C. Compression
10. Blends "A" and "B" are compressed using a bi-layer tablet press.
Example 3: Preparation of Tri-layer Tablet
Figure imgf000013_0001
A. Linagliptin layer
1. Linagliptin, a diluent, and a disintegrant are mixed to yield a premix.
2. An alkalizing agent and a binder are dispersed in water to produce a
granulation fluid.
3. The granulation fluid obtained in step 2 is added to the premix obtained in step 1 to yield granules.
4. The granules obtained in step 3 are dried, sieved, blended with a disintegrant and/or diluents, then lubricated to yield blend "A."
B. Metformin layer
5. A binder is dissolved in purified water to produce a granulation fluid.
6. Metformin hydrochloride and a diluent are added to a fluid bed granulator to obtain a blend.
7. The blend obtained in step 6 is pre-warmed.
8. The granulation fluid prepared in step 5 is sprayed on the pre-warmed blend obtained in step 7 to form granules.
9. The granules obtained in step 8 are dried, sieved, blended with a disintegrant and/or diluents and/or antiadherents, then lubricated to yield blend "B."
C. Intermediate layer
10. A diluent and a disintegrant, alone or in combination, are sifted using a suitable screen, and then lubricated to yield blend "C."
D. Compression
1 1. Blends "A" and "B" are compressed with the intermediate layer of blend "C" using a tri-layer tablet press to form a tri-layer tablet. Example 4:
Figure imgf000015_0001
Procedure:
1. Metformin hydrochloride and corn starch were blended together.
2. Copovidone, linagliptin, and meglumine were dissolved in purified water to form a granulation fluid.
3. The blend obtained in step 1 was granulated using the granulation fluid
obtained in step 2 to obtain a wet mass.
4. The wet mass obtained in step 3 was dried and then milled to obtain granules.
5. The granules obtained in step 4 were blended with colloidal anhydrous silica.
6. The granules obtained in step 5 were lubricated using magnesium stearate.
7. The lubricated blend obtained in step 6 was compressed into a mono-layer tablet.
8. The tablet obtained in step 7 was further coated with an Opadry® dispersion. Table 1 provides stability data of the composition prepared according to Example 4.
Table 1
Figure imgf000015_0002
Example 5:
Figure imgf000016_0001
Procedure:
1. Metformin hydrochloride and corn starch were blended together.
2. Copovidone, linagliptin, and tris(hydroxymethyl)aminomethane were
dissolved in purified water to form a binder solution.
3. The blend obtained in step 1 was granulated using the binder solution
obtained in step 2 to obtain a wet mass.
4. The wet mass obtained in step 3 was dried and then milled to obtain granules.
5. The granules obtained in step 4 were blended with colloidal silicon dioxide.
6. The granules obtained in step 5 were lubricated using magnesium stearate.
7. The lubricated blend obtained in step 6 was compressed into a mono-layer tablet.
8. The tablet obtained in step 7 was further coated with an Opadry® dispersion.
Example 6:
Figure imgf000017_0001
Procedure:
A. Linagliptin granules
1. Linagliptin, mannitol, and corn starch were blended together.
2. Copovidone was dissolved in purified water to prepare a granulation fluid.
3. The blend obtained in step 1 was granulated using the granulation fluid
obtained in step 2 to obtain a wet mass.
4. The wet mass obtained in step 3 was dried and then milled to obtain granules.
B. Metformin hydrochloride granules
5. Metformin hydrochloride and corn starch were blended together.
6. Copovidone was dissolved in purified water to form a granulation fluid.
7. The blend obtained in step 5 was granulated using the granulation fluid
obtained in step 6 to obtain a wet mass.
8. The wet mass obtained in step 7 was dried and milled to obtain granules.
C. Compression
9. The granules obtained in step 4 and step 8 were blended with meglumine and colloidal silicon dioxide. The granules obtained in step 9 were lubricated using magnesium stearate. The lubricated granules obtained in step 10 were compressed to form a mono-layer tablet.
The tablet obtained in step 1 1 was further film-coated using an Opadry dispersion.

Claims

We Claim:
1. A pharmaceutical composition comprising (i) a DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids.
2. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is selected from one or more of linagliptin, sitagliptin, vildagliptin, saxagliptin, alogliptin, anagliptin, carmegliptin, teneligliptin, melogliptin, gemigliptin, dutogliptin, and denagliptin, or a salt or polymorph thereof.
3. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is linagliptin or a salt or polymorph thereof.
4. The pharmaceutical composition according to claim 1, wherein the additional antidiabetic drug is selected from one or more of biguanides, thiazolidinediones, sulfonylureas, insulin, or mixtures thereof.
5. The pharmaceutical composition according to claim 4, wherein the additional antidiabetic drug is metformin or a salt or polymorph thereof.
6. The pharmaceutical composition according to claim 1, wherein the alkalizing agent is selected from one or more of meglumine, triethanolamine, diethanolamine,
monoethanolamine, alkaline hydroxides, alkaline carbonates, alkaline bicarbonates, alkaline phosphates, alkaline sulfates, alkaline borates, alkaline citrates, ammonia,
tris(hydroxymethyl)aminomethane, or mixtures thereof.
7. The pharmaceutical composition according to claim 1, wherein the alkalizing agent is present in an amount of from about 0.25% to about 10% by weight of the composition.
8. The pharmaceutical composition according to claim 1, wherein the alkalizing agent is meglumine.
9. The pharmaceutical composition according to claim 1, wherein the alkalizing agent is tris(hydroxymethyl)aminomethane.
10. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of mono-layer, bi-layer, or tri-layer tablet.
1 1. A process for the preparation of the pharmaceutical composition comprising (i) a DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids and wherein said process comprises the steps of:
(a) granulating the additional antidiabetic drug and one or more pharmaceutically acceptable excipients with a granulation fluid comprising a binder, the alkalizing agent, and the DPP-IV inhibitor to obtain granules;
(b) blending the granules obtained in step (a) with one or more pharmaceutically acceptable excipients;
(c) compressing the granules obtained in step (b) to obtain tablets; and
(d) coating the tablets obtained in step (c).
12. A process for the preparation of the pharmaceutical composition comprising (i) a DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids and wherein said process comprises the steps of:
(a) granulating the DPP-IV inhibitor and one or more pharmaceutically acceptable excipients with a granulation fluid comprising a binder to obtain granules;
(b) granulating the additional antidiabetic drug and one or more pharmaceutically acceptable excipients with a granulation fluid comprising abinder to obtain granules; (c) blending the granules obtained in step (a), the granules obtained in step (b), an alkalizing agent, and one or more pharmaceutically acceptable excipients;
(d) compressing the granules obtained in step (c) to obtain tablets; and
(e) coating the tablets obtained in step (d).
13. The process for the preparation of the pharmaceutical composition according to claim 1 1 or 12, wherein the DPP-IV inhibitor is selected from one or more of linagliptin, sitagliptin, vildagliptin, saxagliptin, alogliptin, anagliptin, carmegliptin, teneligliptin, melogliptin, gemigliptin, dutogliptin, and denagliptin, or a salt or polymorph thereof.
14. The process for the preparation of the pharmaceutical composition according to claim 1 1 or 12, wherein the DPP-IV inhibitor is linagliptin or a salt or polymorph thereof.
15. The process for the preparation of the pharmaceutical composition according to claim 1 1 or 12, wherein the additional antidiabetic drug is metformin or a salt or polymorph thereof.
16. A method for treating diabetes by administering to a patient in need thereof a pharmaceutical composition comprising (i) a DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition comprises an alkalizing agent other than the basic amino acids.
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