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WO2015071889A1 - Oral compositions of saxagliptin - Google Patents

Oral compositions of saxagliptin Download PDF

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Publication number
WO2015071889A1
WO2015071889A1 PCT/IB2014/066137 IB2014066137W WO2015071889A1 WO 2015071889 A1 WO2015071889 A1 WO 2015071889A1 IB 2014066137 W IB2014066137 W IB 2014066137W WO 2015071889 A1 WO2015071889 A1 WO 2015071889A1
Authority
WO
WIPO (PCT)
Prior art keywords
coating
tablets
polymer
core
layer
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.)
Ceased
Application number
PCT/IB2014/066137
Other languages
French (fr)
Inventor
Ravindra Agarwal
Puneet Kumar Gupta
Ravi Kochhar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2015071889A1 publication Critical patent/WO2015071889A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • the present invention relates to oral pharmaceutical compositions comprising saxagliptin and processes for their preparation. It further relates to oral pharmaceutical compositions comprising saxagliptin in combination with other antidiabetic agents.
  • Saxagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor used for the treatment of type 2 diabetes mellitus.
  • DPP-IV dipeptidyl peptidase IV
  • U.S. Patent No. 6,395,767 discloses the compound saxagliptin.
  • DPP-IV is an enzyme that catalyses the conversion of glucagon-like peptide- 1
  • GLP-1 from its active form to its inactive form.
  • Saxagliptin competitively inhibits the DPP-IV enzyme, thereby increasing the endogenous concentration of GLP-1, which further augments insulin secretion and improves the glycemic profile of patients with type 2 diabetes mellitus.
  • U.S. Patent No. 7,951,400 describes saxagliptin as an unstable compound which easily undergoes intramolecular cyclization to form a cyclic amidine, which is not desirable for therapeutic activity. This process of cyclization is accelerated by the use of common processes of formulation, e.g., granulation or compaction. In order to provide a stable formulation wherein saxagliptin is less prone to cyclization, U.S. Patent No.
  • 7,951,400 provides a coated tablet formulation of saxagliptin containing a polyvinyl alcohol based coating.
  • the present invention provides alternative oral pharmaceutical compositions comprising saxagliptin.
  • the present invention provides oral pharmaceutical compositions comprising saxagliptin and processes for their preparation.
  • the oral pharmaceutical compositions are preferably in the form of coated tablets comprising a core and a coating layer surrounding the core, wherein the drug is present in said coating.
  • the present invention also relates to oral pharmaceutical compositions comprising saxagliptin in combination with other antidiabetic agents. Detailed Description of the Invention
  • a first aspect of the present invention provides an oral pharmaceutical composition comprising saxagliptin, wherein said composition comprises:
  • a second aspect of the present invention provides an oral pharmaceutical composition comprising saxagliptin, wherein said composition comprises:
  • the polymer in any one of the layers (b), (c), or (d) is not a polyvinyl alcohol based polymer.
  • a third aspect of the present invention provides an oral pharmaceutical composition comprising saxagliptin, wherein said composition comprises:
  • each of the layers (b), (c), and (d) is not a polyvinyl alcohol based polymer.
  • saxagliptin refers to saxagliptin and its
  • salts or esters may be prepared from an inorganic acid selected from the group comprising hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, bicarbonic acid, sulfuric acid, phosphoric acid, and bisulphonic acid; or an organic acid selected from the group comprising oxalic acid, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, salicyclic acid, p-hydroxybenzoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid
  • Saxagliptin used in the composition of the present invention may be present in its crystalline form, amorphous form, anhydrous form, hydrate form, or mixtures thereof.
  • the term "core,” as used herein, refers to an inert core or a compressed tablet core optionally containing an additional antidiabetic agent other than saxagliptin.
  • the inert core may include an insoluble, swellable, or soluble core.
  • the insoluble or swellable inert core may be made of dicalcium phosphate, microcrystalline cellulose, or any of the marketed inert cores, e.g. , glass beads, silicate beads, sugar spheres, non-pareils, or celphere.
  • the soluble core may include glucose, mannitol, lactose, xylitol, dextrose, or sucrose.
  • the compressed tablet core may comprise pharmaceutically acceptable excipients selected from the group comprising binders, fillers, disintegrants, plasticizers, extended- release polymers, lubricants, glidants, or mixtures thereof, and may be prepared by the process of direct compression or granulation.
  • said core optionally contains an additional antidiabetic agent other than saxagliptin.
  • said core containing an additional antidiabetic agent other than saxagliptin is coated with an extended-release coating.
  • the seal layer optionally contains an additional antidiabetic agent other than saxagliptin.
  • the drug layer optionally contains an additional antidiabetic agent in addition to saxagliptin.
  • the outer layer optionally contains an additional antidiabetic agent other than saxagliptin.
  • composition provides an immediate-release or an extended-release of the additional antidiabetic agent.
  • the additional antidiabetic agent is selected from the group comprising acarbose, miglitol, repaglinide, nateglinide, chlorpropamide, glibenclamide, gliclazide, glimepiride, glipizide, glyclopyramide, tolazamide, tolbutamide, buformin, metformin, phenformin, rosiglitazone, pioglitazone, troglitazone, faraglitazar, englitazone, darglitazone, isaglitazone, reglitazar, rivoglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, sitagliptin, vildagliptin, linagliptin, dutogliptin, alogliptin, canagliflozin, dapagliflozin, remogliflozin, sergliflozin
  • the additional antidiabetic agent is metformin or pharmaceutically acceptable salts or esters thereof.
  • the additional antidiabetic agent is metformin hydrochloride.
  • the coating polymer that is not a polyvinyl alcohol based polymer is selected from the group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, polyvinyl pyrrolidone, polysaccharides, starch and its derivatives, gums, alginates, acrylic acid derivatives, polyethylene glycol, polyalkylene glycols, mannitol, sucrose, lactose, xylitol, and mixtures thereof.
  • coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry ® and Sepifilm ® LP 010, may also be used for coating.
  • an oral pharmaceutical composition comprising saxagliptin wherein said composition is in the form of pellets or tablets.
  • the pellets may further be filled into capsules or compressed into tablets.
  • an oral pharmaceutical composition comprising saxagliptin wherein said composition further comprises pharmaceutically acceptable excipients selected from the group comprising fillers, binders, plasticizers, disintegrants, lubricants, glidants, and mixtures thereof.
  • the coating suspension optionally contains pharmaceutically acceptable excipients selected from the group comprising plasticizers, colorants, antioxidants, solvents, and mixtures thereof.
  • Suitable fillers are selected from the group comprising starch, lactose, sucrose, glucose, sorbitol, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol, pregelatinized starch, and mixtures thereof.
  • Suitable binders are selected from the group comprising methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, poloxamer, gelatin, ethyl cellulose, polyvinyl alcohol, pullunan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, gum arabic, and mixtures thereof.
  • Suitable plasticizers are selected from the group comprising propylene glycol, triethylene glycol, oleic acid, ethylene glycol monooleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, dibutyl sebacate, acetyl triethyl citrate, castor oil, and mixtures thereof.
  • Suitable disintegrants are selected from the group comprising cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodiumcarboxymethyl cellulose, calciumcarboxymethyl cellulose, alginic acid, alginates, pregelatinized starch, starch and its derivatives, low-substituted hydroxypropyl cellulose, and mixtures thereof.
  • Suitable lubricants and glidants are selected from the group comprising colloidal anhydrous silica, magnesium stearate, calcium stearate, stearic acid, talc, hydrogenated castor oil, sucrose esters of fatty acids, and mixtures thereof.
  • Suitable antioxidants are selected from the group comprising tocopherol, L- ascorbic acid and its sodium or calcium salts, ascorbyl palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and mixtures thereof.
  • Suitable solvents are selected from aqueous solvents or non-aqueous solvents.
  • the non-aqueous solvents are selected from the group comprising an ester such as ethyl acetate, n-butyl acetate, or n-hexyl acetate; a ketone such as methyl ethyl ketone or methyl isobutyl ketone; glycol ether; alcohols; hydrocarbons; chlorinated hydrocarbons; and mixtures thereof.
  • Suitable extended-release polymers are selected from the group comprising cellulose esters, such as cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, or cellulose acetate butyrate; cellulose ethers, such as
  • hydroxypropylmethyl cellulose hydroxypropyl cellulose, or ethylcellulose
  • polyvinyl acetate polyvinyl acetate
  • methacrylic acid copolymers and mixtures thereof.
  • the coloring agents of the present invention may be selected from any FDCA approved colors for oral use.
  • Coating may be carried out using a conventional coating pan, a spray coater, a rotating perforated pan, or an automated system, such as a centrifugal fluidizing granulator, a fluidized bed process, or any other suitable automated coating equipment.
  • the oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
  • step (ii) optionally coating the core tablets of step (i) with a coating polymer to obtain seal-coated tablets;
  • step (iii) coating the seal-coated tablets of step (ii) with a layer comprising
  • step (iv) coating the drug -layered tablets of step (iii) with a coating polymer to form an outer layer.
  • the oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
  • step (i) forming core tablets comprising excipients using direct compression; (ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
  • step (iii) coating the seal-coated tablets of step (ii) with a layer comprising
  • step (iv) coating the drug -layered tablets of step (iii) with a coating polymer to form an outer layer wherein the polymer in any one of the layers (ii), (iii), or (iv) is not a polyvinyl alcohol based polymer.
  • the oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
  • step (ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
  • step (iii) coating the seal-coated tablets of step (ii) with a layer comprising
  • the polymer in each of the layers (ii), (iii), and (iv) is not a polyvinyl alcohol based polymer.
  • the oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
  • step (ii) optionally coating the core tablets of step (i) with a coating polymer to obtain seal-coated tablets;
  • step (iii) coating the tablets of step (i) or the seal-coated tablets of step (ii) with a layer comprising saxagliptin and a coating polymer to obtain drug-layered tablets;
  • step (iv) coating the drug -layered tablets of step (iii) with a coating polymer to form an outer layer.
  • the oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
  • step (i) forming core tablets comprising excipients and an additional antidiabetic agent other than saxagliptin using wet granulation; (ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
  • step (iii) coating the seal-coated tablets of step (ii) with a layer comprising
  • step (iv) coating the drug -layered tablets of step (iii) with a coating polymer to form an outer layer
  • the polymer in any one of the layers (ii), (iii), or (iv) is not a polyvinyl alcohol based polymer.
  • the oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
  • step (ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
  • step (iii) coating the seal-coated tablets of step (ii) with a layer comprising
  • step (iv) coating the drug -layered tablets of step (iii) with a coating polymer to form an outer layer
  • the polymer in each of the layers (ii), (iii), and (iv) is not a polyvinyl alcohol based polymer.
  • the oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
  • step (ii) coating the metformin pellets of step (i) with a layer comprising an
  • step (iii) coating the extended-release metformin pellets of step (ii) with a coating polymer to obtain seal-coated pellets; (iv) coating the seal-coated pellets of step (iii) with a layer comprising saxagliptin and a coating polymer to obtain saxagliptin coated pellets;
  • step (v) coating the saxagliptin coated pellets of step (iv) with a coating polymer to form an outer coating layer over the pellets;
  • step (vi) filling the pellets of step (v) into hard gelatin capsules.
  • Core Tablets i) Blend lactose monohydrate, croscarmellose sodium, and microcrystalline cellulose together in a blender.
  • step ii) Lubricate the blend of step i) with magnesium stearate.
  • step iii) Compress the lubricated blend of step iii) into core tablets.
  • step vi) Add the dispersion of step v) slowly to the solution of step vi) under stirring while maintaining the pH at 2.
  • step vii) Coat the core tablets of step iii) with the dispersion of step vi) to form a seal layer over the core.
  • step x) Combine the solution of step viii) with the solution of step ix).
  • step xii) Add the dispersion of step xi) slowly to the solution of step x) under stirring, while maintaining the pH at 2.
  • step xiii) Coat the seal coated tablets of step vii) with the drug dispersion of step xii) to obtain drug-layered tablets.
  • xiv) Dissolve hydroxypropylmethyl cellulose in 0.1 N hydrochloric acid to obtain a clear solution.
  • xv) Coat the drug-layered tablets of step xiii) with the dispersion of step obtain an outer coating layer over the tablets.
  • Lactose monohydrate, croscarmellose sodium, and microcrystalline cellulose were blended together.
  • step i) The blend of step i) was lubricated with magnesium stearate.
  • step iii) The lubricated blend of step ii) was compressed into core tablets.
  • step iv) Hydroxypropylmethyl cellulose was dissolved in 0.1 N hydrochloric acid to obtain a clear solution.
  • the core tablets of step iii) were coated with the dispersion of step iv) to form seal-coated tablets.
  • step vi) was combined with the solution of step vii).
  • step x) The dispersion of step ix) was added slowly to the solution of step viii) under stirring, while maintaining the pH at 2.
  • step v) The seal-coated tablets of step v) were coated with the drug dispersion of step x) to obtain drug -layered tablets.
  • step xiv) The dispersion of step xiii) was added slowly to the solution of step xii) under stirring, while maintaining the pH at 2.
  • step xi) The drug-layered tablets of step xi) were coated with the dispersion of step xiv) to obtain an outer coating layer on the tablets.
  • step ii) Lubricate the blend of step i) with magnesium stearate.
  • step iii) Compress the lubricated blend of step ii) into core tablets.
  • step iii) Coat the core tablets of step iii) with the dispersion of step iv) to form a seal- coated core.
  • step viii) Combine the solution of step vi) with the solution of step vii).
  • step x) Add the dispersion of step ix) slowly to the solution of step viii) under stirring, while maintaining the pH at 2.
  • step xi) Coat the seal-coated tablets of step v) with the drug dispersion of step x) to obtain drug-layered tablets.
  • xii) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
  • step xiv) Add the dispersion of step xiii) slowly to the solution of step xii) under stirring, while maintaining the pH at 2.
  • step xv) Coat the drug-layered tablets of step xi) with the dispersion of step xiv) to obtain an outer coating layer on the tablets.
  • step ii) Lubricate the blend of step i) with magnesium stearate.
  • step iii) Compress the lubricated blend of step ii) into core tablets.
  • step v) Add the dispersion of step v) slowly to the solution of step iv) under stirring, while maintaining the pH at 2.
  • step vii) Coat the core tablets of step iii) with the dispersion of step vi) to form a seal layer over the core.
  • step viii) Add hydroxypropylmethyl cellulose to the drug dispersion of step viii) and maintain the pH at 2.
  • step x) Coat the seal-coated tablets of step vii) with the drug dispersion of step ix) to obtain drug -layered tablets.
  • xii) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a uniform dispersion.
  • step xiii) Add the dispersion of step xii) slowly to the solution of step xi) under stirring, while maintaining the pH at 2.
  • step xiv) Coat the drug-layered tablets of step x) with the dispersion of step xiii) to obtain an outer coating layer.
  • step ii) Lubricate the blend of step i) with magnesium stearate.
  • step iii) Compress the lubricated blend of step ii) into core tablets.
  • step iii) Coat the core tablets of step iii) with the dispersion of step iv) to form a seal layer over the core.
  • stepv i) Add hydroxypropylmethyl cellulose to the drug dispersion of stepv i) and maintain the pH at 2.
  • step viii) Coat the seal-coated tablets of step v) with the drug dispersion of step vii) to obtain drug-layered tablets.
  • step x) Coat the drug-layered tablets of step viii) with the dispersion of step ix) to obtain an outer coating layer on the tablets.
  • step ii) Lubricate the blend of step i) with magnesium stearate.
  • step iii) Compress the lubricated blend of step ii) into core tablets.
  • step iv) Combine the solution of step iv) with the solution of step v).
  • step viii) Add the dispersion of step vii) slowly to the solution of step vi) under stirring, while maintaining the pH at 2. ix) Coat the core tablets of step iii) with the drug dispersion of step viii) to obtain drug -layered tablets.
  • step xii) Add the dispersion of step xi) slowly to the solution of step x) under stirring, while maintaining the pH at 2.
  • step xiii) Coat the drug-layered tablets of step ix) with the dispersion of step xii) to obtain an outer coating layer on the tablets.
  • step iii) Add the dispersion of step i) slowly to the solution of step i) under stirring, while maintaining the pH at 2.
  • step vii) Combine the solution of step v) with the solution of step vi).
  • step viii) Add the dispersion of step viii) slowly to the solution of step vii) under stirring, while maintaining the pH at 2.
  • step x) Coat the seal-coated pellets of step iv) with the drug dispersion of step ix) to obtain drug-layered pellets.
  • step xiii) Add the dispersion of step xii) slowly to the solution of step xi) under stirring, while maintaining the pH at 2.
  • step xiv) Coat the pellets of step x) with the dispersion of step xiii) to obtain an outer coating layer.
  • step xv) Fill the coated pellets of step xiv) into hard gelatin capsule shells at a desired fill weight.
  • step ii) Add hydroxypropylmethyl cellulose and sodiumcarboxymethyl cellulose to the mixture of step i) and mix.
  • step iii) Add magnesium stearate to the mixture of step ii).
  • step iv) Compact the blend of step iii) and then pass the compacts through a screen.
  • step v) Granulate colloidal silicon dioxide with purified water and pass through a screen.
  • step v) Mix the granules of step v) with the granules of step iv) to form a blend.
  • step x) Add the dispersion of step ix) slowly to the solution of step viii) under stirring, while maintaining the pH at 2.
  • step xi) Coat the core tablets of step vii) with the dispersion of step x) to form a seal layer over the core.
  • xiii) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
  • step xiv) Combine the solution of step xii) with the solution of step xiii).
  • step xvi) Add the dispersion of step xv) slowly to the solution of step xiv) under stirring, while maintaining the pH at 2.
  • step xvii) Coat the seal-coated tablets of step xi) with the drug dispersion of step xvi) to obtain drug-layered tablets.
  • xviii) Dissolve hydroxypropylmethyl cellulose in 0.1 N hydrochloric acid to obtain a clear solution.
  • xix) Coat the drug-layered tablets of step xvii) with the dispersion of step xviii) to obtain an outer coating layer on the tablets.
  • step ii) Add hydroxypropylmethyl cellulose and sodiumcarboxymethyl cellulose to the mixture of step i) and mix.
  • step iv) Compact the blend of step iii) and then pass the compacts through a screen.
  • v) Granulate colloidal silicon dioxide with purified water and pass through a screen.
  • step v) Mix the granules of step v) with the granules of step iv) to form a blend.
  • step vii) Coat the core tablets of step vii) with the dispersion of step viii) to form a seal layer over the core.
  • step xii Combine the solution of step x) with the solution of step xi).
  • step xiv) Add the dispersion of step xiii) slowly to the solution of step xii) under stirring, while maintaining the pH at 2.
  • step xv) Coat the seal-coated tablets of step ix) with the drug dispersion of step xiv) to obtain drug -layered tablets.
  • step xviii) Add the dispersion of step xvii) slowly to the solution of step xvi) under
  • step ii) Add hydroxypropylmethyl cellulose and sodiumcarboxymethyl cellulose to the mixture of step i) and mix.
  • step iv) Compact the blend of step iii) and then pass the compacts through a screen.
  • v) Granulate colloidal silicon dioxide with purified water and pass through a screen.
  • step x) Add the dispersion of step ix) slowly to the solution of step viii) under stirring while maintaining the pH at 2.
  • step xi) Coat the core tablets of step vii) with the dispersion of step x) to form a seal layer over the core.
  • step xiii) Add hydroxypropylmethyl cellulose to the drug dispersion of step xii) and maintain the pH at 2.
  • step xiv) Coat the seal-coated tablets of step xi) with the drug dispersion of step xiii) to obtain drug-layered tablets.
  • step xvii) Add the dispersion of step xvi) slowly to the solution of step xv) under stirring, while maintaining the pH at 2.
  • step ii) Add hydroxypropylmethyl cellulose and sodiumcarboxymethyl cellulose to the mixture of step i) and mix.
  • step iv) Compact the blend of step iii) and then pass the compacts through a screen.
  • v) Granulate colloidal silicon dioxide with purified water and pass through a screen.
  • step v) Mix the granules of step v) with the granules of step iv) to form a blend.
  • step vii) Compress the final blend to form core tablets.
  • step vii) Coat the core tablets of step vii) with the dispersion of step viii) to form a seal layer over the core.
  • step xi) Add hydroxypropylmethyl cellulose to the drug dispersion of step x) and maintain the pH at 2.
  • step xii) Coat the seal-coated tablets of step ix) with the dispersion of step xi) to obtain drug -layered tablets.
  • xiii) Disperse hydroxypropylmethyl cellulose in 0.1 N hydrochloric acid to obtain a coating dispersion.
  • step xiv) Coat the drug-layered tablets of step xii) with the dispersion of step xiii) to obtain an outer coating layer on the tablets.
  • Titanium dioxide 2.15
  • step ii) Add hydroxypropylmethyl cellulose and sodiumcarboxymethyl cellulose to the mixture of step i) and mix.
  • step iv) Compact the blend of step iii) and then pass the compacts through a screen.
  • v) Granulate colloidal silicon dioxide with purified water and pass through a screen.
  • step v) Mix the granules of step v) with the granules of step iv) to form a blend.
  • step vii) Compress the final blend to form core tablets.
  • step x) Combine the solution of step viii) with the solution of step ix).
  • step xii) Add the dispersion of step xi) slowly to the solution of step x) under stirring, while maintaining the pH at 2.
  • step xiii) Coat the core tablets of step vii) with the drug dispersion of step xii) to obtain drug -layered tablets.
  • step xvi) Add the dispersion of step xv) slowly to the solution of step xiv) under stirring while maintaining the pH at 2.
  • step vii) Add the dispersion of step vi) slowly to the solution of step v) under stirring, while maintaining the pH at 2.
  • step viii) Coat the extended-release metformin pellets of step iv) with the dispersion of step vii).
  • step xi Combine the solution of step ix) with the solution of step x).
  • step xiii) Add the dispersion of step xii) slowly to the solution of step xi) under stirring, while maintaining the pH at 2.
  • step xvii) Add the dispersion of step xvi) slowly to the solution of step xv) under stirring, while maintaining pH at 2.
  • step xviii) Coat the saxagliptin-coated pellets of step xiii) with the dispersion of step xvii) to obtain an outer coating layer over the pellets.
  • step xix) Fill the pellets of step xviii) into hard gelatin capsule shells at a desired fill weight.

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Abstract

The present invention relates to oral pharmaceutical compositions comprising saxagliptin and processes for the preparation thereof. It further relates to oral pharmaceutical compositions comprising saxagliptin in combination with other antidiabetic agents.

Description

ORAL COMPOSITIONS OF SAXAGLIPTIN
Field of the Invention
The present invention relates to oral pharmaceutical compositions comprising saxagliptin and processes for their preparation. It further relates to oral pharmaceutical compositions comprising saxagliptin in combination with other antidiabetic agents.
Background of the Invention
Saxagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor used for the treatment of type 2 diabetes mellitus. U.S. Patent No. 6,395,767 discloses the compound saxagliptin.
DPP-IV is an enzyme that catalyses the conversion of glucagon-like peptide- 1
(GLP-1) from its active form to its inactive form. Saxagliptin competitively inhibits the DPP-IV enzyme, thereby increasing the endogenous concentration of GLP-1, which further augments insulin secretion and improves the glycemic profile of patients with type 2 diabetes mellitus.
U.S. Patent No. 7,951,400 describes saxagliptin as an unstable compound which easily undergoes intramolecular cyclization to form a cyclic amidine, which is not desirable for therapeutic activity. This process of cyclization is accelerated by the use of common processes of formulation, e.g., granulation or compaction. In order to provide a stable formulation wherein saxagliptin is less prone to cyclization, U.S. Patent No.
7,951,400 provides a coated tablet formulation of saxagliptin containing a polyvinyl alcohol based coating.
The present invention provides alternative oral pharmaceutical compositions comprising saxagliptin.
Summary of the Invention
The present invention provides oral pharmaceutical compositions comprising saxagliptin and processes for their preparation. The oral pharmaceutical compositions are preferably in the form of coated tablets comprising a core and a coating layer surrounding the core, wherein the drug is present in said coating.
The present invention also relates to oral pharmaceutical compositions comprising saxagliptin in combination with other antidiabetic agents. Detailed Description of the Invention
A first aspect of the present invention provides an oral pharmaceutical composition comprising saxagliptin, wherein said composition comprises:
(a) a core;
(b) optionally a seal layer comprising a coating polymer over the core;
(c) a drug layer comprising saxagliptin and a coating polymer over the core or seal-coated core; and
(d) an outer layer comprising a coating polymer over the drug layer.
A second aspect of the present invention provides an oral pharmaceutical composition comprising saxagliptin, wherein said composition comprises:
(a) a core;
(b) a seal layer comprising a coating polymer over the core;
(c) a drug layer comprising saxagliptin and a coating polymer over the seal layer; and
(d) an outer layer comprising a coating polymer over the drug layer
wherein the polymer in any one of the layers (b), (c), or (d) is not a polyvinyl alcohol based polymer.
A third aspect of the present invention provides an oral pharmaceutical composition comprising saxagliptin, wherein said composition comprises:
(a) a core;
(b) a seal layer comprising a coating polymer over the core;
(c) a drug layer comprising saxagliptin and a coating polymer over the seal layer; and
(d) an outer layer comprising a coating polymer over the drug layer
wherein the polymer in each of the layers (b), (c), and (d) is not a polyvinyl alcohol based polymer.
The term "saxagliptin," as used herein, refers to saxagliptin and its
pharmaceutically acceptable salts or esters. These salts or esters may be prepared from an inorganic acid selected from the group comprising hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, bicarbonic acid, sulfuric acid, phosphoric acid, and bisulphonic acid; or an organic acid selected from the group comprising oxalic acid, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, salicyclic acid, p-hydroxybenzoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, sulfanilic acid, stearic acid, alginic acid, galactaric acid, and galacturonic acid.
Saxagliptin used in the composition of the present invention may be present in its crystalline form, amorphous form, anhydrous form, hydrate form, or mixtures thereof.
The term "core," as used herein, refers to an inert core or a compressed tablet core optionally containing an additional antidiabetic agent other than saxagliptin. The inert core may include an insoluble, swellable, or soluble core. The insoluble or swellable inert core may be made of dicalcium phosphate, microcrystalline cellulose, or any of the marketed inert cores, e.g. , glass beads, silicate beads, sugar spheres, non-pareils, or celphere. The soluble core may include glucose, mannitol, lactose, xylitol, dextrose, or sucrose.
The compressed tablet core may comprise pharmaceutically acceptable excipients selected from the group comprising binders, fillers, disintegrants, plasticizers, extended- release polymers, lubricants, glidants, or mixtures thereof, and may be prepared by the process of direct compression or granulation.
According to one embodiment of the present invention, said core optionally contains an additional antidiabetic agent other than saxagliptin.
According to another embodiment of the present invention, said core containing an additional antidiabetic agent other than saxagliptin is coated with an extended-release coating.
According to another embodiment of the present invention, the seal layer optionally contains an additional antidiabetic agent other than saxagliptin.
According to another embodiment of the present invention, the drug layer optionally contains an additional antidiabetic agent in addition to saxagliptin. According to another embodiment of the present invention, the outer layer optionally contains an additional antidiabetic agent other than saxagliptin.
According to another embodiment of the present invention, said oral
pharmaceutical composition provides an immediate-release or an extended-release of the additional antidiabetic agent.
The additional antidiabetic agent is selected from the group comprising acarbose, miglitol, repaglinide, nateglinide, chlorpropamide, glibenclamide, gliclazide, glimepiride, glipizide, glyclopyramide, tolazamide, tolbutamide, buformin, metformin, phenformin, rosiglitazone, pioglitazone, troglitazone, faraglitazar, englitazone, darglitazone, isaglitazone, reglitazar, rivoglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, sitagliptin, vildagliptin, linagliptin, dutogliptin, alogliptin, canagliflozin, dapagliflozin, remogliflozin, sergliflozin, and pharmaceutically acceptable salts or esters thereof.
According to an embodiment of the present invention, the additional antidiabetic agent is metformin or pharmaceutically acceptable salts or esters thereof. In particular, the additional antidiabetic agent is metformin hydrochloride.
The coating polymer that is not a polyvinyl alcohol based polymer is selected from the group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, polyvinyl pyrrolidone, polysaccharides, starch and its derivatives, gums, alginates, acrylic acid derivatives, polyethylene glycol, polyalkylene glycols, mannitol, sucrose, lactose, xylitol, and mixtures thereof.
Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® and Sepifilm® LP 010, may also be used for coating.
According to another embodiment of the present invention, there is provided an oral pharmaceutical composition comprising saxagliptin wherein said composition is in the form of pellets or tablets. The pellets may further be filled into capsules or compressed into tablets.
According to another embodiment of the present invention, there is provided an oral pharmaceutical composition comprising saxagliptin wherein said composition further comprises pharmaceutically acceptable excipients selected from the group comprising fillers, binders, plasticizers, disintegrants, lubricants, glidants, and mixtures thereof. The coating suspension optionally contains pharmaceutically acceptable excipients selected from the group comprising plasticizers, colorants, antioxidants, solvents, and mixtures thereof.
Suitable fillers are selected from the group comprising starch, lactose, sucrose, glucose, sorbitol, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol, pregelatinized starch, and mixtures thereof.
Suitable binders are selected from the group comprising methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, poloxamer, gelatin, ethyl cellulose, polyvinyl alcohol, pullunan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, gum arabic, and mixtures thereof.
Suitable plasticizers are selected from the group comprising propylene glycol, triethylene glycol, oleic acid, ethylene glycol monooleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, dibutyl sebacate, acetyl triethyl citrate, castor oil, and mixtures thereof.
Suitable disintegrants are selected from the group comprising cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodiumcarboxymethyl cellulose, calciumcarboxymethyl cellulose, alginic acid, alginates, pregelatinized starch, starch and its derivatives, low-substituted hydroxypropyl cellulose, and mixtures thereof.
Suitable lubricants and glidants are selected from the group comprising colloidal anhydrous silica, magnesium stearate, calcium stearate, stearic acid, talc, hydrogenated castor oil, sucrose esters of fatty acids, and mixtures thereof.
Suitable antioxidants are selected from the group comprising tocopherol, L- ascorbic acid and its sodium or calcium salts, ascorbyl palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and mixtures thereof.
Suitable solvents are selected from aqueous solvents or non-aqueous solvents. The non-aqueous solvents are selected from the group comprising an ester such as ethyl acetate, n-butyl acetate, or n-hexyl acetate; a ketone such as methyl ethyl ketone or methyl isobutyl ketone; glycol ether; alcohols; hydrocarbons; chlorinated hydrocarbons; and mixtures thereof.
Suitable extended-release polymers are selected from the group comprising cellulose esters, such as cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, or cellulose acetate butyrate; cellulose ethers, such as
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, or ethylcellulose; polyvinyl acetate; methacrylic acid copolymers; and mixtures thereof.
The coloring agents of the present invention may be selected from any FDCA approved colors for oral use.
Coating may be carried out using a conventional coating pan, a spray coater, a rotating perforated pan, or an automated system, such as a centrifugal fluidizing granulator, a fluidized bed process, or any other suitable automated coating equipment.
The oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
(i) forming core tablets comprising excipients using direct compression;
(ii) optionally coating the core tablets of step (i) with a coating polymer to obtain seal-coated tablets;
(iii) coating the seal-coated tablets of step (ii) with a layer comprising
saxagliptin and a coating polymer to obtain drug-layered tablets;
(iv) coating the drug -layered tablets of step (iii) with a coating polymer to form an outer layer.
The oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
(i) forming core tablets comprising excipients using direct compression; (ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
(iii) coating the seal-coated tablets of step (ii) with a layer comprising
saxagliptin and a coating polymer to obtain drug-layered tablets; and
(iv) coating the drug -layered tablets of step (iii) with a coating polymer to form an outer layer wherein the polymer in any one of the layers (ii), (iii), or (iv) is not a polyvinyl alcohol based polymer.
The oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
(i) forming core tablets comprising excipients using direct compression;
(ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
(iii) coating the seal-coated tablets of step (ii) with a layer comprising
saxagliptin and a coating polymer to obtain drug-layered tablets; and
(iv) coating the drug-layered tablets with a coating polymer to form an outer layer
wherein the polymer in each of the layers (ii), (iii), and (iv) is not a polyvinyl alcohol based polymer.
The oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
(i) forming core tablets comprising excipients and an additional antidiabetic agent other than saxagliptin using wet granulation;
(ii) optionally coating the core tablets of step (i) with a coating polymer to obtain seal-coated tablets;
(iii) coating the tablets of step (i) or the seal-coated tablets of step (ii) with a layer comprising saxagliptin and a coating polymer to obtain drug-layered tablets; and
(iv) coating the drug -layered tablets of step (iii) with a coating polymer to form an outer layer.
The oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
(i) forming core tablets comprising excipients and an additional antidiabetic agent other than saxagliptin using wet granulation; (ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
(iii) coating the seal-coated tablets of step (ii) with a layer comprising
saxagliptin and a coating polymer to obtain drug-layered tablets; and
(iv) coating the drug -layered tablets of step (iii) with a coating polymer to form an outer layer
wherein the polymer in any one of the layers (ii), (iii), or (iv) is not a polyvinyl alcohol based polymer.
The oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
(i) forming core tablets comprising excipients and an additional antidiabetic agent other than saxagliptin using direct compression;
(ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
(iii) coating the seal-coated tablets of step (ii) with a layer comprising
saxagliptin and a coating polymer to obtain drug-layered tablets; and
(iv) coating the drug -layered tablets of step (iii) with a coating polymer to form an outer layer
wherein the polymer in each of the layers (ii), (iii), and (iv) is not a polyvinyl alcohol based polymer.
The oral pharmaceutical composition of the present invention may be prepared by a process which comprises the steps of:
(i) coating non-pareil seeds with a layer comprising metformin and a coating polymer to obtain metformin pellets;
(ii) coating the metformin pellets of step (i) with a layer comprising an
extended-release polymer;
(iii) coating the extended-release metformin pellets of step (ii) with a coating polymer to obtain seal-coated pellets; (iv) coating the seal-coated pellets of step (iii) with a layer comprising saxagliptin and a coating polymer to obtain saxagliptin coated pellets;
(v) coating the saxagliptin coated pellets of step (iv) with a coating polymer to form an outer coating layer over the pellets; and
(vi) filling the pellets of step (v) into hard gelatin capsules.
The following examples represent various embodiments of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLES
Example la & Example lb
Figure imgf000010_0001
Procedure:
Core Tablets i) Blend lactose monohydrate, croscarmellose sodium, and microcrystalline cellulose together in a blender.
ii) Lubricate the blend of step i) with magnesium stearate.
iii) Compress the lubricated blend of step iii) into core tablets.
Seal Layer
iv) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
v) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a uniform dispersion.
vi) Add the dispersion of step v) slowly to the solution of step vi) under stirring while maintaining the pH at 2.
vii) Coat the core tablets of step iii) with the dispersion of step vi) to form a seal layer over the core.
Drug Layer
viii) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
ix) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
x) Combine the solution of step viii) with the solution of step ix).
xi) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a uniform dispersion.
xii) Add the dispersion of step xi) slowly to the solution of step x) under stirring, while maintaining the pH at 2.
xiii) Coat the seal coated tablets of step vii) with the drug dispersion of step xii) to obtain drug-layered tablets.
Outer Layer
xiv) Dissolve hydroxypropylmethyl cellulose in 0.1 N hydrochloric acid to obtain a clear solution. xv) Coat the drug-layered tablets of step xiii) with the dispersion of step obtain an outer coating layer over the tablets.
Example 2a
Figure imgf000012_0001
Procedure:
Core Tablets
i) Lactose monohydrate, croscarmellose sodium, and microcrystalline cellulose were blended together.
ii) The blend of step i) was lubricated with magnesium stearate.
iii) The lubricated blend of step ii) was compressed into core tablets.
Seal Layer
iv) Hydroxypropylmethyl cellulose was dissolved in 0.1 N hydrochloric acid to obtain a clear solution. v) The core tablets of step iii) were coated with the dispersion of step iv) to form seal-coated tablets.
Drug Layer
vi) Saxagliptin was added to 0.1 N hydrochloric acid and the pH was adjusted to 2. vii) Polyvinyl alcohol and polyethylene glycol were dissolved in 0.1 N
hydrochloric acid to obtain a clear solution and the pH was adjusted to 2. viii) The solution of step vi) was combined with the solution of step vii).
ix) Talc and titanium dioxide were dispersed in 0.1 N hydrochloric acid to obtain a uniform dispersion.
x) The dispersion of step ix) was added slowly to the solution of step viii) under stirring, while maintaining the pH at 2.
xi) The seal-coated tablets of step v) were coated with the drug dispersion of step x) to obtain drug -layered tablets.
Outer Layer
xii) Polyvinyl alcohol and polyethylene glycol were dissolved in 0.1 N
hydrochloric acid to obtain a clear solution and the pH was adjusted to 2. xiii) Talc and titanium dioxide were dispersed in 0.1 N hydrochloric acid to obtain a uniform dispersion.
xiv) The dispersion of step xiii) was added slowly to the solution of step xii) under stirring, while maintaining the pH at 2.
xv) The drug-layered tablets of step xi) were coated with the dispersion of step xiv) to obtain an outer coating layer on the tablets.
Example 2b
Figure imgf000014_0001
Procedure:
Core Tablets
i) Blend lactose monohydrate, croscarmellose sodium, and microcrystalline cellulose together.
ii) Lubricate the blend of step i) with magnesium stearate.
iii) Compress the lubricated blend of step ii) into core tablets.
Seal Layer
iv) Dissolve hydroxypropylmethyl cellulose in 0.1 N hydrochloric acid to obtain a clear solution.
v) Coat the core tablets of step iii) with the dispersion of step iv) to form a seal- coated core. Drug Layer
vi) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
vii) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
viii) Combine the solution of step vi) with the solution of step vii).
ix) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
x) Add the dispersion of step ix) slowly to the solution of step viii) under stirring, while maintaining the pH at 2.
xi) Coat the seal-coated tablets of step v) with the drug dispersion of step x) to obtain drug-layered tablets.
Outer Layer
xii) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
xiii) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
xiv) Add the dispersion of step xiii) slowly to the solution of step xii) under stirring, while maintaining the pH at 2.
xv) Coat the drug-layered tablets of step xi) with the dispersion of step xiv) to obtain an outer coating layer on the tablets.
Example 3a & Example 3b
Figure imgf000016_0001
Procedure:
Core Tablets
i) Blend lactose monohydrate, croscarmellose sodium, and microcrystalline cellulose together in a blender.
ii) Lubricate the blend of step i) with magnesium stearate.
iii) Compress the lubricated blend of step ii) into core tablets.
Seal Layer
iv) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
v) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a uniform dispersion.
vi) Add the dispersion of step v) slowly to the solution of step iv) under stirring, while maintaining the pH at 2. vii) Coat the core tablets of step iii) with the dispersion of step vi) to form a seal layer over the core.
Drug Layer
viii) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
ix) Add hydroxypropylmethyl cellulose to the drug dispersion of step viii) and maintain the pH at 2.
x) Coat the seal-coated tablets of step vii) with the drug dispersion of step ix) to obtain drug -layered tablets.
Outer Layer
xi) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
xii) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a uniform dispersion.
xiii) Add the dispersion of step xii) slowly to the solution of step xi) under stirring, while maintaining the pH at 2.
xiv) Coat the drug-layered tablets of step x) with the dispersion of step xiii) to obtain an outer coating layer.
Example 4a & Example 4b
Example 4a Example 4b
Ingredients
% w/w (5.0 mg) % w/w (2.5 mg)
Core Tablet
Lactose monohydrate 42.48 42.95
Microcrystalline cellulose 38.63 39.05
Croscarmellose sodium 4.29 4.34
Magnesium stearate 0.43 0.43
Seal Layer
Hydroxypropylmethyl cellulose 1.72 1.74
Hydrochloric acid (0.1 N) q.s. q.s.
Drug Layer
Saxagliptin 2.15 1.07
Hydroxypropylmethyl cellulose 8.58 8.68
Hydrochloric acid (0.1 N) q.s. q.s.
Outer Layer
Hydroxypropylmethyl cellulose 1.72 1.74
Hydrochloric acid (0.1 N) q.s. q.s. Procedure:
Core Tablets
i) Blend lactose monohydrate, croscarmellose sodium, and microcrystalline cellulose together in a blender.
ii) Lubricate the blend of step i) with magnesium stearate.
iii) Compress the lubricated blend of step ii) into core tablets.
Seal Layer
iv) Dissolve hydroxypropylmethyl cellulose in 0.1 N hydrochloric acid to obtain a uniform mixture and adjust the pH to 2.
v) Coat the core tablets of step iii) with the dispersion of step iv) to form a seal layer over the core.
Drug Layer
vi) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
vii) Add hydroxypropylmethyl cellulose to the drug dispersion of stepv i) and maintain the pH at 2.
viii) Coat the seal-coated tablets of step v) with the drug dispersion of step vii) to obtain drug-layered tablets.
Outer Layer
ix) Prepare a coating dispersion of hydroxypropylmethyl cellulose in 0.1 N
hydrochloric acid.
x) Coat the drug-layered tablets of step viii) with the dispersion of step ix) to obtain an outer coating layer on the tablets.
Example 5a & Example 5b
Figure imgf000019_0001
Procedure:
Core Tablets
i) Blend lactose monohydrate, croscarmellose sodium, and microcrystalline cellulose together in a blender.
ii) Lubricate the blend of step i) with magnesium stearate.
iii) Compress the lubricated blend of step ii) into core tablets.
Drug Layer
iv) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
v) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
vi) Combine the solution of step iv) with the solution of step v).
vii) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a uniform dispersion.
viii) Add the dispersion of step vii) slowly to the solution of step vi) under stirring, while maintaining the pH at 2. ix) Coat the core tablets of step iii) with the drug dispersion of step viii) to obtain drug -layered tablets.
Outer Layer
x) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
xi) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a uniform dispersion.
xii) Add the dispersion of step xi) slowly to the solution of step x) under stirring, while maintaining the pH at 2.
xiii) Coat the drug-layered tablets of step ix) with the dispersion of step xii) to obtain an outer coating layer on the tablets.
Exam le 6a & Example 6b
Figure imgf000020_0001
Procedure:
Seal Layer
i) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
ii) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
iii) Add the dispersion of step ii) slowly to the solution of step i) under stirring, while maintaining the pH at 2.
iv) Coat non-pareil seeds with the dispersion of step iii) to obtain seal-coated
pellets.
Drug Layer
v) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
vi) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
vii) Combine the solution of step v) with the solution of step vi).
viii) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
ix) Add the dispersion of step viii) slowly to the solution of step vii) under stirring, while maintaining the pH at 2.
x) Coat the seal-coated pellets of step iv) with the drug dispersion of step ix) to obtain drug-layered pellets.
Outer Layer
xi) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
xii) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
xiii) Add the dispersion of step xii) slowly to the solution of step xi) under stirring, while maintaining the pH at 2. xiv) Coat the pellets of step x) with the dispersion of step xiii) to obtain an outer coating layer.
Capsule Filling
xv) Fill the coated pellets of step xiv) into hard gelatin capsule shells at a desired fill weight.
Example 7
Figure imgf000022_0001
Procedure:
Core Tablets
i) Mix metformin hydrochloride with microcrystalline cellulose in a rapid mixer granulator and sprinkle purified water onto the mixture.
ii) Add hydroxypropylmethyl cellulose and sodiumcarboxymethyl cellulose to the mixture of step i) and mix.
iii) Add magnesium stearate to the mixture of step ii). iv) Compact the blend of step iii) and then pass the compacts through a screen. v) Granulate colloidal silicon dioxide with purified water and pass through a screen.
vi) Mix the granules of step v) with the granules of step iv) to form a blend.
vii) Compress the final blend to form core tablets.
Seal Layer
viii) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
ix) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
x) Add the dispersion of step ix) slowly to the solution of step viii) under stirring, while maintaining the pH at 2.
xi) Coat the core tablets of step vii) with the dispersion of step x) to form a seal layer over the core.
Drug Layer
xii) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
xiii) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
xiv) Combine the solution of step xii) with the solution of step xiii).
xv) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
xvi) Add the dispersion of step xv) slowly to the solution of step xiv) under stirring, while maintaining the pH at 2.
xvii) Coat the seal-coated tablets of step xi) with the drug dispersion of step xvi) to obtain drug-layered tablets.
Outer Layer
xviii) Dissolve hydroxypropylmethyl cellulose in 0.1 N hydrochloric acid to obtain a clear solution. xix) Coat the drug-layered tablets of step xvii) with the dispersion of step xviii) to obtain an outer coating layer on the tablets.
Example 8
Figure imgf000024_0001
Procedure:
Core Tablets
i) Mix metformin hydrochloride with microcrystalline cellulose in a rapid mixer granulator and sprinkle purified water onto the mixture.
ii) Add hydroxypropylmethyl cellulose and sodiumcarboxymethyl cellulose to the mixture of step i) and mix.
iii) Add magnesium stearate to the mixture of step ii).
iv) Compact the blend of step iii) and then pass the compacts through a screen. v) Granulate colloidal silicon dioxide with purified water and pass through a screen. vi) Mix the granules of step v) with the granules of step iv) to form a blend.
vii) Compress the final blend to form core tablets.
Seal Layer
viii) Dissolve hydroxypropylmethyl cellulose in 0.1 N hydrochloric acid to obtain a clear solution.
ix) Coat the core tablets of step vii) with the dispersion of step viii) to form a seal layer over the core.
Drug Layer
x) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
xi) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
xii) Combine the solution of step x) with the solution of step xi).
xiii) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
xiv) Add the dispersion of step xiii) slowly to the solution of step xii) under stirring, while maintaining the pH at 2.
xv) Coat the seal-coated tablets of step ix) with the drug dispersion of step xiv) to obtain drug -layered tablets.
Outer Layer
xvi) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
xvii) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
xviii) Add the dispersion of step xvii) slowly to the solution of step xvi) under
stirring, while maintaining the pH at 2.
xix) Coat the drug-layered tablets of step xv) with the dispersion of step xviii) to obtain an outer coating layer on the tablets. Example 9
Figure imgf000026_0001
Procedure:
Core Tablets
i) Mix metformin hydrochloride with microcrystalline cellulose in a rapid mixer granulator and sprinkle purified water onto the mixture.
ii) Add hydroxypropylmethyl cellulose and sodiumcarboxymethyl cellulose to the mixture of step i) and mix.
iii) Add magnesium stearate to the mixture of step ii).
iv) Compact the blend of step iii) and then pass the compacts through a screen. v) Granulate colloidal silicon dioxide with purified water and pass through a screen.
vi) Mix the granules of step v) with the granules of step iv) to form a blend. vii) Compress the final blend to form core tablets. Seal Layer
viii) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
ix) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
x) Add the dispersion of step ix) slowly to the solution of step viii) under stirring while maintaining the pH at 2.
xi) Coat the core tablets of step vii) with the dispersion of step x) to form a seal layer over the core.
Drug Layer
xii) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
xiii) Add hydroxypropylmethyl cellulose to the drug dispersion of step xii) and maintain the pH at 2.
xiv) Coat the seal-coated tablets of step xi) with the drug dispersion of step xiii) to obtain drug-layered tablets.
Outer Layer
xv) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
xvi) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
xvii) Add the dispersion of step xvi) slowly to the solution of step xv) under stirring, while maintaining the pH at 2.
xviii) Coat the drug-layered tablets of step xiv) with the dispersion of step xvii) to obtain an outer coating layer on the tablets. Example 10
Figure imgf000028_0001
Procedure:
Core Tablets
i) Mix metformin hydrochloride with microcrystalline cellulose in a rapid mixer granulator and sprinkle purified water onto the mixture.
ii) Add hydroxypropylmethyl cellulose and sodiumcarboxymethyl cellulose to the mixture of step i) and mix.
iii) Add magnesium stearate to the mixture of step ii).
iv) Compact the blend of step iii) and then pass the compacts through a screen. v) Granulate colloidal silicon dioxide with purified water and pass through a screen.
vi) Mix the granules of step v) with the granules of step iv) to form a blend. vii) Compress the final blend to form core tablets.
Seal Layer
viii) Dissolve hydroxypropylmethyl cellulose in 0.1 N hydrochloric acid to obtain a uniform mixture and adjust the pH to 2.
ix) Coat the core tablets of step vii) with the dispersion of step viii) to form a seal layer over the core. Drug Layer
x) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
xi) Add hydroxypropylmethyl cellulose to the drug dispersion of step x) and maintain the pH at 2.
xii) Coat the seal-coated tablets of step ix) with the dispersion of step xi) to obtain drug -layered tablets.
Outer Layer
xiii) Disperse hydroxypropylmethyl cellulose in 0.1 N hydrochloric acid to obtain a coating dispersion.
xiv) Coat the drug-layered tablets of step xii) with the dispersion of step xiii) to obtain an outer coating layer on the tablets.
Example 11
Ingredients % w/w
Core Tablet
Metformin hydrochloride 61.57
Microcrystalline cellulose 4.93
Sodiumcarboxymethyl cellulose 1.54
Hydroxypropylmethyl cellulose 16.93
Purified water 2.77
Colloidal silicon dioxide 1.31
Magnesium stearate 0.23
Drug Layer
Saxagliptin 0.30
Polyvinyl alcohol 3.45
Talc 1.29
Titanium dioxide 2.15
Polyethylene glycol 1.73
Hydrochloric acid (0.1 N) q.s.
Outer Layer
Polyvinyl alcohol 0.72
Talc 0.27
Titanium dioxide 0.45
Polyethylene glycol 0.36
Hydrochloric acid (0.1 N) q.s. Procedure:
Core Tablets
i) Mix metformin hydrochloride with microcrystalline cellulose in a rapid mixer granulator and sprinkle purified water onto the mixture.
ii) Add hydroxypropylmethyl cellulose and sodiumcarboxymethyl cellulose to the mixture of step i) and mix.
iii) Add magnesium stearate to the mixture of step ii).
iv) Compact the blend of step iii) and then pass the compacts through a screen. v) Granulate colloidal silicon dioxide with purified water and pass through a screen.
vi) Mix the granules of step v) with the granules of step iv) to form a blend. vii) Compress the final blend to form core tablets.
Drug Layer
viii) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
ix) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
x) Combine the solution of step viii) with the solution of step ix).
xi) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
xii) Add the dispersion of step xi) slowly to the solution of step x) under stirring, while maintaining the pH at 2.
xiii) Coat the core tablets of step vii) with the drug dispersion of step xii) to obtain drug -layered tablets.
Outer Layer
xiv) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
xv) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
xvi) Add the dispersion of step xv) slowly to the solution of step xiv) under stirring while maintaining the pH at 2.
xvii) Coat the drug-layered tablets of step xiii) with the dispersion of step xvi) to obtain an outer coating layer. Example 12
Figure imgf000031_0001
Procedure:
Metformin Layer
i) Dissolve metformin hydrochloride and hydroxypropylmethyl cellulose in purified water, then disperse sodiumcarboxymethyl cellulose into the purified water to obtain a uniform dispersion.
ii) Coat non-pareil seeds with the dispersion of step i) to obtain coated pellets. Extended-Release Layer
iii) Dissolve ethyl cellulose and hydroxypropylmethyl cellulose in an organic solvent to obtain a clear solution.
iv) Coat metformin pellets of step ii) with the solution of step iii). Seal Layer
v) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
vi) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
vii) Add the dispersion of step vi) slowly to the solution of step v) under stirring, while maintaining the pH at 2.
viii) Coat the extended-release metformin pellets of step iv) with the dispersion of step vii).
Drug Layer
ix) Add saxagliptin to 0.1 N hydrochloric acid and adjust the pH to 2.
x) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
xi) Combine the solution of step ix) with the solution of step x).
xii) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
xiii) Add the dispersion of step xii) slowly to the solution of step xi) under stirring, while maintaining the pH at 2.
xiv) Coat the seal-coated pellets of step viii) with the drug dispersion of step xiii). Outer Layer
xv) Dissolve polyvinyl alcohol and polyethylene glycol in 0.1 N hydrochloric acid to obtain a clear solution and adjust the pH to 2.
xvi) Disperse talc and titanium dioxide in 0.1 N hydrochloric acid to obtain a
uniform dispersion.
xvii) Add the dispersion of step xvi) slowly to the solution of step xv) under stirring, while maintaining pH at 2.
xviii) Coat the saxagliptin-coated pellets of step xiii) with the dispersion of step xvii) to obtain an outer coating layer over the pellets.
Capsule Filling
xix) Fill the pellets of step xviii) into hard gelatin capsule shells at a desired fill weight.

Claims

We claim:
1. An oral pharmaceutical composition comprising saxagliptin, wherein said composition comprises:
(a) a core;
(b) optionally a seal layer comprising a coating polymer coated over the core; (c) a drug layer comprising saxagliptin and a coating polymer over the core or seal-coated core; and
(d) an outer layer comprising a coating polymer over the drug layer.
2. An oral pharmaceutical composition comprising saxagliptin, wherein said composition comprises:
(a) a core;
(b) a seal layer comprising a coating polymer over the core;
(c) a drug layer comprising saxagliptin and a coating polymer over the seal layer; and
(d) an outer layer comprising a coating polymer over the drug layer
wherein the polymer in any one of the layers (b), (c), or (d) is not a polyvinyl alcohol based polymer.
3. An oral pharmaceutical composition comprising saxagliptin, wherein said composition comprises:
(a) a core;
(b) a seal layer over the core comprising a coating polymer;
(c) a drug layer over the seal layer comprising saxagliptin and a coating polymer; and
(d) an outer layer over the drug layer comprising a coating polymer;
wherein the polymer in each of the layers (b), (c), and (d) is not a polyvinyl alcohol based polymer.
4. The oral pharmaceutical composition according to claim 1, claim 2, or claim 3, wherein said core is an inert core or a compressed tablet core.
5. The oral pharmaceutical composition according to claim 4, wherein the inert core is an insoluble, swellable, or soluble core.
6. The oral pharmaceutical composition according to claim 4, wherein the compressed tablet core further comprises pharmaceutically acceptable excipients selected from the group comprising binders, fillers, disintegrants, plasticizers, extended-release polymers, lubricants, glidants, or mixtures thereof.
7. The oral pharmaceutical composition according to claim 1, claim 2, or claim 3, wherein said composition further comprises an additional antidiabetic agent.
8. The oral pharmaceutical composition according to claim 7, wherein said composition provides an immediate-release or an extended-release of the additional antidiabetic agent.
9. The oral pharmaceutical composition according to claim 7, wherein the additional antidiabetic agent is selected from the group comprising acarbose, miglitol, insulin, repaglinide, nateglinide, chlorpropamide, glibenclamide, gliclazide, glimepiride, glipizide, glyclopyramide, tolazamide, tolbutamide, buformin, metformin, phenformin,
rosiglitazone, pioglitazone, troglitazone, faraglitazar, englitazone, darglitazone, isaglitazone, reglitazar, rivoglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, sitagliptin, vildagliptin, linagliptin, dutogliptin, alogliptin, canagliflozin, dapagliflozin, remogliflozin, sergliflozin, and pharmaceutically acceptable salts or esters thereof.
10. The oral pharmaceutical composition according to claim 2 or claim 3, wherein the polymer that is not a polyvinyl alcohol based polymer is selected from the group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, polyvinyl pyrrolidone, polysaccharides, starch and its derivatives, gums, alginates, acrylic acid derivatives, polyethylene glycol, polyalkylene glycols, mannitol, sucrose, lactose, xylitol, and mixtures thereof.
11. The oral pharmaceutical composition according to claim 1, wherein said composition is prepared by a process which comprises the steps of:
(i) forming core tablets comprising excipients using direct compression;
(ii) optionally coating the core tablets of step (i) with a coating polymer to obtain seal-coated tablets; (iii) coating the tablets of step (i) or the seal-coated tablets of step (ii) with a layer comprising saxagliptin and a coating polymer to obtain drug-layered tablets; and
(iv) coating the drug-layered tablets of step (iii) with a coating polymer to form an outer layer.
12. The oral pharmaceutical composition according to claim 2, wherein said composition is prepared by a process which comprises the steps of:
(i) forming core tablets comprising excipients using direct compression;
(ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
(iii) coating the seal coated tablets of step (ii) with a layer comprising saxagliptin and a coating polymer to obtain drug-layered tablets;
(iv) coating the drug-layered tablets of step (iii) with a coating polymer to form an outer layer
wherein the polymer in any one of the layers (ii), (iii), or (iv) is not a polyvinyl alcohol based polymer.
13. The oral pharmaceutical composition according to claim 3, wherein said composition is prepared by a process which comprises the steps of:
(i) forming core tablets comprising excipients using direct compression;
(ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
(iii) coating the seal-coated tablets of step (ii) with a layer comprising saxagliptin and a coating polymer to obtain drug-layered tablets; and
(iv) coating the drug-layered tablets of step (iii) with a coating polymer to form an outer layer
wherein the polymer in each of the layers (ii), (iii), and (iv) is not a polyvinyl alcohol based polymer.
14. The oral pharmaceutical composition according to claim 7, wherein said composition is prepared by a process which comprises the steps of: (i) forming core tablets comprising excipients and an additional antidiabetic agent other than saxagliptin using wet granulation;
(ii) optionally coating the core tablets of step (i) with a coating polymer to obtain seal-coated tablets;
(iii) coating the tablets of step (i) or the seal coated tablets of step (ii) with a layer comprising saxagliptin and a coating polymer to obtain drug-layered tablets; and
(iv) coating the drug -layered tablets of step (iii) with a coating polymer to form an outer layer.
15. The oral pharmaceutical composition according to claim 7, wherein said composition is prepared by a process which comprises the steps of:
(i) forming core tablets comprising excipients and an additional antidiabetic agent other than saxagliptin using wet granulation;
(ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
(iii) coating the seal-coated tablets of step (ii) with a layer comprising saxagliptin and a coating polymer to obtain drug-layered tablets; and
(iv) coating the drug -layered tablets with a coating polymer to form an outer layer wherein the polymer in any one of the layers (ii), (iii), or (iv) is not a polyvinyl alcohol based polymer.
16. The oral pharmaceutical composition according to claim 7, wherein said composition is prepared by a process which comprises the steps of:
(i) forming core tablets comprising excipients and an additional antidiabetic agent other than saxagliptin using direct compression;
(ii) coating the core tablets of step (i) with a coating polymer to obtain seal- coated tablets;
(iii) coating the seal-coated tablets of step (ii) with a layer comprising saxagliptin and a coating polymer to obtain drug-layered tablets; and
(iv) coating the drug-layered tablets of step (iii) with a coating polymer to form an outer layer
wherein the polymer in each of the layers (ii), (iii), and (iv) is not a polyvinyl alcohol based polymer.
17. The oral pharmaceutical composition according to claim 9, wherein said composition is prepared by a process which comprises the steps of:
(i) coating non-pareil seeds with a layer comprising metformin and a coating polymer to obtain metformin pellets;
(ii) coating the metformin pellets of step (i) with a layer comprising an extended- release polymer;
(iii) coating the extended-release metformin pellets of step (ii) with a coating polymer to obtain seal-coated pellets;
(iv) coating the seal-coated pellets of step (iii) with a layer comprising saxagliptin and a coating polymer to obtain saxagliptin coated pellets;
(v) coating the saxagliptin coated pellets of step (iv) with a coating polymer to form an outer coating layer over the pellets; and
(vi) filling the pellets of step (v) into hard gelatin capsules.
PCT/IB2014/066137 2013-11-18 2014-11-18 Oral compositions of saxagliptin Ceased WO2015071889A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105030719A (en) * 2015-08-20 2015-11-11 杭州成邦医药科技有限公司 Composition containing alogliptin and pioglitazone
CN105030724A (en) * 2015-08-20 2015-11-11 杭州成邦医药科技有限公司 Composition of anti-diabetic drugs
CN109010298A (en) * 2018-08-31 2018-12-18 迪沙药业集团有限公司 A kind of melbine glipizide compound and preparation method thereof
EP4023217A1 (en) * 2020-12-31 2022-07-06 Sanovel Ilac Sanayi ve Ticaret A.S. Pharmaceutical capsule compositions of alogliptine
JP2022141158A (en) * 2021-03-15 2022-09-29 株式会社パウレック Coated tablet

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US20100074950A1 (en) * 2008-03-14 2010-03-25 Nectid Inc. Anti-diabetic combinations
US7951400B2 (en) 2004-05-28 2011-05-31 Bristol-Myers Squibb Company Coated tablet formulation and method
WO2012031124A2 (en) * 2010-09-03 2012-03-08 Bristol-Myers Squibb Company Drug formulations using water soluble antioxidants
WO2013179307A2 (en) * 2012-05-29 2013-12-05 Mylan Laboratories Limited Stabilized pharmaceutical compositions of saxagliptin
WO2014096982A1 (en) * 2012-12-21 2014-06-26 Wockhardt Limited Stable pharmaceutical compositions of saxagliptin or salts thereof
WO2014122671A2 (en) * 2013-02-08 2014-08-14 Hetero Research Foundation Solid oral compositions of saxagliptin

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US7951400B2 (en) 2004-05-28 2011-05-31 Bristol-Myers Squibb Company Coated tablet formulation and method
US20100074950A1 (en) * 2008-03-14 2010-03-25 Nectid Inc. Anti-diabetic combinations
WO2012031124A2 (en) * 2010-09-03 2012-03-08 Bristol-Myers Squibb Company Drug formulations using water soluble antioxidants
WO2013179307A2 (en) * 2012-05-29 2013-12-05 Mylan Laboratories Limited Stabilized pharmaceutical compositions of saxagliptin
WO2014096982A1 (en) * 2012-12-21 2014-06-26 Wockhardt Limited Stable pharmaceutical compositions of saxagliptin or salts thereof
WO2014122671A2 (en) * 2013-02-08 2014-08-14 Hetero Research Foundation Solid oral compositions of saxagliptin

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105030719A (en) * 2015-08-20 2015-11-11 杭州成邦医药科技有限公司 Composition containing alogliptin and pioglitazone
CN105030724A (en) * 2015-08-20 2015-11-11 杭州成邦医药科技有限公司 Composition of anti-diabetic drugs
CN109010298A (en) * 2018-08-31 2018-12-18 迪沙药业集团有限公司 A kind of melbine glipizide compound and preparation method thereof
EP4023217A1 (en) * 2020-12-31 2022-07-06 Sanovel Ilac Sanayi ve Ticaret A.S. Pharmaceutical capsule compositions of alogliptine
JP2022141158A (en) * 2021-03-15 2022-09-29 株式会社パウレック Coated tablet

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