WO2014184742A1 - Pharmaceutical compositions containing a biguanide and a low dose antidiabetic agent - Google Patents

Pharmaceutical compositions containing a biguanide and a low dose antidiabetic agent Download PDF

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Publication number
WO2014184742A1
WO2014184742A1 PCT/IB2014/061410 IB2014061410W WO2014184742A1 WO 2014184742 A1 WO2014184742 A1 WO 2014184742A1 IB 2014061410 W IB2014061410 W IB 2014061410W WO 2014184742 A1 WO2014184742 A1 WO 2014184742A1
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WO
WIPO (PCT)
Prior art keywords
biguanide
coat
antidiabetic agent
pharmaceutical composition
core
Prior art date
Application number
PCT/IB2014/061410
Other languages
English (en)
Inventor
Sandeep Kumar VATS
Balaram Mondal
Kalaiselvan Ramaraju
Romi Barat Singh
Ajay Kumar Singla
Original Assignee
Ranbaxy Laboratories Limited
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
Priority claimed from US13/892,540 external-priority patent/US20130251795A1/en
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2014184742A1 publication Critical patent/WO2014184742A1/fr

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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
    • A61K9/2072—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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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 relates to pharmaceutical compositions that include a combination of a biguanide present in an extended-release form and a low dose antidiabetic agent present in an immediate-release form.
  • the present invention further relates to processes for preparing such compositions.
  • Type I diabetes or insulin-dependent diabetes
  • Type II diabetes or non-insulin-dependent diabetes (NIDDM)
  • NIDDM non-insulin-dependent diabetes
  • Insulin resistance is a major susceptibility trait of NIDDM and is also a contributing factor in arteriosclerosis, hypertension, lipid disorders, and polycystic ovarian syndrome.
  • Biguanides have been the most widely used class of antidiabetics. They act by increasing insulin activity in peripheral tissues, reducing hepatic glucose output due to inhibition of gluconeogenesis, and reducing the absorption of glucose from the intestine. Metformin, phenformin, buformin, etc., belong to this group. Metformin has been widely prescribed for lowering blood glucose in patients with NIDDM and is marketed in 500 mg, 750 mg, 850 mg, and 1000 mg strengths. However, because it is a short acting drug, metformin requires twice-daily or three-times-daily dosing (500 mg to 850 mg tab, 2 to 3 times per day or 1000 mg tab, twice per day with meals).
  • Adverse events associated with metformin include anorexia, nausea, vomiting, and diarrhea.
  • the adverse events may be partially avoided by taking an extended-release dosage form rather than multiple daily doses. Besides reducing the adverse events, administering an extended-release dosage form provides a reduction in the frequency of administration.
  • to formulate a high dose biguanide like metformin HC1 1000 mg in an extended-release dosage form poses a challenge due to the large size of the dosage form. Further, the use of metformin therapy is limited by the decline in the duration of its efficacy. This problem can be solved by using a biguanide in combination with other antidiabetic agents.
  • a combination therapy of a biguanide and an additional antidiabetic agent would have greater efficacy (an additive and/or synergistic effect) as well as the possibility of reducing the adverse events as a result of using lower doses.
  • compositions comprising linagliptin and metformin.
  • U.S. Publication Nos. 2008/0076811 and 2011/0045062 and PCT Publication No. WO 2007/149797 disclose combinations and compositions comprising vildagliptin and metformin.
  • the present invention provides for a pharmaceutical composition that includes a biguanide in an extended-release form and a low dose antidiabetic agent in an immediate -release form.
  • a biguanide core which includes a therapeutically effective amount of a biguanide or pharmaceutically effective salts thereof, and one or more pharmaceutically acceptable excipients;
  • a low dose antidiabetic agent coat which includes a therapeutically effective amount of a low dose antidiabetic agent or pharmaceutically effective salts thereof, and one or more pharmaceutically acceptable excipients;
  • the composition may be in the form of tablets or capsules.
  • the capsules may include one or more of aggregated particles, pellets, mini tablets, tablets, beads, or granules.
  • the biguanide may be layered onto a pharmaceutically inert core or seed.
  • the inert core or seed may be hydrosoluble or hydroinsoluble.
  • the biguanide core of the present invention may include one or more pharmaceutically acceptable excipients selected from one or more of fillers, binders, disintegrants, anti-adherents, lubricants, glidants, osmogents, coloring agents, and flavoring agents.
  • the biguanide core may additionally contain one or more absorption enhancers and/or one or more swe liable polymers.
  • the seal coat may be applied over the biguanide core or over the extended-release coat.
  • the rate-controlling materials used in the composition include hydrophilic polymers, hydrophobic polymers, water-swellable polymers, other hydrophobic materials, or mixtures thereof.
  • the biguanide used in the composition is selected from the group comprising metformin, phenformin, or buformin, and their pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, and isomers, or mixtures thereof.
  • the biguanide is metformin or its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, or isomers, or mixtures thereof.
  • the low dose antidiabetic agent used in the composition is selected from the group comprising DPP -IV inhibitors such as sitagliptin, linagliptin, vildagliptin, saxagliptin, alogliptin, or dutogliptin; meglitinides such as mitiglinide, repaglinide, or nateglinide; second generation sulphonylureas such as glibenclamide, glipizide, gliclazide, or glimiperide; glucagon-like peptide (GLP-1) analogues such as exenatide; other hypoglycaemics which are used as an adjunct to metformin therapy; or mixtures thereof.
  • DPP -IV inhibitors such as sitagliptin, linagliptin, vildagliptin, saxagliptin, alogliptin, or dutogliptin
  • the low dose antidiabetic agent is a DPP -IV inhibitor or its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, and isomers, or mixtures thereof. More particularly, the low dose antidiabetic agent is linagliptin.
  • the biguanide core may include a mixture of biguanide and a low dose antidiabetic agent, or the low dose antidiabetic agent coat may include a mixture of a low dose antidiabetic agent and biguanide, or both the biguanide core and the low dose antidiabetic agent coat may include a mixture of a biguanide and a low dose antidiabetic agent.
  • the pharmaceutical composition of the present invention may further include an additional antidiabetic agent.
  • the present invention relates to a pharmaceutical composition of a biguanide and a low dose antidiabetic agent that includes:
  • biguanide or pharmaceutically effective salts thereof, and one or more pharmaceutically acceptable excipients are biguanide or pharmaceutically effective salts thereof, and one or more pharmaceutically acceptable excipients;
  • an immediate -release drug coat which includes a biguanide and a low dose antidiabetic agent or pharmaceutically effective salts thereof, and one or more pharmaceutically acceptable excipients;
  • the present invention provides for a process for preparing a pharmaceutical composition.
  • the process includes the steps of:
  • step (ii) optionally coating the cores of step (i) with a seal coat
  • the present invention provides for a method for treating diabetes by administering to a person in need thereof a pharmaceutical composition of a biguanide and a low dose antidiabetic agent.
  • the composition includes:
  • biguanide or pharmaceutically effective salts thereof, and one or more pharmaceutically acceptable excipients are biguanide or pharmaceutically effective salts thereof, and one or more pharmaceutically acceptable excipients;
  • a low dose antidiabetic agent coat which includes a therapeutically effective amount of a low dose antidiabetic agent or pharmaceutically effective salts thereof, and one or more pharmaceutically acceptable excipients;
  • biguanide or pharmaceutically effective salts thereof, and one or more pharmaceutically acceptable excipients;
  • the biguanide used in the composition is selected from the group comprising metformin, phenformin, or buformin and their pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, and isomers, or mixtures thereof.
  • the biguanide may be metformin or its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, or isomers, or mixtures thereof.
  • the amount of the biguanide in the present composition may range from about 25 mg to about 2,000 mg.
  • the extended-release biguanide core may be present as aggregated particles, pellets, mini tablets, tablets, beads, or granules.
  • the biguanide may be layered onto a pharmaceutically inert core or seed.
  • the inert core or seed may be hydrosoluble or hydroinsoluble.
  • microcrystalline cellulose e.g., PROSOLV®
  • cellulose derivatives e.g., powdered cellulose, or mixtures thereof.
  • the biguanide core of the present invention includes one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are known to those skilled in the art and are selected from one or more of fillers, diluents, binders, disintegrants, anti-adherents, lubricants, glidants, osmogents, coloring agents, and flavoring agents.
  • binders include povidones, starches, corn starch, pregelatinized starch, microcrystalline celluloses (MCC), silicified MCC (e.g., PROSOLV ® HD 90), microfine celluloses, lactose, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, stearic acid, gums, hydroxypropyl methylcelluloses or hypromelloses (e.g., Klucel ® EF or Methocel ® E5 Premium), or mixtures thereof.
  • MCC microcrystalline celluloses
  • silicified MCC e.g., PROSOLV ® HD 90
  • microfine celluloses lactose, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, d
  • disintegrants examples include starch, croscarmellose sodium, crospovidone, sodium starch glycolate, or mixtures thereof.
  • anti -adherents examples include magnesium stearate, talc, calcium stearate, glyceryl behenate, polyethylene glycols, hydrogenated vegetable oil, mineral oil, stearic acid, and combinations thereof.
  • osmogents include sodium or potassium chloride; sodium or potassium hydrogen phosphate; sodium or potassium dihydrogen phosphate; salts of organic acids such as sodium or potassium acetate, magnesium succinate, sodium benzoate, sodium citrate or sodium ascorbate; carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, or raffinose; water-soluble amino acids such as glycine, leucine, alanine, or methionine; urea, and the like; a polymer consisting of acrylic acid lightly cross-linked with
  • polyallylsucrose or mixtures thereof.
  • the active ingredient for example a biguanide, may itself act as an osmogent and facilitate the drug release.
  • solvents used for preparing the biguanide core include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water, or mixtures thereof.
  • Eudragit® L or Eudragit® S methacrylic acid-acrylic acid ethyl ester copolymer (e.g., Eudragit® L 100- 55), methacrylic acid esters neutral copolymer (e.g., Eudragit® NE 30 D),
  • the extended-release coat composition may additionally include plasticizers selected from propylene glycol, triethylene glycol, oleic acid, ethyleneglycol monoleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, dibutyl sebacate, acetyl triethyl citrate, acetyl tributyl citrate, castor oil, or mixtures thereof. It may also include opacifiers selected from titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof.
  • hydroxypropylcellulose hydroxypropyl isopropyl cellulose, methoxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropylpentylcellulose,
  • the extended-release biguanide core is coated with an immediate -release drug layer.
  • the immediate-release drug layer comprises a therapeutically effective amount of a low dose antidiabetic agent and optionally a biguanide.
  • the low dose antidiabetic agents used in the composition include, but are not limited to, thiazolidinediones such as troglitazone, rosiglitazone, or pioglitazone;
  • the present invention also encompasses a composition comprising an extended- release biguanide layer and an immediate-release drug layer comprising a biguanide and a low dose antidiabetic agent.
  • the biguanide used in the core and the coat may be the same or different.
  • the ratio of biguanide in the core to that in the coat ranges from about 99: 1 to about 60:40.
  • polyoxyethylene alkyl ethers fatty acids; glycerol fatty acid monoesters; glycerol fatty acid diesters; acetylated glycerol fatty acid monoesters; acetylated glycerol fatty acid diesters; lower alcohol fatty acid esters; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of monoglycerides; lactic acid derivatives of diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers;
  • plasticizers include propylene glycol, triethylene glycol, oleic acid, ethylene glycol monoleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, dibutyl sebacate, acetyl triethyl citrate, acetyl tributyl citrate, castor oil, or mixtures thereof.
  • the immediate-release drug layer may further include one or more film-forming polymers.
  • the film-forming polymers may be hydrophilic polymers.
  • the pharmaceutical composition may optionally be coated with one or more layers of a film coat comprising film-forming agents and/or pharmaceutically acceptable excipients.
  • Metformin hydrochloride and microcrystalline cellulose were mixed uniformly and granulated with a polyvinylpyrrolidone solution in water.
  • step 2 The granules of step 1 were dried in a fluidized bed dryer, and the dried
  • step 2 was compressed into core tablets.
  • Ethyl cellulose, hydroxypropyl methylcellulose, and talc were dispersed in an isopropyl alcohol:water mixture.
  • hydroxypropyl methylcellulose was added to it, followed by polysorbate-80 and pioglitazone hydrochloride.
  • step 7 The ER coated tablets of step 5 were coated with the dispersion of step 6 in a pan coater.
  • Lactose monohydrate, hydroxypropyl cellulose, and sodium lauryl sulphate were dissolved in water/non-aqueous solvent.
  • step 2 The granules of step 1 were dried in a fluidized bed dryer and lubricated with magnesium stearate.
  • step 2 was compressed into core tablets.
  • step 3 The tablets of step 3 were coated with the dispersion of step 4.
  • Metformin hydrochloride and sodium lauryl sulphate were mixed uniformly and granulated with a polyvinylpyrrolidone solution in purified water.
  • step 2 The granules of step 1 were dried in a fluidized bed dryer and lubricated with magnesium stearate.
  • step 2 was compressed into core tablets.
  • step 4 Hydroxypropyl methylcellulose was dispersed in isopropyl alcohol, followed by the addition of purified water. 5. The tablets of step 3 were coated with the dispersion of step 4.
  • Lactose monohydrate and hydroxypropyl cellulose were dissolved in purified water.
  • a film-coating solution was prepared by dispersing Opadry ® white in purified water.
  • polyvinylpyrrolidone were mixed uniformly and granulated with purified water.
  • step 2 The granules of step 1 were dried in a fluidized bed dryer and were mixed with hydroxypropyl methylcellulose and sodium lauryl sulphate, followed by lubrication with magnesium stearate.
  • step 2 was compressed into core tablets.
  • step 3 The tablets of step 3 were coated with a hydro-alcoholic solution of
  • step 8 was added to the solution of step 7.

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention relates to pharmaceutical compositions that include a combination of a biguanide present in an extended-release form and a low dose antidiabetic agent present in an immediate-release form. The present invention further relates to processes for preparing such compositions.
PCT/IB2014/061410 2013-05-13 2014-05-13 Pharmaceutical compositions containing a biguanide and a low dose antidiabetic agent WO2014184742A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13/892,540 2013-05-13
US13/892,540 US20130251795A1 (en) 2010-07-30 2013-05-13 Pharmaceutical compositions containing a biguanide and a low dose antidiabetic agent

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WO2014184742A1 true WO2014184742A1 (fr) 2014-11-20

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US20120093878A1 (en) * 2010-07-30 2012-04-19 Ranbaxy Laboratories Limited Pharmaceutical compositions containing a biguanide and a thiazolidinedione

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