WO2013142314A1 - Formulation de comprimé oral constituée de rosuvastatine à libération immédiate et de metformine à libération prolongée - Google Patents

Formulation de comprimé oral constituée de rosuvastatine à libération immédiate et de metformine à libération prolongée Download PDF

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Publication number
WO2013142314A1
WO2013142314A1 PCT/US2013/031986 US2013031986W WO2013142314A1 WO 2013142314 A1 WO2013142314 A1 WO 2013142314A1 US 2013031986 W US2013031986 W US 2013031986W WO 2013142314 A1 WO2013142314 A1 WO 2013142314A1
Authority
WO
WIPO (PCT)
Prior art keywords
metformin
rosuvastatin
layer
solid dosage
weight
Prior art date
Application number
PCT/US2013/031986
Other languages
English (en)
Inventor
Marie Charmaine DIAS
Original Assignee
Althera Life Sciences, Llc
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 Althera Life Sciences, Llc filed Critical Althera Life Sciences, Llc
Priority to MX2014011167A priority Critical patent/MX2014011167A/es
Priority to EP13765204.6A priority patent/EP2844067A4/fr
Publication of WO2013142314A1 publication Critical patent/WO2013142314A1/fr
Priority to US14/250,610 priority patent/US20140212488A1/en
Priority to US16/795,650 priority patent/US20200222401A1/en

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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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention is directed to solid dosage product and formulation containing a fixed combination of rosuvastatin and metformin such that rosuvastatin is delivered immediately to the patient and metformin is delivered in a controlled fashion over a longer course of time, also described as extended release, as well as to methods of5 making such solid dosage forms and method of treating patients with fixed combination solid dosage forms of immediate release rosuvastatin and extended release metformin.
  • LDL-C Low Density Lipoprotein
  • HDL-C High Density Lipoprotein
  • Apolipoprotein Apolipoprotein
  • ADA American Diabetes Association
  • NCEP National Cholesterol Education Program
  • ESC European joint Task force of European Society of Cardiology
  • EASD European Association for the Study of Diabetes
  • the present invention is an orally consumed fixed combination product that consists of immediate release rosuvastatin and extended release metformin, that is, metformin delivered to patient over an extended period of time that is indicated for simultaneous treatment of type 2 diabetes and hyperlipidemia or reduction in
  • This novel product delivers simultaneous treatment of diabetes and hyperlipidemia overcoming a significant dosing difference between the two individual ingredients and delivers a novel product that reduces low density cholesterol (LDL), potentially cardiovascular risk, and glucose levels in diabetes patients by simultaneously treating hyperglycemia and hyperlipidemia.
  • LDL low density cholesterol
  • the present invention is a novel formulation that consists of immediate release rosuvastatin and extended release metformin such that both rosuvastatin and extended release metformin in one tablet are expected to have same Area Under Curve as two active ingredients taken together individually orally, and pharmaceutically acceptable additives suitable for the preparation.
  • the rosuvastatin is in the form of rosuvastatin calcium and the pharmaceutically acceptable additives are selected from the diluents, disintegrants, glidants, lubricants, colorants and combinations thereof.
  • the present invention overcomes the significant formulation challenge of timing two different release timings of two different drugs.
  • the solid dosage form is a bi-layer tablet.
  • the amount of rosuvastatin employed in such bi-layer tablets preferably ranges from 5mg to 40mg, including lOmg and 20mg.
  • the amount of metformin ranges from 250mg to 2000mg, including 500mg, 750mg, 850mg, lOOOmg, 1250mg and 1500mg.
  • the present invention is directed to a method of making a solid dosage bi-layer form of rosuvastatin to be released in immediate form and metformin to be released in extended release.
  • First stage is to develop the metformin extended release layer with the following steps: (a) Mix the intragranular ingredients in granulator, and granulate the above blend with binding agent; (b) Dry the granules partially, pass through mill and dry the sized granules until optimum LOD obtained; (c) Pass the dried granules through mill and sift the sized granules, and blend the granules; and (d) Lubricate the above granules with magnesium stearate.
  • a rosuvastatin layer blend is created by blending the excipients with rosuvastatin in a blender, and lubricating the ingredients with lubricants such as magnesium stearate.
  • the above blends are compressed in bi-layer tablets with carefully controlled compression pressure. Finally the bi-layer tablets are film-coated.
  • this invention is directed to solid dosage forms of rosuvastatin and metformin made according to the method of the third aspect.
  • the fifth aspect of this invention is directed to a method of treating hyperlipidemia, cardiovascular diseases, simultaneously with type 2 diabetes comprising administering a solid dosage form of rosuvastatin and metformin to a patient in need of such a treatment.
  • the solid dosage form is orally administered to the subject.
  • Rosuvastatin when administered to 10 healthy human volunteers depicts time, and Y-axis depicts % concentration of Metformin or rosuvastatin absorbed relative to maximum concentration over varying time points from 0 to 96 hours.
  • Figure 2 Comparision of release pattern and concentration of Metformin in 10 healthy human volunteers between INVENTION and GLUCOPHAGE.
  • Figure 3 Comparision of release pattern and concentration or Rosuvastatin in 10 healthy human volunteers between INVENTION AND CRESTOR.
  • the present invention is directed to solid dosage product and formulation containing a fixed combination of rosuvastatin and metformin such that rosuvastatin is delivered immediately to the patient and metformin is delivered in a controlled fashion over a longer course of time, also described as extended release, as well as to methods of making such solid dosage forms and method of treating patients with fixed combination solid dosage forms of immediate release rosuvastatin and extended release metformin.
  • the first embodiment of the invention is a fixed combination product that delivers metformin in an extended form and rosuvastatin in an immediate form to the patient.
  • LDL-C Low Density Lipoproteins
  • HDL-C High Density Lipoprotein
  • Apolipoprotein Apolipoprotein
  • ADA American Diabetes Association
  • NCEP National Cholesterol Education Program
  • ESC European joint Task force of European Society of Cardiology
  • EASD European Association for the Study of Diabetes
  • Metformin and rosuvastatin are respectively well known treatments for diabetes and hyperlipidemia respectively.
  • Rosuvastatin is indicated to be consumed or dosed once daily.
  • metformin is indicated for consumption at multiple points of time ranging as every 6-8 hours during the day.
  • this invention created a novel product where the product delivers rosuvastatin immediately when consumed by the patient, whereas metformin is released in a controlled fashion over a longer period of time thereby meeting the multiple dosing requirements of metformin.
  • This invention hence creates a novel product that treats both diabetes and hyperlipidemia with a single oral dosage to be consumed by patients once daily.
  • the second embodiment of this invention is a novel formulation that consists of immediate release rosuvastatin and extended release metformin such that both rosuvastatin and extended release metformin in one tablet are expected to have same Area Under Curve as two active ingredients taken together individually orally, and pharmaceutically acceptable additives suitable for the preparation.
  • the rosuvastatin is in the form of rosuvastatin calcium and the pharmaceutically acceptable additives are selected from the diluents, disintegrants, glidants, lubricants, colorants and combinations thereof.
  • the present invention overcomes the significant formulation challenge of timing two different release timings of two different drugs.
  • the solid dosage form is a bi-layer tablet.
  • the amount of rosuvastatin employed in such bi-layer tablets preferably ranges from 5mg to 40mg, including lOmg and 20mg.
  • the amount of metformin ranges from 250mg to 2000mg, including 500mg, 750mg, 850mg, lOOOmg, 1250mg and 1500mg.
  • the rosuvastatin layer of the formulation consists rosuvastatin as the active ingredient, with excipients such as starch 1-5% of the weight of the rosuvastatin layer, dicalcium phosphate 0.5-5% of the weight of the rosuvastatin layer, Cellulose 20-90% of the weight of the rosuvastatin layer, Crospovidone 2-30% of the weight of the rosuvastatin layer, and lubricants such as sodium stearyl fumarate 0.1-2% of the weight of the rosuvastatin layer.
  • excipients such as starch 1-5% of the weight of the rosuvastatin layer, dicalcium phosphate 0.5-5% of the weight of the rosuvastatin layer, Cellulose 20-90% of the weight of the rosuvastatin layer, Crospovidone 2-30% of the weight of the rosuvastatin layer, and lubricants such as sodium stearyl fumarate 0.1-2% of the weight of the rosu
  • the metformin granules are created by combining metformin with cellulose 0.5-5% of the weight of the metformin layer, a polymer 5-50% of the weight of the metformin layer, and water and organically soluble cellulose such as hydroxypropyl cellulose 0.5-5% of the weight of the metformin layer. These granules are further packed in the polymer to the weight of 5-30% of the weight of the metformin layer along with a lubricant such as magnesium stearate 0.2-5% of the weight of the metformin layer.
  • a lubricant such as magnesium stearate 0.2-5% of the weight of the metformin layer.
  • a third embodiment of the present invention is directed to a method of making a solid dosage bi-layer form of rosuvastatin to be released in immediate form and metformin to be released in extended release.
  • First stage is to develop the metformin extended release layer with the following steps: (a) Mix the intragranular ingredients in granulator, and granulate the above blend with binding agent; (b) Dry the granules partially, pass through mill and dry the sized granules until optimum LOD obtained; (c) Pass the dried granules through mill and sift the sized granules, and blend the granules; and (d) Lubricate the above granules with magnesium stearate.
  • a rosuvastatin layer blend is created by blending the excipients with rosuvastatin in a blender, and lubricating the ingredients with lubricants such as magnesium stearate.
  • the above blends are compressed in bi-layer tablets with carefully controlled compression pressure.
  • the bi-layer tablets are film-coated.
  • a key element of this embodiment of this invention is the compression pressure at which this particular bi-layer tablet is compressed to form the tablet. Given the desire for one ingredient of the tablet to be immediate release and another ingredient of the tablet to be extended release, at the same time they may be manufactured and compressed at the same time created significant challenges.
  • EXAMPLE 1 fixed combination tablet of rosuvastatin 20mg and metformin 750mg
  • First stage developed the metformin extended release layer with the following steps: (a) Mixed the intragranular ingredients in granulator, and granulated the above blend with binding agent; (b) Dried the granules partially, passed through mill and dried the sized granules until optimum LOD obtained; (c) Passed the dried granules through mill and sift the sized granules, and blended the granules; and (d) Lubricated the above granules with magnesium stearate.
  • a rosuvastatin layer blend was created by blending the excipients with rosuvastatin in a blender, and lubricated the ingredients with lubricants such as magnesium stearate.
  • the above blends were compressed in bi-layer tablets with carefully controlled compression pressure. Finally the bi-layer tablets were film-coated.
  • EXAMPLE 2 fixed combination tablet of rosuvastatin lOmg and metformin 500mg
  • First stage developed the metformin extended release layer with the following steps: (a) Mixed the intragranular ingredients in granulator, and granulated the above blend with binding agent; (b) Dried the granules partially, passed through mill and dried the sized granules until optimum LOD obtained; (c) Passed the dried granules through mill and sift the sized granules, and blended the granules; and (d) Lubricated the above granules with magnesium stearate.
  • a rosuvastatin layer blend was created by blending the excipients with rosuvastatin in a blender, and lubricated the ingredients with lubricants such as magnesium stearate.
  • the above blends were compressed in bi-layer tablets with carefully controlled compression pressure. Finally the bi-layer tablets were film-coated.
  • Dissolution is a well established method to test pharmacoequivalence of two products.
  • the pharmacoequivalence of the fixed-combination dosage forms of the present invention was compared with that of the corresponding free-combinations.
  • the invention is able to create a stable formulation that has similar drug release profiles for rosuvastatin and metformin such that metformin is released in an extended release fashion and rosuvastatin is released in an immediate release fashion.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Obesity (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un produit pharmaceutique solide et une formulation contenant une combinaison fixe de rosuvastatine et de metformine de telle sorte que la rosuvastatine est administrée immédiatement au patient et la metformine est administrée de façon contrôlée sur une période de temps plus longue, également décrite comme libération prolongée, ainsi que des procédés de fabrication de telles formes pharmaceutiques solides et un procédé de traitement de patients avec une combinaison fixe de formes pharmaceutiques solides de rosuvastatine à libération immédiate et de metformine à libération prolongée.
PCT/US2013/031986 2012-03-19 2013-03-15 Formulation de comprimé oral constituée de rosuvastatine à libération immédiate et de metformine à libération prolongée WO2013142314A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
MX2014011167A MX2014011167A (es) 2012-03-19 2013-03-15 Formulacion de tableta oral solida de rosuvastatina de liberacion inmediata y metformina de liberacion prolongada.
EP13765204.6A EP2844067A4 (fr) 2012-03-19 2013-03-15 Formulation de comprimé oral constituée de rosuvastatine à libération immédiate et de metformine à libération prolongée
US14/250,610 US20140212488A1 (en) 2012-05-01 2014-04-11 Oral tablet formulation consisting of immediate release rosuvastatin and extended release metformin
US16/795,650 US20200222401A1 (en) 2012-03-19 2020-02-20 Oral Tablet Formulation Consisting of Immediate Release Rosuvastatin and Extended Release Metformin

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201261612563P 2012-03-19 2012-03-19
US61/612,563 2012-03-19
US201261640971P 2012-05-01 2012-05-01
US61/640,971 2012-05-01

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14/250,610 Continuation-In-Part US20140212488A1 (en) 2012-03-19 2014-04-11 Oral tablet formulation consisting of immediate release rosuvastatin and extended release metformin

Publications (1)

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WO2013142314A1 true WO2013142314A1 (fr) 2013-09-26

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EP (1) EP2844067A4 (fr)
MX (1) MX2014011167A (fr)
WO (1) WO2013142314A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060024365A1 (en) * 2002-08-05 2006-02-02 Navin Vaya Novel dosage form
US20060240095A1 (en) * 2003-08-22 2006-10-26 Jean-Louis Junien Pharmaceutical composition comprising a combination of metformin and a statin
US20080187581A1 (en) * 2005-03-16 2008-08-07 Subhash Pandurang Gore Delivery System For Mulitple Drugs
US20100143465A1 (en) * 2007-03-14 2010-06-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030171407A1 (en) * 2002-03-07 2003-09-11 Upsher-Smith Laboratories, Inc. Composition for reducing blood glucose and cholesterol
JP5827952B2 (ja) * 2009-10-09 2015-12-02 ユンジン・ファーム・カンパニー・リミテッドＹｕｎｇｊｉｎ Ｐｈａｒｍ． Ｃｏ． Ｌｔｄ． 速効性と持続性を同時に有する薬剤学的組成物
JP5662475B2 (ja) * 2009-12-30 2015-01-28 ビーシーワールド ファーム． カンパニー リミテッド メトホルミン及びロスバスチンを含む医薬組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060024365A1 (en) * 2002-08-05 2006-02-02 Navin Vaya Novel dosage form
US20060240095A1 (en) * 2003-08-22 2006-10-26 Jean-Louis Junien Pharmaceutical composition comprising a combination of metformin and a statin
US20080187581A1 (en) * 2005-03-16 2008-08-07 Subhash Pandurang Gore Delivery System For Mulitple Drugs
US20100143465A1 (en) * 2007-03-14 2010-06-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2844067A4 *

Also Published As

Publication number Publication date
MX2014011167A (es) 2014-11-14
EP2844067A1 (fr) 2015-03-11
EP2844067A4 (fr) 2015-11-25

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