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
  • 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
  • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • 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
  • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine

Definitions

• the present invention relates to a stable bilayer pharmaceutical tablet composition
• a stable bilayer pharmaceutical tablet composition comprising one layer of the angiotensin II receptor antagonist irbesartan having particle size d90 less than 30 microns and also granulating alone or at least one pharmaceutically acceptable excipients and the other layer of the calcium channel blocker amiodipine besilate.
• the present invention also provides a method of producing said bilayer tablet.
• Amiodipine is a calcium channel blocker developed for the treatment of hypertension and other medical indications as disclosed in USP 4,572,909 and USP 4,879,303. Its chemical name is 3-ethyl-5-methyl-(+-)-2-[(2-aminoethoxy) methyl]-4-(2- chlorophenyl)-1 ,4-dihydro- 6-methylpyridine-3,5-di-carboxylate.
• Amiodipine is marketed as the monobenzenesulfonate salt, amiodipine besilate under the trade name Norvasc® or Istin®. It is available as oral tablets in strengths of 2.5 mg, 5 mg and 10 mg.
• the inactive ingredients in the Norvasc® tablets include microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate and magnesium stearate.
• Amiodipine besilate is slightly soluble in water and has an absolute bioavailability of 64- 90%.
• Irbesartan is described in Bernhart et al., U.S. Patent No. 5,270,317, incorporated herein by reference.
• Irbesartan is a potent, long-acting angiotensin II receptor antagonist which is particularly useful in the treatment of cardiovascular ailments such as hypertension and heart failure.
• Its chemical name is2-n-butyl-4-spirocyclopentane- 1 -[(2'-(tetrazol-5- yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one.
• Irbesartan is marketed by under the trade name Aprovel® or Karvea®.
• Irbesartan is insoluble in water. Irbesartan has a parabolic pH solubility profile in aqueous medium with minimum solubility between pH 2.0 and pH 6.0 and maximum solubility in 0.1 N HCI and pH 7.5 phosphate buffer.
• WO2011001202 A1 discloses solid stable pharmaceutical fixed dose compositions comprising irbesartan, amiodipine besilate and pharmaceutically acceptable excipients, to their preparation and to their therapeutic application.
• Combination therapy is often required in patients with hypertension, and fixed-dose single- pill combinations have been shown to provide an easier regimen for patients, improving adherence.
• Irbesartan/amlodipine is an angiotensin-receptor blocker/calcium-channel blocker fixed- dose single-pill combination, whose constituent drugs exert additive effects when coadministered.
• the dissolution rate of poorly soluble drugs such as irbesartan is strongly related to the particle size distribution.
• the specific surface area increased with decreasing particle size of the drug, resulting in an increase in dissolution rate.
• a second active ingredient such as amlodipine besilate, which is also a fluffy material exhibiting poor flow and low aqueous solubility, can further contribute to problems such as tableting or uniformity of dosage units.
• amlodipine is highly hygroscopic and absorbs moisture, which leads to degradation.
• One of the major routes of degradation is via a catalytic oxidative process, which is pH dependent.
• One of the major degradation products known in the art is 3-ethyl-5-methyl-2- [(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5 dicarboxylate and called Impurity D.
• WO2003/051364 discloses Amlodipine besilate tablets with improved stability of the active ingredient and reduced in weight containing microcrystalline cellulose, a lubricant and a disintegrating agent and the process for the preparation of said tablets.
• WO2008/062435 discloses a stable solid dosage form of amlodipine besilate comprising polyols and having reduced levels of total impurities on stability and especially impurity D.
• WO2011001202 A1 from Sanofi Aventis discloses solid stable pharmaceutical fixed dose compositions comprising irbesartan, amlodipine besilate and pharmaceutically acceptable excipients, wherein irbesartan is physically separated from amlodipine besilate.
• WO2011001202 A1 from Sanofi Aventis discloses solid dosage form is particularly advantageous since amlodipine besilate does not undergo degradation and this combination product shows reduced and controlled impurities even lesser than with regards to individual reference products of same dose when subjected to stress studies and in finished pack.
• the dissolution profile of both irbesartan and amlodipine besilate is not compromised by comparison to the dissolution profile of each active ingredient alone.
• WO2011001202 A1 from Sanofi Aventis discloses irbesartan under the form of coated granules is embedded in an extragranular matrix comprising amlodipine besilate.
• the solid composition of the invention takes the form of a monolayer tablet, preferably film coated.
• the object of the present invention is based on the recognition, which is fixed dose a stable bilayer pharmaceutical tablet composition comprising one layer of irbesartan having particle size d90 less than 30 microns, preferably less than 5 microns and the other of layer amlodipine besilate having adequate drug stability, optimum drug release of both active ingredients and reliable manufacturing process.
• the bilayer pharmaceutical tablet composition characterized in that the level of impurities (w/w %) after 6 months at 40 ⁇ 2°C, 75 ⁇ 5 % RH in the total composition:
• the level of total impurities is less than 2.0% (w/w), preferably less than 1.0% (w/w), b) The level unknown impurities is less than 0.5% (w/w), preferably less than 0.1 %(w/w),
• the level of impurity A for Irbesartan is less than 0.2%(w/w)
• the level of impurity D for Amlodipine is less than 1.0% (w/w), preferably less than 0.5% (w/w).
• the dissolution performances of the bilayer tablet containing the combination of irbesartan and amlodipine besilate of the invention are similar to the dissolution performances of the tablets containing each active ingredient irbesartan or amlodipine alone.
• composition of the invention wherein Irbesartan and Amlodipine besilate are physically separated by both separate wet granulations.
• the solid composition of the invention takes the form of a bilayer tablet, preferably film coated.
• the irbesartan represents between about 40% and about 70% by weight of the total composition.
• amlodipine besilate represents between about 1% and about 10% by weight of the total composition.
• the pharmaceutically acceptable excipients are selected from the group consisting of diluent, disintegrant, antiadherent, binder, lubricant and mixture thereof.
• the amount of Irbesartan is comprised 150 mg or 300 mg of the total weight of the tablet.
• the amount of amlodipine besilate is comprised 6,94 mg or 13,87 mg (equivalent to 5 mg or 10 mg Amlodipine) of the total weight of the tablet.
• the invention is related to a process for the preparation of a stable oral pharmaceutical composition in a form of a bilayer tablet comprising irbesartan and amlodipine besilate, wherein the process comprises the steps of:
• amlodipine besilate iii. granulating amlodipine besilate and one or more pharmaceutically acceptable excipients, with aqueous solution containing a binder or with water to form granules.
• step ii. and iv lubricating the blend of step ii. and iv; optionally after a pre-lubricating step; and vi. compressing the bilayer tablet
• the two actives are present in a bilayer tablet form wherein irbesartan and amlodipine besilate is physically separated from each other.
• compositions suitable for use in the present invention with amlodipine besilate layer is selected from suitable diluents such as Microcrystalline cellulose, Calcium Hydrogen Phosphate, suitable disintegrants such as Crospovidone and suitable lubricants such as magnesium stearate, suitable binders such as povidone.
• suitable diluents such as Microcrystalline cellulose, Calcium Hydrogen Phosphate, suitable disintegrants such as Crospovidone and suitable lubricants such as magnesium stearate, suitable binders such as povidone.
• compositions suitable for use in the present invention with Irbesartan layer is selected from suitable diluents such as Microcrystalline cellulose, suitable disintegrant such as Croscarmellose sodium, suitable antiadherent such as silicone dioxide, suitable lubricants such as Magnesium Stearate, suitable binders such as hypromellose.
• suitable diluents such as Microcrystalline cellulose
• suitable disintegrant such as Croscarmellose sodium
• suitable antiadherent such as silicone dioxide
• suitable lubricants such as Magnesium Stearate
• suitable binders such as hypromellose.
• the reference composition of Amlodipine besilate layer is Norvasc® composition and reference composition of Irbesartan layer is Karvea® composition.
• the bilayer tablet according to the present invention generally contains 150 to 300 mg, of irbesartan and 5 to 10 mg of amlodipine.
• Presently preferred forms are bilayer tablets comprising 300 mg/10 mg, 300 mg/5 mg and 150 mg/5 mg of irbesartan and amlodipine, respectively.
• Irbesartan layer generally comprises 40 to 80 wt.%, preferably 70 to 80 wt.%, of active ingredient; 5 to 20 wt.%, preferably 10 to 20 wt.%, of diluent; 1 to 10 wt. %, preferably 2 to 8 wt.%, of disintegrant, 1 to 5 wt. %, preferably 2 to 4 wt.%, of binder, 0.25 to 5 wt.% , preferably 0.5 to 1 wt.% of antiadherent 0.5 to 1.5 wt. %, preferably 1 wt.%, of lubricant.
• Amlodipine layer generally comprises 5 to 20 wt.%, preferably 5 to 12 wt.%, of active ingredient; 25 to 90 wt.%, preferably 50 to 85 wt.%, of diluent; 1 to 15 wt. %, preferably 1 to 10 wt.%, of disintegrant, 1 to 5 wt. %, preferably 2 to 4 wt.%, of binder, 0.5 to 1.5 wt. %, preferably 1 wt.%, of lubricant.
• the present invention relates to an improvement in bilayer tableting technology and provides a method of producing a bilayer pharmaceutical tablet comprising the steps of; granulating irbesartan alone or at least one pharmaceutically acceptable excipients, with water, to form granules, drying the granules; and granulating amlodipine besilate and one or more pharmaceutically acceptable excipients, with aqueous solution containing a binder, to form granules, drying the granules; lubricating step, then compressing the bilayer tablet, coating the core bilayer tablets.
• the dissolution profiles of the products of the invention are compared to the dissolution profiles of the references products.
• the present invention has a dissolution performance such that 85% or grater of the irbesartan and 85% or grater of the amlodipine contained in the bilayer tablet composition dissolves within 15 minutes, wherein the dissolution performance is measured using USP apparatus 2 placing the bilayer tablet in 900 mL of 0.1 N HCI at 37 ⁇ 0.5°C with a paddle speed of 75 rpm.
• the oral pharmaceutical compositions of the present invention were subjected to accelerated stability studies at the following conditions; 40 ⁇ 2°C, 75 ⁇ 5 % relative humidity RH. These were evaluated on the basis of assay, in vitro dissolution, moisture content and related substances measured between initial and 6-months time points for irbesartan as well as amlodipine besilate. This test is carried on under the following conditions.
• the tablets were packed in to the Opaque duplex (PVC/PVdC) blister pack and such blister were further packed in to the cartons, and cartons were charged on to the stability as per ICH guidelines, and samples were taken out at each stability stage interval and submitted for analysis.
• PVC/PVdC Opaque duplex
• the bilayer pharmaceutical tablet composition has less than 2.0% and more preferably less that 1.0% (w/w) of total impurities in the total composition, less than 0.5% and more preferably less that 0.1 %(w/w) of unknown impurities in the total composition, less than 0.2%(w/w) of impurity A for Irbesartan and less than 1.0% more preferably less that 0.5% (w/w) of impurity D for Amlodipine is found in the composition of the invention after 6 months at 40 ⁇ 2°C, 75 ⁇ 5 % RH.
• Impurity-A from Irbesartan, Impurity-D from Amlodipine, Unknown Impurities and Total Impurities are calculated in %w/w of the total composition

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2015
  • 2015-01-12 EP EP15705399.2A patent/EP3244880A1/de not_active Withdrawn
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