WO2014118721A1 - Formes dosifiées solides orales pharmaceutiques comprenant du valsartan et du nébivolol - Google Patents

Formes dosifiées solides orales pharmaceutiques comprenant du valsartan et du nébivolol Download PDF

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Publication number
WO2014118721A1
WO2014118721A1 PCT/IB2014/058650 IB2014058650W WO2014118721A1 WO 2014118721 A1 WO2014118721 A1 WO 2014118721A1 IB 2014058650 W IB2014058650 W IB 2014058650W WO 2014118721 A1 WO2014118721 A1 WO 2014118721A1
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WO
WIPO (PCT)
Prior art keywords
nebivolol
valsartan
solid dosage
oral solid
dosage form
Prior art date
Application number
PCT/IB2014/058650
Other languages
English (en)
Inventor
Radhanath Mandal
Mona Dhaliwal
Mukesh Kumar Garg
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
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2014118721A1 publication Critical patent/WO2014118721A1/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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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

Definitions

  • the present invention relates to pharmaceutical oral solid dosage forms comprising valsartan and nebivolol as active ingredients in a fixed-dose combination.
  • the invention is further related to methods of preparing such pharmaceutical oral solid dosage forms.
  • Valsartan is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the ATi receptor subtype. It is chemically described as N-(l-oxopentyl)-N-[[2'- ( lH-tetrazol-5 -yl) [1, 1 '-biphenyl] -4-yl]methyl] -L-valine . Valsartan was first disclosed in U.S. Patent No. 5,399,578.
  • Nebivolol is an orally active selective beta-blocker acting on the ⁇ -l receptor subtype. It is chemically described as (lRS,l 'RS)-l,l '-[(2RS,2'SR)bis(6-fluoro-3,4-dihydro-2H-l- benzopyran-2-yl)]-2,2'-iminodiethanol hydrochloride, and is a racemate composed of d- Nebivolol and /-Nebivolol with the stereochemical designations of [SRRR] -nebivolol and [RSSS] -nebivolol, respectively. Nebivolol was first disclosed in U.S. Patent No. 4,654,362.
  • U.S. Patent No. 7,838,552 discloses fixed-dose combinations of valsartan and nebivolol for the treatment of hypertension. This patent does not disclose working examples of any formulation comprising valsartan and nebivolol, or any other beta blocker.
  • the inventors have successfully developed such a pharmaceutical oral solid dosage form comprising valsartan and nebivolol.
  • the present invention provides a pharmaceutical oral solid dosage form which comprises valsartan, nebivolol, and other pharmaceutically acceptable excipients in a fixed-dose combination wherein valsartan and nebivolol are present in separate components.
  • one component is the core and the other component surrounds the core.
  • the components may be formulated as separate layers within a single oral solid dosage form, for example, a bilayered tablet.
  • the components may be formulated as a bilayered tablet wherein one layer of the bilayered tablet comprises valsartan and the other layer comprises nebivolol.
  • the first layer and the second layer of the bilayered tablet are in a side by side arrangement such that the dissolution of valsartan and nebivolol occur independently of each other.
  • the pharmaceutically acceptable excipients include diluents, disintegrants, lubricants, and film-forming agents.
  • the present invention provides a process for the preparation of a pharmaceutical oral solid dosage form which comprises valsartan and nebivolol as active ingredients, and other pharmaceutically acceptable excipients in a fixed-dose combination wherein the process comprises the steps of:
  • the core component comprises valsartan, and nebivolol is coated over the core component.
  • the core component comprises nebivolol, and valsartan is coated over the core component.
  • the solid dosage form is a bilayered tablet wherein one layer comprises valsartan and the other layer comprises nebivolol.
  • Figure 1 depicts a side-by-side configuration of a bilayered tablet that may be used for the tablet containing a nebivolol layer and a valsartan layer.
  • Figure 2 depicts an arrangement in which valsartan is present as a core surrounded by a coating of nebivolol.
  • Figure 3 depicts an arrangement in which nebivolol is present as a core surrounded by a coating of valsartan.
  • Figure 4 depicts a single layered tablet in which an admixture of valsartan and nebivolol is present.
  • oral solid dosage form includes tablets, mini-tablets, capsules, caplets, granules, beads, pellets, multiparticulates, spheroids, or combinations thereof. If the solid dosage form is a tablet, the tablet can be of any suitable shape such as round, spherical, or oval. The tablet may have a monolithic or a multilayered structure.
  • the term "component”, as used herein, means that the portions comprising valsartan or nebivolol are distinct so that valsartan and nebivolol are separate from each other.
  • the component may be a core or a layer over the core.
  • the core component may contain nebivolol, and valsartan may be coated over the nebivolol core component.
  • the core component may contain valsartan, and nebivolol may be coated over the valsartan core component.
  • the components may also be present as layers such as in the case of a layered tablet, e.g., a bilayered tablet.
  • pharmaceutically acceptable excipients includes diluents, binders, disintegrants, wetting agents, lubricants, and film-forming agents.
  • diluents include, but are not limited to, calcium phosphate- dibasic, calcium carbonate, lactose, glucose, microcrystalline cellulose, cellulose powdered, silicified microcrystalline cellulose, calcium silicate, starch, starch pregelatinized, and polyols such as mannitol, sorbitol, xylitol, maltitol, and sucrose.
  • binders include, but not are limited to, starch, pregelatinized starch, carboxymethyl cellulose, sodium cellulose, microcrystalline cellulose, hydroxyproyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crospovidone, and combinations thereof.
  • disintegrants include, but are not limited to, crosslinked cellulose, crosslinked-polyvinylpyrrolidone (crosspovidone), sodium starch glycolate, polyvinylpyrrolidone (polyvidone, povidone), sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose sodium), hydroxypropyl cellulose, hydroxypropyl methylcellulose, xanthan gum, alginic acid, and soy polysaccharides.
  • wetting agents include, but are not limited to, polysorbate, sodium lauryl sulphate, and glyceryl stearate.
  • lubricants include, but are not limited to, sodium lauryl sulfate, talc, magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, and zinc stearate.
  • Suitable glidants include colloidal silicon dioxide and talc.
  • These solid dosage forms may be further coated with one or more functional and/or non-functional coating layers comprising film-forming polymers with or without coating additives.
  • film-forming agents include cellulose derivatives such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose,
  • commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Kollicoat ® Protect and Opadry ® may also be used as film- forming polymers.
  • solvents used for the granulation or for preparing a coating solution include, but are not limited to, methylene chloride, isopropyl alcohol, acetone, propylene glycol, methanol, ethanol, chloroform, ether, water, and combinations thereof.
  • fixed-dose combination includes specific dosage strengths for valsartan and nebivolol in the pharmaceutical oral solid dosage form which include but are not limited to: (1) 5 milligrams of nebivolol and 80 milligrams of valsartan;
  • Valsartan, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide were sifted together through a BSS #18 sieve.
  • step 1 and step 2 were blended in a blender for 15 minutes.
  • step 4 The material of step 3 was compressed into a compact. 5. The compact of step 4 was milled to obtain desired granules.
  • Nebivolol hydrochloride, pregelatinized starch, microcrystalline cellulose, colloidal silicon dioxide, talc, and one part of magnesium stearate were sifted through a BSS # 22 sieve.
  • step 1 The material of step 1 was compressed into a compact.
  • step 2 The compact of step 2 was milled to obtain desired granules.
  • a dispersion of Opadry ® was prepared in water by continuously stirring.
  • step 1 The dispersion of step 1 was sprayed over the bilayered tablets of part C.
  • Valsartan, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide were sifted together through a BSS # 18 sieve.
  • step 1 and step 2 were blended in a blender for 15 minutes.
  • step 3 The material of step 3 was compressed into a compact.
  • step 4 The compact of step 4 was milled to obtain desired granules.
  • Nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium were sifted through a BSS # 22 sieve.
  • step 3 The sifted blend of step 1 was loaded in the product container of a top spray fluidized bed granulator.
  • step 2 The solution of step 2 was sprayed on to the fluidized bed of step 3.
  • step 4 The granules of step 4 were dried.
  • Extra-granular ferric oxide red, colloidal silicon dioxide, croscarmellose sodium, and microcrystalline cellulose were sifted through a BSS # 18 sieve, added to the granules of step 5, and blended for 15 minutes.
  • a dispersion of Opadry ® was prepared in water by continuously stirring.
  • step 1 The dispersion of step 1 was sprayed over the bilayered tablets of step C.
  • Valsartan, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide were sifted together through a BSS # 18 sieve.
  • step 1 and step 2 were blended in a blender for 15 minutes.
  • step 3 The material of step 3 was compressed into a compact.
  • step 4 The compact of step 4 was milled to obtain desired granules.
  • Nebivolol Hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium were sifted through a BSS # 22 sieve.
  • step 3 The sifted blend of step 1 was loaded in the product container of a top spray fluidized bed granulator.
  • step 2 The dispersion of step 2 was sprayed on to the fluidized bed of step 3.
  • step 4 The granules of step 4 were dried.
  • Extra-granular ferric oxide red, colloidal silicon dioxide, croscarmellose sodium, and microcrystalline cellulose were sifted through a BSS # 18 sieve, added to the granules of step 5, and blended in a blender for 15 minutes.
  • Stear-O-WetTM was sifted through a BSS # 60 sieve and added to the blend of step 6.
  • a dispersion of Opadry ® was prepared in water by continuously stirring.
  • step 1 The dispersion of step 1 was sprayed over the bilayered tablets of part C.
  • Valsartan, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide were sifted together through a BSS # 18 sieve.
  • step 1 and step 2 were blended in a blender for 15 minutes.
  • step 3 The material of step 3 was compressed to prepare a compact.
  • step 4 The compact of step 4 was milled to obtain desired granules.
  • Nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium were sifted through a BSS # 22 sieve.
  • step 3 The sifted blend of step 1 was loaded in the product container of a top spray fluidized bed granulator.
  • step 2 The solution of step 2 was sprayed on to the fluidized bed of step 3.
  • step 4 The granules of step 4 were dried.
  • part A step 7
  • part B step 7
  • the final materials of part A (step7) and part B (step 7) were blended in a blender for 15 minutes.
  • a dispersion of Opadry ® was prepared in water by continuously stirring.
  • step 1 The dispersion of step 1 was sprayed over the tablets of part C.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des formes dosifiées solides orales pharmaceutiques, comprenant du valsartan et du nébivolol comme principes actifs dans une combinaison à dose fixe. L'invention concerne en outre des procédés de préparation de telles formes dosifiées solides orales pharmaceutiques.
PCT/IB2014/058650 2013-01-30 2014-01-30 Formes dosifiées solides orales pharmaceutiques comprenant du valsartan et du nébivolol WO2014118721A1 (fr)

Applications Claiming Priority (2)

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IN263DE2013 2013-01-30
IN263/DEL/2013 2013-01-30

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WO2014118721A1 true WO2014118721A1 (fr) 2014-08-07

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4654362A (en) 1983-12-05 1987-03-31 Janssen Pharmaceutica, N.V. Derivatives of 2,2'-iminobisethanol
US5399578A (en) 1990-02-19 1995-03-21 Ciba-Geigy Corp Acyl compounds
US7838552B2 (en) 2004-06-04 2010-11-23 Forest Laboratories Holdings Limited Compositions comprising nebivolol
WO2014031161A1 (fr) * 2012-08-22 2014-02-27 Forest Laboratories Holdings Limited Compositions chimiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4654362A (en) 1983-12-05 1987-03-31 Janssen Pharmaceutica, N.V. Derivatives of 2,2'-iminobisethanol
US5399578A (en) 1990-02-19 1995-03-21 Ciba-Geigy Corp Acyl compounds
US7838552B2 (en) 2004-06-04 2010-11-23 Forest Laboratories Holdings Limited Compositions comprising nebivolol
WO2014031161A1 (fr) * 2012-08-22 2014-02-27 Forest Laboratories Holdings Limited Compositions chimiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHAUDHARY ANKIT ET AL: "Estimation of Valsartan and Nebivolol in pharmaceutical dosage forms by absorption ratio method", INT. J. RES. PHARM. SCI, vol. 1, 14 January 2010 (2010-01-14), pages 108 - 112, XP055114260 *

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