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WO2006010995A1 - Compositions de divalproex de sodium a liberation controlee - Google Patents

Compositions de divalproex de sodium a liberation controlee Download PDF

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Publication number
WO2006010995A1
WO2006010995A1 PCT/IB2004/002568 IB2004002568W WO2006010995A1 WO 2006010995 A1 WO2006010995 A1 WO 2006010995A1 IB 2004002568 W IB2004002568 W IB 2004002568W WO 2006010995 A1 WO2006010995 A1 WO 2006010995A1
Authority
WO
WIPO (PCT)
Prior art keywords
controlled release
divalproex sodium
dosage form
tablet dosage
release composition
Prior art date
Application number
PCT/IB2004/002568
Other languages
English (en)
Inventor
Gour Mukherji
Abhay Mahajan
Original Assignee
Wockhardt 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 Wockhardt Limited filed Critical Wockhardt Limited
Priority to PCT/IB2004/002568 priority Critical patent/WO2006010995A1/fr
Priority to PCT/IB2004/004126 priority patent/WO2006011001A2/fr
Publication of WO2006010995A1 publication Critical patent/WO2006010995A1/fr

Links

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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to a controlled release formulation of divalproex sodium, for once a day administration.
  • the controlled release dosage form demonstrates improved pharmacokinetic profile by minimizing the variance between peak and trough plasma levels of the valproate salt, thus resulting in a reduction in the incidence of side effects.
  • the invention significantly advances the existing art related to the controlled release formulations of divalproex sodium.
  • Divalproex sodium is effective as an anti-epileptic agent used in the treatment of epilepsy, migraine and bipolar disorders. Though the exact three dimensional molecular structure of Divalproex is uncertain, it dissociates to the valproate ion, which itself is a known antiepileptic entity, within the gastrointestinal tract. Valproate is absorbed and produces the desired therapeutic effect. Divalproex sodium is described in more detail in US Patent Nos. 4,988,731 and 5,212,326.
  • Divalproex sodium was first introduced as a delayed release formulation, which may be administered twice a day.
  • This dosage form comprises an enteric coat to minimize gastric irritation.
  • the enteric coat dissolves resulting in faster release of the drug.
  • US Patent No. 4,913,906 to Friedman, et al. discloses a controlled release dosage form of valproic acid, its amide, or one of its salts or esters in combination with polymers and physiologically acceptable additives.
  • the preferred additives are derivatives of cellulose such as carboxymethyl cellulose, ethylcellulose, methylcellulose, hydroxy propyl cellulose, polyvinyl alcohol, polyacrylamide, ethylene vinyl acetate copolymer, polyacrylate, polyurethane, polyvinylpyrrolidone, polymethylmethacrylate, polyvinyl acetate, polyhydroxyethyl methacrylate, and waxes such as paraffin.
  • Sustained release formulations of valpromide were prepared with native proteins, such as soy protein, collagen, gelatin, ovalbumin, milk albumin, casein, etc. Tablets are formulated by applying a pressure of 1000 to 5000 kg/cm2 under controlled atmospheric conditions.
  • US Patent No. 5,009,897 to Blinker, et al. discloses granules having sufficient hardness, suitable for pressing into tablets.
  • the granule comprises a core of divalproex sodium and a coating of a mixture of a polymer and microcrystalline cellulose.
  • Preferred polymer is selected from povidone, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • the polymer material functions as a binder and carrier for the microcrystalline cellulose, while the microcrystalline cellulose itself imparts the excellent compressibility properties to the granules.
  • US Patent No. 5,019,398 to Daste discloses a sustained-release tablet of divalproex sodium in a matrix of hydroxypropyl methylcellulose and hydrated silica. It has been shown that the standard lubricants such as talc or magnesium stearate do not prevent sticking on compression whereas 8 to 10 weight percent of hydrated silica, preferably mixed with 1 to 2 weight percent of colloidal silica, per 100 mg of complex suffice to form a compressible mixture giving a non-friable tablet.
  • the standard lubricants such as talc or magnesium stearate
  • hydrophilic matrix tablet suitable for once a day administration of Divalproex sodium comprising from about 40- 80%w/w of active, 20 - 50% w/w of a hydrophilic polymer, 5 - 15%w/w lactose, 4- 6%w/w microcrystalline cellulose and l-5%w/w silicon dioxide.
  • US Patent No. 6,511,678 to Abbott Laboratories claims a controlled release tablet formulation releasing not more than about 30% valproate after 3 hours, 40 to about 70% after 9 hours, 55 to about 95% after 12 hours and not less than 85% after 18 hours, when measured in a type 2 dissolution apparatus, at 100 rpm, at a temperature of 37+0.5° C, in 500 ml of 0.1N HCl for 45 minutes, followed by 900 ml of 0.05M phosphate buffer containing 75 mM sodium lauryl sulfate, pH 5.5, for the remainder of the testing period.
  • US Patent No. 6,511,678 to Abbott Laboratories claims a controlled release tablet formulation releasing not more than about 30% valproate after 3 hours, 40 to about 70% after 9 hours, 55 to about 95% after 12 hours and not less than 85% after 18 hours, when measured in a type 2 dissolution apparatus, at 100 rpm, at a temperature of 37+0.5° C, in 500 ml of 0.1N HCl for
  • the hydrophilic matrix comprises 10-90% w/w of the drug, 7- 65% w/w of hydroxy propyl methyl cellulose, 0.5-18%w/w of lactose and 0.5-5%w/w of colloidal silicon dioxide. They have also claimed an extended release composition of divalproex sodium with at least one extended release polymer manufactured under controlled atmospheric conditions of 27°C to 35°C and a relative humidity of less than about 40%.
  • the Ranbaxy composition did not make any major changes in the hydrophilic polymer, both qualitatively and quantitatively in comparison to the Abbott '090 patent, but differed in the use of other excipients, like diluents and in controlling the atmospheric conditions.
  • the present invention relates to a controlled release tablet composition for once daily administration of a valproate salt.
  • the composition comprises of divalproex sodium (30 - 50% w/w) as the active valproate salt, and a hydrophilic matrix-forming polymer system (less than 20% w/w) comprising preferably one or more cellulose polymers, and a water insoluble diluent (20 - 50% w/w).
  • the said composition delivers the dose of divalproex sodium in a controlled manner such that when evaluated for "in-vitro" dissolution with an identical strength of a reference tablet formulation Depakote ER tablets, the test product shows a comparable dissolution profile.
  • Divalproex sodium is a freely soluble drug substance in water.
  • the controlled release tablet for once daily administration requires significant control of drug release so that the therapeutic benefit is extended satisfactorily throughout the period of 24 hours.
  • Typical controlled formulations of Divalproex exhibit the variation between peak and trough plasma levels of valproate over a 24-hour dosing period.
  • the US 6,528,090 patent uses a hydrophilic polymer matrix of a cellulose derivative namely hydroxy propyl methyl - A - cellulose at a concentration of more than 20% w/w of the tablet, more preferably around
  • the granules may be prepared either by dry or wet granulation process using a uniform admixture of the drug with hydrophilic polymers and a water insoluble diluent.
  • the resulting granules are blended with required quantity of one or more lubricants and compressed into tablets.
  • Divalproex sodium is hygroscopic and has been known to cause sticking to die and punch surfaces during compression.
  • the tablet compression is carried out at a temperature of 15 - 27 0 C and relative humidity above 40% such that there is minimal or no sticking of the granule material to die and punch surfaces.
  • the PCT application No. WO 03/103635 requires presence of controlled atmospheric conditions of 27 to 35 0 C and a relative humidity of less than 40%, preferably less than 20%.
  • a new oral polymeric controlled release formulation suitable for once-a-day administration of valproate compounds, such as divalproex sodium, has been achieved.
  • This formulation exhibits significant advantages over the sustained release valproate formulations of the prior art.
  • This formulation minimizes the variation between peak and trough plasma levels of valproate over a 24- hour dosing period.
  • This formulation follows a zero-order release pattern thus producing essentially flat plasma levels of valproate, once steady-state levels have been achieved. This results in a significantly lower incidence of side effects for patients consuming such a formulation.
  • the inventors have surprisingly found that the matrix formed by low proportions of hydrophilic polymers of less than 20%w/w, with the inclusion of an insoluble diluent gives adequate control for the release of a highly soluble drug like divalproex sodium.
  • This formulation shows a drug release that is comparable to that obtained with a concentration of 30%w/w of hydrophilic polymer (Reference product).
  • Initial dissolutions with formulations manufactured only with less than 20% w/w hydrophilic polymer revealed a faster drug release profile compared to the reference product.
  • the similarity factor [(f 2)- factor] commonly used to compare in-vitro release was around 50 or even less.
  • composition includes all dosage forms administered by the oral route.
  • the product can be prepared by anyone skilled in the art and contains therapeutically effective amount of a valproate compound, together with other excipients as normally employed for forming such a dosage form.
  • the extended release composition as described includes a pharmaceutical polymer that can control drug release from the pharmaceutical composition.
  • Water soluble or water swellable polymers that can be included in this composition include polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, vinyl acetate copolymers, polyvinyl alcohol, polysaccharides and gums like xanthan gum, cross-linked polyethylene oxide, methacrylic acid copolymers, maleic anhydride / methyl vinyl ether copolymers and derivatives and mixtures thereof.
  • Water-insoluble polymers were selected from methacrylates, acrylic acid copolymers, acrylamides, polyethylenes, polyvinyl alcohol and celluloses like cellulose mono-, di- and tri-acylate, cellulose mono-, di-, and tri-acetate, ethyl cellulose, or cellulose acrylate.
  • the composition under discussion also includes pharmaceutically acceptable inert excipients, like, fillers, binders, lubricants, glidants, and colorants, among others.
  • compositions were selected from calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, cellulose, micro crystalline cellulose, dextrin, dextrose excipient, fructose, kaolin, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, among others.
  • the fillers preferred for inclusion were the water insoluble materials, like, dibasic calcium phosphate.
  • Suitable binders included polyvinylpyrrolidone, carboxyvinyl polymer, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dextrin, maltodextrin, gums like xanthan gum, tragacanth, acacia, and starch among others.
  • the preferred binders were polyvinyl pyrrolidone and xanthan gum.
  • Lubricants included calcium stearate, glyceryl behenate, magnesium stearate, light mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil (Type I) and zinc stearate.
  • Glidants were selected from calcium silicate, magnesium silicate, silicon dioxide and talc.
  • Controlled release tablets were prepared using the following materials in the stated quantities:
  • Divalproex sodium was screened initially through 40-mesh ASTM and mixed intimately with hydroxypropyl methylcellulose, microcrystalline cellulose and dibasic calcium phosphate. Slugs were obtained on compression machine. Slugs were passed through suitable sieves to get final granules less then 18 mesh ASTM screen. The homogeneous granules thus obtained were mixed with silica and magnesium stearate and then compressed using oval shaped punches of size 18.8mm x 9.7 mm.
  • Example 2 Example 2:
  • Controlled release tablets were prepared using the following materials in the stated quantities:
  • Controlled release tablets were prepared using the following materials in the stated quantities:
  • Controlled release tablets were prepared using the following materials in the stated quantities:
  • Controlled release tablets were prepared using the following materials in the stated quantities:
  • Controlled release tablets were prepared using the following materials in the stated quantities:
  • Divalproex sodium was first sifted through 40-mesh ASTNM screen and then mixed with hydroxypropyl methylcellulose and dibasic calcium phosphate in a suitable blender.
  • the solution of Xanthan gum in purified water was prepared separately, and was used for granulating the previously obtained powder mixture.
  • the resultant wet material was passed through 8mm ASTM mesh screen and then dried overnight in tray drier at 50° C to 55° C to obtain dried granules. These dried granules were then passed through 18mm mesh ASTM screen.
  • the homogeneous granulate thus obtained was mixed with the silica and then compressed using oval shape punches of size 18.8mm x 9.7 mm.
  • Controlled release tablets were prepared using the following materials in the stated quantities:
  • Divalproex sodium was first sifted through 40-mesh ASTM screen and then mixed with hydroxypropyl methylcellulose and dibasic calcium phosphate in a suitable blender.
  • the solution of Xanthan gum in purified water was prepared separately, and was used for granulating the previously obtained powder mixture.
  • the resultant wet material was passed through 8mm ASTM mesh screen and then dried overnight in tray drier at 50° C to 55° C to obtain dried granules. These dried granules were then passed through 18mm mesh ASTM screen.
  • the homogeneous granulate thus obtained was mixed with the talc, compitrol and silica and then compressed using oval shape punches of size 18.8mm x 9.7 mm.
  • Example 8 Aqueous coating was carried out on core tablets. Dissolution was carried out in 900 ml of pH 6.8 phosphate buffer at 100 rpm using USP type II apparatus with sinkers. Comparative profiles for Depakote ER 500 mg Tablets and tablets as per example (7) has been shown in Figure 6.
  • Example 8 Aqueous coating was carried out on core tablets. Dissolution was carried out in 900 ml of pH 6.8 phosphate buffer at 100 rpm using USP type II apparatus with sinkers. Comparative profiles for Depakote ER 500 mg Tablets and tablets as per example (7) has been shown in Figure 6. Example 8:
  • Controlled release tablets were prepared using the following materials in the stated quantities:
  • Divalproex sodium was first sifted through 40-mesh ASTM screen and then mixed with hydroxypropyl methylcellulose and dibasic calcium phosphate in a suitable blender.
  • the solution of Xanthan gum in purified water was prepared separately, and was used for granulating the previously obtained powder mixture.
  • the resultant wet material was passed through 8mm ASTM mesh screen and then dried overnight in tray drier at 50° C to 55° C to obtain dried granules. These dried granules were then passed through 18mm mesh ASTM screen.
  • the homogeneous granulate thus obtained was mixed with the talc, compitrol and silica and then compressed using oval shape punches of size 16.0 mm x 8.0 mm.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
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  • Engineering & Computer Science (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur un comprimé à matrice hydrophile convenant à l'administration quotidienne de composés valproate tels que le divalproex de sodium. Le comprimé de l'invention comprend entre environ 30 pour cent en poids et environ 60 pour cent en poids d'un ingrédient actif choisi dans le groupe composé de l'acide valproïque, d'un sel ou d'un ester pharmaceutiquement acceptable de l'acide valproïque, de divalproex de sodium et de valpromide, d'entre environ 6 pour cent en poids et environ 16 pour cent en poids d'un polymère pharmaceutiquement acceptable, de préférence d'une méthylcellulose d'hydroxypropyle, et d'entre environ 20 pour cent en poids et environ 50 pour cent en poids d'une charge, tous les pourcentages en poids étant basés sur le poids total de la forme posologique du comprimé. D'autres aspects de l'invention se rapportent à l'utilisation de ladite formulation dans le traitement de l'épilepsie et à des procédés de fabrication de la forme posologique précitée.
PCT/IB2004/002568 2004-07-23 2004-07-23 Compositions de divalproex de sodium a liberation controlee WO2006010995A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IB2004/002568 WO2006010995A1 (fr) 2004-07-23 2004-07-23 Compositions de divalproex de sodium a liberation controlee
PCT/IB2004/004126 WO2006011001A2 (fr) 2004-07-23 2004-12-13 Compositions de divalproex de sodium a liberation controlee

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2004/002568 WO2006010995A1 (fr) 2004-07-23 2004-07-23 Compositions de divalproex de sodium a liberation controlee

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WO2006010995A1 true WO2006010995A1 (fr) 2006-02-02

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PCT/IB2004/004126 WO2006011001A2 (fr) 2004-07-23 2004-12-13 Compositions de divalproex de sodium a liberation controlee

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103191432A (zh) * 2013-04-27 2013-07-10 中国药科大学 一种水溶性药物骨架缓释片及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4913906A (en) * 1985-02-28 1990-04-03 Michael Friedman Novel controlled release dosage form of valproic acid
US5019398A (en) * 1989-02-27 1991-05-28 Sanofi Pharmaceutical composition providing the sustained-release of valproic acid
US5212326A (en) * 1979-08-20 1993-05-18 Abbott Laboratories Sodium hydrogen divalproate oligomer

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6511678B2 (en) * 1998-12-18 2003-01-28 Abbott Laboratories Controlled release formulation of divalproex sodium

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5212326A (en) * 1979-08-20 1993-05-18 Abbott Laboratories Sodium hydrogen divalproate oligomer
US4913906A (en) * 1985-02-28 1990-04-03 Michael Friedman Novel controlled release dosage form of valproic acid
US4913906B1 (en) * 1985-02-28 2000-06-06 Yissum Res Dev Co Controlled release dosage form of valproic acid
US5019398A (en) * 1989-02-27 1991-05-28 Sanofi Pharmaceutical composition providing the sustained-release of valproic acid

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103191432A (zh) * 2013-04-27 2013-07-10 中国药科大学 一种水溶性药物骨架缓释片及其制备方法

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WO2006011001A2 (fr) 2006-02-02
WO2006011001A3 (fr) 2006-05-18

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