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Patentes

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Número de publicaciónUS20030031705 A1
Tipo de publicaciónSolicitud
Número de solicitudUS 10/189,009
Fecha de publicación13 Feb 2003
Fecha de presentación5 Jul 2002
Fecha de prioridad19 Sep 1997
También publicado comoCA2214895A1, CA2214895C, EP0904781A2, EP0904781A3, US6444225
Número de publicación10189009, 189009, US 2003/0031705 A1, US 2003/031705 A1, US 20030031705 A1, US 20030031705A1, US 2003031705 A1, US 2003031705A1, US-A1-20030031705, US-A1-2003031705, US2003/0031705A1, US2003/031705A1, US20030031705 A1, US20030031705A1, US2003031705 A1, US2003031705A1
InventoresBernard Sherman
Cesionario originalSherman Bernard Charles
Exportar citaBiBTeX, EndNote, RefMan
Enlaces externos: USPTO, Cesión de USPTO, Espacenet
Pharmaceutical composition comprising fenofibrate
US 20030031705 A1
Resumen
The bioavailability of fenofibrate is improved by making a solid dispersion of a disentegrant in the fenofibrate. Method of making said solid dispersion comprising melting the fenofibrate, blending the disintegrant into the melt, and resolidifying the mixture.
Imágenes(11)
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Reclamaciones(4)
What is claimed is:
1. A solid pharmaceutical composition comprising a solid dispersion of a disintegrant in fenofibrate.
2. A composition as in claim 1 wherein the disintegrant is selected from croscarmellose sodium, sodium starch glycolate and crospovidone.
3. A process of making a composition as in either of claims 1 or 2, which comprises the steps of melting the fenofibrate, blending the disintegrant into the molten fenofibrate, and solidifying the mixture.
4. A process as in claim 3 which further comprises the steps of grinding the resulting solid into granules and further processing the granules into capsules or tablets.
Descripción
    FIELD OF INVENTION
  • [0001]
    The present invention relates to pharmaceutical compositions for oral administration comprising fenofibrate which enable improve dissolution and bioavailability.
  • BACKGROUND
  • [0002]
    Fenofibrate is practically insoluble in water. This causes fenofibrate to exhibit a low rate of dissolution in aqueous media (including gastrointestinal fluids), which results in inadequate bioavailability (absorption into systemic circulation) after oral ingestion.
  • [0003]
    In order to make a composition comprising fenofibrate that will enable maximum bioavailability, it is necessary to incorporate into the composition a feature that increases the rate of dissolution of the drug to enable it to dissolve in the gastrointestinal fluids.
  • [0004]
    Several ways of increasing the rate of dissolution of drugs having low solubility in water are known in the prior art.
  • [0005]
    One approach is micronization. In this approach, the drug is milled to fine particles, typically having a mean diameter of only a few microns. A second approach is to include a surfactant in the composition.
  • [0006]
    For the drug fenofibrate, neither micronization alone nor use of a surfactant alone enables maximum bioavailability. U.S. Pat. No. 4,895,726 discloses that the rate of dissolution and the bioavailability of fenofibrate can be maximized by comicronization of fenofibrate. In this process the fenofibrate is first mixed with the surfactant and then the mixture is micronized.
  • [0007]
    A composition made according to the invention of U.S. Pat. No. 4,895,726 is sold in Canada as elsewhere under the tradename Lipidil Micro. The need for microcomposition and use of a surfactant adds to the cost of capsules containing fenofibrate.
  • [0008]
    In view of the limitations of the prior art, it is an object of the present invention to enable maximum bioavailability of fenofibrate without the need for micronization and without the need for use of a surfactant.
  • DESCRIPTION OF THE INVENTION
  • [0009]
    It has been found the rate of dissolution and the bioavailability of fenofibrate can be substantially improved by making a solid dispersion of a disintegrant in the fenofibrate. The solid dispersion can be made by heating and melting the fenofibrate, blending the disintegrant into the molten fenofibrate and then cooling and solidifying the mixture.
  • [0010]
    Fenofibrate has a melting point of about 80° C. and can be melted without decomposition.
  • [0011]
    A disintegrant will be understood to be a substance which is hydrophilic and swells upon absorption of water. Disintegrants are used as excipients (inactive ingredients) in pharmaceutical tablets and capsules so that, when a tablet or capsule is ingested, the disintegrant will cause the tablet or capsule to absorb gastrointestinal fluid and, as a result, to swell and disintegrate, so as to release the active drug for dissolution and absorption
  • [0012]
    The most commonly used disintegrant is starch.
  • [0013]
    Disintegrants with very high capacity to absorb water and swell are known as “super-disintegrants”, which include such substances as croscarmellose sodium, sodium starch glycolate and crospovidone.
  • [0014]
    As aforesaid, a solid dispersion comprising a disintegrant dispersed in the fenofibrate can be made by melting the fenofibrate blending the disintegrant into the molten fenofibrate and then cooling and solidifying the mixture The solid can then be ground into granules for further processing into tablets or capsules.
  • [0015]
    Because of the very intimate mixing achieved by mixing the disintegrant into the fenofibrate in the molten state, it follows that each granule or particle of the ground-up solid dispersion will be an approximately uniform mixture of fenofibrate and disintegrant.
  • [0016]
    The solid dispersion is thus intrinsically different from a mixture achieved simply by physical mixing of fenofibrate in solid form and disintegrant, because in a physical mix each particle remains either pure fenofibrate or pure disintegrant.
  • [0017]
    It will be understood that in the process of making a solid dispersion, within the scope of the present invention, ingredients other than the fenofibrate and disintegrant may be included in the molten blend and thus incorporated into the solid dispersion. Such other ingredients may include, for example, water-soluble or water-insoluble ingredients which serve as surfactant, diluent, or for other purposes.
  • [0018]
    Alternatively, other ingredients may be mixed with the granules of solid dispersion, and the mix so achieved may be further processed into tablets or capsules.
  • [0019]
    The invention will be further illustrated by the following example, which is intended to be illustrative but not limiting of the scope of the invention.
  • EXAMPLE 1
  • [0020]
    4800 g of fenofibrate was placed in a stainless steel pot, which was slowly heated until the fenofibrate was melted. 1200 g of croscamellose sodium was then blended into the molten fenofibrate, and the mix was then poured into trays and allowed to cool and solidify to form a solid dispersion.
  • [0021]
    The solid was then removed from the trays and milled through a #10 screen to produce granules.
  • [0022]
    5 kilos of the resulting granules were then mixed with other ingredients as follows:
    solid dispersion granules  5.0 kilos
    lactose monohydrate 2.84 kilos
    stearic acid 0.14 kilos
    colloidal silicon dioxide 0.02 kilos
    8.00 kilos
  • [0023]
    This mixture was then filled into 2-piece hard gelatin capsules with a net fill weight of 400 mg per capsule. Each capsule thus contained 250 mg of the solid dispersion, which in turn comprised 200 mg of fenofibrate.
  • [0024]
    For these capsules, it was found that the dissolution rate and bioavailability was equivalent to that of commercially available Lipidil Micro capsules containing 200 mg of co-micronized fenofibrate and surfactant.
Citas de patentes
Patente citada Fecha de presentación Fecha de publicación Solicitante Título
US4879301 *26 Abr 19887 Nov 1989Hoei Pharmaceutical Co., Ltd.Antiallergic and antiinflammatory benzothiazolinone derivatives
US5545628 *10 Ene 199513 Ago 1996Galephar P.R. Inc.Pharmaceutical composition containing fenofibrate
US5667807 *23 May 199516 Sep 1997Bayer AktiengesellschaftThermal granulation process
US5776495 *27 Jun 19967 Jul 1998Laboratoires EffikProcess for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions
US5939099 *1 Feb 199617 Ago 1999Basf AktiengesellschaftSolid active extrusion compound preparations containing low-substituted hydroxypropylcellulose
US5945127 *9 Mar 199631 Ago 1999Basf AktiengesellschaftStorage-stable drug form
US6018033 *13 May 199725 Ene 2000Purdue Research FoundationHydrophilic, hydrophobic, and thermoreversible saccharide gels and forms, and methods for producing same
Citada por
Patente citante Fecha de presentación Fecha de publicación Solicitante Título
US792762723 May 200719 Abr 2011Elan Pharma International, Ltd.Nanoparticulate fibrate formulations
US793191723 May 200726 Abr 2011Elan Pharma International, Ltd.Nanoparticulate fibrate formulations
US20030224058 *21 Feb 20034 Dic 2003Elan Pharma International, Ltd.Nanoparticulate fibrate formulations
US20040058009 *27 Oct 200325 Mar 2004Elan Pharma International, Ltd.Nanoparticulate fibrate formulations
US20040087656 *27 Oct 20036 May 2004Elan Pharma International, Ltd.Nanoparticulate fibrate formulations
US20050276974 *23 May 200315 Dic 2005Elan Pharma Internationl, Ltd.Nanoparticulate fibrate formulations
US20070264348 *26 Feb 200715 Nov 2007Elan Pharma International, Ltd.Nanoparticulate fibrate formulations
US20070298115 *23 May 200727 Dic 2007Elan Pharma International, Ltd.Nanoparticulate fibrate formulations
US20080095851 *23 May 200724 Abr 2008Elan Pharma International, Ltd.Nanoparticulate fibrate formulations
US20080138424 *31 Oct 200712 Jun 2008Elan Pharma Internationa, Ltd.Nanoparticulate fibrate formulations
US20080241070 *28 Mar 20082 Oct 2008Elan Pharma International Ltd.Fenofibrate dosage forms
US20090012184 *9 Feb 20068 Ene 2009Abbott Gmbh & Co. KgProduction of Dosage Forms Comprising a Solid Dispersion of a Microcrystalline Agent
Clasificaciones
Clasificación de EE.UU.424/452, 424/465
Clasificación internacionalA61K9/14, A61K31/215, A61K9/20, A61K31/216
Clasificación cooperativaA61K31/216, A61K9/2054
Clasificación europeaA61K9/20H6F2, A61K31/216