EP1183017A1 - Formulations comprenant des agents regulateurs des lipides - Google Patents

Formulations comprenant des agents regulateurs des lipides

Info

Publication number
EP1183017A1
EP1183017A1 EP00937680A EP00937680A EP1183017A1 EP 1183017 A1 EP1183017 A1 EP 1183017A1 EP 00937680 A EP00937680 A EP 00937680A EP 00937680 A EP00937680 A EP 00937680A EP 1183017 A1 EP1183017 A1 EP 1183017A1
Authority
EP
European Patent Office
Prior art keywords
composition
lipid
excipient
fenofibrate
regulating agent
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00937680A
Other languages
German (de)
English (en)
Inventor
Devalina Law
Steven L. Krill
Eric A. Schmitt
James J. Fort
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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 Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1183017A1 publication Critical patent/EP1183017A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present invention relates to novel formulations comprising lipid-regulating agents.
  • 2- [4- (4-chlorobenzoyl) phenoxy] -2 -methyl-propanoic acid, 1-methylethylester, also known as fenofibrate, is representative of a broad class of compounds having pharmaceutical utility as lipid regulating agents. More specifically, this compound is part of a lipid-regulating agent class of compounds commonly known as fibrates, and is disclosed in U.S. Patent No. 4,058,552.
  • Fenofibrate has been prepared in several different formulations, c.f., U.S. Patent No. 4,800,079 and U.S. Patent No. 4,895,726.
  • U.S. Patent No. 4,895,726 discloses a co-micronized formulation of fenofibrate and a solid surfactant .
  • U.S. Patent No. 4,961,890 discloses a process for preparing a controlled release formulation containing fenofibrate in an intermediate layer in the form of crystalline microparticles included within pores of an inert matrix.
  • the formulation is prepared by a process involving the sequential steps of dampening said inert core with a solution based on said binder, then projecting said fenofibrate microparticles in a single layer onto said dampened core, and thereafter drying, before said solution based on said binder dissolves said fenofibrate microparticles, and repeating said three steps in sequence until said intermediate layer is formed.
  • EP0793958A2 discloses a process for producing a fenofibrate solid dosage form utilizing fenofibrate, a surface active agent and polyvinyl pyrrolidone in which the fenofibrate particles are mixed with a polyvinyl pyrrolidone solution. The thus obtained mixture is granulated with an aqueous solution of one or more surface active agents, and the granules thus produced are dried.
  • PCT Publication No. WO 82/01649 discloses a fenofibrate formulation having granules that are comprised of a neutral core that is a mixture of saccharose and starch.
  • the neutral core is covered with a first layer of fenofibrate, admixed with an excipient and with a second microporous outer layer of an edible polymer.
  • U.S. Patent No. 5,645,856 describes the use of a carrier for hydrophobic drugs, including fenofibrate, and pharmaceutical compositions based thereon.
  • the carrier comprises a digestible oil and a pharmaceutically-acceptable surfactant component for dispersing the oil in vivo upon administration of the carrier, which comprises a hydrophilic surfactant, said surfactant component being such as not to substantially inhibit the in vivo lipolysis of the digestible oil.
  • Gemfibrozil is another member of the fibrate class of lipid-regulating agents.
  • U.S. Patent No. 4,927,639 discloses a disintegratable formulation of gemfibrozil providing both immediate and sustained release, comprising a tablet compressed from a mixture of a first and second granulation, and a disintegration excipient operable to effect partial or complete disintegration in the stomach.
  • U.S. Patent 4,925,676 discloses a disintegratable gemfibrozil tablet providing both immediate and enteric release, which is compressed from a mixture of a first granulation of gemfibrozil with at least one acid- disintegratable binder, and a second granulation formed from the first granulation, but regranulated or coated with an alkali-disintegratable formulation of at least one substantially alkali-soluble and substantially acid- insoluble polymer.
  • statins Another class of lipid-regulating agents are commonly known as statins, of which pravastatin and atorvastatin are members.
  • U.S. Patents 5,030,447 and 5,180,589 describe stable pharmaceutical compositions, which when dispersed in water have a pH of at least 9, and include a medicament which is sensitive to a low pH environment, such as prevastatin, one or more fillers such as lactose and/or microcrystalline cellulose, one or more binders, such as microcrystalline cellulose (dry binder) or polyvinylpyrrolidone (wet binder) , one or more disintegrating agents such as croscarmellose sodium, one or more lubricants such as magnesium stearate and one or more basifying agents such as magnesium oxide.
  • prevastatin one or more fillers such as lactose and/or microcrystalline cellulose
  • binders such as microcrystalline cellulose (dry binder) or polyvinylpyrrolidone (wet binder)
  • the present invention is directed to a solid formulation comprising the mixture of a lipid-regulating agent and an excipient, such as polyethylene glycol, in which said agent and said excipient form a eutectic mixture.
  • an excipient such as polyethylene glycol
  • the size reduction obtained through the preparation of a dispersion is usually difficult to obtain.
  • a dispersion of crystalline lipid-regulating agent is prepared in the excipient such that said agent and said excipient form a eutectic mixture.
  • the resulting formulation results in an increase in drug solubility and oral bioavailability, and an improved dissolution rate.
  • the formulation may be administered directly, diluted into an appropriate vehicle for administration, encapsulated into hard gelatin shells or capsules or compressed into tablets for administration, or administered by other means obvious to those skilled in the art.
  • Figure 1 is a graph showing the plasma concentration in fed dogs of the formulation of Example 1 and a reference compound .
  • the bulk lipid-regulating agent may be prepared by any available method, as for example the compound fenofibrate may be prepared by the procedure disclosed in U.S. Patent No. 4,058,552, or the procedure disclosed in U.S. Patent No. 4,739,101, both herein incorporated by reference.
  • composition comprising the lipid-regulating agent and the excipient in a ratio such that the melting point of both the lipid regulating agent and the excipient is reduced to a single value lower than the melting point of either component is first determined.
  • This composition i.e. the composition at which the two components exhibit a single melting point, is called the eutectic mixture.
  • a composition of the lipid-regulating agent and the excipient ranging from about 0.5% (w/w) to about 10% higher than the eutectic mixture, is then heated to a sufficient temperature to obtain a clear solution. The solution is then cooled until a solid mass is formed.
  • these components at the above mentioned composition range may be dissolved in a suitable solvent to obtain a clear solution. In this latter case, it is necessary to remove the solvent to obtain the solid mass.
  • the solid mass may then be ground, sized and optionally formulated into an appropriate de1ivery system .
  • the delivery system of the present invention results in increased dissolution rate and bioavailability, and improved dissolution rate of the lipid-regulating agent.
  • eutectic mixture refers to a two phase crystalline system that has a melting point that is lower than that of either pure component of the mixture. The presence of a eutectic mixture can be determined by thermal analysis and powder x-ray diffractometry .
  • Suitable excipients include, for example, polyethylene glycol (PEG) , pentaeythritol, pentaeythritol tetraacetate, succinic acid, urea, polyoxyethylene stearates, and poly- ⁇ - caprolactone, or more preferably, PEG.
  • PEG polyethylene glycol
  • the suitable solvents include, for example, methanol-water, ethanol-water, or other water-miscible organic solvent in which the lipid-regulating agent and the polymers have appreciable solubility.
  • Suitable excipients include, for example, lactose, starch, magnesium stearate, or other pharmaceutically-acceptable fillers, diluents, lubricants, or disintegrants that might be needed to prepare a capsule or tablet .
  • Fenofibrate and PEG in a ratio of 15:85 was heated to about 85°C until a clear solution was obtained. The solution was then cooled over an ice bath resulting in the formation of a solid mass. The resulting dry solid mass was then ground and sized through a 60-100 mesh screen. 446.7 mg. of the granular formulation (containing 67 mg. fenofibrate) was filled into individual capsules.
  • statin and PEG Mixtures of a statin and PEG are prepared and the melting points of these mixtures are determined to locate the eutectic composition. Then the statin and PEG in a ratio that is preferably less than the eutectic composition or to about 10% higher than the eutectic composition is melted to obtain a clear solution, then the solution is cooled over ice bath to form a solid mass. This solid mass is ground and sifted between 60-100 mesh and filled into capsules to contain the appropriate desired dose.
  • the plasma concentrations of fenofibric acid were determined by HPLC. Concentrations were normalized to a 6.7 mg/kg dose in each dog.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (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)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation solide faite d'un mélange d'agent régulateur des lipides et d'un excipient, en l'occurrence un mélange eutectique.
EP00937680A 1999-05-28 2000-05-23 Formulations comprenant des agents regulateurs des lipides Withdrawn EP1183017A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US32318399A 1999-05-28 1999-05-28
US323183 1999-05-28
PCT/US2000/014109 WO2000072829A1 (fr) 1999-05-28 2000-05-23 Formulations comprenant des agents regulateurs des lipides

Publications (1)

Publication Number Publication Date
EP1183017A1 true EP1183017A1 (fr) 2002-03-06

Family

ID=23258077

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00937680A Withdrawn EP1183017A1 (fr) 1999-05-28 2000-05-23 Formulations comprenant des agents regulateurs des lipides

Country Status (5)

Country Link
EP (1) EP1183017A1 (fr)
JP (1) JP2003500439A (fr)
CA (1) CA2374117A1 (fr)
MX (1) MXPA01012225A (fr)
WO (1) WO2000072829A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7276249B2 (en) 2002-05-24 2007-10-02 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US8273794B2 (en) * 2004-05-14 2012-09-25 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
GB2441499B (en) * 2006-09-08 2011-09-14 Jasin El Sammadoni Slimming Spray
EP2200588B1 (fr) 2007-09-25 2019-03-20 Solubest Ltd. Compositions comprenant des composés actifs lipophiles et procédé pour leur préparation
KR101569227B1 (ko) 2008-03-11 2015-11-13 아스카 세이야쿠 가부시키가이샤 고체 분산체와 그 의약 조성물, 그리고 그들의 제조 방법

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4895726A (en) * 1988-02-26 1990-01-23 Fournier Innovation Et Synergie Novel dosage form of fenofibrate

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2157201C3 (de) * 1970-11-13 1974-12-12 Boehringer Mannheim Gmbh, 6800 Mannheim Verbesserte feste orale Applikationsform von Raubasin
IT1180507B (it) * 1984-06-29 1987-09-23 Roberto Valducci Procedimento per la preparazione di etofibrato o sostanze di pari o simili caratteristiche, in microgunuli-ritardo e prodotto ottenuto con tale procedimento
AU671811B2 (en) * 1991-12-18 1996-09-12 Warner-Lambert Company A process for the preparation of a solid dispersion

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4895726A (en) * 1988-02-26 1990-01-23 Fournier Innovation Et Synergie Novel dosage form of fenofibrate

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
1999, PHARMACEUTICAL PRESS, LONDON *
See also references of WO0072829A1 *

Also Published As

Publication number Publication date
MXPA01012225A (es) 2002-08-12
JP2003500439A (ja) 2003-01-07
WO2000072829A1 (fr) 2000-12-07
CA2374117A1 (fr) 2000-12-07

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