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WO1993010775A1 - Procede et composition destines au developpement d'une forme galenique de gemfibrosil a liberation regulee - Google Patents

Procede et composition destines au developpement d'une forme galenique de gemfibrosil a liberation regulee Download PDF

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Publication number
WO1993010775A1
WO1993010775A1 PCT/US1992/008782 US9208782W WO9310775A1 WO 1993010775 A1 WO1993010775 A1 WO 1993010775A1 US 9208782 W US9208782 W US 9208782W WO 9310775 A1 WO9310775 A1 WO 9310775A1
Authority
WO
WIPO (PCT)
Prior art keywords
gemfibrozil
release
control agent
formulation
cellulose
Prior art date
Application number
PCT/US1992/008782
Other languages
English (en)
Inventor
Isaac Ghebre-Sellassie
Uma Iyer
Original Assignee
Warner-Lambert Company
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 Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to EP92921783A priority Critical patent/EP0614358A1/fr
Priority to JP5510096A priority patent/JPH07503236A/ja
Publication of WO1993010775A1 publication Critical patent/WO1993010775A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis

Definitions

  • the present invention relates to controlled release gemfibrozil formulations.
  • the present invention is directed to formulations having both immediate and controlled release of gemfibrozil.
  • Gemfibrozil or 5-(2 / 5-dimethylphenoxy)-2,2- dimethylpentanoic acid, is a widely used antihyper- lipoproteinemic agent. While apparently absorbed throughout the gastrointestinal tract, maximum absorption appears to occur in the upper gastrointestinal tract, notwithstanding the poor solubility of the drug at acidic pH's.
  • controlled release formulations In recent years, for patient convenience, it has become desirable to provide controlled release formulations. In self-medicating patients, where efficacious blood serum levels of the active ingredient are imperative, controlled release formulations are particularly useful. In addition, controlled release formulations are useful for those patients who may easily forget to take medication.
  • an improved formulation of gemfibrozil can be prepared from a single granulation which provides a loading dose and controlled release of gemfibrozil.
  • the formulation is prepared by contacting gemfibrozil particles, preferably finely divided particles, with a release-control agent.
  • the release- control agent is present in an amount whereby immediate release of free or partially- ree active takes place as well as controlled release.
  • the release-control agent may be selected from acrylic acid series polymers, acrylic acid series copolymers and other substantially acid-insoluble alkali soluble polymers such as cellulose phthalates, poly(meth)acrylic acids and the like.
  • the release-control agent is dispersed or suspended in an aqueous solution.
  • a particularly preferred release-control agent is Aquacoat® ECD 30, an aqueous suspension of ethyl cellulose containing 30% solids.
  • the ratio of gemfibrozil to the release-control agent is key to obtaining the desired release pattern.
  • the overall ratio which provides free or partially-free active and controlled active is from about 11:0.5 to about 11:5 by weight.
  • the ratio of the active, such as gemfibrozil, to the release-control agent is from about 11:0.75 to about 11:3 by weight, while in a most preferred embodiment, the ratio is from about 11:0.85 to about 11:1.25 by weight.
  • gemfibrozil particles are blended with an excipient such as microcrystalline cellulose or lactose prior to the particles being contacted with the release-control agent.
  • a method of preparing the above-described formulation which includes contacting gemfibrozil particles, which are preferably finely divided, with a sufficient amount of a release- control agent to provide both immediate (e.g., free or partially free active) and release-controlled active.
  • the release-control agent is present as an aqueous suspension or dispersion, while the active and release-control agent are contacted for use in the formulation by granulating.
  • a method of preparing a compressed tablet having both immediate and controlled release of gemfibrozil is also provided.
  • a gemfibrozil formulation having both immediate and controlled release properties that offers time and labor savings when compared to formulations requiring the preparation of multiple granulations.
  • the single granulation also overcomes uniformity problems associated with blending and compressing separate immediate and sustained release granules into tablets.
  • a formulation which includes gemfibrozil particles contacted with a release-control agent in an amount sufficient to provide a loading dose and controlled release of the active.
  • the contacting of the gemfibrozil with the release- control agent is preferably carried out by granulation techniques known in the art.
  • the granulation may be performed by agitation type apparatus, rotation type apparatus, centrifugal type apparatus, fluidized bed- ype apparatus, or the like.
  • the gemfibrozil preferably in the form of finely divided particles, can be granulated either alone or after being mixed with excipients prior to contacting the control agent.
  • the active-containing formulation of the present invention is characterized as being substantially alkali- soluble and substantially acid-insoluble. These properties advantageously delay the usually immediate release of active in the acid environment of the upper gastrointestinal tract and, allow release of active in the alkaline environment of the lower gastrointestinal tract.
  • Suitable alkali-soluble and acid-insoluble polymers include cellulose phthalates, polyvinyl phthalates, cellulose succinates, cellulose butyrates, poly(meth)acrylic acids and partially esterified poly(meth)acrylic acids.
  • Preferred agents are cellulose phthalates and partially esterified poly(meth)acrylic acids.
  • the use of "meth" as a prefix in parenthesis for the (meth)acrylic copolymers indicates that the polymer molecule is derived from one or both of acrylic and methacrylic species.
  • the copolymer can be derived from partially esterified acrylic acid and methacrylic acid in which the ester groups are methyl and ethyl.
  • Other conventional comonomers may be present in the copolymers as long as they do not detract from the copolymer 1 s usefulness in the present system.
  • a particularly suitable release-control agent is that sold by FMC Corporation, Philadelphia, Pa. under the name of Aquacoat® ECD-30, this being in the form of a 30% aqueous dispersion of ethyl cellulose having a low particle size and a narrow particle size distribution.
  • Aquacoat® ECD-30 also useful is Eudragit 30D, a copolymer anionic in character based on partially esterified poly(meth)acrylic acid (ratio of free carboxyl groups to esterified carboxyl groups being about 1:1) and having a mean molecular weight of about 250,000.
  • molten pharmaceutically-acceptable wax such as stearic acid, stearyl alcohol, PEG 3350, etc. may be selected as the release-control agent. Mixtures of the above release-control agents are also contemplated.
  • the release-control agent is preferably in the form of an aqueous suspension, an aqueous emulsion, an aqueous dispe-i-sion, water containing organic solvent, or organic solution.
  • the amount of the release-control agent contained in the formulation is a key feature of the present invention. It has been discovered that the ratio of the active ingredient, here gemfibrozil, to the release-control agent contacted under conditions suitable for granulation can be used to provide desired release characteristics for the resultant product. For example, when granulation of the active is undertaken using an aqueous dispersion of a release-control agent such as Aquacoat®, the result is that some of the granules formed will have sustaining properties while other granules will not. This is believed to be as a result of the amount of release-control agent available for intimate contact with the active particles.
  • the ratio of release-control agent to active ingredient under granulation conditions provides a composition whereby the active is free or partially-free of release-control agent and wherein a certain amount of active is bound to the release-control agent.
  • the release pattern of the active can be extremelyly tailored over a broad range of release periods. For example, when the ratio of the active to the release-control agent is relatively high, the release rate is relatively low since a small portion of the active will be coated with a large quantity of the release control agent as the granulation is formed. The inverse of this relationship is also true. When the ratio of the active to the release- control agent is relatively low, the amount of drug released per unit time is relatively high. Between these two relative extremes, a complete spectrum of predictable release profiles is possible. In one embodiment the ratio of gemfibrozil to the release-control agent is from about 11:0.5 to about 11:5 by weight.
  • the ratio of gemfibrozil to the release-control agent is from about 11:0.75 to about 11:3 by weight, while in a most preferred embodiment, the ratio is from about 11:0.85 to about 11:1.25 by weight.
  • the above ratios provide formulations which conveniently allow once a day dosing.
  • the gemfibrozil particles may also be blended with excipients such as cellulose derivatives or lactose prior to granulation with the release-control agent.
  • the cellulose derivatives include materials such as microcrystalline cellulose, water-soluble hydroxyalkyl celluloses and mixtures thereof.
  • the formulation may also contain one or more processing aids such as separating agents, plasticizers, stabilizers, lubricants and the like which can be present in relatively minor amounts.
  • processing aids such as separating agents, plasticizers, stabilizers, lubricants and the like which can be present in relatively minor amounts.
  • Useful separating or anti-tackiness agents include kaolin, talc, magnesium trisilicate, silicon dioxide, calcium carbonate and the like. Talc is preferred.
  • Lubricants including magnesium stearate, calcium stearate, zinc stearate, colloidal silicon dioxide, stearic acid, and polyethylene glycol also can be added to assist in the formulation.
  • the formulation may also include a disintegration excipient.
  • Suitable disintegration excipients include one or more water dispersable cellulose derivatives such as microcrystalline cellulose, sodium croscarmellose, starch, starch derivatives such as sodium carboxymethy1starch, and cross-linked polyvinyl pyrrolidone. Coloring agents may also be included if desired.
  • the particle size (diameter) of the granulation may range from 10 to about 325 mesh and preferably from about 20 to about 200 mesh.
  • the gemfibrozil formulation may then be compressed into tablets or included in capsules and the like depending on the preference of the artisan.
  • the resultant dosage forms may be prepared so that the dosage form maintains its shape, slightly or substantially disintegrates or erodes after ingestion.
  • a method of preparing the novel gemfibrozil formulation includes contacting gemfibrozil particles, preferably finely divided, with a release-control agent such as one of the agents described herein in an amount sufficient to provide both immediate and controlled release of the active from the formulation.
  • a release-control agent such as one of the agents described herein in an amount sufficient to provide both immediate and controlled release of the active from the formulation.
  • the contacting of the gemfibrozil with the release-control agent is carried out by granulation with, the ingredients present in the ratios set forth above.
  • the granulation was prepared by mixing gemfibrozil and microcrystalline cellulose in a 600 L Collette Gral for about two minutes with a mixer at low speed until a uniform mixture of the ingredients was obtained.
  • the Antifoam AF Emulsion and triethyl citrate were dispersed in the Aquacoat® ECD-30 (30% solids) using a Lightnin® mixer; Syloid 244 was then added to the dispersion and stirring was continued. The dispersion was then added to the mixture in the Gral while mixing. Mixing was continued after the addition of the dispersion for two minutes with the granulator on medium speed. After the release-control agent was evenly distributed, purified water was added to make a granulation.
  • Controlled release tablets containing gemfibrozil were prepared according to the following formula:
  • a 20 cu.ft. P-K blender was charged with the granulation along with microcrystalline cellulose and croscarmellose sodium. The ingredients were tumble blended for about five minutes. A portion of the granulation was removed from the blender and tumble mixed for five minutes with Syloid 244 and calcium stearate. The resulting mixture was then passed through a 20 # screen and returned to the blender. Mixing was continued for another five minutes. The resultant granulation was then compressed into tablets weighing about 850 milligrams. The tablets were then film coated with 10% w/w solution of Opadry® in a 48" Accela Cota® machine and then polished with candelilla wax, to provide the finished product with a smooth outer coat.
  • dissolution of the film coated tablets prepared as a result of Example 2 was demonstrated by dissolving the tablets in a solution having 0.2M phosphate buffer and an alkaline pH of 7.5, as a model of the prevailing conditions of the lower G.I. tract.
  • the results of the tests conducted using the product of Example 2 are set forth in the Table below.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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Abstract

L'invention décrit des formulations de gemfibrosil préparées à partir d'une granulation unique de gemfibrosil et d'un agent de régulation de libération. Ce dernier est présent en une dose suffisante pour produire à la fois la libération immédiate et régulée de gemfibrosil. Un procédé de préparation de la formulation, et un comprimé sont également décrits.
PCT/US1992/008782 1991-11-26 1992-10-15 Procede et composition destines au developpement d'une forme galenique de gemfibrosil a liberation regulee WO1993010775A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP92921783A EP0614358A1 (fr) 1991-11-26 1992-10-15 Procede et composition destines au developpement d'une forme galenique de gemfibrosil a liberation regulee
JP5510096A JPH07503236A (ja) 1991-11-26 1992-10-15 制御放出性ジェムフィブロジル剤形の開発のための方法および組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US79837591A 1991-11-26 1991-11-26
US798,375 1991-11-26

Publications (1)

Publication Number Publication Date
WO1993010775A1 true WO1993010775A1 (fr) 1993-06-10

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ID=25173228

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/008782 WO1993010775A1 (fr) 1991-11-26 1992-10-15 Procede et composition destines au developpement d'une forme galenique de gemfibrosil a liberation regulee

Country Status (5)

Country Link
EP (1) EP0614358A1 (fr)
JP (1) JPH07503236A (fr)
CA (1) CA2123677A1 (fr)
MX (1) MX9206790A (fr)
WO (1) WO1993010775A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4171091B2 (ja) * 1996-11-15 2008-10-22 味の素株式会社 錠剤組成物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0297866A2 (fr) * 1987-07-01 1989-01-04 The Boots Company PLC Agents thérapeutiques
US4925676A (en) * 1989-02-02 1990-05-15 Warner-Lambert Company Extended release gemfibrozil composition
US4927639A (en) * 1989-02-02 1990-05-22 Warner-Lambert Company Modified release gemfibrozil composition
WO1991000085A1 (fr) * 1989-06-26 1991-01-10 Warner-Lambert Company Compositions pharmaceutiques a liberation entretenue

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0297866A2 (fr) * 1987-07-01 1989-01-04 The Boots Company PLC Agents thérapeutiques
US4925676A (en) * 1989-02-02 1990-05-15 Warner-Lambert Company Extended release gemfibrozil composition
US4927639A (en) * 1989-02-02 1990-05-22 Warner-Lambert Company Modified release gemfibrozil composition
WO1991000085A1 (fr) * 1989-06-26 1991-01-10 Warner-Lambert Company Compositions pharmaceutiques a liberation entretenue

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 89, no. 2, 10 July 1978, Columbus, Ohio, US; abstract no. 12095k, NIXON J.R. ET AL 'release of drugs from suspended and tabletted microcapsules' page 367 ;column 2 ; *

Also Published As

Publication number Publication date
EP0614358A1 (fr) 1994-09-14
CA2123677A1 (fr) 1993-06-10
MX9206790A (es) 1993-05-01
JPH07503236A (ja) 1995-04-06

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