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WO2000001363A2 - Formulation pharmaceutique keratinisee enrobee - Google Patents

Formulation pharmaceutique keratinisee enrobee Download PDF

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Publication number
WO2000001363A2
WO2000001363A2 PCT/GB1999/001952 GB9901952W WO0001363A2 WO 2000001363 A2 WO2000001363 A2 WO 2000001363A2 GB 9901952 W GB9901952 W GB 9901952W WO 0001363 A2 WO0001363 A2 WO 0001363A2
Authority
WO
WIPO (PCT)
Prior art keywords
particles
drug
gelling
binding
acid
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.)
Ceased
Application number
PCT/GB1999/001952
Other languages
English (en)
Other versions
WO2000001363A3 (fr
Inventor
Austen John Woolfe
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.)
Norton Healthcare Ltd
Original Assignee
Norton Healthcare Ltd
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 Norton Healthcare Ltd filed Critical Norton Healthcare Ltd
Priority to EP99928067A priority Critical patent/EP1119348A2/fr
Priority to AU45194/99A priority patent/AU4519499A/en
Publication of WO2000001363A2 publication Critical patent/WO2000001363A2/fr
Anticipated expiration legal-status Critical
Publication of WO2000001363A3 publication Critical patent/WO2000001363A3/fr
Ceased legal-status Critical Current

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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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

Definitions

  • This invention relates to enteric coated pharmaceutical formulations and methods of production.
  • Some drugs when given orally should not be released immediately into the stomach but should be formulated so that they are only available for absorption m the upper or lower intestine or colon.
  • the reasons for a delay until they are passed out of the stomach vary, but include: instability in an acid medium, for example omeprazole; possible erosion and damage to the stomach wall by non- steroidal antl-mflammatory drugs for example diclofenac and gastric upset, for example some erythromycm salts.
  • An enteric layer is a coating of a substance which is insoluble m the acid medium of the stomach but which is soluble at the higher pH encountered in the intestine.
  • Such materials are used as film coatings on tablets. Suitable film coating materials include methyl methacrylate polymers (as sold under the trade mark Eudragit), cellulose acetate phthalate, polyvmyl acetate phthalate and hydroxypropyl methyl phthalate.
  • Such dosage forms are capsules containing multiple particles, pellets or tablets.
  • Such particles, pellets or tablets may consist of a core containing the drug with an overcoating of an enteric film.
  • the core may be a conventional tablet, an extruded bead containing the drug or a non-pareil overcoated with a layer of drug.
  • Capsules are widely used but have the drawback that the dosage cannot be varied easily as with a conventional tablet with a score- line which enables the tablet to be reasonably accurately divided into two or more parts containing known quantities of drug.
  • a method of making an oral pharmaceutical dosage form of an aqueous soluble drug includes the steps of: forming a solution containing the drug, a soluble polymer and a binding or gelling agent into drops, contacting the drops with an acid precipitating medium, allowing the polymer to precipitate to form particles containing the dissolved drug, drying the particles, wherein the gelling or binding agent retards or prevents migration of the drug towards the surface of the particles during drying.
  • the particles may be incorporated into a tablet or filled into a gelatin capsule.
  • an oral pharmaceutical dosage form comprises an aqueous soluble drug, a soluble polymer, a gelling or binding agent and one or more inert excipients, the gelling or binding agent being adapted to retard or prevent migration of the drug towards a surface of the dosage form.
  • the dosage form preferably comprises a tablet or capsule containing particles of the formulation.
  • the particles may be formed by sonicating or other pressure wave methods to break up the stream of drug/polymer solution as it enters the acid medium.
  • a preferred soluble polymer is hydroxypropyl methyl cellulose phthalate. This polymer is suitable for enteric coating applications because it is insoluble in gastric fluid but dissolves rapidly at the higher pH values found m the small intestine. This polymer may be precipitated m accordance with the invention by contacting the drops with aqueous acid, for example 5 to 20% preferably 10 to 15% citric acid.
  • Suitable polymers which may be used include methyl methacrylate polymers (as sold under the trade mark Eudragit), cellulose acetate phthalate, polyvmyl acetate phthalate and hydroxypropyl methyl phthalate.
  • binding or gelling agents may be employed, including polymers, cellulosic materials, sugars, coacervatmg and complexmg agents.
  • Polyvmyl pyrrolidone, methacrylate acid esters and gelatin may be used.
  • Cellulosic polymers including hydroxypropyl methyl cellulose, methyl cellulose and cellulose suspensions are preferred.
  • Other compounds include cyclodextrms , polydextroses and modified starches.
  • the amount of the gelling agent may lie m the range 20 to 200% w/w of the weight of active ingredient. An amount of 1 to 10%, preferably 2 to 6% by weight may be employed.
  • the method of production of the dosage form includes the step of exposing the particles to photolytic radiation prior to drying m order to cause the gelling and binding agent to cross-link.
  • Alternative formulations incorporate one or more water absorbing agents, for example a partially hydrated hydrogel adapted to absorb the drug containing aqueous solution within the core of the bead during drying.
  • a partially hydrated hydrogel may be added to the concentrated drug/polymer solution immediately prior to precipitation of the particles.
  • the drying technique is preferably selected to minimise migration of the drug during evaporation.
  • Water or alkali soluble drugs suitable for formulation in accordance with this invention include omeprazole, diclofenac, sodium valproate, steroids, antibiotics etc.
  • the method m accordance with this invention may be selected so that the rate of formation of the particles is accelerated to reduce diffusion of the drug during the formation of the particles.
  • Precipitation of the polymer may be enhanced using an acid, for example hydrochloric acid which is stronger than the previously employed citric acid. This results m more rapid bead formation, reducing the liability to drug diffusion during the precipitation step.
  • the particles may be filled into capsules or mixed with inert excipients and compressed into tablets.
  • the inert excipients may also include another active substance or substances if a product is required with two or more drugs where only one needs enteric coating. For example diclofenac with misoprostol.
  • the inert excipients will include fillers, binders, lubricants, colours and will preferably include microcrystalline cellulose which has good carrying capacity for the particles.
  • the tablets may be provided with one or more break lines to facilitate division into smaller doses. They may also be over coated with a standard film or sugar coating m case of taste problems, light instability or discolouration of the tablets. If a varied release profile in the intestine is required, a mixture of particles from different batches with different amounts of polymer may be used. Methacrylate polymers are preferred for this aspect. In this aspect, uncoated drug fine powder may be added to the tablet mixture to give some immediate release of drug.
  • a polymer solution was prepared by dissolving HPMCP (2- 10 %w/v) and polyvmyl pyrrolidone (PVP) in an alkaline solution of sodium bicarbonate (2 %w/v) . Particles were formed by adding -10 ml of the HPMCP dropwise, into -100 ml of citric acid solution (,5-25 %w/v) at a temperature of ca 0-5°C with constant stirring.
  • the emulsion was left to continue stirring for a further 2 hr, after which the particles were filtered off and washed 3 times with distilled water. The particles were dried m a freeze-drier for at least 12 hr .
  • Tables 1-3 show the formulations used in the preparation of particles on a low speed stirrer.
  • Particles made from 2% w/v HPMCP did not form as the solution was viscous enough for the particles to maintain their form in the emulsion medium.
  • 5% w/v HPMCP particles were elongated in the shape but the 10% w/v particles were rounded.
  • the particles produced on the lower 2 speed settings were relatively evenly shaped (especially the 15% w/v citric prepared on the lowest speed; 300 rpm) as the speed is increased to >650 rpm the shapes are irregular and elongated.
  • Particles were prepared in the same way on the Silversun mixer as for the low speed mixer described above except a larger vessel for the preparation was used and a larger volume of citric acid due to the requirements for high speed mixing.
  • the particles obtained indicated that an increase in the concentration of the polymer solution improved the shape of the particles but could result in some glassy particles and slight stickiness.
  • Increasing the citric acid content did not appear to have a significant affect on the particles except when the HPMCP concentration is also high as this resulted sticky particles.
  • Increasing the speed appeared to have a negligible effect on the size and shape of the particles .
  • Particles using PVP as a gelling agent may be prepared the same way as described previously.
  • Diclofenac sodium may be introduced into the bead formulation in the following ways :
  • Bead formation and highest entrapment efficiency was achieved when first dissolving the diclofenac sodium in ethanol and then mixing with the NaHC0 solution the ratio 10/90 ethanol/NaHC0 3 solution, prior to dissolving the HPMCP. As the volume of ethanol increases the viscosity of the polymer solution decreases and particles are not formed.

Landscapes

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

Abstract

L'invention concerne un procédé de préparation d'une forme de dosage phamaceutique orale d'un médicament soluble aqueux, consistant à former une solution contenant ledit médicament, un polymère soluble et un agent de liaison ou gélifiant sous forme de gouttes; à mettre en contact lesdites gouttes avec un milieu de précipitation acide permettant au polymère de précipiter, pour former des particules contenant le médicament dissous; à sécher les particules, l'agent de liaison ou gélifiant retardant ou empêchant la migration des médicaments vers la surface des particules pendant le séchage.
PCT/GB1999/001952 1998-07-01 1999-06-30 Formulation pharmaceutique keratinisee enrobee Ceased WO2000001363A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP99928067A EP1119348A2 (fr) 1998-07-01 1999-06-30 Formulation pharmaceutique keratinisee enrobee
AU45194/99A AU4519499A (en) 1998-07-01 1999-06-30 Enteric coated pharmaceutical formulation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9814214.4A GB9814214D0 (en) 1998-07-01 1998-07-01 Enteric coated pharmaceutical formulation
GB9814214.4 1998-07-01

Publications (2)

Publication Number Publication Date
WO2000001363A2 true WO2000001363A2 (fr) 2000-01-13
WO2000001363A3 WO2000001363A3 (fr) 2001-05-25

Family

ID=10834730

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1999/001952 Ceased WO2000001363A2 (fr) 1998-07-01 1999-06-30 Formulation pharmaceutique keratinisee enrobee

Country Status (4)

Country Link
EP (1) EP1119348A2 (fr)
AU (1) AU4519499A (fr)
GB (1) GB9814214D0 (fr)
WO (1) WO2000001363A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001051031A3 (fr) * 2000-01-11 2001-12-27 Norton Healthcare Ltd Formulation pharmaceutique gastro-resistante

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63287543A (ja) * 1987-05-19 1988-11-24 Eisai Co Ltd マイクロカプセルの製造方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 110, no. 14, 3 April 1989 (1989-04-03) Columbus, Ohio, US; abstract no. 116331, OWAKI, TAKAYUKI ET AL: "Preparation of nontoxic microcapsules" XP002118557 & JP 63 287543 A (EISAI CO., LTD., JAPAN) 24 November 1988 (1988-11-24) *
DATABASE WPI Week 8327 Derwent Publications Ltd., London, GB; AN 1983-701728 XP002118558 & HU 25 023 A (EGYT GYOGYSZERVEGYESZETI GYAR), 30 May 1983 (1983-05-30) *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001051031A3 (fr) * 2000-01-11 2001-12-27 Norton Healthcare Ltd Formulation pharmaceutique gastro-resistante

Also Published As

Publication number Publication date
WO2000001363A3 (fr) 2001-05-25
EP1119348A2 (fr) 2001-08-01
AU4519499A (en) 2000-01-24
GB9814214D0 (en) 1998-09-02

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