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EP1185250A2 - Formulation pharmaceutique gastro-resistante - Google Patents

Formulation pharmaceutique gastro-resistante

Info

Publication number
EP1185250A2
EP1185250A2 EP01900496A EP01900496A EP1185250A2 EP 1185250 A2 EP1185250 A2 EP 1185250A2 EP 01900496 A EP01900496 A EP 01900496A EP 01900496 A EP01900496 A EP 01900496A EP 1185250 A2 EP1185250 A2 EP 1185250A2
Authority
EP
European Patent Office
Prior art keywords
drug
particles
binding
solution
gelling
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Withdrawn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
EP01900496A
Other languages
German (de)
English (en)
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
Publication of EP1185250A2 publication Critical patent/EP1185250A2/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Withdrawn legal-status Critical Current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
    • 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 in 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 anti-inflammatory drugs for example diclofenac and gastric upset, for example some erythromycin salts.
  • An enteric layer is a coating of a substance which is insoluble in 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, polyvinyl acetate phthalate and hydroxypropyl methyl phthalate.
  • methyl methacrylate polymers as sold under the trade mark Eudragit
  • cellulose acetate phthalate cellulose acetate phthalate
  • polyvinyl acetate phthalate polyvinyl acetate phthalate
  • hydroxypropyl methyl phthalate 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 a drug includes the steps of: forming a solution or suspension containing the drug, a soluble polymer and a binding or gelling agent, contacting the solution or suspension with an acid precipitating medium, allowing the polymer to precipitate to form particles containing the dissolved or suspended 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.
  • the solution or suspension may be formed into drops and the drops are contacted with acid medium.
  • the solution may be added directly into the acid medium with stirring or agitation to give the particles.
  • the particles may comprise a fine powder suitable for formulation.
  • an oral pharmaceutical dosage form comprises a 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 dosage form may comprise an undried or partially dried particle for use in manufacture of such a tablet or capsule.
  • 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 (HPMCP) .
  • HPPMCP hydroxypropyl methyl cellulose phthalate
  • HP-50 manufactured by Shin-Etsu Co Ltd.
  • This polymer may be precipitated in accordance with the invention by contacting the drops or solution 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, polyvinyl acetate phthalate and hydroxypropyl methyl phthalate.
  • binding or gelling agents may be employed, including polymers, cellulosic materials, sugars, coacervating and complexing agents.
  • Polyvinyl pyrrolidone (PVP) preferably with a molecular weight in the region of 30,000 is preferred. PVP has been found to be beneficial in solubilising drugs such as diclofenac, particularly in combination with HPMC.
  • Methacrylate acid esters and gelatin also may be used.
  • Cellulosic polymers including hydroxypropyl methyl cellulose, methyl cellulose and cellulose suspensions. Other compounds include cyclodextrins , polydextroses and modified starches.
  • the amount of the gelling agent may lie in the range 1 to 50% w/w of the weight of formulation.
  • An amount of 1 to 10%, preferably 6 to 8% by weight may be particularly suitable.
  • the solution or suspension containing the drug, soluble polymer and binding or gelling agent comprises an aqueous solution or suspension including the following:
  • a drug selected from diclofenac and proton pump inhibitors for example omeprazole, lansoprazole, pantoprazole and rabeprazole; 10 - 20%, preferably 12 - 15% of hydroxypropylmethyl cellulose phthalate.
  • compositions result in particles which are not sticky after drying.
  • Use of 5 - 10% polyvinylpyrrolidone, especially 7 - 8% together with 12 - 15%, preferably 14% HCMCP is preferred for formation of evenly shaped oval or spherical non-sticky particles.
  • the method of production of the dosage form includes the step of exposing the particles to photolytic radiation prior to drying in 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.
  • Drugs suitable for formulation in accordance with this invention include diclofenac and proton pump inhibitors including omeprazole; lansoprazole, pantoprazole and rabeprazole; sodium valproate; steroids; antibiotics etc.
  • Aqueous soluble drugs may be formulation from solution.
  • Insoluble or poorly soluble drugs may be formulated from suspensions .
  • An amount of 0.2 - 10% diclofenac, preferably 1 - 10% w/v is preferred in the initial solution or suspension.
  • the amount of drug chosen may be selected to give an appropriate dosage in the final product.
  • the method in 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 in more rapid particle 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.
  • Tablets in accordance with this invention 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 in case of taste problems, light instability or discolouration of the tablets.
  • a mixture of particles from different batches with different amounts of polymer may be used.
  • Methacrylate polymers are preferred for 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 polyvinyl 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 in 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 .
  • Particles were ell rounded in shape but in the case of the highest concentration of citric acid (25% w/v) the dried particles appeared glassy in colour and sticky rather than opaque and dry as for the others. They also appeared slightly shrunken in size by comparison. 15% w/v citric was considered to give the best particles.
  • 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 in 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 in 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 3 solution in 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

La présente invention concerne un procédé de fabrication d'une dose posologique de produit pharmaceutique oral à base d'un médicament hydrosoluble. A cet effet, on commence par former une solution ou une suspension du médicament, un polymère soluble et un agent de liaison ou de gélification. On met ensuite cette solution ou suspension en contact avec un milieu de précipitation acide permettant au polymère de se précipiter en particules contenant le médicament dissout. Enfin, on fait sécher les particules. L'utilité de l'agent de gélification ou de liaison est d'influencer ou d'interdire la migration du médicament vers la surface des particules pendant le séchage.
EP01900496A 2000-01-11 2001-01-10 Formulation pharmaceutique gastro-resistante Withdrawn EP1185250A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0000482A GB0000482D0 (en) 2000-01-11 2000-01-11 Enteric coated pharmaceutical formulation
GB0000482 2000-01-11
PCT/GB2001/000072 WO2001051031A2 (fr) 2000-01-11 2001-01-10 Formulation pharmaceutique gastro-resistante

Publications (1)

Publication Number Publication Date
EP1185250A2 true EP1185250A2 (fr) 2002-03-13

Family

ID=9883444

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01900496A Withdrawn EP1185250A2 (fr) 2000-01-11 2001-01-10 Formulation pharmaceutique gastro-resistante

Country Status (4)

Country Link
EP (1) EP1185250A2 (fr)
AU (1) AU2532601A (fr)
GB (1) GB0000482D0 (fr)
WO (1) WO2001051031A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5709354B2 (ja) 2005-11-14 2015-04-30 アリアド・ファーマシューティカルズ・インコーポレイテッド ｍＴＯＲ阻害剤投与によるがん患者の治療
US20080161335A1 (en) 2006-11-14 2008-07-03 Vladyka Ronald S Oral formulations
WO2019072877A1 (fr) * 2017-10-10 2019-04-18 Capsugel Belgium Nv Compositions multiparticulaires gélifiantes

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69331906T2 (de) * 1992-08-05 2002-12-19 F.H. Faulding & Co. Ltd., Underdale Granulierte pharmazeutische zusammensetzung
US6096340A (en) * 1997-11-14 2000-08-01 Andrx Pharmaceuticals, Inc. Omeprazole formulation
GB9814214D0 (en) * 1998-07-01 1998-09-02 Norton Healthcare Ltd Enteric coated pharmaceutical formulation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0151031A3 *

Also Published As

Publication number Publication date
AU2532601A (en) 2001-07-24
WO2001051031A3 (fr) 2001-12-27
GB0000482D0 (en) 2000-03-01
WO2001051031A2 (fr) 2001-07-19

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