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WO1997034585A1 - Gelules transparentes dures - Google Patents

Gelules transparentes dures Download PDF

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Publication number
WO1997034585A1
WO1997034585A1 PCT/EP1997/001352 EP9701352W WO9734585A1 WO 1997034585 A1 WO1997034585 A1 WO 1997034585A1 EP 9701352 W EP9701352 W EP 9701352W WO 9734585 A1 WO9734585 A1 WO 9734585A1
Authority
WO
WIPO (PCT)
Prior art keywords
oil
capsule
particles
dosage form
oral dosage
Prior art date
Application number
PCT/EP1997/001352
Other languages
English (en)
Inventor
Timothy James Grattan
Marsh Hayward
Original Assignee
Smithkline Beecham Plc
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 Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO1997034585A1 publication Critical patent/WO1997034585A1/fr

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4858Organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release

Definitions

  • This invention relates to an oral dosage form comprising a partially or wholly transparent swallow capsule which contains particles suspended or dispersed in a liquid vehicle, characterised in that the capsule is of the hard-shelled type, typically a hard-shell gelatin capsule.
  • the capsule fill is a combination of a pharmaceutically acceptable liquid and pharmaceutically acceptable particles.
  • the particles are of a size and are present in the dosage form in a quantity such that whilst the liquid fills the internal capsule space, the particles do not, so mat when the capsule is moved the particles will shift position in the liquid. Such a presentation makes tampering more evident.
  • WO 95/00125 discloses a soft-shelled gelatin capsule containing particles in a liquid vehicle.
  • This invention provides a novel capsule preparation wherein a partially or wholly transparent hard-shelled capsule contains a mixture which comprises particles containing at least one beneficial agent and a non-toxic, transparent or translucent liquid carrier which may also contain a beneficial agent, wherein the particles fill less than the internal volume of the capsule.
  • a beneficial agent such as a vegetable oil may be used as the liquid carrier and particles comprising or containing a beneficial agent are present at a concentration such that when the particles settle, there remains a portion of the oil which does not contain particles.
  • Capsule preparations according to the present invention offer an advantage over soft gel capsules with respect to easier processing conferring reduced manufacturing costs and a smaller product which is easier to swallow. Processing methods available for filling hard-shell capsules also avoid potential damage to the particles containing the beneficial agenf which may impair performance.
  • this invention relates to a method for providing a tamper- evident dosage form which method comprises filling a partially or wholly transparent hard-shelled capsule with a mixture comprising particles which contain at least one beneficial agent and a translucent or transparent non-toxic liquid carrier which may also contain a beneficial agent and wherein the particles fill less than the internal volume of the capsule.
  • this invention relates to an oral dosage lorm comp ⁇ sing a partially or wholly transparent hard-shelled capsule, preferably a hard-shelled gelatin capsule, containing a translucent or transparent liquid in which particles are suspended which are insoluble in the liquid and wherein the particles are not so numerous as to fill completely the capsule.
  • a translucent or transparent liquid in which particles are suspended which are insoluble in the liquid and wherein the particles are not so numerous as to fill completely the capsule.
  • the partially or wholly transparent capsule and the translucent or transparent liquid allow the moving particles to be seen. Visible, moveable particles make it easier to detect capsules which have imperfections such as capsules where extraneous material has been introduced into the capsule or where the fill has leaked out for some reason.
  • Such a system is particularly useful for ale ⁇ ing the end user to the fact there may be some imperfection in the capsule, such as might occur when capsules are tampered with.
  • this dosage form Three parts make up this dosage form, the hard-shelled capsule, a compatible non ⁇ toxic liquid for suspending the particles, and particles containing a beneficial agent, sized so that numerous particles are contained in the finished dosage form without interfering with their movement in the suspending liquid and which do not adhere to the capsule wall or coagulate in die suspending liquid.
  • all of the capsule wall will be transparent or translucent. In another embodiment, a portion of the capsule wall will have a different refractive index or will transmit more light than another portion of the capsule.
  • one portion of the capsule may be opaque whilst another portion may be transparent or translucent.
  • a preferred formulation comprises a hard gelatin shell containing a light oil of moderate viscosity and particles which do not dissolve in the oil, form aggregates or adhere to the gelatin capsule wall. Particles will be present in numbers such that a portion of the oil will be particle-free when the capsule is at rest. The particles will be visible to the naked eye through the capsule wall in normal lighting conditions irrespective of capsule orientation. The viscosity of the suspending agent will be such that the particles can move readily widiin the capsule when it is tipped or rolled out of its resting plane.
  • any suitable material known to me an may be used to form me shell.
  • Hard-shell capsules made from natural and synthetic materials are known in the art.
  • gelatin examples include gelatin, starch and cellulose etiiers such as methyl cellulose.
  • gelatin is the preferred material.
  • Hard-shelled gelatin capsules are well documented in me literature and are well known to manufacturers and technicians alike. They may comprise, in addition to gelatin, materials such as cross-linking or polymerising agents, plasticisers, stabilisers, antioxidants, light absorbing agents for protecting light-sensitive fills, preservatives and me like. Any non-toxic liquid that is pharmaceutically acceptable and compatible wim me chosen capsule material and me particles suspended in it may be used. It should be flowable at or about ambient temperature to a degree which does not interfere with particle movement.
  • the density of the liquid is less than that of the particles suspended in it so diat the particles will sink or flow widiin the liquid when the capsule is tilted in normal use.
  • Combinations of two or more liquids may be used and preferably mey will be miscible liquids.
  • the liquid must be sufficiently translucent for observing the suspended particles. Additives such as preservatives, colouring agents, stabilisers, UV absorbing agents, processing aids and the like may be inco ⁇ orated into the liquid provided they too are compatible wim the particles and the chosen capsule material.
  • the liquid may also contain a beneficial agent in which case the agent should be soluble in the liquid and should not cause the liquid to become opaque.
  • Suitable liquids include oils and polyols such as glycols, poiyalkylene glycols, glycerol esters, fatty acids, polycarbonates and syrups.
  • Waxes which are liquid at room temperature, e.g. Labrafac Lipophile, Labrafil M1944CS, Labrasol, Transcutol, Peceol, and Plurol manufactured by Gatefosse, Elmsford, New York, USA; non-ionic surfactants e.g.
  • polyoxyemylene (20) sorbitan monooleate or sorbitan laurate; triethyl citrate, acetyl triemyl citrate, tri-n-butyl citrate, or acetyl tri-n-butyl citrate manufactured by Morflex, Greensboro, NC, USA; glycerly triacetate; polyoxyethylene-polyoxypropylene polymer; diethylene glycol monoemyl ether or any other liquids which do not solubilise either the capsule shell material or the particles can also be used. Vegetable oils or mineral oils which are GRAS materials an enjoy a long history of use in the pharmaceutical formulation arts are also preferred.
  • a list of useful vegetable oils will include castor bean oil, coconut oil, peanut oil, palm kernel oil, canola oil, avocado oil, evening primrose oil, rice bran oil, borage oil, sunflower oil, soyabean oil, palm oil, corn oil, and sunflower oil. All will perform well in the context of the preferred hard-shelled gelatin capsule. This list is not intended to be exhaustive; any liquid can be used so long as it is safe for human or animal consumption and has me requisite physical properties noted above.
  • any form of particle may be used in the dosage form of the invention, so long as it contains or comprises a beneficial agent, is stable in the suspending liquid, is visible to me naked eye, and moves within me capsule when it is tilted.
  • beneficial agent means any compound or material which has a beneficial effect on a mammal when consumed for its intended use in me manner prescribed.
  • a drug is a beneficial agent for me purposes of this definition.
  • omer compounds or materials which can have a subjective or objective beneficial effect on the user and which are to be included widiin the meaning of this term.
  • Nutritional agents such as vitamins, minerals, or amino acid supplements are beneficial to those needing to supplement their diet.
  • Flavours and sweeteners provide a subjective benefit and a source of energy as well, and are also included.
  • Drugs and drug delivery are of greatest interest herein.
  • the word "drug” is used in its broadest sense and includes any agent which exhibits a pharmacological effect on me user and which can be administered orally in the form of particles as described herein. Any solid or liquid form of a drug can be used provided it can be manufactured into a particulate form, as is true for any compound or material which constitutes a beneficial agent for the purposes of this invention.
  • Bom fat soluble and water soluble drugs may be used.
  • Drugs for treating pain and inflammation and cough cold, and allergy symptoms are of particular interest. They include drugs for treating inflammation, pain and pyrexia; antihistamines, nasal decongestants; expectorants; sedatives as used in cough and cold remedies, and the like.
  • Paracetamol, aspirin or another non-steroidal anti-inflammatory drug such as ibuprofen, naproxen or ketoprofen, phenylpropanolamine hydrochloride, caramiphen edisylate, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, and chlorpheniramine maleate are most preferred.
  • particles size, density, stability, lack of adhesion to the capsule wall and lack of agglomeration are me only limiting factors. So far as size is concerned, me principal consideration will be that of creating a particle of a size such tiiat the particles are visible to the naked eye under normal lighting conditions, while making them small enough to flow in the suspending liquid and tumble over one another when the capsule is tilted.
  • Preferred particles will be in the range of about 100 to 1500 microns.
  • Particle size can vary in any given capsule, just so long as the variance is not so great that the larger particles obscure the smaller ones.
  • the preferred particle size is between about 420 and 840 microns (about 20-40 mesh). Sizing can be achieved by any appropriate means. Large particles can be reduced by grinding and sieving through screens until the right size cut is achieved. Small particles can be built up to a desired size by conventional coating technologies. All these processes are well known in the formulation arts.
  • Particles may for example be round, irregular, oblong, elliptical, or square. Particles can have different shapes so long as the particles can flow freely over one another when the capsule is tilted. Round or spherical particles in the form of beads are preferred.
  • Particles can comprise pure agent or a mixture of pure agent and excipients and can be manufactured by methods well known in the art, including for example extrusion/marumerisation and prilling.
  • the particle may be coated with a protective layer which may or may not affect how fast the particle dissolves and releases the active ingredient. Coating may be included for functional and/or aesthetic reasons and may be effected by methods well known in the art.
  • Pan coating for example, is a well established technology that provides a basic pellet. Another approach is to create a core or seed and then to add one or more layers of a coating to the core.
  • red, white and blue particles will be much more apparent than what will be observed if all the particles are white.
  • Dyes or lakes of any sort may be used provided they are non-toxic and do not have an untoward or deleterious effect on the user.
  • particles will be manufactured to be heavier than the carrier liquid.
  • the liquid carrier may have higher density than the particles so that when the capsule is tilted, the liquid will shift and push the less dense particles to another location within the capsule.
  • Particle stability as well as intrinsic stability of the beneficial agent are factors which must be taken into consideration when matching particle and liquid, and the composition of the capsule wall-forming material.
  • the particle should remain chemically inert when in contact with the liquid and the capsule wall-forming materials and should not dissolve in the suspending liquid to any significant extent.
  • the particle will be insoluble in the suspending liquid.
  • Particle coatings known to be soluble in a given carrier liquid should accordingly be avoided when formulating coated beads.
  • gelatin materials used to make hard-shell gelatin capsules contain substantial amounts of water which may have a deleterious affect on the particles .
  • liquid vehicles containing substantial amounts of water could have a deleterious effect on gelatin capsules.
  • Each formulation must be addressed on a case-by-case basis is within the skill of one trained in the formulation arts.
  • Dosage forms according to the present invention provide means for delivering poorly bioavailable drugs together with absorption enhancers.
  • Absorption enhancers may be dissolved in the liquid vehicle whilst the drug is contained in particulate form.
  • a further variation can be to incorporate a drug substance in solution or as a very fine suspension in the liquid vehicle.
  • a drug substance incorporated in this manner may function as a loading dose which will be rapidly absorbed into the blood stream to provide immediate therapeutic benefit.
  • continuous release of drug substances over an extended time period may be achieved from beads suspended in the liquid vehicle.
  • the liquid vehicle may be modified to solubilise the drug.
  • the liquid vehicle may comprise two or more phases, namely a component in which a drug is soluble and a component which a drug is insoluble.
  • drugs having different solubility profiles may be incorporated.
  • Dosage forms of the invention may also be used to deliver drug substances which interact with one another by dissolving one drug in the liquid vehicle and confining a second drug to particulate form.
  • different drugs can be contained in separate particles or beads.
  • a hard-shell capsule according to the invention will be a capsule filled with a liquid which contains particles where the volume of the particles does not amount to more than about 90% of the internal volume of the capsule.
  • the particles will be present in an amount which fills between about 40 to 80% of the capsules' internal volume.
  • Hard-shell capsules of any form or shape can be used in this invention, limited only by the availability of manufacturing methods and the requirement that when in use the shape does not have a restriction point which interferes with particle or liquid movement to a degree that obviates the benefits of this invention.
  • a suitable capsule is the commercially available hard-gel capsule which is formed from two co-operating parts.
  • the junction is suitably provided wid a seal to preclude leakage of the carrier liquid.
  • Suitable means for sealing hard-shell capsules are known in the art.
  • Capsule-filling apparatus are available which can fill capsules with liquid vehicle and particles, either sequentially or simultaneously to provide a dosage form according to the invention.
  • Ibuprofen beadlets were prepared as described in WO 93/00991. Beadlets are sugar coated and introduced into a standard hard-shell gelatin capsule (size 0) together with corn oil to provide 400mg ibuprofen per capsule. The two halves of the capsule shell are sealed by applying a gelatin band to the junction between the body and the cap of the capsule.
  • Sugar starch beadlets (approximate diameter 0.5mm) are sprayed with an ethanolic solution of dextrometiiorphan hydrobromide in a suitable coating column, to give white spherical beads containing approximately 10% dextrometiiorphan hydrobromide. These beads are then sprayed with an aqueous suspension containing ethyl cellulose, hydroxypropylmethyl cellulose and triethyl acetate in the same coating column to give white spherical beads containing approximately 9% dextrometiiorphan hydrobromide and 10% polymeric coating.
  • the beads are then filled into the bodies of transparent colourless hard gelatin capsule shells (size 1) together with an aliquot of edible rape seed oil which substantially fills the body of the capsule shell, the capsule shell caps are subsequently fitted to the capsule body and the two halves of the capsule are sealed with a band of transparent gelatin to give transparent colourless hard gelatin capsules containing rape seed oil and dextrometiiorphan hydrobromide sustained release beadlets, whereby each capsule contains approximately 40mg dextrometiiorphan hydrobromide.
  • Sugar starch beadlets (approximate diameter 0.5mm) are sprayed with an aqueous solution of chlo ⁇ heniramine maleate in a suitable coating column, to give white spherical beads containing approximately 1 % chlo ⁇ heniramine maleate. These beads are then sprayed with an aqueous suspension containing ethyl cellulose, hydroxypropylmethyl cellulose and triethyl acetate in the same coating column to give white spherical beads containing approximately 0.9% chlo ⁇ heniramine maleate and 10% polymeric coating.
  • the beads are then filled into the bodies of transparent orange hard gelatin capsule shells (size 1) togetiier with an aliquot of edible rape seed oil which substantially fills the body of the capsule shell, the capsule shell caps are subsequently fitted to the capsule body and the two halves of the capsule are sealed with a band of transparent gelatin, to give transparent orange coloured hard gelatin capsules containing rape seed oil and chlo ⁇ heniramine maleate sustained release beadlets, whereby each capsule contains approximately 4mg chlo ⁇ heniramine maleate.
  • Sugar starch beadlets (approximate diameter 0.5mm) are sprayed with an ethanolic solution of pseudoephedrine hydrochloride in a suitable coating column, to give white spherical beads containing approximately 10% pseudoephedrine hydrochloride. These beads are then sprayed with an aqueous suspension containing ethyl cellulose, hydroxypropylmethyl cellulose and triethyl acetate in the same coating column to give white spherical beads containing approximately 9% pseudoephedrine hydrochloride and 10% polymeric coating.
  • the beads are then filled into the bodies of transparent colourless hard gelatin capsule shells (size 0) togetiier with an aliquot of edible coconut oil which substantially fills the body of the capsule shell, the capsule shell caps are subsequently fitted to the capsule body and the two halves of the capsule are sealed with a band of transparent gelatin, to give transparent colourless hard gelatin capsules containing coconut oil and pseudoephedrine hydrochloride sustained release beadlets, whereby each capsule contains approximately 120mg pseudoephedrine hydrochloride.
  • Polymer coated beadlets from Example 2 and Example 3 are mixed together in a ratio of approximately 1: 1 and then filled into the bodies of transparent orange hard gelatin capsule shells (size 00) together with an aliquot of edible rape seed oil which substantially fills the body of the capsule shell, the capsule shell caps are subsequently fitted to the capsule body and the two halves of the capsule are sealed with a band of transparent gelatin, to give transparent orange coloured hard gelatin capsules containing rape seed oil, chlo ⁇ heniramine maleate sustained release beadlets and dextrometho ⁇ han hydrobromide sustained release beadlets, whereby each capsule contains approximately 4mg chlo ⁇ heniramine maleate and 40mg dextrometho ⁇ han hydrobromide.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (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)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)

Abstract

Formes galéniques orales comportant des gélules à enveloppe dure partiellement ou totalement transparentes renfermant des particules qui contiennent un agent bénéfique en suspension dans un véhicule liquide. Les formes galéniques préférées comportent des gélules à enveloppe dure de gélatine.
PCT/EP1997/001352 1996-03-21 1997-03-17 Gelules transparentes dures WO1997034585A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9605948.0 1996-03-21
GBGB9605948.0A GB9605948D0 (en) 1996-03-21 1996-03-21 Novel formulations

Publications (1)

Publication Number Publication Date
WO1997034585A1 true WO1997034585A1 (fr) 1997-09-25

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/001352 WO1997034585A1 (fr) 1996-03-21 1997-03-17 Gelules transparentes dures

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GB (1) GB9605948D0 (fr)
WO (1) WO1997034585A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7229639B2 (en) * 2002-03-11 2007-06-12 Warner-Lambert Company Ibuprofen containing hard shell capsules
EP1228125A4 (fr) * 1999-09-14 2009-09-02 Smithkline Beecham Corp Procede relatif a la formation de granules a revetement aqueux
US8957095B2 (en) 2009-10-26 2015-02-17 Sephoris Pharmaceuticals, Llc Treatment of sunburn using analgesics and antihistamines

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000125A1 (fr) * 1993-06-18 1995-01-05 Smithkline Beecham Corporation Particules encapsulees dans une enveloppe souple en gelatine
WO1995001787A1 (fr) * 1993-07-09 1995-01-19 Smithkline Beecham Corporation Particules encapsulees dans la gelatine formant une enveloppe souple
WO1996041622A1 (fr) * 1995-06-09 1996-12-27 R.P. Scherer Corporation Capsules gelatineuses molles contenant un materiau particulaire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000125A1 (fr) * 1993-06-18 1995-01-05 Smithkline Beecham Corporation Particules encapsulees dans une enveloppe souple en gelatine
WO1995001787A1 (fr) * 1993-07-09 1995-01-19 Smithkline Beecham Corporation Particules encapsulees dans la gelatine formant une enveloppe souple
WO1996041622A1 (fr) * 1995-06-09 1996-12-27 R.P. Scherer Corporation Capsules gelatineuses molles contenant un materiau particulaire

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1228125A4 (fr) * 1999-09-14 2009-09-02 Smithkline Beecham Corp Procede relatif a la formation de granules a revetement aqueux
US7229639B2 (en) * 2002-03-11 2007-06-12 Warner-Lambert Company Ibuprofen containing hard shell capsules
US8957095B2 (en) 2009-10-26 2015-02-17 Sephoris Pharmaceuticals, Llc Treatment of sunburn using analgesics and antihistamines
US9895360B2 (en) 2009-10-26 2018-02-20 Sephoris Pharmaceuticals, Llc Treatment of sunburn using analgesics and antihistamines
US10751331B2 (en) 2009-10-26 2020-08-25 Sephoris Pharmaceuticals, Llc Treatment of sunburn using analgesics and antihistamines

Also Published As

Publication number Publication date
GB9605948D0 (en) 1996-05-22

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