WO1998042319A2 - Compositions non aqueuses pour administration par voie orale - Google Patents

Compositions non aqueuses pour administration par voie orale Download PDF

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Publication number
WO1998042319A2
WO1998042319A2 PCT/EP1998/001580 EP9801580W WO9842319A2 WO 1998042319 A2 WO1998042319 A2 WO 1998042319A2 EP 9801580 W EP9801580 W EP 9801580W WO 9842319 A2 WO9842319 A2 WO 9842319A2
Authority
WO
WIPO (PCT)
Prior art keywords
oil
composition
emulsifier
biologically active
soluble
Prior art date
Application number
PCT/EP1998/001580
Other languages
English (en)
Other versions
WO1998042319A3 (fr
Inventor
Maarten Van Den Braak
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
Priority to EP98916998A priority Critical patent/EP0973503A2/fr
Priority to AU70371/98A priority patent/AU7037198A/en
Publication of WO1998042319A2 publication Critical patent/WO1998042319A2/fr
Publication of WO1998042319A3 publication Critical patent/WO1998042319A3/fr

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to compositions suitable for oral administration comprising oils or oil soluble ingredients useful in the maintenance and/or promotion of health, in capsule form.
  • WO94/06310 discloses an aqueous composition for the preparation of optically clear products for use in human and animal healthcare comprising 0.1 to 2.0 % w/w of an oil soluble ingredient as a 20-30%w/w dispersion in a suitable oil or 0.1 to 5.0% w/v as the pure crystalline ingredient, 2-20% w/w of an emulsifier having an HLB value of between 10 and 18 or where a blend of emulsifiers is employed, a calculated HLB value of between 10 and 18 and 0.1 %w/w of an antioxidant or a mixture of antioxidants.
  • WO 95/24832 discloses similar aqueous compositions for the preparation of optically clear products based on biologically active oils.
  • the present invention provides an essentially non-aqueous composition for use in human or animal healthcare comprising a biologically active oil or an oil-soluble ingredient or a biologically active oil or an oil-soluble ingredient as a dispersion in a suitable carrier oil, dispersed in a physiologically acceptable emulsifier or emulsifier mixture having an HLB (hydrophilic/lipophilic balance) value of between 10 and 18 and encapsulated in a capsule material that is soluble in gastric juice.
  • HLB hydrophilic/lipophilic balance
  • Biologically active oil or oil-soluble ingredient/emulsifier compositions for encapsulation may be prepared using the techniques described in WO 94/06310 or WO 95/24832 but omitting the addition of water to the compositions described in those documents.
  • the entire disclosures of WO 94/06310 and WO 95/24832 are incorporated herein by reference.
  • an essentially non-aqueous composition for encapsulation may be prepared by: a) dispersing an antioxidant in an emulsifier or mixture of emulsifiers having an HLB (hydrophilic/lipophilic balance) value of between 10-18 while heating to a temperature of approximately 40°C; b) dispersing one or more oil-soluble ingredients, or one or more oil-soluble ingredients as a dispersion in a suitable carrier oil, in the mixture in a) above while heating to between about 80 - 200°C so as to yield a transparent mixture.
  • HLB hydrophilic/lipophilic balance
  • an essentially non-aqueous composition for encapsulation may be prepared by: a) mixing a biologically active oil with an antioxidant or antioxidant mixture b) dispersing the oil-antioxidant mixture in an emulsifier or mixture of emulsifiers having an HLB value of from 10 to 18, while heating to between 50-150°C so as to yield a transparent mixture.
  • the antioxidant in a) is dispersed initially with the emulsifier before mixing with the biologically active oil.
  • an essentially non-aqueous composition for encapsulation is prepared using techniques described in PCT/EP96/04168, published as WO 97/10725 after the priority date of this application, by mixing a biologically active oil or oil soluble ingredient, or a biologically active oil or oil soluble ingredient as a dispersion in a suitable carrier oil, with an emulsifier mixture having an HLB (hydrophilic lipophilic balance) value of between 10 and 18, heating to between 25 and 150 °C, if required, so as to yield a transparent mixture and, where heat has been applied, cooling the said transparent mixture to room temperature.
  • HLB hydrophilic lipophilic balance
  • the emulsifier mixture is a combination of a primary surfactant and a secondary surfactant or cosurfactant, wherein the fatty acid profile of the emulsifier mixture matches the fatty acid profile of the oil or oil soluble ingredient or oil dispersion of the oil or oil soluble ingredient and the HLB of the primary surfactant is greater than that of the cosurfactant.
  • a composition for encapsulation according to the invention is prepared by mixing 0.15-50% w/w of a biologically active oil or oil soluble ingredient, or a biologically active oil or oil soluble ingredient as a dispersion in a suitable carrier oil, with 50-99.85%w/w of emulsifier until a transparent mixture is formed, if necessary at elevated temperature and with subsequent cooling.
  • the weight ratio of total oil or oil soluble ingredient to emulsifier is preferably between 1 : 1 and 1 :7 and, where a cosurfactant is present, the ratio of primary surfactant to cosurfactant is preferably between 10: 1 and 200: 1.
  • the weight ratio of primary surfactant to polymeric alcohol is between 1 :1 and 1: 10.
  • the ratio of total oil or oil soluble ingredient to emulsifier is between 1 : 1 and 1 :5.
  • the ratio primary surfactant to cosurfactant is between 20: 1 and 50:1, and is most suitably about 30:1.
  • the material used for encapsulation is typically a water-soluble material such as gelatin.
  • Soft gelatin capsules are preferred. When swallowed by a human or animal, the capsule disintegrates in the stomach, releasing the oil or oil-soluble ingredient emulsifier composition for emulsification in the gastric juice and making the oil or oil-soluble ingredient available for absorption.
  • PCT/EP96/04168 assists in the formation of emulsions with increased bioavailability.
  • Encapsulation of the oil or oil-soluble ingredient/emulsifier composition is carried out conventionally, for example using procedures described in The Pharmaceutical CODEX , Twelfth Edition, Ed Walter Lund, P23-24 1994.
  • the encapsulated composition of the present invention is a product with desirable properties, particularly high dispersability in the stomach following oral administration, using ingredients which have hitherto been found to be difficult to solubilise satisfactorily in this kind of product. Further advantages of an encapsulated formulation over the aqueous compositions of the prior art include the convenience of a low volume, solid dosage form and the avoidance of any undesirable taste which may be associated with any of the ingredients when administered in a liquid dosage form.
  • compositions of the present invention over known compositions is one of economy since it allows products with minimal amounts of emulsifiers to be developed.
  • the compositions are particularly useful for incorporation of biologically active materials into preparations that result in a microdispersed form in the stomach which facilitates uptake.
  • Certain biologically active oils and oil soluble ingredients are vitamins and provitamins such as vitamins A, D, E, carotenoid pigments and nutritionally important fatty acids.
  • biologically active oils are oils of natural origin for example from the seeds or flowers of the Ribes, Boraginaceae, Labiataea , Onagraceae and Curcubitaceae species, oils of fungal origin, fish oils or other natural oils.
  • Preferred oils include evening primrose oil, borage/starflower oil and blackcurrant seed oil.
  • compositions of the invention contain a total amount of oil in the range 0.15- 50 %, preferably 10- 50% by weight.
  • Oils for use in the present invention can be extracted from natural sources by processes known in the art. Oils are commercially available, for example, from Sigma Chemical Co., Poole, Dorset.
  • the compositions can contain more than one biologically active oil.
  • compositions suitable for use in the capsule composition according to the invention include carotenoid pigments, eg. ⁇ -carotene and oil soluble vitamins, eg. tocopherols such as tocopherol acetate (vitamin E).
  • carotenoid pigments eg. ⁇ -carotene
  • oil soluble vitamins eg. tocopherols such as tocopherol acetate (vitamin E).
  • compositions containing carotenoids, such as lycopene and ⁇ -carotene as an oil soluble ingredient are particularly useful.
  • carotenoids such as lycopene and ⁇ -carotene as an oil soluble ingredient
  • Particularly suitable sources of ⁇ -carotene include both natural and synthetic ⁇ -carotene as dispersions in oil (as available from various commercial sources including those mentioned herein).
  • the biologically active oils and oil-soluble ingredients may be mixed or dispersed with other suitable oils in particular, consumable oils for example, corn, peanut, safflower, olive and rapeseed oils as well as many essential oils.
  • Emulsifiers for use in compositions of the invention may be any anionic, cationic , amphoteric or non-ionic emulsifiers which are suitable for consumption by humans or animals.
  • the emulsifiers are non-ionic emulsifiers or mixtures of emulsifiers having an HLB (hydrophilic/lipophilic balance) of 12 -16 and most preferably have an HLB value of 15.
  • HLB hydrophilic/lipophilic balance
  • Suitable emulsifiers include Tween 60 (polyoxyethylene(20)sorbitan monostearate, Tween 40 (polyoxyethylene(20)sorbitan monopalmitate), Tween 80 (polyoxyethylenesorbitan monooleate) and Span 80 (sorbitan monooleate) available from ICI Speciality Chemicals, Leatherhead, Surrey or from Sigma Chemical
  • Preferred emulsifier mixtures include mixtures of Tween 80 and Span 80 or Tween 80 and Tween 40.
  • the emulsifier mixture is a binary or tertiary blend of emulsifiers, for example blends of Tween 60 with a sucrose ester emulsifier (manufactured by Mitsubishi Kasei Food Corporation, Ichikawa Building, 13-3 Ginza 5-Chome, Chuo-ku, Tokyo 104, Japan) or blends of Tween 60 and sucrose ester and a polyglycerol ester of a fatty acid (available from Grindsted Products Limited., Northern Way, Bury St. Edmunds, Suffolk).
  • the amount of emulsifier or emulsifier mixture in the composition is selected as an amount which will vary depending upon which specific biologically active oil or oil- soluble ingredient is used, its method of preparation, and how much is included.
  • the composition advantageously comprises in addition an antioxidant which can be for example, ⁇ -tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) or a mixture of such antioxidants.
  • an antioxidant which can be for example, ⁇ -tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) or a mixture of such antioxidants.
  • Particularly preferred antioxidants are ⁇ -tocopherol, ascorbyl palmitate and ascorbic acid.
  • compositions of the present invention containing biologically active oils and oil- soluble ingredients are believed to disperse in a micellar form or as microemulsions in an aqueous environment because they exhibit certain characteristics eg. transparency when viewed by transmitted light in test dissolutions. Therefore a further advantage of the capsule compositions according to the present invention is that the fine dispersion of these oils and oil-soluble ingredients in the stomach will help to promote their efficient uptake by body tissues when the composition is administered orally as a capsule. Whilst the small particle size of the particles of biologically active oils and oil soluble ingredients favour their uptake, the simultaneous presentation or ingestion of these materials with an emulsifier will also encourage efficient transfer of these substances across membranes.
  • the dispersed microemulsions also have acid resistance. This is advantageous because prior to absorption from the intestinal tract, the microemulsion is able to survive the strongly acid conditions of the stomach.
  • a method of administration of a biologically active oil or an oil-soluble material to a human or animal by oral administration of a capsule composition according to the invention also provides a method of improving the bioavailability of a biologically active oil or oil- soluble ingredient in a human or animal body comprising orally administering a capsule composition according to the invention.
  • compositions also contain antioxidant cofactors such as zinc, selenium and manganese which are needed for the body's naturally occurring antioxidant enzymes.
  • Further nutritive ingredients may be added, such as other vitamins and minerals as described in "The Food Labelling Regulations 1984" Statutory Instrument No. 1305 (1984) H.M.S.O, London.
  • processing aids can be incorporated. Such aids may include ingredients which influence pH, redox potential, enzyme activity, hydrogen bonding and/or other aspects. Processing aids are for example sulphur dioxide, other antioxidants, metal salts, acids (eg. phosphoric and citric acid), alkalis, surfactants such as lecithin and starch plasticisers eg. calcium chloride.
  • ingredients which may be subject to a loss of nutritional value are suitably added at a late stage of the process.
  • the product can be produced in light or oxygen excluding containers prior to encapsulation to increase protection of materials sensitive to light or oxygen induced degradation.
  • compositions for encapsulation incurs the risk of degradation of certain oils or oil-soluble ingredients unless suitable precautions are taken.
  • suitable precautions For example it may be desirable to incorporate an antioxidant in the initial stages of preparation or to exclude oxygen by heating the mixture in an atmosphere of nitrogen.
  • carotene and tocopherol including active derivatives thereof
  • capsules to deliver high bioavailability carotenes and Vitamin E by oral administration for use in medicine.
  • the invention is illustrated by the following Examples.
  • the improved bioavailability of materials delivered by capsule compositions of this invention can be assessed by the test regime set out after the Examples.
  • the ⁇ -carotene and tocopheryl acetate are dispersed in the two emulsifiers and the mixture is heated to 140 °C with stirring. At this point the mixture should remain transparent. Finally, the mixture is cooled rapidly to room temperature.
  • Example 2 The resultant mixture is encapsulated in gelatin capsules so as to contain approx. 15 mg ⁇ -carotene per capsule.
  • Example 2
  • the ⁇ -carotene is dispersed in the two emulsifiers and the mixture is heated to 140 °C with stirring. At this point the mixture should remain transparent. Finally, the mixture is cooled rapidly to room temperature.
  • the resultant mixture is encapsulated in gelatin capsules so as to contain approx. 15 mg ⁇ -carotene per capsule.
  • the tocopheryl acetate is dispersed in the emulsifier and polyethylene glycol with stirring at room temperature.
  • the mixture should remain transparent.
  • the resultant mixture is encapsulated in gelatin capsules so as to contain approx. 15 mg tocopheryl acetate per capsule.
  • %w/w ⁇ -carotene (crystalline) 12.8 emulsifier (polysorbate 60) 77.0 emulsifier (sugar ester S- 1170) 3.2 emulsifier (Triodan) 3.2 ⁇ -tocopherol (antioxidant) 3.8
  • ⁇ -Tocopherol is dispersed in a mixture of the three emulsifiers, followed by the ⁇ - carotene and the mixture is heated to 140 °C with stirring. At this point the mixture should remain transparent. Finally, the mixture is cooled rapidly to room temperature. The resultant mixture is encapsulated in gelatin capsules so as to contain approx. 15 mg ⁇ -carotene per capsule.
  • Capsule formulations of this invention can be tested to assess improved bioavailability as follows:
  • the study is designed to give information on the initial rate of uptake and amplitude of response for each dosage form.
  • Test materials Capsules containing 15mg beta-carotene, either test material according to the invention or Roche Products Redoxon capsules. Placebo capsule containing corn oil. Capsules to be swallowed with 250ml water.
  • Experimental Design :

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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Abstract

L'invention concerne des compositions essentiellement non aqueuses, qui sont adaptées pour être administrées par voie orale et qui contiennent une huile biologiquement active ou un ingrédient soluble dans l'huile ou une huile biologiquement active ou un ingrédient soluble dans l'huile se présentant sous forme de dispersion dans une huile pouvant servir de véhicule. Ces compositions sont dispersées dans un émulsifiant physiologiquement acceptable ou un mélange émulsifiant ayant un rapport hydrophile-lipophile situé entre 10 et 18 et elles sont encapsulées dans une capsule soluble dans le suc gastrique. L'invention concerne également la production et l'utilisation de ces compositions nouvelles pour le maintien et/ou la promotion de la santé.
PCT/EP1998/001580 1997-03-20 1998-03-13 Compositions non aqueuses pour administration par voie orale WO1998042319A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP98916998A EP0973503A2 (fr) 1997-03-20 1998-03-13 Compositions non aqueuses pour administration par voie orale
AU70371/98A AU7037198A (en) 1997-03-20 1998-03-13 Non-aqueous compositions for oral administration

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9705813.5A GB9705813D0 (en) 1997-03-20 1997-03-20 Novel compositions
GB9705813.5 1997-03-20

Publications (2)

Publication Number Publication Date
WO1998042319A2 true WO1998042319A2 (fr) 1998-10-01
WO1998042319A3 WO1998042319A3 (fr) 1998-12-17

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ID=10809593

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Application Number Title Priority Date Filing Date
PCT/EP1998/001580 WO1998042319A2 (fr) 1997-03-20 1998-03-13 Compositions non aqueuses pour administration par voie orale

Country Status (5)

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EP (1) EP0973503A2 (fr)
AU (1) AU7037198A (fr)
GB (1) GB9705813D0 (fr)
WO (1) WO1998042319A2 (fr)
ZA (1) ZA982334B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002056709A1 (fr) * 2001-01-17 2002-07-25 R.P. Scherer Technologies, Inc. Compositions ingerables contenant une huile odoriferante
WO2005039307A1 (fr) * 2003-10-22 2005-05-06 Adisseo France S.A.S. Procede zootechnique pour l'administration d'un derive de vitamine e et formulation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0196085A2 (fr) * 1985-03-28 1986-10-01 Eisai Co., Ltd. Compositions à absorption améliorée contenant de l'ubidécarénone
FR2643263A1 (fr) * 1989-02-23 1990-08-24 Glaxo Canada Composition pharmaceutique a base de ranitidine
WO1991002520A1 (fr) * 1989-08-17 1991-03-07 Cortecs Limited Compositions pharmaceutiques
WO1994006310A1 (fr) * 1992-09-15 1994-03-31 Smithkline Beecham Plc Nouvelles compositions
DE4322826A1 (de) * 1993-07-08 1995-01-12 Galenik Labor Freiburg Gmbh Pharmazeutisches Präparat
EP0670166A2 (fr) * 1994-03-01 1995-09-06 Eli Lilly And Company Compositions pharmaceutiques administrables par voie buccale
WO1995024832A1 (fr) * 1994-03-15 1995-09-21 Smithkline Beecham Plc Compositions stables, optiquement transparentes
WO1997010725A1 (fr) * 1995-09-23 1997-03-27 Smithkline Beecham Plc Nouveau procede

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JPS6067424A (ja) * 1983-09-22 1985-04-17 Nisshin Flour Milling Co Ltd 制癌剤
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JPH08259451A (ja) * 1995-03-24 1996-10-08 Lion Corp 天然カロチノイドを包含した多芯型構造のマイクロカプセル又はその用途

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Publication number Priority date Publication date Assignee Title
EP0196085A2 (fr) * 1985-03-28 1986-10-01 Eisai Co., Ltd. Compositions à absorption améliorée contenant de l'ubidécarénone
FR2643263A1 (fr) * 1989-02-23 1990-08-24 Glaxo Canada Composition pharmaceutique a base de ranitidine
WO1991002520A1 (fr) * 1989-08-17 1991-03-07 Cortecs Limited Compositions pharmaceutiques
WO1994006310A1 (fr) * 1992-09-15 1994-03-31 Smithkline Beecham Plc Nouvelles compositions
DE4322826A1 (de) * 1993-07-08 1995-01-12 Galenik Labor Freiburg Gmbh Pharmazeutisches Präparat
EP0670166A2 (fr) * 1994-03-01 1995-09-06 Eli Lilly And Company Compositions pharmaceutiques administrables par voie buccale
WO1995024832A1 (fr) * 1994-03-15 1995-09-21 Smithkline Beecham Plc Compositions stables, optiquement transparentes
WO1997010725A1 (fr) * 1995-09-23 1997-03-27 Smithkline Beecham Plc Nouveau procede

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CHEMICAL ABSTRACTS, vol. 118, no. 8, 22 February 1993 Columbus, Ohio, US; abstract no. 66767, XP002080683 & S.K.COLE ET AL.: "STUDIES USING A NONIONIC SURFACTANT-CONTAINING DRUG DELIVERY SYSTEM DESIGNED FOR HARD GELATIN CAPSULE COMPATIBILITY" INT. J. PHARM., vol. 88, no. 1-3, 1992, pages 211-220, *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002056709A1 (fr) * 2001-01-17 2002-07-25 R.P. Scherer Technologies, Inc. Compositions ingerables contenant une huile odoriferante
JP2004520355A (ja) * 2001-01-17 2004-07-08 アール．ピー． シェーラー テクノロジーズ インコーポレイテッド 臭気性オイルを含有する摂取可能な組成物
US9532585B2 (en) 2001-01-17 2017-01-03 R.P. Scherer Technologies, Llc Ingestible compositions containing an odoriferous oil
WO2005039307A1 (fr) * 2003-10-22 2005-05-06 Adisseo France S.A.S. Procede zootechnique pour l'administration d'un derive de vitamine e et formulation
AU2004283508B2 (en) * 2003-10-22 2010-07-15 Adisseo France S.A.S. Veterinary method for administering a vitamin E derivative and formulation

Also Published As

Publication number Publication date
WO1998042319A3 (fr) 1998-12-17
EP0973503A2 (fr) 2000-01-26
AU7037198A (en) 1998-10-20
GB9705813D0 (en) 1997-05-07
ZA982334B (en) 1998-12-01

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