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WO1999011240A1 - Microemulsions de carotenoides - Google Patents

Microemulsions de carotenoides Download PDF

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Publication number
WO1999011240A1
WO1999011240A1 PCT/EP1998/005502 EP9805502W WO9911240A1 WO 1999011240 A1 WO1999011240 A1 WO 1999011240A1 EP 9805502 W EP9805502 W EP 9805502W WO 9911240 A1 WO9911240 A1 WO 9911240A1
Authority
WO
WIPO (PCT)
Prior art keywords
carotene
beta
microemulsion
expression
cancer
Prior art date
Application number
PCT/EP1998/005502
Other languages
English (en)
Inventor
Maarten Van Den Braak
Nicholas Leslie Meyers
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 EP98945297A priority Critical patent/EP1009381A1/fr
Priority to JP2000508343A priority patent/JP2001514207A/ja
Publication of WO1999011240A1 publication Critical patent/WO1999011240A1/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to compositions for use in cancer prevention and treatment and novel compositions and processes for preparing said compositions.
  • agents which have been shown to have useful activity in cancer prevention and treatment based on in vitro studies or models are difficult to formulate for therapeutic use.
  • agents which are oil soluble, such as carotenoids are relatively difficult to administer orally and/or topically, compared to more easily administered aqueous formulations.
  • Carotenoids are naturally-occurring pigments of the terpenoid group which can be found in plants, algae and bacteria. They include 'carotene' (a mixture of alpha and beta-carotenes but mostly beta-carotene), alpha-carotene, beta-carotene, gamma-carotene, lycopene, zeaxanthin, lutein (alpha-xanthophyll), bixin (e.g, from solvent extracted annatto), capsanthin (paprika), canthaxanthin, astaxanthin, actinioerythrol, violerythrin, beta-8'-apo-carotenal (apo-carotenal), beta-12'-apo-carotenal and esters of hydroxyl- or carboxyl-containing members thereof. Many of the carotenoids occur in nature as cis and trans-isomeric forms, while synthetic compounds are frequently racemic mixtures.
  • beta-carotene levels correlate with dietary vitamin A intake (Van Eenwyk, J., Davis, F.G & Bowen, P.E. (1991) "Dietary and serum carotenoids and cervical intraepithelial neoplasia” Int. J. Cancer 48: 34-38; de Vet, H.C., Knipschild, P.G., Grol, M.E., Schouten, H.J & Sturmans, F. (1991) "The role of beta-carotene and other dietary factors in the aetiology of cervical dysplasia: results of a case-controlled study" Int. J. Epidemiol. 20: 603-610) and several studies have correlated low intake of vitamin A with increased risk of cervical dysplasia (Liu, T., Wilson, N.P., Craig, C.B., Tamura, T., Soong,
  • Beta-carotene has been shown to inhibit oral carcinogenesis in several animal models e.g, (Schwartz, J.L., Shklar, E., Flynn, E & Trickier, D. (1990) "The administration of beta- carotene, regression of oral carcinoma in the hamster cheek pouch and the associated enhancement of the immune response" Adv. Exp. Med. Biol. 262: 77-93) and a number of clinical studies have shown that beta-carotene can produce regression of oral leukoplakia (Kaugars, G.E., Silverman, S., Lovas, J.G., Brandt, R.B., Riley, W.T., Dao, Q., Singh, V.N & Gallo, J. (1994).
  • beta-carotene appears to enhance immune system performance by increasing NK cell proliferation and T-cells expressing surface MHC-Ia, therefore allowing them to present viral antigen (Prabhala, R.H., Garewal, H.S., Hicks, M.J., Sampliner, R.E & Watson, R.R. (1991) "The effects of 13-cis-retinoic acid and beta-carotene on cellular immunity in humans" Cancer 67: 1556-1560).
  • Carotenoids can inhibit chemically induced neoplastic transformation in vitro, probably via positive regulation of connexin gene expression, in particular connexin-43, which is involved in cell-cell communication (Bertram, J.S. (1993) "Cancer prevention by carotenoids: Mechanistic studies in cultured cells” Ann. New York Acad. Sci. 691 : 177-191; Zhang, L.X., Cooney, R.V & Bertram, J.S. (1992) "Carotenoids up-regulate connexin-43 gene expression independent of their provitamin A or antioxidant properties" Cancer Res.
  • gap-junction communication is known to be perturbed upon transformation with HPV-16 (Ennaji, M.M., Schwartz, J.L., Mealing, G., Belbaraka, L., Parker, C, Parentaux, M., Jouis Subscribe, H. , Arella, M., Whitfield, J.F and Phipps, J (1995) "Alterations in cell-cell communication in human papillomavirus type 16-transformed rat myoblasts" Cell Mol. Biol.
  • carotenes could be effective in inhibiting and/or reversing cellular neoplastic transformation in a variety of tissues, many of these e.g, oro-pharangeal carcinoma, are typically difficult to treat using oral formulations and rely upon high systemic bioavailability and there are to date no effective formulations available to successfully treat such indications.
  • human volunteers subjected to a carotene-rich diet for 3 months demonstrated elevated serum and GI tissue concentrations of beta-carotene and up- regulation of Cx43 expression in colon (Frommel, T.O., Litez, H & Mobarhan, S.
  • WO 95/27483 (Schlipalius et at) describes a carotenoid agent for inhibiting the conversion of epithelial cells to tumours after being subjected to UV radiation in vitro.
  • the agent was prepared by heating the crystalline suspension of beta-carotene in soyabean oil and adding glycerol monooleate. This is dispersed in the glycerol-water phase by high shear mixing followed by homogenisation (8,000 to 10,000 psi) at 60-70°C followed by heat processing. Optionally 0.3% (w/v) antioxidant tocopherol are added.
  • carotenoid in the form of a dispersion such as this would be poorly bioavailable.
  • WO 95/18605 claims beta-carotene 'ultramicroemuls ions' for the treatment of some tumours, psoriasis and eczema.
  • the concentrates claimed comprise 0.1 to 10% (w/v) carotene , 0 to 10% (w/v) active pharmaceutical substance, 1 to 40% (w/v) co-emulsifier solvent, 0.1 to 90 % (w/v) surfactant, 0 to 10% (w/v) vitamin and 0 to 10% (w/v) radical catcher, as well as carrier substances and/or diluents.
  • All the examples provided contain between 5 and 90% of a powerful surfactant Invadin JFC 800% which is a drug compatible tertiary octylphenylpolyoxyethylene with 9 or 10 oxyethylene groups.
  • the concentrates disclosed show some efficacy in in vitro proliferation tests on cell lines from pulmonary cancers and leukaemias. The concentrates are not spontaneously gel forming and there is no provision for their use in the area of preventative treatments or pre-cancerous states.
  • the present invention provides compositions for use in the treatment and/or prevention of cancer in particular of the cervix, skin, oral cavity, oro-pharynx and/or gastrointestinal tract (including the upper and lower bowels).
  • the present invention provides the use of a composition comprising an effective amount of an oil soluble carotenoid agent in the form of a microemulsion, obtainable by dispersing the agent in emulsifers and heating to 140 degrees C to obtain a transparent mixture and diluting with water, in the manufacture of a medicament for the treatment of cancer.
  • a composition comprising an effective amount of an oil soluble carotenoid agent in the form of a microemulsion, obtainable by dispersing the agent in emulsifers and heating to 140 degrees C to obtain a transparent mixture and diluting with water, in the manufacture of a medicament for the treatment of cancer.
  • the compositions are as provided in WO 94/06310 and WO 97/10725, the subject matter of which is incorporated herein by reference.
  • the present invention provides new highly bioavailable carotenoid gels, in particular beta-carotene gels, for treatment and/or prevention of HPV-mediated transformation in cervical epithelium.
  • compositions of the present invention are particularly advantageous in the treatment and/or prevention of low-grade cervical cancer and/or cervical dysplasia.
  • Physicians and opinion leaders agree that dysplasia or atypias of the cervical epithelium, detected by cervical smear test, pose a significant clinical management problem.
  • Current recommended practice is surveillance of the cervix for up to two years, during which time there is no available treatment until such time as the lesion progresses to CIN I , at which time surgical excision or ablation using laser therapy can be applied (Shafi, M.I & Luesley, D.M. (1995) "Management of low grade lesions: follow-up or treat?" Baillieres Clin. Obstet. Gynaecol. 9: 121-131).
  • the spontaneously forming gels of the invention are obtainable by mixing 1-2% of beta-carotene as a 30% dispersion in oil with 20-50% of an emulsifier or emusifier mix, heating to 140°C with stirring and adding water slowly with stirring as the mixture thickens.
  • the invention extends to the spontaneously forming gels for use in therapy.
  • the advantage of the present invention is that treatment and/or further prophylaxis can be conveniently commenced immediately upon diagnosis (using oral preparations, gels, pessaries etc).
  • Particularly advantageous are topically applied beta-carotene and/or other carotenoid- containing gels which are specifically applied to the site of the lesion and permit highly effective tissue penetration and high local tissue bioavailability of the active ingredients, enabling clinical effects to be observed more readily than via supra-dietary ingestion of beta- carotene.
  • These treatments could also be used as an adjunct to conventional surgical or laser therapies.
  • compositions of the present invention can be administered topically, either across mucosal surfaces or the stratum corneum; enterally (oral or rectal) or parenterally.
  • the dosage of the active ingredient depends on the age and condition of the subject, lesion severity as well as the route of administration.
  • Preferred formulation presentations may include: an intra-vaginal cap covered with gel, a gel for topical application on the skin, a cream, ointment, lotion, foam, pessary, suppository, capsule, lozenge, mouthwash, spray, aerosol, medicine, or beverage suitably prepared using methods known in the art.
  • Example 1 Microemulsion formulations prepared for in vitro studies in dermal epithelial cells.
  • Beta-carotene gel composition is dispersed in the two emulsifiers and the mixture is heated to 140°C with stirring before dilution by slowly combining with hot or cold water with stirring as the mixture gradually thickens to a gel.
  • Example 3 Beta-carotene gel composition
  • the beta-carotene is dispersed in the emulsifier and the mixture is heated to 140°C with stirring. At this point the mixture should remain transparent. Hot (or cold) water is slowly combined with this mixture with stirring as the mixture gradually thickens to a gel.
  • the carotene sources were as follows: All-trans beta-carotene (Roche CWD beadlets obtained from Hoffman-La Roche, Basel , Switzerland)(1437 & 5428); Cis and trans beta-carotene (Henkel CWS/F beadlets, obtained from Henkel, Little Island, Co Cork, Ireland)(2856 & 1793); Alpha-carotene, cis and trans beta-carotene (Quest Caroteen powder, obtained from Quest, Kilnagleary, Co Cork, Ireland)(320 & 9381) . These were formulated into dispersions (opaque, cloudy) or microemulsions as follows.
  • the samples were weighed directly into a 500ml volumetric flask and made up to near volume with warm water (deionised water). To aid dispersion, the flasks were sonicated for 5-10 minutes, then when cool they were made up to volume. These solutions were used directly for the preparation of all the cold water dispersible samples.
  • 1.665g of carotene source and 12.515g of the emulsifier mixture (the emulsifier mixture was 30.018g Tween 80 + 0.909g span 80 and was common to all microemulsions) was heated to 140°C and boiling water added in approximately 75mls. The microemulsion was cooled rapidly and made to lOOmls. 20mls of the concentrated microemulsion was diluted to volume in a 500ml volumetric flash with deionised water to give solution containing 20mg/ 100ml beta- carotene.
  • HPLC organotypic keratinocyte
  • cytokeratins are not expressed in these cells and hence were not studied.
  • HaCaT cells Normal Human Keratinocytes (HaCaT cells, immortalised through spontaneous loss of p53 (Khan, M.A., Jenkins, G.R., Tolleson, W.H., Creek, K.E and Pirisi, L (1993) "Retinoic acid inhibition of human papillomavirus type 16-mediated transformation of human keratinocytes" Cancer Res. 53: 905-909).
  • HaCaT cells Normal Human Keratinocytes
  • Henkel dispersion ( 1793) 0.133 NS -ve control microemulsion (6420) 0.036 p ⁇ 0.05
  • tumourigenic clones of HaCaT cells transformed with the ras oncogene demonstrate increased expression of the suprabasal keratins 1 and 10 when grown in vitamin A-depleted medium, a trend that can be reversed by supplementation with all-trans retinoic acid.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur l'utilisation de compositions comprenant un agent caroténoïde soluble dans l'huile se présentant sous la forme d'une microémulsion dans le traitement du cancer, et sur de nouvelles formulations formant spontanément un gel caroténoïde.
PCT/EP1998/005502 1997-09-04 1998-08-26 Microemulsions de carotenoides WO1999011240A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP98945297A EP1009381A1 (fr) 1997-09-04 1998-08-26 Microemulsions de carotenoides
JP2000508343A JP2001514207A (ja) 1997-09-04 1998-08-26 カロチノイドマイクロエマルジョン

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9718636.5 1997-09-04
GBGB9718636.5A GB9718636D0 (en) 1997-09-04 1997-09-04 Novel composition and use

Publications (1)

Publication Number Publication Date
WO1999011240A1 true WO1999011240A1 (fr) 1999-03-11

Family

ID=10818436

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/005502 WO1999011240A1 (fr) 1997-09-04 1998-08-26 Microemulsions de carotenoides

Country Status (4)

Country Link
EP (1) EP1009381A1 (fr)
JP (1) JP2001514207A (fr)
GB (1) GB9718636D0 (fr)
WO (1) WO1999011240A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016169942A1 (fr) 2015-04-22 2016-10-27 Basf Se Nanoparticules, nanoémulsions et leur formation avec micronisation à chambre de mélange
CN112056558A (zh) * 2020-09-21 2020-12-11 华南农业大学 一种水包油类胡萝卜素微乳液及其制备方法
CN114128824A (zh) * 2021-12-09 2022-03-04 北京林业大学 一种含红曲黄色素的功能性玉米油纳米乳液的制备方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6890961B2 (en) * 2002-02-01 2005-05-10 Micelle Products, Inc. Clear micellized formulations of β-carotene and method of treating leukoplakia
US7435846B2 (en) * 2006-08-18 2008-10-14 Industrial Organica, S.A. De C.V. Absorption and bioavailability of carotenoids, formulations and applications

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994006310A1 (fr) * 1992-09-15 1994-03-31 Smithkline Beecham Plc Nouvelles compositions
WO1994021231A1 (fr) * 1993-03-22 1994-09-29 Betatene Limited Agent therapeutique pour le traitement de melanomes
US5536504A (en) * 1993-11-19 1996-07-16 Marigen S.A. Ultramicroemulsions from spontaneously dispersible concentrates containing xanthophyll esters and having antitumor activity
WO1997010725A1 (fr) * 1995-09-23 1997-03-27 Smithkline Beecham Plc Nouveau procede

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994006310A1 (fr) * 1992-09-15 1994-03-31 Smithkline Beecham Plc Nouvelles compositions
WO1994021231A1 (fr) * 1993-03-22 1994-09-29 Betatene Limited Agent therapeutique pour le traitement de melanomes
US5536504A (en) * 1993-11-19 1996-07-16 Marigen S.A. Ultramicroemulsions from spontaneously dispersible concentrates containing xanthophyll esters and having antitumor activity
WO1997010725A1 (fr) * 1995-09-23 1997-03-27 Smithkline Beecham Plc Nouveau procede

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016169942A1 (fr) 2015-04-22 2016-10-27 Basf Se Nanoparticules, nanoémulsions et leur formation avec micronisation à chambre de mélange
CN112056558A (zh) * 2020-09-21 2020-12-11 华南农业大学 一种水包油类胡萝卜素微乳液及其制备方法
CN114128824A (zh) * 2021-12-09 2022-03-04 北京林业大学 一种含红曲黄色素的功能性玉米油纳米乳液的制备方法

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Publication number Publication date
GB9718636D0 (en) 1997-11-05
JP2001514207A (ja) 2001-09-11
EP1009381A1 (fr) 2000-06-21

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