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WO1993003720A2 - Methodes et compositions pour le traitement des brulures solaires - Google Patents

Methodes et compositions pour le traitement des brulures solaires Download PDF

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Publication number
WO1993003720A2
WO1993003720A2 PCT/CA1992/000353 CA9200353W WO9303720A2 WO 1993003720 A2 WO1993003720 A2 WO 1993003720A2 CA 9200353 W CA9200353 W CA 9200353W WO 9303720 A2 WO9303720 A2 WO 9303720A2
Authority
WO
WIPO (PCT)
Prior art keywords
skin
tocopherol
day
tocopherol acetate
active ingredient
Prior art date
Application number
PCT/CA1992/000353
Other languages
English (en)
Other versions
WO1993003720A3 (fr
Inventor
John R. Trevithick
Original Assignee
Trevithick John R
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 Trevithick John R filed Critical Trevithick John R
Publication of WO1993003720A2 publication Critical patent/WO1993003720A2/fr
Publication of WO1993003720A3 publication Critical patent/WO1993003720A3/fr

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Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E

Definitions

  • This invention relates to compositions of vitamin E esters (tocopherol esters) and uses thereof. More particularly, it relates to skin treating compositions of tocopherol esters and uses thereof.
  • Vitamin E acetate also known as tocopherol acetate, has the full chemical name 3,4-dihydro-2,5,7,8- tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-l-benzopyran-6- ol acetate, and the chemical formula:
  • vitamin E tocopherol
  • Tocopherol itself is used as an antioxidant, e.g. in vegetable oils and shortenings. Its antioxidant activity is derived from the presence of the free phenolic hydroxyl group on the chromanol ring.
  • the free hydroxyl group can act as a scavenger of free radicals or singlet oxygen, usually being itself oxidised to the tocopheroxy radical, semiquinone or quinone. Accordingly, tocopherol is subject to air oxidation on storage.
  • the phenolic hydroxyl group is esterified, as in tocopherol acetate, the storage stability of the compound is much improved, but the antioxidative properties are lost.
  • tocopherol acetate rather than tocopherol itself, in areas where the antioxidative properties are not of importance.
  • UVA near ultraviolet
  • visible radiation reported a partial impairment of the cutaneous antioxidant defense system, and a decrease (not statistically significant) in the natural tocopherol level.
  • the level of tocopherol in skin is low by comparison to that in most tissues of the body.
  • Roshchupkin et.al.. “Archives of Dermatological Research,” (1979), 266:91-94, essentially the same research group, showed protection by tocopherol and butylated hydroxytoluene, but not tocopherol acetate, when applied to the skin before exposure to UV radiation of the wavelength considered responsible for sunburn. They stated, "a- tocopherol acetate, which has, in contrast to a-tocopherol, almost no antioxidative activity, was inefficient".
  • the present invention is based upon the discovery that the 6-(Cl-C4)lower alkylcarbonyloxy derivatives, and the carboxylated and polyethyleneoxycarbonyl substituents thereof, of tocopherol, as exemplified by tocopherol acetate, tocopherol succinate and tocopherol polyethylene- glycol succinate, are surprisingly effective in alleviating the effects of sunburn, when applied topically to a sunburnt area of human or animal skin. This is despite all the prior art indications that the effects of sunburn are associated with oxidative effects on skin, so that treatment would be expected to be effective with materials having antioxidative properties, which are properties which these tocopherol esters do not possess to any significant extent. Whilst it is not intended that this invention should be interpreted as limited by any potential theory of mechanism, it is postulated that the effectiveness of these ester materials could be a consequence of their possible hydrolysis to free acid in the mammalian cells after topical application.
  • a method for treating or alleviating the effects of sunburn on human or animal skin which comprises applying topically to the area of sunburnt skin an effective amount of a 6-(Cl-C4)lower alkylcar- bonyloxy derivative, or a carboxylated or polyethyleneoxy- carbonyl substituent thereof, of tocopherol, in association with a skin compatible and acceptable carrier.
  • a pharmaceutical preparation for topical application to human or animal skin to alleviate the effects of sunburn thereon comprising an effective amount of a 6-(Cl-C4)lower alkylcarbonyloxy derivative, or a carboxylated or poly- ethyleneoxycarbonyl substituent thereof, of tocopherol, in association with a skin compatible and acceptable carrier.
  • a method for treating or alleviating the effects of sunburn on human or animal skin which comprises applying topically to the area of sunburnt skin an effective amount of ⁇ -carotene, optionally in association with a skin compatible and acceptable carrier.
  • ⁇ -carotene is a provitamin A, and is naturally occurring in both plants and animals, as well as being manufactured synthetically. It is commonly used as a yellow coloring agent for foods, as a vitamin A precursor, and as an ultraviolet screen.
  • a pharmaceutical preparation of topical application to human or animal skin to alleviate the effects of sunburn thereon said preparation comprising an effective amount of ⁇ -carotene optionally in association with a skin compatible and acceptable carrier.
  • the preferred active ingredient for use in the present invention is tocopherol acetate, tocopherol succinate or tocopherol polyethylene glycol succinate.
  • Tocopherol acetate is a liquid oil. Because it is a lipid or fat, it can diffuse across skin cell membranes, enter cells and be associated with other hydrophobic membranous structures present in the cells, for instance mitochondria, and membranes of the endoplasmic reticulum and nuclear membranes. Tocopherol polyethylene glycol succinate and tocopherol succinate have the added property of limited water solubility.
  • tocopherol acetate to sunburnt skin, promptly after the exposure to sunburning UV irradiation, has been found to reduce both erythema(skin reddening)skin sensitivity and skin thickness or swelling observed after sunburn, and to promote more rapid healing, as evidenced by the earlier appearance of epidermal desquamation or "peeling" of the skin after sunburn. This has been demonstrated in experiments using hairless mouse models, a model frequently used for testing human sunscreens. Free tocopherol, on the other hand is irritating to the skin of hairless mice when applied topically, resulting in mild increase in erythema.
  • compositions of the present invention are suitably prepared as ointments, creams, lotions, emulsions, aerosols, liposomes or gels, optionally with appropriate inert but skin compatible carrier or base materials.
  • the compositions suitably contain from about 1 to 100% by weight of active ingredient, preferably from about 1-10% by weight of active ingredient.
  • Suitable inert base carriers are well known to those skilled in the art of topical formulation compounding, and include petroleum jelly, lanolin, wax, cold creams, plant seed oils such as sesame, canola, corn oil, etc, mineral oil, yristyl acetate, myritol 318* etc.
  • Other active ingredients such as sunscreens, insect repellents, anti-microbials and topical anaesthetics can also be included in the formulations.
  • Appropriate dosage rates of the active ingredient, to be applied on a per square centimetre area of sunburnt skin, are in the approximate range 25 - 10,000 micrograms, depending of course upon the severity of the sunburn. For mild cases, dilute preparations are best applied, to give a topical application towards the lower end of the above range.
  • Preferred dosages are in the range 50 - 5,000 micrograms per square centimetre, and most preferably and most commonly for sunburns of average severity, in the range from about 100 - 1,000 micrograms per square centimetre.
  • composition according to the invention should preferably be applied to the affected area as soon as possible after the sunburn has been experienced, but beneficial effects are still obtained with topical application up to at least eight hours after the burn. If the recommended, preferred dosage is applied to the affected area very shortly after the burn has been experienced, a second topical application is not normally necessary, but some benefits .may accrue, particularly in cases of severe burn, by second or even third applications, at about 24 hour intervals.
  • trademark ⁇ -carotene is suitably used in the same amounts as in the case of tocopherol acetate and the like, and by the same administration method sand regimens.
  • it is compounded in neutral base, e.g. corn oil or similar carriers, as used with tocopherol acetate.
  • Skh-l hairless mice used in these experiments were from two groups: young (6 - 8 week old) females, and retired breeding males approximately 1 year old at the time of the experiment.
  • erythema index Prior to each UV exposure daily measurements of erythema index were taken using an erythema meter ⁇ (Dia-stron, Sandhurst, Surrey, England), at a site on the upper back approximately 1 cm above the top of the V-shaped wedge between the haunches, at a place which approximated the highest position or hump of the back of the resting mouse. A minimum of 18 readings of the erythema index were usually obtained each day at approximately the same time of day.
  • mice were obtained in an initial experiment for 2 days prior to UVB (peak 310 nm) exposure and in all later experiments for 6 days prior to irradiation with UVB. This trained the mice to the procedure and also permitted a stable baseline erythema index to be obtained over a number of days. The pre- exposure erythema index was obtained by averaging these values.
  • the erythema index is effectively a measure of skin colour.
  • Red and green light is shone on the affected area, whereupon the hemoglobin in the skin absorbs the green light but reflects back the red light.
  • a ratio of red to green reflected light is obtained, and the redder the colour of the skin, the more red light is reflected and the higher the erythema index recorded.
  • the index is recorded in numbers from 10 - 300, the higher the number the redder the colouration or discolouration of the skin area.
  • mice were placed in one litre glass beakers (Corning, 10 cm diameter x 15 cm high) containing 100 ml dry measure of cedar chips (2-3mm square) and usually 2 food pellets (Agway Prolab diet: RMH 3000) and a small piece of apple and/or raisin, so that they would stay in a prone position during the irradiation while feeding, and not stand up for prolonged periods: standing would alter the UV dose received at the central back position chosen for monitoring.
  • Mice were exposed for defined periods of time, and the dose of the erythema- producing UVB was calculated from the dose measure at the same location using a UVB meter (UVX Digital Radiometer, UVP, San Gabriel, CA.
  • composition containing the tocopherol acetate composition to the incident area of the mice was done by applying 100% pure material to the area by means of a swab so that the entire incident area was covered by a thin film or coating of the material. It was applied at a concentration of approximately 5 mg/cm 2 , gently rolling the oil-soaked cotton applicator longitudinally along the back of the mouse.
  • the erythema index was monitored following UVB exposure.
  • a minimum of 18 readings of the erythema index were recorded each day at the area of skin located at the peak of the back, approximately 5 cm anterior to the base of the tail.
  • the difference in erythema reading was obtained by averaging the values for each post-exposure day and subtracting the pre-exposure value from the average daily value.
  • mice were used to compare (a) irradiated ( unirradiated (c) irradiated and treated and (d) unirradiated and treated mice.
  • mice For experiments 2 and 3, three groups were used: (a) irradiated (8 mice) (b) Irradiat and treated (8 mice) and (c) unirradiated control (6 mice).
  • Example 2 The skin sensitivity of the same region of the back was measured using a nylon fibre esthesiometer (Cachet and Bonner model, Luneau, Chartres, France) as previously described to measure corneal sensitivity to touch 3 .
  • the experiment was conducted as a part of Example l, with same group of young male mice and the same exposed skin areas, just a few minutes after the tests on the exposed skin areas reported in Example 1 had been conducted.
  • UV-exposed mice were more sensitive than unexposed mice (p ⁇ 0.04), and the UV-exposed tocopherol acetate-treated mice (p ⁇ 0.07), but the UVB- exposed tocopherol acetate-treated mice were not significantly different from the unexposed mice (p ⁇ 0.32).
  • the difference between the UV-irradiated and control unirradiated groups was still marginally significant (p ⁇ 0.07) and the tocopherol acetate-treated irradiated group was marginally significantly different from the untreated irradiated group (p ⁇ 0.1), but not from the untreated control group (p ⁇ 0.36).
  • Magnetic resonance imaging (MRI) of three anaesthetized mice weree used to measure skin thickness at the central back, by axial sectional images of 2 mm thickness of the thorax-upper abdomen using a Bruker MSL 80 Imaging Spectroscopy System.
  • a 5.6 cm field of view and 256 matrix yielded an inplane pixel dimension of 217 microns.
  • the normal mouse skin was measured in an axial section positioned in the middle of the hump of the mouse back.
  • the section showing minimum skin thickness in the sagittal view the one in which the skin of the back was most parallel to the horizontal plane), was chosen for measurement.
  • the effect of varying the percent of tocopherol acetate in the topically applied fluid was determined.
  • the increase in skin thickness was decreased by 0.18 x 10 "2 mm/day per percent tocopherol acetate in the medium (P ⁇ 0.02).
  • the skin would be predicted to be 0.18 mm thinner after one day and 0.36mm thinner after two days, as compared with untreated skin. This assumes an effect which changes linearly with time after exposure or treatment, which may not be a correct assumption.
  • a young human being was exposed to sub-tropical sunshine for two hours, in May in the northern hemisphere, as a result of which moderately severe skin sunburn was experienced.
  • ⁇ -carotene as a 30% w/w composition in corn oil was used to alleviate UV radiation effects on skh-mice as described in the previous examples.
  • the histology of UV exposed skin was observed after 48 hours, following immediate ⁇ -carotene application after UVB.
  • the skin thickness increase normally caused thereby was decreased by 25% (p ⁇ 0.04) at 24 hours, and decreased by 44% (p ⁇ 0.034) at 48 hours, as a result of ⁇ -carotene application, when compared to untreated, UV-exposed skh mouse.

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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)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Ce traitement des brûlures solaires de la peau humaine ou animale consiste à appliquer sur la zone touchée une composition topique contenant un ester de tocophérol comme l'acétate de tocophérol ou le polyéthylène glycol succinate de tocophérol comme substance active.
PCT/CA1992/000353 1991-08-16 1992-08-14 Methodes et compositions pour le traitement des brulures solaires WO1993003720A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US74569291A 1991-08-16 1991-08-16
US745,692 1991-08-16

Publications (2)

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WO1993003720A2 true WO1993003720A2 (fr) 1993-03-04
WO1993003720A3 WO1993003720A3 (fr) 1993-04-01

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PCT/CA1992/000353 WO1993003720A2 (fr) 1991-08-16 1992-08-14 Methodes et compositions pour le traitement des brulures solaires

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995030420A1 (fr) * 1994-05-06 1995-11-16 Alcon Laboratories, Inc. Utilisation de derives tocopheryle de vitamine e dans des compositions ophtalmiques
WO1996030022A1 (fr) * 1995-03-29 1996-10-03 Alcon Laboratories, Inc. Formulations acidiferes topiques ophtalmiques comportant un medicament acide, de la vitamine e tpgs, du chlorure de benzalkonium et de la cafeine
GB2317111A (en) * 1996-09-09 1998-03-18 Hadasit Med Res Service Irradiation protection method
WO1997045098A3 (fr) * 1996-05-31 1998-08-13 Giorgio Panin Esters de la vitamine e pour application locale
US6193985B1 (en) 1994-05-16 2001-02-27 A/S Dumex (Dumex Ltd) Tocopherol compositions for delivery of biologically active agents

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4154823A (en) * 1976-06-10 1979-05-15 Schutt Steven R Skin treatment compositions and methods of using same
CA1257200A (fr) * 1984-03-07 1989-07-11 Roshdy Ismail Agents pour le traitement et la protection de la peau
JPH01151516A (ja) * 1987-12-08 1989-06-14 Shionogi & Co Ltd ビタミンｅ配合外用剤

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995030420A1 (fr) * 1994-05-06 1995-11-16 Alcon Laboratories, Inc. Utilisation de derives tocopheryle de vitamine e dans des compositions ophtalmiques
US5886030A (en) * 1994-05-06 1999-03-23 Alcon Laboratories, Inc. Use of vitamin E tocopheryl derivatives in ophthalmic compositions
US6193985B1 (en) 1994-05-16 2001-02-27 A/S Dumex (Dumex Ltd) Tocopherol compositions for delivery of biologically active agents
WO1996030022A1 (fr) * 1995-03-29 1996-10-03 Alcon Laboratories, Inc. Formulations acidiferes topiques ophtalmiques comportant un medicament acide, de la vitamine e tpgs, du chlorure de benzalkonium et de la cafeine
WO1997045098A3 (fr) * 1996-05-31 1998-08-13 Giorgio Panin Esters de la vitamine e pour application locale
AU713816B2 (en) * 1996-05-31 1999-12-09 Giorgio Panin Esters of vitamin E as products for topical application
EP1342473A1 (fr) * 1996-05-31 2003-09-10 BIO.LO.GA. S.r.l. Ester de vitamine E pour application topique
GB2317111A (en) * 1996-09-09 1998-03-18 Hadasit Med Res Service Irradiation protection method
US5948823A (en) * 1996-09-09 1999-09-07 Hadasit Medical Research Services & Development Company Ltd. Irradiation protection method
GB2317111B (en) * 1996-09-09 2000-06-14 Hadasit Med Res Service Irradiation protection method
DE19733892C2 (de) * 1996-09-09 2002-06-20 Hadasit Med Res Service Bestrahlungsschutz-Verfahren

Also Published As

Publication number Publication date
AU2434992A (en) 1993-03-16
WO1993003720A3 (fr) 1993-04-01

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