CA2170591A1 - Treatment of medical disorders associated with free radical formation - Google Patents

Treatment of medical disorders associated with free radical formation

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Publication number
CA2170591A1
CA2170591A1 CA002170591A CA2170591A CA2170591A1 CA 2170591 A1 CA2170591 A1 CA 2170591A1 CA 002170591 A CA002170591 A CA 002170591A CA 2170591 A CA2170591 A CA 2170591A CA 2170591 A1 CA2170591 A1 CA 2170591A1
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Canada
Prior art keywords
alpha
cholestane
beta
pentahydroxy
patient
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CA002170591A
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French (fr)
Inventor
Theodore Macrides
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JW Broadbent Nominees Pty Ltd
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Individual
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63Steroids; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/08Anti-ageing preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Birds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method for the treatment of biochemical damage or a medical disorder associated with free radical formation in a patient comprises administering to the to the patient an effective amount of a bile alcohol or a derivative thereof, particularly 5.beta.-scymnol, 5.beta.-scymnol sulphate, 5.alpha.-cyprinol or 5.alpha.-cyprinol sulphate. The invention includes treatment of photodamage to the skin and/or hair of a patient associated with free radical formation resulting from UV irradiation as well as treatment of inflammatory disorders or conditions of the skin. Compositions, including topical compositions, are also included.

Description

WO 95tlO283 ~ 1 ~7 o ~ PCT/AU94/00619 "TREATMENT OF MEDICAL DISORDERS ASSOCIATED
WITH FREE iRADlCAL FORMATION"

The present invention reiates to the treatment of medical disorders arising from biochemical and celluiar damage resulting from the action of free radicals in animals, including humans.
BACKGROUND OF THE INVENTION

A free radical is any species capable of independent existence that contains one or more unpaired electrons. Such species show paramagnetism 15 and may be highly reactive. The formation and reactions of free radicals havebeen reviewed generally by Halliwell and Gutteridge (1984), while Slater t1984) has provided a discussion of cell injuries that are mediated by free radical intermediates, as well as general concepts relevant to free radical processes and to rnechanisms of protection against such types of injury.

Some biological processes generate more or less stable intermediates that contain an unpaired electron, which can either be donated, or paired with an additional electron from the surroundings. Such intermediates are called free radicals, and they may be the products of various enzymatic and non-enzymatic 25 reactions, some of which are vital for body functions, e.g. reduction of ribonucleoside diphosphates for DNA synthesis and the generation of prostaglandins in the prostaglandin synthase reaction. The latter is essential for inflammatory response following cell injury, and a number of other functions.
Most organisms contain chemical antioxidants such as a-tocopherol (vitamin E), 30 ascorbic acid and different radical and peroxide-inactivating enzymes, e.g.
superoxide dismutase, catalase and glutathione peroxidase, which act as endogenous protecting agents against free radical damage.

WO 95/10283 59 ~ - 2 - PCTIAU94/00619 Free radicals of various types are becoming increasingly associated with a broad range of conditions and diseases such as ischaemic or reperfusion injury, atherosclerosis, thrombosis and embolism, allergic/inflammatory conditions such as bronchial asthma, rheumatoid arthritis, conditions related to Alzheimer's 5 disease, parkinson's disease and ageing, cataract, diabetes, neoplasms and toxicity of anti-neoplastic or immunosuppressive agents and chemicals. One possible explanation for these conditions and diseases is that, for unknown reasons, the endogenous protecting agents against radical damage are not sufficiently active to protect the tissue against radical damage. Lipid peroxidation 10 caused by excess generation of radicals may constitute one significant damaging pathway in the above conditions and diseases. Administration of additional antioxidants, which inhibit radical reactions, e.g. Iipid peroxidation, would thus provide a way of preventing or curing the above conditions and diseases.

Free radicals cause cellular damage by different mechanisms such as oxidation of thiol groups of proteins, DNA strand breaks and lipid peroxidation.The properties of free radicals include: high reactivity with a consequent extremely short life span, self perpetuating and diverse chemical reactivity, low chemical specificity and the ability to be generated both in vivo and in vitro.

The main sources of free radicals are cellular, and environmental. Free radical production may also be increased during vascular disease states, e.g.
inflammation and during unfavourable metabolic conditions such as hypoxia and tissue ischaemia. Free radicals have also been proposed to cause oxidative 25 damage to biological molecules involved in the development of many severe disorders of humans, including atherosclerosis, cancer and parasitic viral infections.

Free radical molecular species include, but are by no means limited to, 30 hydroxyl, peroxyl, hypochlorite, superoxide and alkoxy radicals, and reactivemolecules such as hydrogen peroxide. They also include singlet oxygens which WO 95tlO283 9 ~ PCT/AU94/00619 are not free radicals but are certainly reactive and capable of causing cellulardarnage.

As a result of the relative instability of free radicals and their potential to 5 damage cells and tissues, there are both enzymes and small-molecular-weight molecules with antioxidant capabilities that are able to protect against the adverse effects of free radical reactions. There is therefore a critical balance between free radical generation and antioxidant defences in cells and tissues. Two types of antioxidants can be identified, namely biological and non-enzymatic biological 10 antioxidants. In the former class are the well defined enzymes such as superoxide dismutase, catalase and selenium glutathione peroxidase. Non-enzymatic biological antioxidants include tocopherols, carotenoids, bilirubin, ascorbic acid, uric acid and metal-binding proteins as typical examples.

The damaging effects of sunlight on the skin are well known. In addition to the major short term hazard of erythema (i.e. sunburn) primarily caused by UVradiation, there are also long term hazards associated with UV radiation exposure including malignant changes in the skin surface (i.e. skin cancer) and prematureageing of the skin.

In International Patent Application No. PCT/US91/02400 (WO 91/16035) it is pointed out that ultraviolet light induces inflammation of the skin and harmful photochemical reactions therein. During exposure and as repair of the UV
damage takes place, super-oxide (2-) radicals are formed in the skin. UV
25 irradiation also causes some microvascular damage in the skin, leading to local haemorrhage and "leakage" of blood cells into the dermis Iron from the haemoglobin accumulates in the extra-cellular matrix of the tissue as Fe+2 and Fe+3. It is known that iron catalytically participates in the conversion of superoxide radicals to hydroxyl radicais, a species which is known to be very 30 damaging to tissue. Another process which is damaging to tissue is membrane lipid peroxidation, which is also accelerated by iron. (See Halliwell and Gutteridge, 1985.) 59 ~ PCT/AU94/00619 In tissue injured by physical means, infection, or a toxic compound, cell destruction may occur accompanied by the release of iron "transit pools". This free iron can then be used to shown to react with H2O2 to form hydroxyl free radicals (OH') according to the Fenton reaction, since Fe2' has been shown to react with H2O2 in vivo, as follows:

Fe2+ + 2 ~ Fe2+ - 2 + Fe3+ + 2-2O2- + 2H+ H2O2 + 2 H2O2 + Fe2+, OH' + OH' + Fe3+ (Fenton reaction) (Halliwell et al. 1986) In addition to their role in UV radiation induced tissue damage, oxygen radicals are known to be capable of reversibly or irreversibly damaging compounds of all biochemical classes, including nucleic acids, proteins and free15 amino acids, lipids and lipoproteins, carbohydrates, and connective tissue macromolecules. These compounds may have an impact on such cell activities as membrane function, metabolism, and gene expression. (See Halliwell et al.
1985, 1986.) Clinical conditions in which oxygen radicals are thought to be involved include those concerning multiorgan involvement, including inflammatory-immune injury such as glomerulonephritis (idiopathic, membranous), vasculitis (hepatitis B virus, drugs), autoimmune disease; ischaemia-reflow states; drug and toxin-induced reactions; iron overload such as idiopathic haemochromatosis, dietary iron overload (red wine, beer brewed in iron pots), th~i~ssemia and other chronic anaemias; nutritional deficiencies, such as Kwashiorkor, vitamin E deficiency;
alcohol; radiation injury; ageing, such as disorders of "premature ageing", immune deficiency of age; cancer and amyloid diseases. Additional conditions in which oxygen radicals are thought to be involved include those concerning primary single organ involvement including erythrocyte related conditions, such as phenylhydrazine, primaquine, lead poisoning, protoporphyrin photo-oxidation, malaria, sickle-cell anaemia, fauvism, Fanconi anaemia; lung related conditions w095~l02g3 2 1 705 9 ~ PCTIAU94/00619 such as cigarette-smoking effects, emphysema, hyperoxia, bronchopulmonary dysplasia, oxidant pollutantsS acute respiratory distress syndrome, mineral dustpneumoconiosis, bleomycin toxicity, paraquat toxicity; heart and cardiovascular system related conditions, such as alcohol cardiomyopathy, Keshan disease 5 (selenium deficiency), atherosclerosis, doxorubicin toxicity; kidney related conditions, such as nephrotic antiglomeruiar basement membrane disease, aminoglycoside nephrotoxicity, heavy metal nephrotoxicity, renal grant rejection;
gastrointestinal tract related conditions, such as endotoxin liver injury, carbon tetrachloride liver injury, diabetogenic action of alloxan, free-fatty-acid-induced 10 pancreatitis, nonsteroidal-anti-inflammatory-drug induced lesions; joint abnormalities, such as rheumatoid arthritis; brain related conditions, such as hyperbaric oxygen, neurotoxins, senile dementia, Parkinson disease-MPTP, hypertensive cerebrovascular injury, cerebral trauma, neuronal ceroid lipofuscinoses, allergic encephalomyelitis and other demyelinating diseases, 15 ataxia-telangiectasia syndrome, potentiation of traumatic injury, aluminium overload, a-~B-lipoproteinaemia; eye related conditions, such as solar radiation, thermal injury, porphyria, contact dermatitis, photosensitive dyes, and bloom syndrome. (See Cross et al. , 1987).

Free radicals are therefore potentially dangerous in living systems, and it is biologically advantageous for cells to control the amount of radicals allowed to accumulate. The chelating effect of iron bound to protein, such as in transferring, renders the iron almost completely inactive in accelerating lipid peroxidation and hydroxyl radical formation. Other protective mechanisms include catalase, which 25 exists to remove H202 within cells, converting it to H20. Glutathione peroxidase also reduces H202 to H20 through the involvement of glutathione, itself an antioxidant that may quench radicals, as do other molecules such as ascorbate, urate, glucose and metallothioniens (Halliwell et al., 1986).

In view of the potential danger of free radicals in living systems, a great deal of attention has been given to compounds which act as free radical scavengers, the use of which will regulate biochemical and cellular damage 2 ~ 7 5 9 ~ PCT/AU94/00619 resulting from free radical reactions in living systems (see, for example, International Patent Applications No. PCT/US91/02400 above, and No.
PCT/US91/02398 - WO/9116034, both of which disclose chelator compositions for use as free radical scavengers, particularly in protecting against photodamage 5 of the skin).

SUMMARY OF THE INVENTION

It has now been found that compounds within the class of bile alcohols and 10 their derivatives are effective free radical scavengers, particularly hydroxyl radical scavengers.

The bile alcohols are a group of polyhydroxylated steroids derived structurally from 5a-cholestane or 5,~-cholestane (also known as coprostane).
15 They include, for example, the compounds known as 5~-scymnol (3a, 7a, 12a, 24, 26, 27-hexahydroxy-5,~-cholestane) and 5a-cyprinol (3a, 7a, 12a, 26, 27-pentahydroxy-5a-cholestane).

Scymnol is an unusual bile alcohol in that the terminal methyl groups, C26 20 and C27 together with C24, are present as alcohols. The natural bile salt occurs as the 27-sulphate sodium salt and was first isolated by Hammerstein in 1898 from the gall bladders of the shark Scymnus borealis .

OH OH

OH i~ H OH if ~A~ CH2CH
r'~~~ CH20H ~ CH20SO,H
30HO ~ ' ~U HO ~ ~J .~

5~-Scymnol 5~-Scymnol sulphate 3 2 ~ 70 S ~ 1 PCT/AU9~/00619 According to the present invention, there is provided a method for the treatment of biochemical damage or a medical disorder associated with free radical formation in a patient which comprises administering to the patient an effective amount of a bile alcohol or a derivative thereof.
The present invention also extends to a composition for use in the treatment of biochemical damage or a medical disorder associated with free radical formation in a patient, which comprises an effective amount of a bile alcohol or a derivative thereof, together with a pharmaceutically acceptable carrier 10 or diluent.

Whilst the present invention is principally directed to the treatment of human patients, it is to be understood that in its broadest aspect the inventionalso extends to the treatment of non-human patients, especially non-human 15 mammals.

The medical disorders associated with free radical formation which may be treated in accordance with the present invention include those described above arising from biochemical damage to nucleic acids, proteins and free amino acids,20 lipids and lipoproteins, carbohydrates and connective tissue macromolecules.
They include, in particular, the results of photodamage to the skin following UVirradiation so that in one particular aspect, the present invention includes a method and composition as described above for the treatment of photodamage to the skin and/or hair of a patient associated with free radical formation resulting 25 from UV irradiation.

Inflammatory disorders of the skin, including erythema associated with exposure to solar or ultraviolet radiation, sunburn, eczema, dermatoses, inflamed lesions of acne and other inflammatory skin conditions, may also be associated 30 with free radical formation, and accordingly, may be treated in accordance with the present invention.

PCT/~U94/006 19 WO95/10283 ~ q ,~ - 8 -Accordingly, in yet another aspect, the present invention includes a method and a composition as described above for the treatment of inflammatory disordersor conditions of the skin of a patient.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
DETAILED DESCRIPTION OF THE INVENTION

The bile alcohols which may be used in the method or composition of this invention include any of the group of polyhydroxylated steroids derived structurally 15 from 5a-cholestane or 5a-cholestane (or coprostane).

Preferred bile alcohols are compounds in this group which include at least one hydroxyl group, preferably two or three hydroxyl groups, at positions 24, 25, 26 and/or 27 of the cholestane molecule. Most preferred are bile alcohols with hydroxyl groups at positions 26 and 27 of the cholestane molecule.

Particularly preferred bile alcohols for use in accordance with the present invention include:
5a-scymnol (3a, 7a, 12a, 24R, 26, 27-hexahydroxy-5a-cholestane) 5,~-scymnol (3a, 7a, 12a, 24R, 26, 27-hexahydroxy-5a-cholestane) 5a-cyprinol (3a, 7a, 12a, 26, 27-pentahydroxy-5a-cholestane) 5,~-cyprinol (3a, 7a, 12a, 26, 27-pentahydroxy-5,~-cholestane) 5a-bufol (3a, 7a, 12a, 25, 26-pentahydroxy-5a-cholestane) 5~B-bufol (3a, 7a, 12a, 25, 26-pentahydroxy-5,~-cholestane) 5a-chimaerol (3a, 7a, 12a, 24, 26-pentahydroxy-5a-cholestane) 5,~-chimaerol (3a, 7a, 12a, 24, 26-pentahydroxy-5~B-cholestane) 5a-ranol (3a, 7a, 12a, 24R, 26-pentahydroxy-27-nor-5a-cholestane) 2 1 7 0 5 9 1 PCT/AU9~/00619 WO 95/102~3 _ 9 5~-ranol (3a, 7~, 12a, 24R, 26-pentahydroxy-27-nor-5,a-cholestane) 5a-dermophol (3a, 7a, 12a, 25, 26, 27-hexahydroxy-5a-cholestane) 5,~-dermophol (3a, 7a, 12a, 25, 26, 27-hexahydroxy-5,~-cholestane).

The derivatives of bile alcohols which may be used in accordance with the present invention include esters with inorganic acids such as sulphuric acid or organic acids such as acetic acid, propionic acid and butyric acid.

Particularly preferred bile alcohol derivatives for use in accordance with the present invention include:
5,~-scymnol sulphate 5a-cyprinol sulphate.

In accordance with this invention, the bile alcohols or derivatives will 15 norrnally be administered orally, rectally, dermally or topically, or by injection, in the form of pharmaceutical preparations comprising an effective amount of the active substance in a pharmaceutically acceptable dosage form.

Suitable pharmaceutically acceptable dosage forms are well known and are 20 described, by way of example, in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Pennsylvania, USA. The dosage form may be a solid, semisolid or liquid preparation. Usually the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and 25 between 0.2 and 50% by weight for preparations suitable for oral administration.
Derrnal or topical administration would normally utilise 0.1-10% by weight, morespecifically 0.5-5% by weight, of the active substance in a suitable dermal or topical carrier or vehicle.

To produce pharmaceutical preparations containing the active substance in the form of dosage units for oral application, the selected compound may be mixed with a solid excipient, e.g. Iactose, saccharose, sorbitol, mannitol, starches ' q '\ PCT/AU94/00619 WO 95/10283 2. ~ 7 ~ 3 such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared 5 as described above, may be coated with a concentrated sugar solution which maycontain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like.
Alternatively, the tablet can be coated with a polymer known to the man skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish 10 between tablets containing different active substances or different amounts of the active substances.

For the preparation of soft gelatine capsules, the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules15 may contain granules of the active substance using either the abovementioned excipients for tablets e.g. Iactose, saccharose, sorbitol, mannitol, starches (e.g.
potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into hard gelatine capsules.

Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.2% to about 20% by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain colouring agents, flavouring agents, saccharine and 30 carboxymethyl-cellulose as a thickening agent or other excipients known to the man in the art.

WO 95/102~3 2 1 7 0 5 9 1 PCT/AU94/006 19 .

Preparations for parenteral applications by injection can be prepared in an aqueous solution or suspension of the active substance, preferably in a concentration of from about 0.5% to about 10% by weight. These preparations may also contain stabilising agents and/or buffering agents and may conveniently5 be provided in various dosage unit ampoules.

Where the active substance of this invention is to be used for the treatment of photodamage to the skin and/or hair of a patient associated with free radicalformation resulting from UV radiation, the active substance is preferably 10 formulated so as to be administered topically. In such formulations, an effective amount of the active substance is incorporated into a suitable carrier material as a topical pharmaceutical/cosmetic composition which may be made up in a variety of product types including, for example, lotions, creams, oils, gels, sticks, sprays, ointments, pastes, mousses and cosmetics.

Suitable topical pharmaceutical/cosmetic carrier materials for such compositions are also well known and are described by way of example in International Patent Application No. PCT/US91/02400. As described therein, in addition to the active substance and suitable carrier material, such topical 20 pharmaceutical/cosmetic compositions may also include one or more penetrationenhancing agent(s), and/or anti-inflammatory agent(s), as well as sunscreen or sunblock agent(s) to enhance protection of the skin against the effects of UV
irradiation.

In work leading to the present invention it has been shown that the bile alcohols, particularly 5~-scymnol and 5a-cyprinol, and their derivatives, particularly 5,t~-scymnol sulphate and 5a-cyprinol sulphate, are surprisingly effective free radical scavengers, particularly of hydroxyl radicals.

One test system used to determine the scavenging potential of these compounds is a simple, non-biological free radical generating and detection system. It is the frequently used thiobarbituric acid (TBA) reaction, most PCT/AU9~/006 19 WO 95/10283 ~9! ~ - 12 -commonly used for the detection of lipid peroxidation in biological systems. Themethod however has been utilised due to its ability to assess iron-dependent free radical damage to carbohydrates (Gutteridge, 1981 ) and hydroxyl radical scavenging capabilities of systems (Moorhouse et al., 1987).
Deoxyribose is utilised as the target for hydroxyl radical attack which breaks down to produce a three carbon compound malondialdehyde (MDA) which forms a characteristic chromogenic adduct with two molecules of TBA (Gutteridge,1981). The three test compounds used as measures of comparison were the 10 known free radical scavengers, promethazine, mannitol and dimethyl sulphoxide(DMSO). Mannitol has been utilised as a model scavenger widely by Moorhouse et al. (1987) however its scavenging ability is somewhat less than that of promethazine, a known hepatoprotector against carbon tetrachloride free radical attack. Moorhouse et al., (1987) have also found that dimethyl sulphoxide is a 15 potent free radical scavenger. Through the use of these compounds, a qualitative analysis of the abilities of test compounds as free radical scavengers can be ascertained.

Further details of these tests, and of the activity of the test compounds as 20 free radical scavengers, are set out in the Examples below.

As noted above, free radicals may be generated on the surface of skin by the action of the environment, particularly ultraviolet radiation (UVR). In the absence of a sunscreen there is nothing to attenuate the effect of UVR and so 25 the potential for free radical formation must be highest in the outermost layers of the skin. Topical application of antioxidants and free radical scavengers has been shown to provide a wide range of benefits to living skin. In most cases it has not been shown that the protectant molecule has penetrated to the viable tissues, but the half life of a free radical is so short that it is diffficult to imagine 30 any other mechanism (notwithstanding that free radicals can set up a chain ofreactions). Oxygen free radicals and other reactive oxygen species have been shown to be involved in UVR damage to the skin. Although the predominant WO95/102~3 ~ 1 7 ~5 9 1 PCT/AU94/00619 damage is due to the direct action of UVB on DNA, at wavelengths above 327nm (UVA) the predominant effect is due to the action of UVR on other molecules, generating free radicals that then affect DNA. Peroxidation by UVR of the lipid causes damage to cell membranes at the subcellular level, leading to cell S damage. The adverse effects of photosensitisation (erythema and oedema) have been minimised by topical application of free radical scavengers. Free radical scavengers also suppress the formation of erythema, sunburn cells, peroxidation of lipids, increased production of ornithine decarboxylase, promotion and initiation of skin cancer, and premature aging of the skin. It has been reported that 10 antioxidant therapy with Vitamin E produced a favourable effect on facial skin melanoderma in women; melanoderma is associated with abnormally high concentrations of lipid peroxide caused by UVR. It has also been shown that injection of superoxide dismutase, a free radical scavenger that occurs naturally in the skin, significantly prevented the depletion of Langerhans cells in the skin 15 of guinea pigs that had been exposed to UVR (Langerhans cells are an important part of the skin's immune system), and that a garlic extract which contains several antioxidants was able to reduce the immunosuppressive effects of UVR
on hairless mice.

There is a considerable interest in finding a sunscreen for hair. The benefits that are sought are to prevent loss of colour, particularly on hair which has been artificially coloured; and to prevent damage (weathering) to the structure of the hair which leads to split ends, loss of hair cuticles, roughness and general weakening and loss of condition. These adverse effects are mainly caused by exposure to UVR and are mediated by free radical formation.
Manufacturers of hair products have tried to use conventional sunscreen actives (e.g. cinnamates and PABA derivatives) to protect hair, but to be very effectivethey must be deposited in such large amounts that they leave the hair greasy andgenerally in an unnatural state. A free radical scavenger such as a bile alcoholor a derivative thereof may be effective in much smaller amounts, and so not adversely affect the other hair properties, and may favourably influence the greasiness of skin and hair. Perception of greasiness is a function of the total WO 95/10283 "1'~ 1 ~5 quantity of sebum and of its viscous properties. The latter are a function of the degree of crystallinity of the sebum and will be influenced by peroxidative processes against which free radical scavengers can protect.

Acne is a chronic inflammatory disease of the pilosebaceous units which is most prevalent in teenage years. It is characterised by the formation of bothinflammatory and non inflammatory lesions which affect primarily the face, neck and trunk. Four major factors are involved in the pathogenesis: increased sebum production, an abnormality of the microbial flora, cornification of the pilosebaceous duct and the production of inflammation. Topical therapy is usually effective for the management of mild to moderate acne, however patients with severe acne usually require oral and topical treatment. Benzoyl peroxide is wellestablished as a topical agent in the treatment of acne as it is an effective keratolytic, comedolytic, antimicrobial and anti-inflammatory agent. It has now lS been shown that the bile alcohols and derivatives are effective anti-inflammatory agents when applied topically to the skin.

The following Examples illustrate the free radical scavenging activity of the bile alcohols and derivatives thereof in accordance with this invention.

A. METHOD
The method used for this investigation is essentially that described by Gutteridge (1981). A combination of ascorbic acid (0.1 mM), ferrous ammonium sulphate (0.22 mM) and EDTA (0.23 mM), added in this order, produced a hydroxyl radical generating system which after being sparged in nitrogen was added to a solution of deoxyribose (1.0 mM) in phosphate buffer (20 mM, pH 7.4).
To the test system 120 ,ul of the hydroxyl radical scavenger was added and 30 to the control an equal volume of water. A blank tube was set up for each runcontaining water and scavenger without deoxyribose. Each test and control were prepared in triplicate.

WO 95/10283 2 1 7 o ~ 9 ~ PCTtAU94/00619 .

Hydroxyl radical attack proceeded for 30 minutes at 37C after which time the solution pH was reduced by addition of trichloroacetic acid (TCA (1 ml of 2.8% w/v) and TBA (1 ml of 1% w/v in 0.05 M NaOH). Upon heating at low pH
the chromogen was determined by its absorbance at 532 nm.

Ascorbate is almost invariably contaminated with iron salts and is able to initiate the reaction alone, hence its inclusion in the iron salt solution avoided premature initiation of the reaction during preincubation. In order to avoid false results through iron contamination, all glassware used in the procedure was 10 washed with concentrated hydrochloric acid and rinsed twice with milli Q water.
All solutions were also made up with milli Q water.

B. RESULTS
Table 1 shows that 5,~-scymnol gave very high levels of protection against 15 deoxyribose damage as did 5a-cyprinol. The sulphated bile salts were not as protective, giving levels of protection similar to promethazine and DMSO.

Figure 1 shows the combined inhibition studies from 3 experiments for the scavengers. Rate constants for 5,~-scymnol and 5,~-scymnol sulphate were 20 determined from their respective slopes from Lineweaver-Burk plots and calculated to be 0.267 M~1 S~' and 0.195 M-'S-' respectively. The rate constant for mannitol was determined in the same manner as the bile salts and calculated to be 0.49 M-'S-'.

At low molecular concentrations, cholic acid appeared to be a very effective scavenger (Figure 2), intermediate in its effect to that of 5,a-scymnol and 5~-scymnol sulphate. As the scavenger concentration increased however, unlike the effect shown by 5,a-scymnol, scavenging ability of cholic acid was lost.

In order to determine whether the action of 5,~-scymnol was indeed that of a radical scavenger and not due to the prior formation of a colourless scymnol-TBA adduct, 5,~-scymnol was added to the reaction mixture after incubation but wo 95/10283 ~ 5 9 PCT/AU9~/00619 prior to the addition of TBA. The results of this run replicated that of the control species indicating that a chromogen was not formed between 5,~-scymnol and TBA.

5 TABLE 1 Effect of hydroxyl radical scavengers on damage by systems generating hydroxyl radicals.
Scavenger (10mM) % Inhibition % Inhibition (with EDTA) (without EDTA) 5,~-scymnol 97 i 2 64 + 5 5,~-scymnol sulphate 72 i 3 42 i 4 5a-cyprinol 86 i 4 5a-cyprinol sulphate 74 i 6 Promethazine 69 i 3 Dimethyl sulphoxide 69 i 1 Mannitol 28 i 2 Cholic acid 57 i 6 The hydroxyl radicals were generated via the Fenton reaction with deoxyribose used as the target for radical attack. The reaction was run for 30 minutes at 37C. Results are expressed as the average of three experiments 20 S.E.M.

C. DISCUSSION
The system used in this investigation demonstrated the great ability with which 5,~-scymnol can protect against hydroxyl radical damage to an extent 25 greater than that of mannitol, promethazine and DMSO, which are well known and effective free radical scavengers.

~ 1 7 PCT/AU94/00619 WO 95/10283 ~ I / 0 5 9 1 5,~-Scymnol and 5,a-scymnol sulphate were iess effective in scavenging hydroxyl radicals when EDTA was removed as a chelating agent from the system.
This indicates the ineffectiveness of the bile salts as chelators and the importance of chelators in biological systems.
The apparent radical scavenging ability for hydroxyl radicals shown by 5~-scymnol may be attributed to the hydroxy methyl groups at C26 and C27. The precursor, cholic acid which does not possess the unique 1,3 diol structure was assayed for comparison. Cholic acid has a terminal carboxylic acid at C24, 10 therefore it can be suggested that the effectiveness of 5,~-scymnol as a scavenger is due to the C26 and C27 hydroxy methyl groups, since the remainder of the molecule has an identical 5,~-steroid structure to that of cholic acid.

The in vifro studies here establish evidence that both 5,~-scymnol and 5,a-15 scymnol sulphate, and 5a-cyprinol and 5a-cyprinol sulphate, are hydroxy radical scavengers with significant potential in vivo, with the effectiveness possibly being attributed to the C26 and C27 hydroxy methyl groups. They both demonstrate second order rate constants of significant orders of magnitude greater than mannitol, a known radical scavenger (Moorhouse et al., 1987).

E~CAMPLE 2 The compounds 5,~-scymnol and its 27-sulphate ester have been tested 25 usir~g in vitro systems for their ability to function as a biological antioxidant against a number of reactive oxygen species (ROS) which are normal byproducts of rnetabolism and play a major role in free-radical induced toxicity.

The tests were designed to evaluate the antioxidant capacity of the test 30 compounds and to compare their effectiveness with the lipid- and water-soluble forms of vitamin E as appropriate against the following ROS: hydroxyl, superoxide, lipid- and water-soluble peroxyl radicals, and hydrogen peroxide.

WO 95/l0283 2. ~ 7 ~ 5 q ~ --Trolox [6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid] is a hydrophilic analogue of a-tocopherol with antioxidant activity more active than BHA, BHT, nordihydroguaiaretic acid (NDGA) and propyl gallate (PG).

There is a wide range of ROS which can arise physiologically from a variety of sources. Compounds such as the bile alcohols and their derivatives can be tested using in vitro systems for their ability to function as biologicalantioxidants against a number of ROS which are formed naturally in vivo or following an external event such as injury, infection or the like. The study wasdesigned to evaluate the antioxidant capacit,v of the test compounds and to compare their efficiencies with lipid- and water-soluble forms of vitamin E and vitamin C as appropriate against the following ROS:

ROS TEST SYSTEM
15 A Superoxide radical Hypoxanthine/xanthine oxidase production of urate. Comparison with Trolox and vitamin C.

B Hydroxyl radicals Fenton reaction-induced thiobarbituric acid reaction products (TBARs) in liposomes.
Comparison with Trolox and vitamin C.

C Hydrogen peroxide Horseradish peroxidase-induced oxidation of guaiacol by measurement of the guaiacol-peroxidase reaction.
D Microsomal lipid peroxidation Microsomes were isolated from rat livers and their peroxidation in the presence of iron ions and ascorbic acid was measured by thiobarbituric acid (TBA).
E Peroxyl radical scavenging Theabilityofthecompoundstoscavenge alkylperoxyl radicals generated in the aqueous .

phase by the controlled thermolysis of 2,2'-azo-bis-(2-amidinopropane)dihydrochloride(ABAP) .

Table 2 below summarises the observations made concerning the activity 5 of the test compounds in quenching ROS in these test systems.

Compounds Test Trolox 5a-Scymnol 5~-Scymnol sulphate A Superoxide radicals strong moderate weak B Hydroxyl radicals strong strong moderate C Hydrogen peroxide strong moderate- weak strong D Microsomal lipid strong moderate weak peroxidation E Peroxyl radical strong moderate- weak scavenging weak The ~ssessment to quench radicals is Strong +++
Moderate ++
Weak +

These results indicate that in all cases tested, 5~-scymnol exhibits a moderate ability to act as an antioxidant against the reactive oxygen species (ROS) which are implicated in free radical induced toxicity.

The aim of this study was thus to compare the efficacy and skin tolerance of topical 5,~-scymnol sulphate with 5% benzoyl peroxide in the treatment of mild to moderate acne.

WO 95/10283 ~ ~ 7 Q 5~ ~ PCT/AU94/00619 .

METHODS

A total of 70 patients with mild to moderate acne entered this prospective double blind trial which compared two topical medicaments. Mild to moderate 5 acne was defined as primarily open and closed comedones and some superficial inflamed lesions (papules not pustules). 44 male and 26 female were included according to certain criteria, i.e. they were older than 12 years, free from intercurrent disease, and not taking systemic antibiotics, corticosteroids, retinoids, anticonvulsants or androgens in the 30 days prior to starting the trial. No topical 10 acne therapy was allowed in the two weeks before the trial. Female patients were not to have commenced or ceased the oral contraceptive pill in the six months before the trial, and males were to be without beards and moustaches.
The patients were randomised into two treatment arms; 5% benzoyl peroxide (n=35) and 5,~-scymnol sulphate (n=35).
5,a-scymnol sulphate (Isolutrol) was supplied as a solution with a concentration of 0.15gm/100ml (purified by McFarlane Marketing (Aust.) Pty.Ltd.).
The benzoyl peroxide was a commercially available 5% water-based solution. All treatments were pre-packed in identical numbered packages.

The trial was designed as a double blind study and the patients were instructed not to describe to the invesligator any characteristics of the product such as colour, smell or consistency. An initial baseline assessment was carriedout and patients were reassessed at two, four, eight and twelve weeks. The 25 severity of each patient's acne was determined using the "counting technique"described by Burke and Cunliffe (1984). All patient assessments were carried oulby the same investigator.

The parameters used to assess the relative efficacy of each treatment 30 were changes in the number of superficial inflamed lesions, as well as non-inflamed lesions (open and closed comedones) over the duration of the trial. An assessment of skin tolerance was also conducted at each review with respect to .

burning and stinging, erythema, scaiing, pruritus and dryness. These were graded from 0-nil, 1-mild, 2-moderate to 3-severe, and the patient was asked to comment on any adverse effects experienced.

5 Statistical Analysis.
Reductions in the number of superficially inflamed and non-inflamed lesions between baseline and final review were statistically analysed using a paired Student's t-test. The grades assessing skin tolerability for both groups at each review were analysed using an unpaired Student's t-test. A p value of less 10 than 0.05 was regarded as significant.

RESULTS

The mean age of patients was 18.6 years (range 13-35 years). There was 15 no significant difference between the two study groups with respect to age, sex, duration of acne, or baseline assessment of facial erythema, pruritus, burning and stinging, dryness, and scaling.

Baseline counts of superficial inflamed lesions were 23.9i3.0 in the 20 isolutrol group and 33.3+4.9 in the benzoyl peroxide group (mean i SEM) and there was no stali~lically significant difference between the two groups at baseline. Both isolutrol and benzoyl peroxide were effective in reducing the number of superficially inflamed lesions throughout the trial (see Figure 3). This reduction between baseline and final review was statistically significant in both the 25 isolutrol and the benzoyl peroxide group (p~0.001).

Baseline counts of non-inflamed lesions were 23.4i5.0 in the isolutrol group and 25.5+4.5 in the benzoyl peroxide group (mean + SEM) and there was no statistically significant difference between the two groups at baseline. Benzoyl 30 peroxide was effective in reducing the number of non-inflamed lesions throughout the trial (p~0.001). The reduction in non-inflamed lesions between baseline and final review was not significant for the isolutrol group (p=0.06, see Figure 4).

PCT/AU9~/006 1 9 7 0 ~

Clinical assessment for skin dryness, erythema, pruritus and scaling showed a significant difference between the isolutrol group and the benzoyl peroxide groups at two weeks (p~0.05) and four weeks (p<0.05), eight weeks (p~0.05) and 12 weeks tp~0.05), the benzoyl peroxide showed increased dryness, 5 erythema, pruritus and scaling. Clinical assessment for skin burning showed a significant difference between the isolutrol group and the benzoyl peroxide group at two weeks (p~0.05), the benzoyl peroxide showing increased skin burning.
There was no significant difference between the treatment groups for the clinical assessment of skin burning at four, eight or 12 weeks. Overall, 94% of benzoyl 10 peroxide treated patients reported unwanted effects during the trial, whereas only 34% of isolutrol treated patients reported such problems (see Table 3).

TABLE 3 The percentage of patients reporting side effects during the trial within each treatment group.
Benzoyl Isolutrol peroxide Burning 34% 0.3%
Erythema 49% 9.0%
Scaling 72% 9.0%
Pruritus 43% 14%
Dryness 83% 31%

DISCUSSION
The results of this study reveal that Isolutrol is an effective treatment for 25 the reduction in the severity of acne. Isolutrol is as effective as benzoyl peroxide in reducing the numbers of inflamed lesions however, unlike benzoyl peroxide, Isolutrol is not capable of significantly reducing the numbers of non-inflamed lesions. It is possible that this difference may be due to the different modes of action and the particular effficacy of Isolutrol in reducing the number of inflamed 30 lesions indicates that Isolutrol has anti-inflammatory properties in addition to reducing hyperseborrhoea.

WO95/102~3 ~ 1 7~9 1 PCT/AU94/00619 .

Clinical assessment of side-effects showed that Isolutrol was more acceptable than benzoyl peroxide in the first month of treatment. Dryness, pruritus, burning, erythema and scaling are well known irritant effects of benzoyl peroxide and were problems commonly experienced by patients using benzoyl 5 peroxide in this trial. Thus Isolutrol may prove to be a useful adjunct to the treatment regime of patients unable to tolerate benzoyl peroxide.

WO 95tlO283 2 ~ 7 ~9 ~ PCT/AU94/00619 REFERENCES:

1. Burke, B.M. and Cunliffe, W.J. (1984). Br. J. Dermatol. 111, 83-92.

2. Cross, C.E. ef al. (1987). Annals of Internal Medicine, 107(4), 526-545.

3. Gutteridge, J. (1981). FEBS Leff. 128, 343-346.
4. Halliwell, B. and Gutteridge, J.M.C. (1984). Biochem. J., 219, 1-14.
5. Halliwell, B. and Gutteridge, J.M.C. (1985). "Free Radicals in Biology and Medicine", Clarendon Press, Oxford, England, p.147.
6. Halliwell, B. and Gutteridge, J.M.C. (1986). Arch. Biochem. Biophys. 246, 501-514.
7. Moorhouse, C. et al. (1987), FEBS Leff. 213, 23-28.
8. Slater, T.F. (1984). Biochem. J. 222, 1-15.

Claims (24)

CLAIMS:
1. A method for the treatment of biochemical damage or a medical disorder associated with free radical formation in a patient, which comprises administering to the patient an effective amount of a bile alcohol or a derivative thereof.
2. A method according to claim 1, wherein said patient is a human patient.
3. A method according to claim 1 or claim 2, wherein the bile alcohol is a compound which includes at least one hydroxyl group at positions 24, 25, 26 and/or 27 of the cholestane molecule.
4. A method according to claim 3, wherein the bile alcohol is a compound which includes hydroxyl groups at positions 26 and 27 of the cholestane molecule.
5. A method according to claim 4, wherein the bile alcohol is selected from the group consisting of:

5.alpha.-scymnol (3.alpha., 7.alpha., 12.alpha., 24R, 26, 27-hexahydroxy-5.alpha.-cholestane) 5.beta.-scymnol (3.alpha., 7.alpha., 12.alpha., 24R, 26, 27-hexahydroxy-5.beta.-cholestane) 5.alpha.-cyprinol (3.alpha., 7.alpha., 12.alpha., 26, 27-pentahydroxy-5.alpha.-cholestane) 5.beta.-cyprinol (3.alpha., 7.alpha., 12.alpha., 26, 27-pentahydroxy-5.beta.-cholestane) 5.alpha.-bufol (3.alpha., 7.alpha., 12.alpha., 25, 26-pentahydroxy-5.alpha.-cholestane) 5.beta.-bufol (3.alpha., 7.alpha., 12.alpha., 25, 26-pentahydroxy-5.beta.-cholestane) 5.alpha.-chimaerol (3.alpha., 7.alpha., 12.alpha., 24, 26-pentahydroxy-5.alpha.-cholestane) 5.beta.-chimaerol (3.alpha., 7.alpha., 12.alpha., 24, 26-pentahydroxy-5.beta.-cholestane) 5.alpha.-ranol (3.alpha., 7.alpha., 12.alpha., 24R, 26-pentahydroxy-27-nor-5.alpha.-cholestane) 5.beta.-ranol (3.alpha., 7.alpha., 12.alpha., 24R, 26-pentahydroxy-27-nor-5.beta.-cholestane) 5.alpha.-dermophol (3.alpha., 7.alpha., 12.alpha., 25, 26, 27-hexahydroxy-5.alpha.-cholestane) 5.beta.-dermophol (3.alpha., 7.alpha., 12.alpha., 25, 26, 27-hexahydroxy-5.beta.-cholestane).
6. A method according to any one of claims 1 to 5, wherein the bile alcohol derivative is an ester with an inorganic or organic acid.
7. A method according to claim 6, wherein the ester is a sulphuric acid, acetic acid, propionic acid or butyric acid ester.
8. A method according to claim 1 or claim 2, which comprises administering to the patient an effective amount of 5.beta.-scymnol, 5.beta.-scymnol sulphate, 5.alpha.-cyprinol or 5.alpha.-cyprinol sulphate.
9. Use of a bile alcohol or a derivative thereof, in the manufacture of a composition for the treatment of biochemical damage or a medical disorder associated with free radical formation in a patient.
10. A composition for use in the treatment of biochemical damage or a medical disorder associated with free radical formation in a patient which comprises an effective amount of a bile alcohol or a derivative thereof, together with a pharmaceutically acceptable carrier or diluent.
11. A composition according to claim 10, wherein the bile alcohol is a compound which includes at least one hydroxyl group at positions 24, 25, 26 and/or 27 of the cholestane molecule.
12. A composition according to claim 11, wherein the bile alcohol is a compound which includes hydroxyl groups at positions 26 and 27 of the cholestane molecule.
13. A composition according to claim 12, wherein the bile alcohol is selected from the group consisting of:

5.alpha.-scymnol (3.alpha., 7.alpha., 12.alpha., 24R, 26, 27-hexahydroxy-5.alpha.-cholestane) 5.beta.-scymnol (3.alpha., 7.alpha., 12.alpha., 24R, 26, 27-hexahydroxy-5.beta.-cholestane) 5.alpha.-cyprinol (3.alpha., 7.alpha., 12.alpha., 26, 27-pentahydroxy-5.alpha.-cholestane) 5.beta.-cyprinol (3.alpha., 7.alpha., 12.alpha., 26, 27-pentahydroxy-5.beta.-cholestane) 5.alpha.-bufol (3.alpha., 7.alpha., 12.alpha., 25, 26-pentahydroxy-5.beta.-cholestane) 5.beta.-bufol (3.alpha., 7.alpha., 12.alpha., 25, 26-pentahydroxy-5.alpha.-cholestane) 5.alpha.-chimaerol (3.alpha., 7.alpha., 12.alpha., 24, 26-pentahydroxy-5.alpha.-cholestane) 5.beta.-chimaerol (3.alpha., 7.alpha., 12.alpha., 24, 26-pentahydroxy-5.alpha.-cholestane) 5.alpha.-ranol (3.alpha., 7.alpha., 12.alpha., 24R, 26-pentahydroxy-27-nor-5.alpha.-cholestane) 5.beta.-ranol (3.alpha., 7.alpha., 12.alpha., 24R, 26-pentahydroxy-27-nor-5.beta.-cholestane) 5.alpha.-dermophol (3.alpha., 7.alpha., 12.alpha., 25, 26, 27-hexahydroxy-5.alpha.-cholestane) 5.beta.-dermophol (3.alpha., 7.alpha., 12.alpha., 25, 26, 27-hexahydroxy-5.beta.-cholestane).
14. A composition according to any one of claims 10 to 13, wherein the bile alcohol derivative is an ester with an inorganic or organic acid.
15. A composition according to claim 14, wherein the ester is a sulphuric acid, acetic acid, propionic acid or butyric acid ester.
16. A composition according to claim 10, which comprises an effective amount of 5.beta.-scymnol, 5.beta.-scymnol sulphate, 5.alpha.-cyprinol or 5.alpha.-cyprinol sulphate.
17. A method for the treatment of photodamage to the skin and/or hair of a patient associated with free radical formation resulting from UV irradiation, which comprises administering to the patient an effective amount of a bile alcohol or a derivative thereof.
18. A method according to claim 17, wherein the bile alcohol or derivative is applied topically to the skin and/or hair of the patient.
19. Use of a bile alcohol or a derivative thereof in the manufacture of a composition for the treatment of photodamage to the skin and/or hair of a patient associated with free radical formation resulting from UV irradiation.
20. A method for the treatment of an inflammatory disorder or condition of the skin of a patient, which comprises administering to the patient an effective amount of a bile alcohol or a derivative thereof.
21. A method according to claim 20, wherein the bile alcohol or derivative is applied topically to the skin of the patient.
22. Use of a bile alcohol or a derivative thereof in the manufacture of a composition for the treatment of an inflammatory disorder or condition of the skin of a patient.
23. A composition for use in a method according to claim 17 or claim 20, which comprises an effective amount of a bile alcohol or a derivative thereof, together with a topical pharmaceutical/cosmetic carrier material.
24. A composition according to claim 23, further comprising one or more penetration enhancing agent(s), anti-inflammatory agent(s) and/or sunscreen or sunblock agent(s).
CA002170591A 1993-10-12 1994-10-12 Treatment of medical disorders associated with free radical formation Abandoned CA2170591A1 (en)

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