EP0724438A1

EP0724438A1 - Ibuprofen and flurbiprofen as anti-pruritic agents

Info

Publication number: EP0724438A1
Application number: EP94931531A
Authority: EP
Inventors: Kenneth Donald The Boots Company Plc Vaughan
Original assignee: Boots Co PLC
Current assignee: Boots Co PLC
Priority date: 1993-10-20
Filing date: 1994-10-19
Publication date: 1996-08-07
Also published as: NO961589L; AU8058694A; WO1995011017A1; PL314036A1; FI961716A; SK48896A3; AU690155B2; HUT74448A; JPH09504018A; CA2174619A1; FI961716A0; HU9601031D0; CZ112496A3; NO961589D0

Abstract

Use of ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts for the treatment (including cosmetic treatment) of pruritus (itching) in animals, including human beings, by topical administration is disclosed. Also described are pharmaceutical compositions having anti-pruritic activity comprising ibuprofen, flurbiprofen and/or their salt or salts as an anti-pruritic agent or agents, preferably the only anti-pruritic agent or agents. The compositions may also comprise a pharmaceutically acceptable diluent or carrier, a thickening agent, a pH adjusting agent, a preservative agent, and a humectant. Use of ibuprofen, flurbiprofen and/or their salt or salts in the preparation of a medicament for treating pruritus and use of the above compositions to treat pruritus in animals, including human beings, is also claimed. Preferably, if the pruritus treated according to the invention has been induced by irradiation with UV-B radiation, the anti-pruritic agent is other than solely ibuprofen.

Description

IBUPROFEN AND FLURBIPROFEN AS ANTI-PRURITIC AGENTS

The present invention relates to use of ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts for treating pruritus in animals including human beings, the ibuprofen, flurbiprofen and/or pharmaceutically acceptable salt or salts being administered topically; use of ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts in the preparation of a medicament for treating pruritus topically; and pharmaceutical compositions comprising ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts as anti- pruritic agent or agents, the compositions having anti- pruritic activity. The compositions are suitable for treatment of itching animal, preferably human, skin when applied topically thereto.

Pruritus, or itching, is an unpleasant condition of the skin surface. Although pruritus is a complex phenomena, it may be defined crudely as the skin sensation which evokes the motor response of scratching. The causes of pruritus are due to many different conditions . Some causes are local and can easily be removed, for example slight mechanical irritation such as contact with rough, woollen underclothing, or parasites such as lice or scabies. Some causes of pruritus are more general and can result in a condition which is chronic.

In pruritic conditions, examples of which are described hereinafter, itching may be so constant as to be unbearable. Often the habit of scratching can be acquired, which in the course of time renders the skin rough and thickened, and this of itself aggravates and keeps up the itchiness. Sometimes the condition becomes so chronic and the skin is so changed by scratching that the pruritus becomes incurable.

It can be seen therefore that alleviation of the symptoms of pruritus is very important in its treatment both to reduce discomfort and to discourage scratching. Notwithstanding that in many cases complete cure will only be effected by treatment of the underlying condition, for example diabetes mellitus, it is nevertheless desirable to treat the pruritus directly as well as its underlying cause.

Ibuprofen, the chemical name of which is 2-(4- isobutylphenyDpropionic acid and flurbiprofen, the chemical name of which is 2- (2-fluoro-4-biphenylyl) - propionic acid, are well known medicaments. Ibuprofen and flurbiprofen are known to have anti-inflammatory, antipyretic and analgesic activity. Known uses of ibuprofen and flurbiprofen include the treatment of pain and inflammation in musculoskeletal disorders such as rheumatic disease, and the treatment of pain in a variety of other disorders, for example headache, neuralgia and dysmenorrhoea. Ibuprofen and flurbiprofen have been ingredients in many different topical compositions, for treatment of the indications described above.

The state of the art at the earliest priority date of the present invention is now discussed.

International application WO 92/22585 (Patent Biopharmaceutics Inc) discloses a composition for treating the symptoms of haemorrhoids and other anorectal diseases (which includes, inter alia, pruritus) using hyaluronic acid as the sole anti- pruritic ingredient. A disclosure that any, unspecified anti-inflammatory agent might be added as an additional optional ingredient to this composition does not suggest that the anti-inflammatory agent would have any other activity, or would be added for any other purpose than optionally to add anti-inflammatory properties to the anti-pruritic composition.

The abstract of United States patent 3,686,183 (Syntex Corp.) asserts:

'The α substituted arylacetic acids are useful as anti-inflammatory, analgesic, anti-pyretic and anti-pruritic agents'. This document makes no further reference to anti- pruritic activity of these compounds. The invention claimed in US 3,686,183 relates to a process for racemising α substituted arylacetic acids. Specific compounds claimed and described are naphthalene acetic acids, which teaches away from selecting ibuprofen and flurbiprofen neither of which are specifically disclosed. US 3,686,183 does not describe any experiments or produce any data to support the incidental assertion in the abstract of anti-pruritic activity in relation to a broad class of compounds. This reference in the abstract must be considered highly speculative and is not supported by the document which it abstracts.

The previous two disclosures do not specifically refer to ibuprofen and/or flurbiprofen and therefore are not of particular relevance, but are evidence of the general state of the art.

At least fifty papers in the medical literature disclose anedoctal evidence that systemically (usually orally) administered ibuprofen may be associated with pruritic symptoms for a small minority of patients. This is evidenced by, for example, the review paper 'Cutaneous Reactions to Rheumatological Drugs' (Clin. Rheum. Dis., 1982, 8(2), 493-516, Bailin P.L. et al) in which pruritus is stated to be 'a commonly mentioned' cutaneous adverse reaction after ingestion of ibuprofen.

These references clearly indicate that there was a technical prejudice against using systemic ibuprofen as anti-pruritic agent at the earliest priority date of the present application.

In addition to the numerous references to pruritic effects associated with systemic administration of ibuprofen, one paper discloses a 'minor intolerance phenomena' including 'slight local itching' on topical application of a gel comprising 5% ibuprofen to treat 'rheumatic afflictions', (see Therapiewoche Schweiz, 1992, 8 (10), 764-768, Bahoud) .

The article. 'Drug-induced Photosensitivity' in The Pharmaceutical Journal [245 (6592)], 7 July 1990, pages 19-21, lists ibuprofen as one of many systemic drugs reported to cause photosensitivity reactions including pruritus if the skin is exposed to UV radiation (200- 400 nm) . General mention is made in passing that topical as well as systemic preparations of photosensitising drugs can induce phototoxic reactions. No specific reference is made to topical ibuprofen preparations, or side effects from their use.

An English abstract of Japanese patent application J62-223118 (Hisamitsu) discloses a topical cream containing an ibuprofen derivative (ibuprofen piconol) for treating skin diseases such as atopic dermatitis or chronic eczema. There is no suggestion that this composition has activities other than those previously known for ibuprofen, indeed, there is some anecdotal evidence that topical application of ibuprofen piconol is associated with minor pruritic symptoms in a small number of patients (for example, Skin Res 1985, 27, 115- 125, Yoshida H et al; Skin Res 1988, 30 (3), 385-396, Udea H et al; and Nippon Hifuka (Nishinihon J Dermatol) , 1991, 53 (4) , 695-698) .

The minor pruritic effects associated with the above topical compositions may not be associated with ibuprofen, but could arise from other factors or ingredients, for example, the pH of the composition, the excipients and/or the ibuprofen ester (ibuprofen piconol) .

Anecdotal evidence for use of non-steroidal antiinflammatory agents (NSAID) which include ibuprofen is disclosed in Journal of American Academy of Dermatology, April 1993, pages 603-609. This article incidentally discloses that 5 out of a random sample of 68 elderly dermatologists in replying to a questionnaire suggested that oral treatment with a NSAID such as ibuprofen might be used to treat pruritus.

An article entitled 'Medical Myths - Poison Ivy: A Rash of Rumours' (Consumer Reports Health Letter, June 1991, page 45) states in passing that over the counter (OTC) pain relievers (including ibuprofen) relieve itching caused by poison ivy, poison oak or sumac. No evidence is supplied for this assertion, and from the context it is not clear whether the relief claimed is analgesic, anti-inflammatory or reducing the pruritus symptoms. In contrast to the above anecdotal references there is a case report (Anaesthesiology, 1992, 76(6), 1056-

1057, Valley M.A. et al) that a rash and pruritus caused by a Herpes simplex viral infection: 'did not resolve . . . with the administration of

. . . non-steroidal anti-inflammatory agents

( . . . [inter alia] ibuprofen . . .)'.

The anecdotal references which might suggest treating pruritus with ibuprofen are also refuted by the scientific evidence available at the earliest priority date of the present application. In a randomized, double-blind, cross-over study conducted with patients in which inflammation had been induced by UV-B radiation, no evidence was found that orally administered ibuprofen had a statistically significant effect over placebo in treating the pruritic symptoms so induced. (Arch. Dermatol. - Volume 121, April 1985, page 508-512) . The term UV-B radiation (ultra-violet B radiation) is defined herein as electromagnetic radiation having a wavelength in the inclusive range from 280 n to 320 nm.

It has been reported anecdotally from a single patent report that relief for simultaneous pain and pruritus in breast cancer might be obtained by oral use of flurbiprofen (see The Lancet, 26 September 1981, page 696) . R. Winkelmann, Medical Clinics of North America, volume 66, No.5, September 1982, also refers in passing to 'only anecdotal reports' for antipruritic activity of [non salicylate] 'non-steroidal agents, as flurbiprofen' . These documents do not refer to ibuprofen and such references to antipruritic activity for flurbiprofen are anecdotal only and have no scientific support. These reports are also contradicted by a study in which administration of flurbiprofen tablets was associated with cutaneous effects, including pruritus, in 5 out of 68 arthritic patients (Lille Medical, 1980, Vol. 25(3), pages 100-101).

Thus, at best anecdotal references at the earliest priority date of the present invention to treatment of pruritus using systemically administered ibuprofen or flurbiprofen are unclear, contradictory and/or lack scientific support. There is no explicit reference in the prior art to use of topical preparations of ibuprofen and/or flurbiprofen to treat pruritus.

Therefore the skilled person who at the earliest priority date of the present invention might have been led by incidental anecdotal evidence in some of the documents cited above, to use (either systemically or otherwise) ibuprofen or flurbiprofen to treat pruritus, would have been immediately dissuaded from so doing by the results of the systematic study for (inter alia) antipruritic activity of orally administered ibuprofen

(where the pruritus was induced by UV-B radiation) which taught that the anecdotal evidence was unfounded. In addition, the conflicting nature of the anecdotal evidence for use of ibuprofen or systemic flurbiprofen to treat pruritus and the technical prejudice against systemic use of ibuprofen as an anti-pruritic agent at the earliest priority date of the present application acted as further disincentives at that date for a skilled person to use to use (either systemically or otherwise) ibuprofen or flurbiprofen to treat pruritus.

Surprisingly, in view of the above described prior art, it is has now been discovered that in addition to their known activities described above, ibuprofen, flurbiprofen and/or one or more of their pharmaceutical acceptable salt or salts are useful as anti-pruritic agent or agents in the topical treatment and alleviation of the symptoms of pruritus. Preferably if the pruritus has been induced by irradiation with UV-B radiation, the anti-pruritic agent or agents comprise other than solely ibuprofen (for example flurbiprofen or flurbiprofen and ibuprofen together) .

The present invention provides for use of ibuprofen flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts for the topical treatment of pruritus in animals, preferably human beings. In a method according to the present invention, ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts are administered topically to animals, preferably human beings, suffering from pruritus, the ibuprofen, flurbiprofen and/or their pharmaceutically acceptable salt or salts being applied to the affected area to achieve an anti-pruritic response and being present in an anti-pruritically effective amount. Preferably if the pruritus has been induced by UV-B radiation, the anti-pruritic agent or agents comprise other than solely ibuprofen.

Both ibuprofen and flurbiprofen contain a single chiral centre at an asymmetrically substituted carbon atom, and therefore both exist in enantiomeric forms.

^• Racemic ibuprofen consists of a 50:50 mixture of (+)2-

(4-isobutylphenyl)propionic acid and (-)2-(4- isobutylphenyDpropionic acid. It will be understood that the term ibuprofen as used herein includes the racemic mixture, the S(+)- and R(-) -enantiomers separately and any mixture thereof sufficient to give an anti-pruritic response. Similarly racemic flurbiprofen consists of a 50:50 mixture of (+) 2-(2-fluoro-4- biphenylyDpropionic acid and (-) 2-(2-fluoro-4- biphenylyDpropionic acid. It will also be understood that the term flurbiprofen as used herein includes the racemic mixture, the (+) and (-) enantiomers separately and any mixtures thereof sufficient to give an anti- pruritic response.

Ibuprofen and/or flurbiprofen may form salts with organic or inorganic bases. The terms ibuprofen and/or flurbiprofen salt and/or salts as used herein include all such salts of these compounds which are pharmaceutically acceptable (i.e. non-toxic at therapeutically effective doses) and are present in amounts sufficient to give an anti-pruritic response. Particularly suitable salts of ibuprofen and/or flurbiprofen comprise alkali metal salts (for example sodium and/or potassium salts) , alkaline earth metal salts (for example magnesium and/or calcium salts) , aluminium salts, ammonium salts, salts of suitable organic bases (for example salts of alkylamines and/or N-methyl-D-glutamine) , salts of amino acids (for example salts of arginine and/or lysine) .

A preferred salt of ibuprofen is sodium ibuprofen, more preferably S(-)sodium ibuprofen. It will be readily understood that these salts may also exist as racemates, separate enantiomers and/or mixtures thereof and the terms ibuprofen and/or flurbiprofen salt and/or salts as used herein include racemates, separate enantiomers or any mixtures thereof of all pharmaceutically acceptable ibuprofen and/or flurbiprofen salt or salts present in an amount sufficient to give an anti-pruritic response. It will be appreciated that such salts, provided they are pharmaceutically acceptable, may be used in therapy in place of ibuprofen and/or flurbiprofen. Such salts are prepared from ibuprofen and/or flurbiprofen with a suitable base in a conventional manner. Ibuprofen, flurbiprofen and/or their salt or salts may exist in more than one crystal form and references to these compounds herein include each crystal form and mixtures thereof sufficient to give an anti-pruritic response. Ibuprofen, flurbiprofen and/or their salt or salts may also exist in the form of solvates, for example hydrates, and references to these compounds herein include each solvate and mixtures thereof present in an amount sufficient to give an anti-pruritic response.

The anti-pruritic activity of ibuprofen, flurbiprofen and/or their pharmaceutically acceptable salts has been demonstrated by means of tests on animals, including human beings, such as those described hereinafter in the Examples. Thus both ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts are useful in the treatment of pruritus in animals, preferably human beings. Preferably, if the pruritus has been induced by UV-B radiation, the anti-pruritic agent or agents comprise other than solely ibuprofen. The ibuprofen, flurbiprofen and/or their pharmaceutically acceptable salt or salts are administered topically, more preferably to itching animal skin, most preferably itching human skin. Whilst the precise amount of ibuprofen, flurbiprofen and/or their pharmaceutically acceptable salt or salts administered topically to treat pruritus as outlined herein, will depend on a number of factors, for example the severity of the condition, the animal being treated and the age and past medical history of the patient, and will lie within the sound discretion of any administering veterinary, physician and/or pharmacist, a suitable daily dose of ibuprofen, flurbiprofen and/or their pharmaceutically acceptable salt or salts for administration to animals, preferably human beings, to treat pruritus may be generally from about lmg to about 10,000mg, more usually from about 5mg to about 5000mg, most usually from about lOmg to about lOOOmg, given in a single dose or in divided doses at one time or more times during the day.

As will be appreciated by the person skilled in the art, pruritic symptoms may occur on normal and abnormal skins and may be caused by a number of metabolic pathways (reference is made to R Winkelmann, Medical Clinics of North America, Vol 66, No 5, September 1982) . Some pruritic conditions may arise from one or both of the following non-prostaglandins mechanisms, namely via histamine and serotonin production. Examples of causes of pruritus include one or more of any of the following: induction by UV-radiation (for example sunburn) ; external non-UV stimuli (for example contact with fibres [such as wool and/or synthetic fibres] , aqueous contact [aquagenic pruritus] and/or cholinergic pruritus [related to heat and/or exercise] ) ; enteral and/or parenteral contact with histamine- producing substances (for example food substances and/or plants) ; administration of drugs (for example opiates, barbiturates and/or salicylamilides) ; toxic products (for example bile salts and/or urea) released due to failure of body organs (for example kidney and/or liver failure) ; pruriginous disease (for example leprosy) ; stimulation of (or other changes in) nerve endings, fibres and/or receptors in the skin; psychogenic causes; and xerosis (abnormal dryness) of the skin in the elderly.

Pruritus, or itching, may be classified amongst the following conditions (see Winkelmann 1982) :

Physiologic itch is a short-lived cutaneous response to the usual environmental and body stimuli which may or may not elicit scratching, and is to be distinguished form tickle which is considered to be moving touch plus its affective response.

Pathologic itch is an intense cutaneous discomfort occurring with pathologic change in the skin or body which usually elicits vigorous scratching or other effort at relief.

Spontaneous itch is itching unrelated to pathologic change in the skin or cutaneous nerves and elicited by toxic or metabolic change within the body. This may be physiologic or pathologic itch.

Focal itch is a locus of pathologic itching caused by cutaneous nerve or other tissue change.

Scattered itch is multiple, distant areas of pruritus and may exist in the skin following an itching excitation in only one skin area. Referred itch is a more recent name for scattered itch but often in the same dermatome.

Conversion itch is a condition described in 1964 by Winkelmann to account for the change of a usual sensory experience into itch, as touch or tickle to itch in atopic skin of normal appearance.

Itchy skin is an area of hyperresponsiveness to stimuli for itch about a primary stimulus zone for itch or a primary skin inflammation. This is analogous to the hyperalgesic zone about a skin spot stimulated to pain.

Central neural itch is itching stimulated and/or maintained by the central nervous system. Cutaneous changes are not primary.

In addition various diseases or disorders have pruritus as one of their main symptoms. They may comprise any of the conditions listed below:

Dermatitis, or eczema, is a superficial inflammation of the skin, and is characterised by vesicles (when acute) , redness, oedema, oozing, crusting, scaling and usually itching.

Contact dermatitis is an acute or chronic inflammation of the skin which is often sharply demarcated. It is produced by contact between the skin and some substance or stimulus to which the skin is sensitive, for example those described above.

Atopic dermatitis is a chronic, itching superficial inflammation of the skin usually occurring in individuals with a personal family history of allergic disorders (for example hay fever, asthma) due to an inherited state of hypersensitivity. It is also known as infantile eczema as it often starts in infants at about the age of 3 to 4 months.

Seborrhoeic dermatitis is an inflammatory scaling disease of the scalp, face and occasionally other areas of the body which produces variable amounts of itching.

Nummular dermatitis is a chronic dermatitis characterised by inflamed, coin-shaped, vesicular, crusted, scaly and usually pruritic lesions.

Pompholyx is a chronic condition characterised by deep- seated itchy vesicles on the palms, sides of the fingers and soles of the feet. When it occurs on the fingers and hands it is known as cheiropompholyx. On the toes and feet it is known as podopompholyx.

Generalised exfoliative dermatitis is a severe widespread erythema and scaling of the skin. Itching may be severe or absent.

Localised scratch dermatitis is a chronic, superficial, pruritic inflammation of the skin.

Impetigo is a superficial, vesiculopustular skin infection seen chiefly in children. It is usually caused by the staphylococcus aureus. Itching is common and scratching may spread the infection, as the discharge from the vesicles is infectious.

Ecthyma is an ulcerative form of impetigo.

Scabies is a transmissible, parasitic skin infection caused by the mite Sarcoptes Scabies. The condition is characterised by superficial burrows, intense pruritus and secondary skin infection. The intense itching of this condition gives scabies its popular name of 'itch'.

Pediculosis is infestation by lice.

Urticaria (otherwise known as hives or nettle rash) results in local wheals and erythema in the dermis. Food allergy is a common cause of urticaria, which is generally agreed to be an allergic reaction on behalf of the sufferer to some substance to which they are hypersensitive. Pruritus is generally the first symptom, occurring shortly after exposure to the substance which causes the condition.

Lichen simplex and lichen planus are recurrent, pruritic, inflammatory eruptions characterised by small, discrete, angular papules that coalesce into rough scaly patches with consequent thickening and hardening of the skin.

Miliaria (prickly heat) is an acute, inflammatory, pruritic eruption due to retained extravasated sweat, often affecting people travelling to the tropics. A similar condition can occur in some people upon getting warm in bed or at the start of spring or autumn when changes in the size of blood vessels in the skin take place.

Dermatitis herpetiformis is a chronic eruption characterised by clusters of intensely pruritic vesicles, papules and urticaria-like lesions.

A very aggravated form of itching may occur at the anus, known as pruritus ani. This is often caused by threadworms. An equally troublesome form of itching known as pruritus vulvae can occur around the vagina and may be associated with excessive vaginal discharge.

Elderly humans often suffer from pruritus as the skin becomes thin and inelastic. This is commonly seen as cold weather itch on the legs of old people when their skin becomes drier in the colder weather. Pruritus in the elderly may be due to a primary skin disease, a systemic disease or may have multifactorial or idiopathic causes. It is believed that xerosis is the most common cause of itching in the elderly.

Other more systemic conditions that may give rise to pruritus comprise obstructive biliary disease, uraemia, lymphomas, leukaemias, polycythemia rubra vera, and diabetes mellitus. Jaundice and glomerulo-nephritis may also be accompanied by itchiness in a milder degree.

Animals that may be treated by the methods of the present invention and/or with the compositions of the present invention (described hereinafter) , comprise human beings as well as non-human animals and the term 'animal' as used herein should be construed as including human beings. Non-human animals that may be so treated comprise those commonly encountered as domestic pets (for example cats, dogs, rabbits and/or guinea pigs); those used commercially (for example livestock [such as pigs, cows and/or sheep] and/or working animals [such as horses] ) and/or those animals kept in zoos or wildlife parks for example zebra, lions and/or elephants) .

The present invention should not be considered limited to those animals mentioned above and could in principle be used for the treatment of any animals including non-mammals (for example reptiles and/or birds) . Aquatic animals, (for example fish and/or aquatic mammals) may also be treated with a topical formulation of the invention that is waterproof or water resistant. It may also be possible to treat wild animals in their natural environments using the methods and compositions of the present invention as part of a more general management strategy, for example in a game reserve or national park.

Methods and/or compositions of the present invention may be particularly useful in preventing non- known animals from scratching their itching skin or hide. Scratching may be therapeutically undesirable as it may cause damage or aggravate any underlying condition, and/or may be cosmetically undesirable as it may blemish the skin or hide. Inhibition of scratching may be particularly important (either as a method of therapy or as a non-therapeutic cosmetic treatment) for animals with a high cultural and/or economic value (for example endangered species bred in captivity for possible re-introduction into the wild [such as pandas] , highly prized animals [such as racehorses] and/or animals bred for their skin to produce leather or fur [such as mink] ) .

Preferably the animal treated by the methods of, or with the compositions of, the present invention is a mammal, more preferably a human being.

A further aspect of present invention also provides a pharmaceutical composition comprising ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts as anti- pruritic agent or agents, the composition having anti¬ pruritic activity. Preferably the ibuprofen, flurbiprofen and/or their pharmaceutically acceptable salt or salts are the only anti-pruritic agent or agents. The composition is in a form suitable for topical application, preferably in a form suitable for application to itching animal, preferably human, skin.

A still further aspect of the present invention also provides for use of ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts in the preparation of a topical medicament for treating pruritus.

The present invention further provides a method of treating pruritus on animals, including human beings, using the compositions described herein. Preferably if ibuprofen is the sole anti-pruritic agent the pruritus treated according to this method has been induced by other than UV-B radiation.

As mentioned above, pruritus often arises as symptom produced by an underlying condition. Use of a topical medicament of the present invention may alleviate pruritic symptoms with or without a therapeutical effect on any underlying condition.

Itching may induce scratching of the skin. Scratching is often therapeutically undesirable because it may aggravate the pruritus and/or any underlying condition but also may be cosmetically undesirable, for example, because it may produce or worsen unsightly blemishes on the skin. Relief from itching sufficient to reduce and/or eliminate the urge to scratch may produce a cosmetically desirable effect independent of any curative and/or other therapeutic effect on the pruritus and/or any underlying condition. For example, if the degree of scratching required to produce an undesirable therapeutic effect is significantly greater than that required to produce a cosmetically undesirable effect, then treatment to reduce the urge to scratch may not necessarily have a concurrent therapeutic effect. Thus topical application of compositions of the present invention to reduce and/or eliminate itching, (and hence the urge to scratch) may have utility as a non- therapeutic method of cosmetic treatment.

Therefore the present invention further provides a non-therapeutic method of cosmetic treatment for inhibiting in animals, including human beings the urge to scratch the skin elicited by itching, comprising applying topically to the animal a composition comprising ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts. The cosmetic treatment of the present invention acts to reduce the degree of scratching by an animal by an amount sufficient to result in a corresponding reduction and/or elimination of the cosmetically undesirable effects caused by such scratching. Compositions suitable for use in such a topical treatment may comprises those compositions known to persons skilled in the art of cosmetics formulation and/or the pharmaceutical compositions described herein.

The method of therapy, treatment (including cosmetic treatment) , use and/or compositions described herein may be applied in conjunction with any other compatible therapy, treatment (including cosmetic treatment) and/or composition also for the treatment (including cosmetic treatment) of pruritus, and/or the treatment of any other condition (for example any condition which may be the underlying cause of the pruritic symptoms) .

The amount of the ibuprofen, flurbiprofen and/or their pharmaceutically acceptable salt or salts in the topical formulation should be such that an anti- pruritically effective amount of this compound or these compounds is delivered during the period of time for which the topical formulation is intended to be on the skin. The formulation should remain on the skin for at least that period of time necessary to produce an effective anti-pruritic response in the area of skin treated. For any given formulation of the invention the delay before onset of any anti-pruritic effect depends on many factors including the nature of the pruritus, the area and type of skin being treated and the species and age of patient, as well as the nature of the formulation. Typically for an adult human patient, the delay before onset of an anti-pruritic effect may be from about a few seconds to about an hour or more, more usually from about one to twenty minutes.

Preferably topical compositions of the present invention comprise ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts in an amount from about 1% to about 25% by weight, more preferably from about 2% to about 15% by weight, most preferably from about 2.5% to about 10% by weight of the composition.

Formulations used in methods of, or as compositions of, the present invention may provide a local and/or systemic therapeutic and/or cosmetic effect, and may be administered in a prophylactic manner, for example to prevent the onset of pruritus and/or to prevent the urge to scratch the skin. Such formulations, or compositions, may be formulated in a manner known to those skilled in the art to give a controlled release, for example rapid release or sustained release, of , ibuprofen, flurbiprofen and/or their pharmaceutically acceptable salt or salts. It will readily be understood that in the topical formulations of the present invention described hereinafter, the ibuprofen and/or flurbiprofen ingredient may be replaced or supplemented by any pharmaceutically acceptable salt or salts of ibuprofen and/or flurbiprofen compatible with the ingredients used in the formulation.

Suitable topical compositions of the present invention, or topical formulations for use in methods of the present invention, may comprise a matrix in which the ibuprofen and/or flurbiprofen, are dispersed so that the compound or compounds are held in contact with the skin in order to administer the compound or compounds transdermally. Suitable matrices for topical application may comprise topical delivery devices such as cataplasms, poultices, patches or impregnated bandages.

A composition suitable for transdermal delivery may be prepared by mixing the ibuprofen and/or flurbiprofen with a topical vehicle (for example a mineral oil, petrolatum, light liquid paraffin and/or a wax [such as paraffin wax and/or beeswax] ) together with a potential transdermal accelerant such as dimethyl sulphoxide and/or propylene glycol. Alternatively, the ibuprofen and/or flurbiprofen may be mixed with and/or dispersed in, a pharmaceutically acceptable foam, paste, salve, lotion, cream, ointment, emulsion and/or gel base, and/or applied in the form of a spray. A suitable cream may be prepared by incorporating the ibuprofen and/or flurbiprofen in petrolatum and/or light liquid paraffin, dispersed in an aqueous medium using a surfactant. A suitable ointment may be prepared by mixing the ibuprofen and/or flurbiprofen with a mineral oil, petrolatum and/or a wax (for example paraffin wax and/or beeswax) . A suitable gel may be prepared by mixing the ibuprofen and/or flurbiprofen with a topical vehicle comprising a gelling agent (for example basified Carbomer BP) in the presence of water.

Preferably compositions of the present invention comprise a pharmaceutically acceptable diluent or carrier, more preferably an aqueous solvent, most preferably purified water.

Preferably compositions of the present invention also comprise a thickening agent in an amount from about 0.1% to about 10% by weight, more preferably from about 0.2% to about 5% by weight, most preferably from about 0.5% to about 3% by weight of the composition. The thickening agent may comprise hydroxyethyl cellulose, and/or a carboxyvinyl cross polymer (for example that available commercially from B.F. Goodrich Limited under the trade name Carbopol 980NF) .

Preferably compositions of the present invention further comprise a pH adjusting agent, more preferably a basic pH adjusting agent. Preferably the pH adjusting agent is present in an amount which is sufficient to activate the thickening agent, if present, and which will keep the pH of the composition within a pharmaceutically and cosmetically acceptable range that will not damage the skin. More preferably the pH of the composition is from about 5.0 to about 9.0. Subject to the aforementioned, the pH adjusting agent, is preferably present in an amount from a trace amount to about 15% by weight, more preferably from about 0.01% to about 12% by weight, most preferably from about 0.1% to about 10% by weight of the composition. T h e p H adjusting agent may comprise sodium citrate, sodium hydroxide, potassium hydroxide and/or N,N,N',N'- tetrakis (2-hydroxypropyl) ethylenediamine (available commercially under the trade name Quadrol) .

Compositions of the present invention may additionally comprise a preservative. Preferably the preservative is present in an amount from a trace amount to about 5% by weight, more preferably from about 0.1% to about 3% by weight, most preferably from about 0.5% to about 2% by weight of the composition. The preservative may comprise bronopol, sodium dehydroacetate , polyhexamethy1enebiguanide hydrochloride, isothiazolone diazolidinylurea and/or 2- phenoxyethanol (available commercially under the trade name Phenoxetol Nipa) .

Compositions of the present invention may further comprise a humectant to improve the feel of the composition on the skin. Preferably the humectant is present in an amount from about 1% to about 30% by weight, more preferably from about 5 to about 20% by weight, most preferably from about 7% to about 15% by weight of the composition. The humectant may comprise a glycol which is defined herein as one or more organic compounds each having at least two hydroxy groups preferably on adjacent atoms. More preferably the glycol may comprise polyethylene glycol, glycerin and/or any mixture of these.

If a composition of the present invention is a gel. such a gel may be a clear gel comprising a clarifying agent, preferably a denaturated alcohol, more preferably denaturated ethanol. Preferably the clarifying agent is present in an amount from about 5% to about 60% by weight of the composition. If a composition of the present invention is an emulsion, such an emulsion may be either an oil-in-water or a water-in-oil emulsion.

The oil phase of an emulsion that may comprise a composition of the present invention may comprise one or more of the following ingredients and/or any mixture of these: hydrocarbon oils (for example paraffin and/or mineral oils) ; waxes (for example beeswax and/or paraffin wax; natural oils (for example sunflower oil, apricot kernel oil, shea butter and/or jojoba oil) ; silicone oils (for example dimethicone, cyclomethicone and/or cetyldimethicone) ; fatty acid esters (for example isopropyl palmitate and/or isopropyl myristate) ; and fatty alcohols (for example cetyl alcohol and/or stearyl alcohol) ;

In a preferred oil-in-water emulsion that may comprise a composition of the present invention, the oil phase comprises from about 5% to about 30% by weight, more preferably from about 10% to about 20% by weight of the composition.

Emulsifiers that may be used in a composition of the present invention may be any emulsifiers known in the art for use in water-in-oil or oil-in-water emulsions. Those compositions of the present invention that are emulsions can be prepared by using an emulsifier and/or a mixture of emulsifiers selected from known emulsifiers acceptable for use in topical compositions which may comprise one or more of the following ingredients and/or any mixtures of these. sesquioleates (for example sorbitan sesquioleates [such as that available commercially from ICI under the trade name Arlacel 83]); ethoxylated esters of derivatives of natural oils (for example polyethoxylated esters of hydrogenated castor oils [such as that available commercially from ICI under the' trade name Arlacel 989]); silicone emulsifiers (for example silicone polyols [such as those available commercially from Th. Goldschmidt AG under the trade name ABIL WS05 and from Dow Corning under the trade designation Silicone Fluid 3225C] ) ; fatty acid soaps (for example potassium stearate) ; ethoxylated fatty alcohols (for example those available commercially from ICI under the trade name Brij and from Croda under the trade name Cithrol GMS A/S) ; sorbitan esters (for example those available commercially from Croda under the trade name Crill) ; ethoxylated sorbitan esters (for example those available commercially from ICI under the trade name Tween) ; ethoxylated fatty acid esters (for example ethoxylated stearates [such as that available commercially from ICI under the trade name Myrj] ) ; ethoxylated mono-, di-, and/or tri-glycerides (for example those available commercially from Alfa Chemicals under the trade name Labrafil) ; and ethoxylated fatty acids (for example those available commercially from Alfa Chemicals under the .trade name

Tefose) .

The amount of emulsifier optionally present in a water-in-oil emulsion that may comprise a composition of the present invention is preferably in the range from about 0.1% to about 20% by weight of the composition.

The amount of emulsifier optionally present in an oil-in-water emulsion that may comprise a composition of the present invention is preferably in the range from about 0.1% to about 20% by weight of the composition.

If a composition of the present invention is other than an emulsion, an emulsifying ingredient and/or surfactant (for example one of those emulsifiers listed above) , may still be present (for example in the amounts given above) as a surface active agent to promote greater therapeutic activity in the composition when it is applied topically.

The compositions of the present invention may additionally comprise one or more other component, components and/or any mixture of these, which will be well known to those skilled in the art and may be selected from: emulsion stabilisers (for example stearyl alcohols and/or cetyl alcohols) and/or emulsion stabilising salts

(for example sodium chloride, sodium citrate and/or magnesium sulphate) , preferably in an amount from about

0.1% to about 5% by weight of the composition; sequestrants (for example tetra sodium ethylene diamine tetra acetate dihydrates [such as that available commercially from Rhone Poulenc under the tradename Sequestene NA4] ) , preferably in an amount from a trace amount to about 1% by weight of that composition; anti-oxidants (for example DLα tocopherol acetate and/or butylated hydroxytoulene) , preferably in an amount from about a trace amount to about 1% by weight of the composition; emollients (for example mineral oil, polymethylsiloxane, sweet almond oil, petroleum jelly, isopropyl myristate and/or triglycerides of fatty acids [such as lauric triglyceride, capric/caprylic triglyceride, and/or mixed triglycerides {eg that available commercially from Huls UK Ltd under the trade name Miglyol 810}]), preferably in an amount from about 0.1% to about 30% by weight of the composition; moisturisers (for example D-panthenol), preferably in an amount from a trace amount to about 1% by weight of the composition; film formers to assist spreading on the surface of the skin (for example alkylated polyvinylpyrrolidone) , preferably in an amount from a trace amount to about 1% by weight of the composition; and perfumes and/or colouring.

The invention will now be illustrated with reference to the following non-limitative Examples, in which all percentages given are by weight of ingredient per total weight of the composition. In the Examples 2-phenoxyethanol, which is a preservative, is available commercially under the tradename Phenoxetol Nipa; carboxyvinyl crosspolymer, which is a thickening agent, is available commercially from B.F. Goodrich Limited under the tradename Carbopol 980 NF; N,N,N',N'-tetrakis (2-hydroxypropyl)ethylene diamine, which is a basic pH adjusting agent, is available commercially under the tradename Quadrol; and ethoxylated fatty alcohol, which is a surface active agent, is available commercially from ICI under the tradename Brij 92.

Example 1 % w/w

Ibuprofen 5.0

Polyethylene glycol 300 BP (humectant) 10.0 2-Phenoxyethanol (Phenoxetol Nipa) 1.0 Carbovinyl crosspolymer (Carbopol 980NF) 0.5 Sodium hydroxide BP pellets (pH adjuster) 0.085

Purified water BP (diluent) to 100

The ingredients above were mixed together to form an opaque gel composition. The gel composition of Example 1 was applied to the skin of the ankle of a human volunteer which was itching, had flaky skin and was red and inflamed. The composition was found to reduce the itching sensation and within a short time the skin flakiness. This surprising effect was independent of any anti-inflammatory, anti-pyretic or analgesic response which might be expected to result from application of ibuprofen.

A guinea pig was suffering from pruritus to the extent that hair was eliminated from the skin and a red patch had developed on the skin the size of a penny. Some of the gel made up as Example 1 was applied to the sore and this was repeated daily for one week. Within this time the red patch disappeared and the hair started to regrow in the affected area. The guinea pig made a continuous recovery without relapse.

Example 2 % w/w

(S+)Ibuprofen 2.5

Carboxyvinyl crosspolymer (Carbopol) 2.0 Denatured ethanol (clarifying agent) 5.0 Sodium hydroxide (pH adjuster) 1.525

2-Phenoxyethanol (Phenoxetol) 1.0

Purified water (diluent) to 100

The above ingredients were mixed together to form a clear gel composition, which has anti-pruritic activity when applied topically as described in Example 1.

Example 3 % w/w

Flurbiprofen 2 . . 5

Polyethylene glycol (humectant) 10 , . 0 2-Phenoxyethanol (Phenoxetol) 1 , . 0 Carboxyvinyl crosspolymer (Carbopol) 0 . . 5 Sodium hydroxide (pH adjuster) 0 . . 085 Purified water (diluent) to 100

The above ingredients were mixed together to form an opaque gel composition, which has anti-pruritic activity when applied topically as described in Example 1.

Example 4 % w/w

Flurbiprofen 2.5

Carboxyvinyl crosspolymer (Carbopol) 2.0

Denatured ethanol (clarifying agent) 50.0 Polyethylene glycol (humectant) 5.0

Glycerin (humectant) 5.0

Purified water (diluent) to 100

Example 5 % w/w

Flurbiprofen 10 . 0

Denatured ethanol (clarifying agent) 40 , . 0 Carboxyvinyl crosspolymer (Carbopol) 2 . 6 N,N,N',N'-tetrakis (2-hydroxypropyl) ethylene diamine [Quadrol] 9 . . 0 Propylene glycol (humectant) 2 , . 0 Ethoxylated fatty alcohol (Brij 92) 2 . . 0 Purified water (diluent) to 100

Claims

1. Use of ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts as an anti-pruritic agent or agents for the treatment of pruritus on animals, the ibuprofen, flurbiprofen and/or their salt or salts being applied topically to the animal.

2. Use of ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts as claimed in claim 1, in which, if pruritus has been induced by UV-B radiation, the anti-pruritic agent or agents comprise other than solely ibuprofen.

3. Use of ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts as claimed in either proceeding claim, in which the animal is a human being.

4. Use of ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts in the preparation of a medicament for treating pruritus.

5. A pharmaceutical composition comprising ibuprofen, flurbiprofen and/or one or more of their pharmaceutically acceptable salt or salts as anti¬ pruritic agent or agents, the composition having anti¬ pruritic activity.

6. A composition as claimed in claim 5, comprising from about 1% to about 25% ibuprofen, flurbiprofen and/or one of more of their pharmaceutically acceptable salt or salts by weight of the composition.

7. A composition as claimed in either of claims 5 or 6, comprising a pharmaceutically acceptable diluent or carrier.

8. A composition as claimed in any of claims 5 to 7, comprising a thickening agent.

9. A composition as claimed in any of claims 5 to 8, comprising a pH adjusting agent.

10. A composition as claimed in claim 9, in which the pH adjusting agent is basic.

11. A composition as claimed in any of claims 5 to 10, comprising a preservative.

12. A composition as claimed in any of claims 5 to 11, comprising a humectant.

13. A composition substantially as described herein with reference to the examples.

14. A method of treating pruritus in animals using a composition as claimed in any of claims 5 to 13, in which the composition is applied topically to an animal.

15. A method of treatment as claimed in claim 14, in which, if the pruritus has been induced by UV-B radiation, the anti-pruritic agent or agents comprise other than solely ibuprofen.

16. A method of treatment as claimed in either of claims 14 or 15, in which the animal is a human being.

17. A non-therapeutic method of cosmetic treatment for inhibiting in animals the urge to scratch the skin elicitied by itching comprising applying topically to the animal a composition as claimed in any of claims 5 to 13.

18. A method of cosmetic treatment as claimed in claim 17, in which the animal is a human being.