SK48896A3 - Application of ibuprofen and flurbiprofen as anti-pruritic agents and and pharmaceutical compositions for this use - Google Patents

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

Technical field

The invention relates to the use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts thereof for the treatment of itching in animals including humans, wherein ibuprofen, flurbiprofen and / or the pharmaceutically acceptable salt or salts are administered topically; further use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts thereof for the preparation of a medicament for the topical treatment of itching; and pharmaceutical compositions comprising ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts thereof as an itch relieving agent or agents, which compositions exhibit itching relieving activity. These compositions are suitable for treating itchy skin of an animal, preferably a human, when topically applied to the skin.

BACKGROUND OF THE INVENTION

Itching is an unpleasant condition of the skin surface. Although itching is a complex phenomenon, it can be defined roughly as a feeling on the skin that produces a motor response - scraping. Itching causes a number of different conditions. Some causes are local and can be easily eliminated, for example mild mechanical irritation, such as contact with rough woolen linen, or parasites, such as lice or scabies. Some causes of itching are general and can result in a chronic condition.

In itchy conditions, examples of which are described further below, itching can be as permanent as it is unbearable. Often a scraping habit is obtained, which later causes the skin to rake and thicken, which in itself worsens and maintains itching. Sometimes the condition is so chronic and the skin is so scraped that itching becomes incurable.

Thus, it is clear that alleviation of itching symptoms is very important in the treatment both to reduce discomfort and to prevent scratching. Notwithstanding that in many cases complete cure can only be achieved by treating one's own disease, such as diabetes mellitus, it is more or less desirable to treat itch directly, as well as its own cause.

Ibuprofen, whose chemical name is 2- (4-isobutylphenyl) propionic acid, and flurbiprofen, whose chemical name is 2- (2-fluoro-4-biphenylyl) propionic acid, are well known drugs. Ibuprofene and flurbiprofene are known to have anti-inflammatory, antipyretic and analgesic effects. Known uses of ibuprofen and flurbiprofen include the treatment of pain and inflammation in musculoskeletal diseases such as rheumatism, and the treatment of pain in many other conditions, such as headache, neuralgia and dysmenorrhoea. Ibuprofen and flurbiprofen are used as components of a variety of different topical formulations for the treatment of the above indicated indication areas.

Further, the prior art is discussed at an earlier priority date of the invention.

International Application WO 92/22585 (Patent Biopharmaceutics Inc.) discloses a composition for the treatment of symptoms of hemorrhoids and other anorectal diseases (including, but not limited to, itching) using hyaluronic acid as the sole component to relieve itching. Indication that any unspecified anti-inflammatory agent may be added to this composition as an additional component, if any, does not indicate that the anti-inflammatory agent would have any other effects or that it would be added for any purpose other than the possible addition of anti-inflammatory properties of the composition, which relieves itching.

Description U.S. Patent No. 3,686,183 (Syntex Corp.) states that the ¹¹ α-substituted aryl acetic acids are useful as anti-inflammatory, analgesic, antipyretic agents and antipruritic.

Furthermore, this document does not in any way suggest the efficacy of these compounds in relieving itching. The invention claimed in US 3,686,483 relates to a process for racemizing α-substituted arylacetic acids. Particularly claimed and described compounds are naphthaleneacetic acids, resulting in the choice of ibuprofen and flurbiprofen, none of which are specifically mentioned. U.S. Pat. No. 3,686,183 does not disclose any experiments or discloses any data supporting the random disclosure of the effects of a wide group of compounds on itching relief in the annotation. The mentioned mention in the annotation must be considered highly speculative and not supported by the document summarizing the annotation.

The previous two documents do not specifically relate to ibuprofen and / or flurbiprofen and therefore are not very relevant, but are general facts about the state of the art. At least fifty papers in the medical literature provide concise evidence that ibuprofen can be administered systemically (mostly orally). associated with itching symptoms in a small number of patients. This is illustrated, for example, by the summary of Cutaneous Reactions to Rheumatological Drugs (Clin. Rheum. Dis., 1982, 8 (2), 493-516, Bailin PL et al.), Which states that itching is a commonly mentioned skin adverse reaction. after using ibuprofen.

These references clearly indicate that at the time of the earlier priority date of the application, there was a technical prejudice against the systemic use of ibuprofen as an itching reducing agent.

In addition to a number of references to itching associated with systemic administration of ibuprofen, one report describes minor manifestations of intolerance, including mild local itching in the topical application of a 5% ibuprofen gel for the treatment of rheumatic diseases (see Therapiewoche Schweiz, 1992, (10), 764-768; Bahoud).

Article Drug-induced Photosensitivity in The Pharmaceutical Journal (245 (6592)), July 7, 1990, p. 19-21, reports on ibuprofen, as one of many of the systemic drugs mentioned, that causes photosensitivity reactions, including itching, when the skin is exposed to ultraviolet radiation (200-400 nm). A general superficial mention is made that both local and systemic photosensitive drug formulations can induce phototoxic reactions. No specific mention is made of formulations containing ibuprofen for topical application or of the side effects of their use.

The English abstract of Japanese patent application J 62-223118 (Hisamitsu) discloses a topical cream containing an ibuprofen derivative (ibuprofen piconol) for the treatment of skin diseases such as atopic dermatitis or chronic eczema. There is no indication that this agent exhibits effects other than the previously known effects of ibuprofen, and there is indeed some concise evidence that local administration of ibuprofen piconol in a small number of patients is associated with mild itching symptoms (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 mild pruritus associated with the aforementioned topical formulations may not be related to ibuprofen, but may be due to other factors or components such as the pH of the formulation, carriers and / or excipients and / or the presence of an ibuprofen ester (ibuprofen piconol).

Brief evidence of the use of non-steroidal antiinflammatory agents (NSAIDs), including ibuprofen, is reported in the Journal of American Academy of Dermatology, April 1993, p. 603-609. This article states, in a secondary context, that 5 of a random sample of 68 elderly dermatologists in response to a questionnaire stated that oral NSAIDs such as ibuprofen could be used to treat itching.

The article entitled Medical Myths - Poison Ivy: A Rash of Rumors (Consumer Reports Health Letter, June 1991, p. 45) briefly states that normally marketed pain relievers (including ibuprofen) alleviate itch caused by summits of Rhus, Rhus diversiloba, or Sumachom Rhus vernix. There is no evidence of this claim, and it is not clear from the context whether the alleged alleviation is due to analgesic effects, anti-inflammatory effects, or reduction of itching symptoms.

Contrary to the abovementioned brief references, there is a case report (Anaesthesiology, 1992, 76 (6), 1056-1057, Valley M.A. et al.) Stating that the rash and itching caused by Herpes simplex virus infection:

is not solved ... by administering ... nonsteroidal anti-inflammatory agents (... (inter alia) ibuprofen ...).

Brief references that might indicate the treatment of itching with ibuprofen are also denied by the scientific evidence available at the earlier priority date of the application. In a random double-blind, cross-over study conducted in patients with UV-B-induced inflammation, there was no evidence that orally administered ibuprofen had a statistically significant effect compared to placebo-treatment of the itchy itching. Dermatol., Volume 121, April 1985, pp. 508-512. The term UV-B-radiation (ultraviolet B-radiation) is defined herein as electromagnetic radiation with a wavelength in the range 280 nm to 320 nm inclusive.

In a single patent report, it was briefly stated that oral use of flurbiprofen can alleviate pain at the same time as itching in breast cancer (see The Lancet, September 26, 1981, p. 696). R. Winkelmann, Medical Clinics of North America, Volume 66, no. 5, Sept. 1982, also briefly reports only brief reports on the efficacy of (non-salicylate) non-steroidal agents such as flurbiprofen in relieving itching. These documents do not relate to ibuprofen and references to the efficacy of flurbiprofen in relieving itching are rare and not scientifically substantiated. These reports also deny a study in which the administration of flurbiprofen containing tablets was associated with skin effects, including itching, in five out of 68 arthritic patients (Lille Medical, 1980, Volume 25 (3), pp. 100-101).

Brief references, until the earlier priority date of the application, to the treatment of itching using systemically administered ibuprofen or flurbiprofen are therefore at best unclear, contradictory and / or lack scientific support. There is no literal reference in the prior art to the use of topical formulations containing ibuprofen and / or flurbiprofen for the treatment of itching.

A practitioner who, at an earlier priority date of the application, could be guided by random brief references in one of the above cited documents to use (either systemic or otherwise) ibuprofen or flurbiprofen for the treatment of itching would immediately be discouraged by the results of a systematic study inter alia) the effects of orally administered ibuprofen in relieving itching (where itching was induced by UV-B-radiation), which shows that the abovementioned brief references are unfounded. In addition, the contradictory nature of brief references to the use of ibuprofen or systemic use of flurbiprofen for the treatment of itching and technical prejudice against the systemic use of ibuprofen as an itch relieving agent would, at an earlier priority date of the application, act on the practitioner at that time. another) ibupro7 hairdryer or flurbiprofen to treat itching.

SUMMARY OF THE INVENTION

In view of the prior art described above, it has now surprisingly been found that, in addition to their known effects as described above, ibuprofen, flurbiprofen and / or one or more of their pharmaceutically acceptable salts are useful as an itch relieving agent or agents in topical treatment and relieving itching symptoms. . If itching was induced by irradiation with UV-B radiation, the itching agent (s) preferably includes a substance other than ibuprofen alone (e.g. flurbiprofen or flurbiprofen and ibuprofen together).

The invention relates to the use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts thereof for the topical treatment of itching in animals, preferably humans. In the process of the invention, ibuprofen, flurbiprofen and / or one or more of their pharmaceutically acceptable salts are administered topically to animals, preferably people suffering from itching, wherein ibuprofen, flurbiprofen or / and their pharmaceutically acceptable salt or salts are applied to the affected area to achieve relieving itching in response, and are present in an amount effective to relieve itching. If itching has been induced by irradiation with UV-B radiation, the itching agent or agents preferably comprises a substance other than ibuprofen alone.

Both ibuprofen and flurbiprofen contain a single chiral center on an asymmetrically substituted carbon atom and thus both exist in enantiomeric forms. Racemic ibuprofen is a 50:50 mixture of (+) - 2- (4-isobutylphenyl) propionic acid and (-) - 2- (4-isobutylphenyl) propionic acid, and the term ibuprofen, as used herein, includes a racemic mixture, The S (+) - and R (-) enantiomers individually and any mixture sufficient to induce itching relief in response.

Similarly, racemic flurbiprofen consists of a mixture of (+) - 2- (2-fluoro-4-biphenylyl) propionic acid and (-) - 2- (2-fluoro-4-biphenylyl) propionic acid in a 50:50 ratio. It is also clear that the term flurbiprofen as used herein, includes the racemic mixture, the (+) - and (-) - enantiomers individually, and any mixture thereof, sufficient to cause itch relief in response.

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

A preferred salt of ibuprofen is sodium ibuprofen, more preferably S (-) - sodium ibuprofen. Of course, it is clear that these salts may also exist in the form of racemates, individual enantiomers or / and mixtures thereof, and the terms salt and / or salts of ibuprofen and / or flurbiprofen as used herein include racemates, individual enantiomers and any mixtures thereof, all pharmaceutically acceptable salts of ibuprofen and / or flurbiprofen, present in an amount sufficient to induce itching in response.

It will be appreciated that such salts, when pharmaceutically acceptable, may be used in therapy instead of ibuprofen and / or flurbiprofen. Such salts are prepared from ibuprofen and / or flurbiprofen in a conventional manner by reaction with suitable bases. Ibuprofen, flurbiprofen and / or a salt or salts thereof may exist in more than one crystalline form, and references to these compounds herein include any crystalline form and mixtures thereof, sufficient to cause itching relief in response. Ibuprofen, flurbiprofen and / or a salt or salts thereof may also exist in the form of solvates, for example hydrates, and references to these compounds herein include any solvate and mixtures thereof, present in an amount sufficient to cause itching relief in response.

The efficacy of ibuprofen, flurbiprofen and / or their pharmaceutically acceptable salts in relieving itching has been demonstrated using animal tests, including humans, as described in the Examples below. Thus, both ibuprofen and flurbiprofen and / or one or more of their pharmaceutically acceptable salts are suitable for the treatment of itching in animals, preferably humans. If itching has been induced by irradiation with UV-B radiation, the itching agent (s) includes a substance other than ibuprofen. Ibuprofen, flurbiprofen and / or a pharmaceutically acceptable salt or salts thereof are administered topically, more preferably to the itchy skin of an animal, most preferably to the itchy skin of a human.

Although the exact amount of ibuprofen, flurbiprofen and / or a pharmaceutically acceptable salt or salts thereof administered locally for the treatment of itching, will depend on a number of factors such as the severity of the condition, the animal and age and prior medical interventions in the patient. on the proper discretion of the attending veterinarian, physician and / or pharmacist, a suitable daily dose of ibuprofen, flurbiprofen and / or a pharmaceutically acceptable salt or salts thereof for administration to an animal, particularly a human, for the treatment of itching, may usually range from about 1 mg to about 10000 mg , more typically from about 5 mg to about 5000 mg, most preferably from about 10 mg to about 1000 mg, administered as a single dose or in divided doses one or more times per day.

As is known to the person skilled in the art, itching symptoms may occur on normal and abnormal skin and may be caused by a variety of metabolic pathways (see R. Winkelmann, Medical Clinics of North America, Vol. 66, No. 5, September 1982). Some pruritus may occur by one or both of the following non-prostaglandin mechanisms, namely through the production of histamine and serotonin. Examples of itching include one or more of the following:

induction by UV-radiation (e.g. sunburn), external stimuli other than UV-radiation (e.g. contact with fibers (such as wool and / or synthetic fibers), contact with water (aquagenic itching) or / and cholinergic itching (related to heat or (and exercise)), enteral or parenteral contact with histamine-producing materials (e.g. food and / or plants), administration of drugs (e.g. opiates, barbiturates or / and salicylamilides), toxic products (e.g. bile salts and / or urea) released due to failure body organs (e.g., kidney and / or liver failure), itching-associated diseases (e.g., leprosy), stimulation of the nerve endings, fibers or / and receptors in the skin (or other changes in these nerve endings, fibers or receptors in the skin), psychogenic causes, and xerosis (abnormal dryness) of the skin in the elderly.

Itching can be divided into the following conditions (see Winkelmann 1982):

Physiological itching is a short-term skin response to normal environmental stimulation and normal body stimulation, which may or may not cause scratching, and should be distinguished from tickling, which is considered a movement-related touch plus an emotional response.

Pathological itching is an intense skin discomfort occurring in a pathological change to the skin or body that usually causes intense scratching or other relief efforts.

Spontaneous pruritus is pruritus unrelated to a pathological change in the skin or skin nerves and is caused by a toxic or metabolic change in the body. It may be physiological or pathological itching.

Focal itching is a local pathological itching caused by a change in the skin nerve or other tissue.

Diffuse pruritus is pruritus in many distant places and can occur on the skin after itching irritation in only one spot on the skin.

Relative itching is a newer name for diffuse itching, but a part in the same dermatoma.

Metamorphic itching is a condition described by Winkelmann in 1964 and means a change in the normal sensory experience of itching, such as a change of touch or ticking to itching in the atopic skin of normal appearance.

Itchy skin is the itching area around the primary primary skin inflammation. in the case of hyperalgesia stimulated to pain.

hyperresponsiveness to stimulate the itch stimulation zone or This is an analogous phenomenon as in the zone around the skin site

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

In addition, itching is one of the main symptoms of a number of diseases or disorders. These may include any of the conditions described below:

Dermatitis, or eczema, is a superficial inflammation of the skin and is characterized by blisters (if acute), red discoloration, edema, swelling, scab, scaly and usually itching.

Contact dermatitis is an acute or chronic inflammation of the skin, which is often strictly limited. It is caused by contact between the skin and a particular material or stimulus to which the skin is sensitive, for example as described above.

Atopic dermatitis is a chronic, itchy, superficial skin inflammation commonly found in individuals with a personal family history of allergic diseases (such as hay fever, asthma) due to the inherited property of hypersensitivity. It is also known as infantile eczema since it often starts in infants aged approximately 3 to 4 months.

Seborrheic dermatitis is an inflammatory disease associated with scaling of the skin on the top of the head, cheeks and, exceptionally, other parts of the body that cause various intense itching.

Numular dermatitis is a chronic dermatitis characterized by inflamed, blistered, rough, scaly and usually itchy coin-shaped lesions.

Pomfolyx is a chronic condition characterized by deep itchy blisters on the palms, sides of the toes and the feet of the feet. If present on the fingers and hands, it is known as cheiropompholyx. It is known as pedopompholyx on the toes.

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

Localized scratch dermatitis is a chronic, superficial, itchy inflammation of the skin.

Impetigo is a superficial, vesicle-pustular skin infection that occurs mainly in children. It is usually caused by Staphylococcus aureus. Itching is common and by scratching the infection can spread because the bleed outflow is infectious.

Ektyma is a ulcerous form of impetigo.

Scabies is a transmissible parasitic skin infection caused by Sarcoptes scabies. This condition is characterized by superficial corridors, intense itching and secondary skin infection. The intense itch in this state gave him the name scabies ”.

Lice is an attack by all.

The urticaria results in local skin edema and erythema of the skin. A common cause of urticaria, which is generally considered to be an allergic reaction afflicted by a substance to which it is hypersensitive, is food allergy. Itching is usually the first symptom to occur shortly after exposure to the substance causing the condition.

Hawked and Hawked Hawks are returning, itchy, igniting rashes characterized by small, separate, angular buds that combine into rough scaly patches, with subsequent thickening and hardening of the skin.

Miliaria (sweatshells) is an acute, inflammatory, itchy rash caused by a detained extravasation thereafter, which often affects people traveling to the tropics. A similar condition may occur in some people when they are warm in their bed, or in early spring or autumn, when there are changes in the size of the blood vessels in the skin.

Dermatitis herpetiformis is a chronic rash characterized by clusters of intense itching blisters, pimples and urticaria-like lesions.

A very unpleasant form of itching, known as pruritus ani (rectal itching), can occur on the rectum. It is often caused by crumbs. An equally severe form of pruritus known as pruritus vulvae may occur around the vagina and may be associated with excessive vaginal discharge.

Older people often suffer from itching because their skin becomes thinner and inflexible. This is usually seen as itchy cold weather on the feet of old people as their skin becomes dry in colder weather. Itching in the elderly may be caused by a primary skin disease, a systemic disease, or may have multifactorial or idiopathic causes. Xerosis (dry skin) is thought to be the most common cause of itching in the elderly.

Other more systemic diseases that can cause itching include obstructive bile disease, uremia, lymphoma, leukemia, polycythemia rubra vera, and diabetes mellitus. Jaundice and glomerulonephritis may, to a lesser extent, also be accompanied by itching.

Animals that can be treated by the methods of the invention and / or the compositions of the invention (as described below) include humans as well as non-human animals, and the term animals as used herein includes human beings. Non-human animals that can be treated include common pets (e.g. cats, dogs, rabbits or / and guinea pigs), commercially used animals (e.g. farm animals (such as pigs, cows or / and sheep) or / and animals used for work (such as horses) and / or animals kept in a zoo or in nature parks (for example, zebras, lions or / and elephants).

The invention is not limited to the animals listed above and can in principle be used for the treatment of any animal, including non-mammal animals (e.g., snakes or birds). Aquatic animals (e.g., fish and / or aquatic mammals) may also be treated with a topical formulation of the invention that is sealed against water penetration or water resistant. It is also possible to treat wild animals in their natural habitat using the methods and compositions of the invention as part of a general management strategy, for example in reserves and national parks.

In particular, the methods and / or compositions of the invention may be suitable for preventing the scraping of itchy skin in non-human animals. Scratching may be therapeutically undesirable because it may cause damage or make a related disease more difficult and / or may be cosmetically undesirable because it may damage the skin. Inhibition of scratching may be particularly important (either as a method of therapy or as a non-therapeutic cosmetic treatment) in animals of high cultural and / or economic value (eg endangered captive species for possible re-introduction into the wild (such as pandas), very expensive animals (such as racehorses) and / or animals reared for their skins to produce hides or skins (such as mink).

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

In another embodiment, the invention also provides a pharmaceutical composition comprising ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts thereof as an itching reducing agent or agents, a composition having an itching reducing effect. Preferably, ibuprofen, flurbiprofen and / or a pharmaceutically acceptable salt or salts thereof are the only itch relieving agent or the only itch relieving agent. The composition is in a form suitable for topical application, preferably in a form suitable for application to the itchy skin of an animal, preferably a human.

In another embodiment, the invention also provides the use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts thereof for the preparation of a medicament for topical application for the treatment of itching.

The invention further provides a method of treating itching in animals, including humans, using the compositions described herein. If ibuprofen is the only itching relieving agent, itching has been treated in this manner, preferably induced by means other than UV-B radiation.

As mentioned above, itching often occurs as a symptom caused by some underlying disease. The use of the medicament for topical application according to the invention may alleviate itching symptoms with or without therapeutic effect on any underlying disease.

Itching may cause skin scraping. Scratching is often therapeutically undesirable because it may aggravate itching and / or any underlying disease, but may also be cosmetically undesirable, for example, because it can induce or aggravate unsightly skin damage. Relieving itching, sufficient to reduce and / or eliminate the need for scratching, may produce a cosmetically desirable effect independently of any therapeutic and / or other therapeutic effect on itching and / or any underlying disease. For example, if the degree of scratching required to produce an undesirable therapeutic effect is substantially higher than the level necessary to produce a cosmetically undesirable effect, the treatment to reduce the need for scratching does not necessarily have a simultaneous therapeutic effect. Thus, topical application of the composition of the invention to reduce and / or eliminate itching (and thus the need for scraping) can be used as a non-therapeutic method of cosmetic treatment.

Accordingly, the invention further provides a non-therapeutic method of cosmetic treatment to reduce the need for itch-induced skin scraping in animals, including humans, comprising topically administering to the animal a composition comprising ibuprofen, flurbiprofen and / or one or more of their pharmaceutically acceptable salts. The cosmetic treatment according to the invention acts to reduce the degree of scratching in the animal to an extent sufficient to cause a corresponding reduction and / or elimination of the cosmetically undesirable effects caused by such scratching. Formulations suitable for use in such topical treatment may include those known to those skilled in the art of cosmetic formulation and / or pharmaceutical compositions as described herein.

The method of therapy, treatment (including cosmetic treatment), use and / or compositions described herein may be administered in combination with any other compatible therapy, treatment (including cosmetic treatment), and / or the composition also for treatment (including cosmetic treatment) of itching and / or by treating any other condition (e.g., any condition that may be the root cause of itching symptoms).

The amount of ibuprofen, flurbiprofen and / or a pharmaceutically acceptable salt or salts thereof in a topical formulation should be such that, over the time the topical formulation is to be applied to the skin, the amount of the compound or compounds is effective in relieving itching. The formulation should remain on the skin for at least the time necessary to induce effective relief of itching in response to the treated skin area. In any formulation of the invention, the delay before the onset of any itch relieves depends on a number of factors, including the nature of the itch, the area and type of skin to be treated and the type and age of the patient, as well as the nature of the formulation. Typically, in a patient who is an adult onset of relieving itching, the delay may last from about a few seconds to about 1 hour or more, more typically from about one to twenty minutes.

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

The formulations used in the methods of the invention, or as compositions of the invention, may produce a local and / or systemic therapeutic and / or cosmetic effect, and may be administered prophylactically, for example, to prevent itching and / or to prevent skin scraping. Such formulations or compositions may be prepared in a manner known to those skilled in the art to achieve controlled release, for example, rapid release or delayed release of ibuprofen, flurbiprofen and / or a pharmaceutically acceptable salt or salts thereof.

It will be understood that in the topical formulations of the invention described below, ibuprofen and / or flurbiprofen may be replaced or supplemented with any pharmaceutically acceptable salt or salts of ibuprofen and / or flurbiprofen that are compatible with the ingredients used in the formulation.

Suitable topical application formulations of the invention or topical application formulations for use in the methods of the invention may comprise a matrix in which ibuprofen and / or flurbiprofen are dispersed such that the compound or compounds are maintained in contact with the skin for transdermal administration of the compound or compounds. Suitable topical application matrices may include topical administration devices such as cataplasms, wraps, patches or impregnated dressings.

A composition suitable for transdermal administration can be prepared by mixing ibuprofen and / or flurbiprofen with a topical carrier (such as mineral oil, petrolatum, light liquid paraffin and / or wax (such as paraffin wax and / or beeswax)) together with an accelerating agent. Alternatively, ibuprofen and / or flurbiprofen may be mixed and / or dispersed in a pharmaceutically acceptable foam, paste, ointment, lotion, cream, emulsion and / or gel basis and / or applied in the form of a spray. A suitable cream may be prepared by incorporating ibuprofen and / or flurbiprofen into petrolatum and / or light liquid paraffin dispersed in an aqueous medium using a surfactant, and a suitable ointment may be prepared by mixing ibuprofen and / or flurbiprofen with mineral oil, paraffin or / and wax (e.g. paraffin wax; and / or A suitable gel may be prepared by mixing ibuprofen and / or flurbiprofen with a topical carrier comprising a gelling agent (e.g., alkalized Carbomer BP) in the presence of water.

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

The compositions of the invention preferably also contain a thickening agent in an amount of 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. means. Thickening agents may include hydroxyethylcellulose and / or a carboxyvinyl crosslinked polymer (for example, a polymer commercially available from B.F. Goodrich Limited under the trade name Carbopol 980 NF).

The compositions of the invention preferably further comprise a pH adjusting agent. Preferably, the pH adjusting agent is present in an amount sufficient to activate the thickening agent, if present, and which maintains the pH of the composition within a pharmaceutical 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. In view of the above, the pH adjusting agent is preferably present in an amount of from 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. means. PH adjusting agents may include sodium citrate, sodium hydroxide, potassium hydroxide and / or N, N, N ', N'-tetrakis (2-hydroxypropyl) ethylenediamine (commercially available under the trade name Quadrol).

The compositions of the invention may further comprise a preservative. The preservative is preferably present in an amount of from 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. means. Preservatives may include bronopol, sodium dehydroacetate, polyhexamethylenebiguanide hydrochloride, isothiazolone-diazolidinylurea and / or 2-phenoxyethanol (commercially available under the tradename Phenoxetol Nipa).

The compositions of the invention may further comprise a humectant to improve the tactile sensation when the composition is applied to the skin. Preferably, the humectant is present in an amount of 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. means. Humectants may include a glycol as defined herein as one or more organic compounds, each having at least two hydroxyl groups, preferably at adjacent atoms. More preferably, the glycols may include polyethylene glycol, glycerin and / or any mixture thereof.

When the composition of the invention is a gel, the gel may be a clear gel containing a clarifying agent, preferably a denatured alcohol, more preferably a denatured ethanol. Preferably, the clarifier is present in an amount of from about 5% to about 60% by weight. means.

When the composition of the invention is an emulsion, the emulsion may be either an oil-in-water emulsion or a water-in-oil emulsion.

The oily phase of the emulsion which may form the composition of the invention may comprise one or more of the following components and / or any mixture thereof:

hydrocarbon oils (e.g. paraffin and / or mineral oils), waxes (e.g. beeswax and / or paraffinic wax), natural oils (e.g. sunflower oil, apricot oil, shea or / and jojoba oil), silicone oils (e.g. dimethicone) , cyclomethicone and / or cetyldimethicone), fatty acid esters (e.g. isopropyl palmitate and / or isopropyl myristate), and fatty alcohols (e.g. cetyl alcohol and / or stearyl alcohol).

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

The emulsifiers that can be used in the composition of the invention may be any emulsifier known in the art for use in water-in-oil or oil-in-water emulsions. Such emulsion formulations of the invention may be prepared using an emulsifier and / or a mixture of emulsifiers selected from the group consisting of known emulsifiers acceptable for use in topical application formulations, which may contain one or more of the following ingredients and / or any mixture thereof:

sesquioleate (e.g., sorbitan sesquioleate (such as a compound commercially available from ICI under the trade name Arlacel 83)), ethoxylated esters of natural oil derivatives (e.g., polyethoxylated esters of hydrogenated castor oil (such as a compound commercially available from ICI under the trade name Arlacel 989) ), silicone emulsifiers (e.g., silicone polyols (such as those commercially available from Th. Goldschmidt AG under the trade name ABIL WS05 and from Dow Corning under the trade name Silicone Fluid 3225C)), fatty acid soaps (e.g. potassium stearate) , ethoxylated fatty alcohols (e.g., commercially available from ICI under the trade name Br ija from Croda under the trade name Cithrol GMS A / S), sorbitan esters (e.g. substances commercially available from Croda under the trade name Crill), ethoxylated sorbitan esters ( for example, substances commercially available from ICI under the trad ethoxylated fatty acid esters (e.g. ethoxylated stearates (e.g., a commercially available from ICI under the trade name Myrj)), ethoxylated mono-, di- or / and triglycerides (e.g., substances commercially available from Alfa Chemicals under the trade name Labrafil), and ethoxylated fatty acids (e.g., those commercially available from Alfa Chemicals under the trade name Tefose).

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

The amount of emulsifier optionally present in the oil-in-water emulsion, which may constitute the composition of the invention, is preferably in the range of about 0.1% to about 20% by weight. means.

However, when the composition of the invention is in a form other than an emulsion, an emulsifier and / or a surfactant (e.g., one of the emulsifiers listed above) may be present (e.g. in the above amounts) as a surfactant to promote greater therapeutic efficacy of the composition. local application.

The compositions of the invention may further comprise one or more additional ingredients and / or any mixture thereof, which are well known to those skilled in the art and may be selected from the following ingredients:

emulsion stabilizers (e.g. stearyl alcohols and / or cetyl alcohols) and / or emulsion stabilizing salts (e.g. sodium chloride, sodium citrate and / or magnesium sulfate), preferably in an amount of from about 0.1% to about 5% by weight. of the composition, complexing agents (for example tetranatriumethylenediamine tetraacetate dihydrates (such as the substance commercially available from Rhône Poulenc under the trade name Seguestene NA4)), preferably in an amount of trace amount to about 1% by weight. antioxidants (e.g. DLα-tocopherol acetate and / or butylated hydroxytoluene), preferably in an amount of from about trace amount to about 1% by weight. a composition, plasticizers (e.g., mineral oil, polymethylsiloxane, almond oil, petrolatum, isopropyl myristate and / or fatty acid triglycerides (such as lauric triglyceride, capric acid / caprylic acid triglyceride) and / or mixed triglycerides (e.g. from Huls UK Ltd under the trade name Miglyol 810 µl), preferably in an amount of from about 0.1% to about 30% by weight. a humectant (e.g. D-panthenol), preferably in an amount of from trace amount to about 1% by weight. of the composition, film-forming agents to promote spreading on the skin surface (e.g., alkylated polyvinylpyrrolidone), preferably in an amount of from trace amount to about 1% by weight. and fragrances and / or coloring agents.

The invention is further illustrated by the following non-limiting examples. All percentages in the examples are given by weight of the component relative to the total weight of the composition. In the examples, 2-phenoxyethanol, which is a preservative, is commercially available under the trade name Phenoxetol Nipa, a carboxyvinylated crosslinking polymer which is a thickening agent, commercially available from BF Goodrich Limited under the trade name Carbopol 980 NF, N, N, N ' N'-tetrakis- (2-hydroxypropyl) ethylenediamine, which is a basic pH adjusting agent, is commercially available under the trade name Quadrol, and ethoxylated fatty alcohol, which is a surfactant, is commercially available from ICI under the trade name Brij 92 .

DETAILED DESCRIPTION OF THE INVENTION

Example 1% w / w ibuprofen polyethylene glycol 300 BP (humectant)

5.0

10,0

2-Phenoxyethanol (Phenoxetol Nipa) a carboxyvinyl crosslinked polymer

1.0 (Carbopol 980 NF) sodium hydroxide pellets

0.5 (pH adjusting agent) purified water (diluent)

0.085 to 100

The above ingredients are mixed together to form a dull gel composition. The gel composition of Example 1 was applied to the skin of a human volunteer who was affected by itching and had scaly skin that was red and inflamed. The composition has been found to reduce the itching sensation and, in a short time, also the scaling of the skin. This surprising effect was independent of any anti-inflammatory, antipyretic or analgesic response that could be expected as a result of ibuprofen administration.

The guinea pig suffered from itching to such an extent that hair was removed from the skin and a red coin-sized spot formed on the skin. A portion of the gel prepared in Example 1 was applied to this sore spot, and this was repeated daily for one week. At that time, the red spot disappeared and hair in the affected area began to grow again. The guinea pig was continuously recovering without recurrence.

Example 2% w / w (S +) ibuprofen carboxyvinyl crosslinked polymer (Carbopol) denatured ethanol (clarifier) sodium hydroxide (pH adjusting agent)

2 — Phenoxyethanol (Phenoxetol) Purified water (thinner)

2.5

2.0

5.0

1,525

1.0 to 100

The above ingredients are mixed together to form a clear gel composition which, when topically applied as described in Example 1, exhibits an itching-reducing effect.

Example 3% w / w flurbiprofen 2.5 polyethylene glycol (humectant) 10.0

2-phenoxyethanol (Phenoxetol) 1.0 carboxyvinyl crosslinked polymer (Carbopol) 0.5 sodium hydroxide (pH adjusting agent) 0.085 purified water (diluent) up to 100

The above ingredients are mixed together to form a dull gel composition which, when topically applied as described in Example 1, exhibits an itching-reducing effect.

Example 4% w / w flurbiprofen 2.5 carboxyvinyl crosslinked polymer (Carbopol) 2.0 denatured ethanol (clarifier) 50.0 polyethylene glycol (humectant) 5.0 glycerin (humectant) 5.0 purified water (diluent) up to 100

The above ingredients are mixed together to form a clear gel composition which, when topically applied as described in Example 1, exhibits an itching-reducing effect.

Example 5% w / w flurbiprofen 10.0 denatured ethanol (clarifier) 40.0 carboxyvinyl crosslinked polymer (Carbopol) 2.6 N, N, N ', N'-tetrakis (2-hydroxypropyl) ethylenediamine (Quadrol) 9.0 propylene glycol (humectant) 2.0 ethoxylated fatty alcohol (Brij 92) 2.0 purified water (thinner) up to 100

The above ingredients are mixed together to form a clear gel composition which, when topically applied as described in Example 1, exhibits an itching-reducing effect.

Claims (10)

PATENT CLAIMS Use of ibuprofen, flurbiprofen and / or one or more of their pharmaceutically acceptable salts as an itch relieving agent or agents for the treatment of itching in an animal in which ibuprofen, flurbiprofen and / or a salt or salt thereof is applied topically to the animal. Use of ibuprofen, flurbiprofen and / or one or more of their pharmaceutically acceptable salts according to claim 1, characterized in that, if the itching has been induced by UV-B radiation, the itching agent (s) comprises a substance other than ibuprofen alone. Use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts thereof according to any one of claims 1 or 2, characterized in that the animal is a human. r Use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts thereof for the preparation of a medicament for topical application for the treatment of itching. A method of treating itching in an animal using a topical pharmaceutical composition comprising ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts thereof as an itching or alleviating agent, characterized in that the composition is applied topically to the animal. 6. The method of claim 5, wherein, if the itching has been induced by UV-B radiation, the itching agent or agents comprises a substance other than Ibuprofen. The method of treatment of any one of claims 5 or 6, wherein the animal is a human. 8. A non-therapeutic cosmetic treatment method for inhibiting the need to scrape the itch-induced skin in an animal, comprising topically administering to the animal a topical pharmaceutical composition comprising ibuprofen, flurbiprofen and / or one or more of their pharmaceutically acceptable salts as an alleviating agent or agent. itching. 9. The method of claim 8, wherein the animal is a human. A pharmaceutical composition for topical application, characterized in that it comprises ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts thereof as an itching or alleviating agent, wherein the composition exhibits an itching-reducing effect when topically applied, with the agent itching is a substance other than flurbiprofen or ibuprofen only.