HUT74448A - Process for preparing pharmaceutical compns. contg. ibuprofen and flurbiprofen for use as anti-pruritic agents - Google Patents

Description

If the itching was triggered by UV-B radiation, the anti-itching agent (s) also contains an anti-itching ingredient other than ibuprofen.

The invention further relates to the use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts thereof in the preparation of a topical medicament for the treatment of itching.

The present invention further provides a method of treating skin itching in the hippocampus of animals and embryos, wherein ibuprofen, f-μbbiprofen and / or one or more pharmaceutically acceptable topicals thereof are used.

or a salt thereof

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The present invention also relates to a non-therapeutic method of cosmetic treatment for the prevention of pruritus-induced skin pruritus in animals and humans, wherein the above-mentioned pharmaceutical composition (s) is / are applied topically.

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S.B.G. & Κ

International Patent Office

H-1062 Budapest. Andrássy út 113 · Phone: 34-24-950, Fax: 34-24-323

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J

Ibuprofejfes flurbiprofep aHtahnase for the treatment of pruritus <<Cv '· · · ν'.

THE BOOTS COMPANY PLC, NOTTINGHAM, GB

Inventor:

VAUGHAN Kenneth Donald, NOTTINGHAM, GB

Date of filing: 19.10.1994

Priorities: 20.10.1993, 9321671.1, GB

3/15/1994, 9405024.2, GB

3/15/1994, 9405025.9, GB

International Application Number: PCT / EP94 / 03442

International Publication Number: WO '? /) / T ^: ' ···· ····

The present invention relates to the use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof in the treatment of pruritus in animals, including man, wherein ibuprofen, flurbiprofen and / or a pharmaceutically acceptable salt thereof topically applied; and a medicament for the topical treatment of pruritus of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof; and the use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof, in the manufacture of a medicament for use as an anti-itch agent or agents having anti-itch effect. The compositions are suitable for treating itching of the skin of an animal, preferably human, when applied topically.

Itching of the skin (pruritus, itching) is an unpleasant condition of the skin surface. Although itching is a complex phenomenon, it is roughly defined as a feeling of the skin that triggers the motor response of scratching. Certain causes of itching of the skin are more general and can lead to chronic conditions.

In itchy conditions, examples of which are described below, the itching may be so persistent that it becomes intolerable. Scratching can often become a habit, which over time makes the skin rough and thick, which in itself exacerbates and maintains itching. This condition sometimes becomes so chronic and the skin changes from scratching so that itching becomes incurable.

62,339 / BE • ·

It can therefore be seen that relief of symptoms is very important in the treatment of itching of the skin, both in terms of reducing discomfort and avoiding scratching. Although in many cases perfect healing is achieved only by treating the underlying condition, such as diabetes, it is desirable to treat the pruritus directly as well as the underlying cause.

Ibuprofen, whose chemical name is 2- (4-isubutyl-phenyl) -propionic acid, and flurbiprofen, whose chemical name is 2- (2-fluoro-4-biphenylyl) -propionic acid, are well known therapeutic agents. Ibuprofen and flurbiprofen were known to have anti-inflammatory, antipyretic and analgesic effects. Known applications of ibuprofen and flurbiprofen include the treatment of pain and inflammation in musculoskeletal disorders such as rheumatoid arthritis and the treatment of pain in a number of other disorders such as headache, neuralgia and menstrual dysmenorrhea. The active ingredients of ibuprofen and flurbiprofen are topical preparations for many of the indications described above.

The state of the art at the time of the earliest priority of the present invention is discussed below.

WO 92/22585 (Biopharmaceutics Inc.) discloses a composition for the treatment of symptoms of hemorrhoids and other anal disorders (including pruritus), containing hyaluronic acid as the sole anti-pruritus ingredient62.339 / BE. ···· ···· glaze. The statement that any unspecified anti-inflammatory agent may be added to the composition as an optional ingredient may not have any other function, or that it may be added to the anti-itch preparation, if appropriate, in addition to enhancing its anti-inflammatory properties. for any other purpose.

U.S. Patent No. 3,686,183 (Syntex Corp.) states, in its extract, that "the substituted aryl acetic acid derivatives can be used as anti-inflammatory, analgesic, antipyretic and anti-itching agents. The anti-itch activity of these compounds is not further mentioned in this document. U.S. Patent No. 3,686,183 relates to a process for the racemization of α-substituted arylacetic acid derivatives. The specific compounds listed and described in the claims are naphthyl acetic acid derivatives which do not indicate excretion of ibuprofen and flurbiprofen; none of them are specifically named. U.S. Patent No. 3,686,183 does not mention any experiment, nor does it provide any data to support the assertion of anti-itch activity randomly mentioned in the extract for a broad class of compounds. This reference to the extract is to be considered as highly speculative and is not supported by the document which is abstracted.

The previous two communications do not specifically address

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ibuprofen and / or flurbiprofen and are therefore not particularly related, but are intended to illustrate the general state of the art.

In the medical literature, at least fifty articles reveal evidence that systemic (usually orally) ibuprofen may be associated with symptoms of pruritus in a small minority of patients. This is made clear, for example, in the article "Cutaneous Reactions to Rheumatological Drugs" by P.L.Bailin et al., Clin. Rheum. Dis. , 8J2, 493-516 (1982)], in which itching of the skin is said to be a "commonly mentioned adverse effect on the skin following ibuprofen intake."

These references clearly indicate that, at the earliest priority of the present invention, technical prejudice prevailed over the systemic use of ibuprofen as an anti-itch.

In addition to a number of references discussing skin pruritus associated with systemic use of ibuprofen, see [Therapiewoche Schweiz, 8 (10), 764-768 (1992); For the treatment of rheumatic complaints, the topical application of a 5% ibuprofen gel to treat "rheumatic complaints" mentions "slight symptoms of intolerance" including mild local itching.

In the July 7, 1990 issue of The Pharmaceutical Journal, "Drug-induced Photosensitivity" [245, 19-21 (6592)], ibuprofen is listed as one of several systemic drugs that have been reported to cause photosensitivity reactions, including pruritus they cause the skin to be exposed to UV radiation

62.339 / BE. (200-400 nm). It is generally mentioned that topical and systemic formulations of photosensitizing drugs can induce phototoxic reactions. No specific reference is made to ibuprofen formulations for topical use or adverse reactions resulting from their use.

Japanese patent application J62-223118 (Hisamitsu) discloses a topical cream containing ibuprofen derivative (ibuprofen piconol) for the treatment of skin diseases such as atopic dermatitis or chronic eczema. However, no mention is made of the fact that this formulation also exhibits activity previously unknown to ibuprofen, and even provides some evidence that local administration of ibuprofen piconol is accompanied by mild itching symptoms in a small number of patients [see, e.g., H. Yoshida et al. , Skin. 27: 115-125 (1985); H. Udea et al., Skin Rés., 30 (3), 385396 (1988); and Nippon Hifuka (Nishinihon J.Dermatol.), 53 (4), 695-698 (1991).

The slight itching symptoms associated with the use of the above topical formulations may not be related to ibuprofen, but may be due to other factors or ingredients, such as the pH of the formulation, excipients and / or ibuprofen piconol.

The use of non-steroidal anti-inflammatory agents (NSAIDs), including ibuprofen, is reported in the April 1993 issue of the Journal of the American Academy of Dermatology 603-609. pages. Incidentally, this article has to do with 68 randomly selected

Five of the older dermatologists instilled in response to a questionnaire stated that oral treatment with an NSAID, such as ibuprofen, could be used to treat itchy skin.

An additional article in Medical Myths - Poison Ivy: The Rash of Rumors (Consumer Report Health Letter, June 1991, p. 45) states that over-the-counter (OTC) painkillers, including ibuprofen, relieve itching caused by poison ivy (poison ivy, poison oak, sumac). No evidence is provided for this claim, and it is not clear from the context whether the claimed relief is manifested in reducing pain, reducing inflammation, or reducing symptoms of itching.

Contrary to the above references, there is a case description [M.A. Valley et al., Anesthesiology, 76 (6), 1056-1057 (1992)] that a rash and itching caused by a Herpes simplex viral infection "did not disappear ... non-steroidal anti-inflammatory drugs (ibuprofen, among others). .. application.

The references suggesting the treatment of itchy skin with ibuprofen are also refuted by the scientific evidence available at the earliest priority of the present invention. In a randomized, double-blind, crossover study in patients, where inflammation was induced by UV-B radiation, there was no evidence of a statistically significant effect of ibuprofen orally administered on the placebo in the treatment of the symptoms of such itching. [Arch. Dermatol. , 121, April, 508-512. (1985)]. UV-B radiation

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280 nm (ultraviolet B radiation) is defined herein as the range of electromagnetic radiation from a to 320 nm.

A patent publication touchingly mentions that relief of breast cancer can be achieved by the simultaneous oral administration of flurbiprofen for pain and itching (see The Chain, September 26, 1981, p. 696), R. Winkelmann also makes a reference [Medical Clinics of North America, 66 (5), September (1982)], "is purely adamant reports about the anti-itch effect of non-salicylate, a non-steroidal agent such as flurbiprofen. These documents do not refer to ibuprofen and such references to the anti-itch effect of flurbiprofen are purely narrative and have no scientific substantiation. These reports are also contradicted by a study in which flurbiprofen tablets were used in five out of 68 patients with arthritis with skin symptoms including pruritus (Lilié Medical, 25 (3): 100-101 (1980)).

Thus, references to ibuprofen or flurbiprofen systemically used to treat itching at the earliest priority of the present invention are, at best, unclear, contradictory, and / or lacking scientific support. There is no explicit reference in the prior art to the treatment of pruritus with topical formulations of ibuprofen and / or flurbiprofen.

Therefore, one of ordinary skill in the art who, at the time of the earliest priority of the present invention, is referred to in the above-referenced document 62.339 / BE. ···· ·· »· · • ··. . ·· • · · ·. . ·

........ ·.:.

possible evidence of the use of ibuprofen or flurbiprofen (either systemically or otherwise) to treat itching, including the anti-itch activity of orally administered ibuprofen (where pruritus was induced by UV-B radiation) the results of his study would immediately have advised him not to do so because they suggested that the mendemond testimony was unfounded. In addition, the contradictory nature of testimony to treat skin itching with ibuprofen or systemic flurbiprofen, and the technical prejudice against systemic use of ibuprofen as an anti-itch agent, which prevailed over the earliest priority of the present invention, to treat itchy skin using either ibuprofen or flurbiprofen (systemically or otherwise).

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 pharmaceutically acceptable salts or salts thereof may be used as an anti-itch agent or agents for topical treatment and alleviation of . If the itching of the skin is triggered by irradiation with UV-B radiation, the anti-itch agent or agents will preferably not only contain ibuprofen alone (e.g., containing flurbiprofen or flurbiprofen and ibuprofen together).

The invention relates to skin viscera in animals, preferably in humans

for the topical treatment of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof. In the method according to the invention, ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof, for the topical application of ibuprofen, flurbiprofen and / or their pharmaceutically acceptable salts or salts, is applied to the affected area to induce an anti-itch response

If the itching of the skin is caused by UV-B radiation, the anti-itch agent (s) preferably contains not only ibuprofen alone.

Both ibuprofen and flurbiprofen contain a single chiral center at an asymmetrically substituted carbon atom and therefore both exist in enantiomeric forms. Racemic ibuprofen is (+) -2- (4-isobutylphenyl) propionic acid and (-) - 2- (4)

-isobutylphenyl) -propionic acid (50:50). It is noted that the term ibuprofen, as used herein, refers to the racemic mixture, the S (+) - and R (-) - enantiomers, individually, and any mixture thereof sufficient to provide an anti-itch effect. Similarly, racemic flurbiprofen is a 50:50 mixture of (+) - 2- (2-fluoro-4-biphenylyl) -propionic acid and (-) - 2- (2-fluoro-4-biphenylyl) -propionic acid. It is also noted that the name flurbiprofen, as used herein, refers to the racemic mixture, the (+) and (-) enantiomers, individually, and to any mixture thereof that is sufficient to produce an anti-itch effect.

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Ibuprofen and / or flurbiprofen may form salts with organic or inorganic bases.

The term ibuprofen and / or flurbiprofen salt and / or salts, as used herein, refers to all salts of these compounds which are pharmaceutically acceptable (i.e., present in therapeutically effective amounts in amounts sufficient to provide a non-toxic response).

Particularly suitable salts of ibuprofen and / or flurbiprofen include alkali metal salts (such as sodium and / or potassium salts), alkaline earth metal salts (such as magnesium and / or calcium salts), aluminum salts, ammonium salts, and salts of suitable organic bases (e.g. salts and / or N-methyl-D-glutamine salts), salts of amino acids (such as arginine and / or lysine salts).

A preferred salt of ibuprofen is the ibuprofen sodium salt, more preferably the S (-) - ibuprofen sodium salt. It is readily understood that these salts may also exist in the form of racemates, separate enantiomers and / or mixtures thereof, and the terms ibuprofen and / or flurbiprofen salt and / or salts, as used herein, apply to any pharmaceutically acceptable salt of ibuprofen and / or flurbiprofen. the racemates, the individual enantiomers of the salts, and any of the wheels present in sufficient amounts to provide an anti-itch response.

It will be appreciated that these salts, provided they are pharmaceutically acceptable, may be used in therapy with ibuprofen and / or flurbiprofen, with a suitable base prepared in a conventional manner.

Ibuprofen, flurbiprofen and / or their salts or salts in one

62.339 / BE may exist in several crystalline forms, and references herein to these compounds apply to any crystal form and mixtures thereof that are sufficient to elicit an anti-itch response. Ibuprofen, flurbiprofen and / or their salts or salts may also exist in the form of solvates such as hydrates, and references herein to these compounds apply to any solvate and mixtures thereof in sufficient amounts. present to give an anti-itch effect.

Ibuprofen, flurbiprofen and / or pharmaceutically acceptable salts thereof may be prepared using the methods described in the Examples for anesthetic cones, including human.

activity has been demonstrated in animal tests, so that both ibuprofen and flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof can be used in the treatment of itching in animals, preferably humans. If the itching is caused by UV-B radiation, the anti-itching agent (s) preferably contains other than ibuprofen. Ibuprofen, flurbiprofen and / or their pharmaceutically acceptable salts or salts are applied topically to the itchy animal skin, most preferably to the itchy human skin.

While the exact amount of topically used ibuprofen, flurbiprofen and / or their pharmaceutically acceptable salts or salts for the treatment of itching will depend on a number of factors, such as the severity of the condition, the animal being treated, the age and history of the patient, and and / or the judgment of a pharmacist,

However, a suitable daily dose of ibuprofen, flurbiprofen and / or their pharmaceutically acceptable salts or salts for treating itching in animals, preferably humans, is generally from about 1 mg to about 10,000 mg, usually from about 5 mg to about 5,000. from about 10 mg to about 1000 mg, in single or divided doses throughout the day, given one or more times.

One of ordinary skill in the art will appreciate that itching symptoms can occur on normal and pathological skin and can be caused by many metabolic pathways; reference is made to R. Winkelmann (Medical Clinics of North America, 66 (5), September 1982). Certain conditions for itching of the skin may be due to one or both of the following non-prostaglandin mechanisms, namely histamine or serotonin production. Examples of causes of pruritus include one or more of the following:

Induced by UV radiation (e.g. sunburn);

external non-UV stimulus (e.g. contact with fibers (such as wool and / or synthetic fibers), contact with water (aquagen) and / or cholinergic itch (itch associated with heat and / or exercise));

enteral and / or parenteral contact with histamine-producing substances (e.g., food and / or plants);

the use of medicaments (such as opium preparations, barbiturates and / or salicylamides);

Release of toxic products (such as bile salts and / or urea) as a result of malfunctioning of certain organs of the body (such as renal and / or hepatic failure);

itching disease (such as leprosy);

stimulation of nerve endings (or other changes therein); fibers and / or receptors in the skin;

psychological causes; and xerosis (abnormal dryness of the skin) in old age.

Types of pruritus (itching) can be classified as follows (see Winkelmann's 1982 article):

Physiological itching is a short-term skin response to normal environmental and physical stimuli, which may or may not induce scratching, and is distinguished from tickle, which is considered to be the trigger for the touch and sensitive response.

Pathological itching is an intense discomfort of the skin that occurs as a result of a pathological change in the skin or body and usually results in severe scratching or other attempts to relieve it.

Spontaneous itching is an itch that is unrelated to pathological changes in the skin or nerves in the skin and is triggered by toxic or metabolic changes within the body. It may be physiological or pathological itching.

Focal itch is a type of pathological itch that is caused by a change in the nerve or other tissue of the skin.

Scattered itch is a multiple pruritus of the skin that extends far apart, and

62. 339 / BE β · · · can occur on the skin only after itching in one area of the skin.

Synergistic itching (referred to as itch) is a more recent name for itching that is diffuse but often occurs in the same dermatome.

Conversion itch is a condition described by Winkelmann in 1964 to explain the usual sensory experience of touching or tingling on normal-looking atopic skin.

Itchy skin is an area of hypersensitivity to the itching stimulus around a primary itching zone or primary dermatitis. It is similar to a hypersensitive area around a pain stimulated skin spot.

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

In addition, itching of the skin is a major symptom of various diseases or disorders. These may include any of the following conditions:

Dermatitis (dermatitis) or eczema is a superficial inflammation of the skin characterized by the appearance of blisters (if acute), redness, edema, moisturization, scarring, peeling and usually itching.

Contact dermatitis is often a sharply defined acute or chronic inflammation of the skin. This is triggered by low contact between the skin and a substance or stimulus to which the skin is sensitive, such as any of the above.

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Atopic dermatitis is a chronic itchy superficial inflammation of the skin that usually occurs in individuals with a family history of allergic disorders due to hereditary hypersensitivity (such as hay fever, asthma). It is also known as infantile eczema, as it often begins in infants aged 3-4 months.

Seborrhoeic dermatitis is an inflammatory, peeling disease of the scalp, face, and possibly other areas of the body that can cause varying degrees of itching.

Nummular dermatitis is a chronic inflammation of the skin characterized by inflamed, coin-shaped, blistering, scarring, peeling and usually itchy lesions.

Pompholyx is a chronic condition characterized by deep, itchy blisters on the palms, the sides of the fingers and the soles of the feet. If it occurs on the fingers and hands, it is known as cheiropompholyx. If it occurs on the toes and feet, it is known as podopompholyx.

General peeling dermatitis is a severe, extensive erythema and peeling of the skin. Itching can be severe, but it does not necessarily occur.

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

Impetigo is a superficial (vesiculopustular) skin infection that occurs mainly in children. Usually caused by staphylococcus aureus. Itching is common and scratching can spread the infection because the bladder secretion is contagious.

Ecthyma is an ulcerative form of impetigo.

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Scabies is a parasitic skin infection caused by the Sarcoptes Scabies mite and transmitted to another individual. The condition is characterized by superficial scars, severe itching and secondary skin infection. Because of the intense itching nature of this condition, the English term "itch (itching) was used to describe scabies.

Lice (pediculosis) is a living infection caused by a lice.

Hives (urticaria, callus, nettle rash) cause local blisters and erythema in the cutaneous layer of the skin. Food allergy is a common cause of urticaria, which is generally believed to be an individual's allergic reaction to a substance to which he is hypersensitive. Itching is usually the first symptom that occurs shortly after contact with the substance causing the condition.

Ringworm (Lichen Simplex and Lichen Plans) forms recurrent, itchy, inflammatory skin rashes characterized by small, discrete and coarse, scaly patches of papules, with consequent thickening and hardening of the skin.

Miliaria, prickly heat is an acute, inflammatory, itchy skin rash caused by leaking sweat that often affects tropical travelers. Similar conditions may occur in some people when they warm in bed or at the beginning of spring and autumn when the size of blood vessels in the skin changes.

Dermatitis herpetiformis is a chronic rash with intensely itching blisters,

Bundles of papules and urticaria-like wounds are characteristic.

A very severe form of itching can occur in the anus, known as pruritus ani. This is often caused by nematodes. A similarly unpleasant form of itching is known as pruritus vulvae and occurs around the vagina, which may be accompanied by abundant vaginal discharge.

Older people often suffer from itching as the skin becomes thinner and less elastic. This is commonly seen as itching due to cold weather on the feet of old people when their skin becomes drier in colder weather. In the elderly, itching of the skin may be caused by some primary skin condition, some systemic disease, or may be multifactorial or idiopathic causes. It is believed that dry skin (xerosis) is the most common cause of itching in the elderly.

Other more systemic conditions that can cause pruritus of the skin include biliary obstruction, uremia, lymphoid tumors, leukemias, polycythaemia rubra vera and diabetes mellitus. Jaundice and glomerulonephritis may also be accompanied by less itching.

Animals which may be treated by the methods of the invention and / or the compositions of the invention described below include human beings and non-human beings of the animal kingdom, and "animal, as used herein, shall be understood to include it occupies man. Non-human creatures that can be treated in this way generally include pet animals (such as cats, dogs, rabbits and / or guinea pigs); commercially as a livestock animal

replicators (such as pigs, cows and / or sheep); draft animals (such as horses) and / or animals kept in zoos or wildlife reserves (such as zebras, lions and / or elephants).

The invention is in no way intended to be applicable to any of the aforementioned animals, and may in principle be used in the treatment of any animal, including non-mammalian animals (such as crawlers and / or birds). Aquatic animals (such as fish and / or aquatic mammals) may also be treated with a waterproof or waterproof topical composition of the invention. Wild animals can also be managed in their natural environment using the methods and compositions of the invention as part of a more general management strategy, such as in an animal sanctuary or national park.

The methods and / or compositions of the present invention may be particularly useful for non-human fauna to avoid scratching their itchy skin or skin. Scratching may be therapeutically undesirable as it can cause damage or aggravate any underlying condition and / or cosmetically undesirable because it can contaminate the skin or the skin. Prevention of scratching may be particularly important (either as a therapeutic method or as a non-therapeutic cosmetic treatment) for animals of high cultural and / or economic value [such as endangered, endangered species (such as pandas), high value animals (e.g. racing horses) and / or leather goods or fur for animals bred for their skin (eg mink)].

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

In a further aspect of the invention there is provided a pharmaceutical composition comprising ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof as an anti-itch agent or agents, which composition has an anti-itch activity. Preferably, ibuprofen, flurbiprofen and / or their pharmaceutically acceptable salts or salts form the sole anesthetic agent (s). The composition is in a form suitable for topical application, preferably in the form of itchy animal skin, preferably human skin.

In another aspect, the invention provides the use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof for the manufacture of a medicament for the local treatment of pruritus.

The invention further provides a method of treating itching in animals, including man, using the compositions described herein. Accordingly, ibuprofen according to the method is preferably used as the sole anti-itch agent when itching is caused by a cause other than UV-B radiation.

As mentioned above, itching of the skin often occurs as a symptom of some other underlying condition. The use of a topical medicament according to the present invention may alleviate the symptoms of itching, with or without a therapeutic effect on the underlying pseudoprint.

Itching can cause scratching of the skin. Scratching is therapeutically undesirable because it can exacerbate itching and / or any underlying condition, but it can also be cosmetically undesirable, for example, because it can leave skin blemishes or make the condition worse. To the extent that itching is reduced to reduce and / or eliminate scratching pressure, it may have a cosmetically desirable effect, regardless of whether it has any healing and / or other therapeutic effect on the pruritus of the skin and / or any underlying condition. For example, if the amount of scratching required to produce an undesirable therapeutic effect is significantly greater than that required to produce a cosmetically undesirable effect, the treatment to reduce the pressure on scratching does not necessarily have a therapeutic effect. Thus, topical application of the compositions of the present invention to reduce and / or relieve itching (and therefore scratching obsession) may be beneficial as a non-therapeutic mode of cosmetic treatment.

Therefore, the invention further provides a non-therapeutic method of cosmetic treatment in animals, including man, to inhibit the itching of skin scratching by itching comprising ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable or a composition comprising a salt or salts thereof is administered topically to the animal. The cosmetic treatment of the present invention works by reducing the degree of scratching of the animal to an extent that

62.339 / BE is sufficient to provide a satisfactory reduction in the cosmetically undesirable effects caused by such scratching. Such topical formulations may include those known to those skilled in the art of cosmetics and / or pharmaceutical formulations described herein.

The therapeutic method, treatment (including cosmetic treatment) described herein, use and / or compositions may be used in conjunction with any other compatible therapy, treatment (including cosmetic treatment) and / or composition for the treatment (including cosmetic treatment) of skin itching, and / or any other condition (for example, any condition underlying the itching of the skin).

The amount of ibuprofen, flurbiprofen and / or their pharmaceutically acceptable salts or salts in the topical formulation should be such that an anti-itch effective amount of this compound or compounds is present during the time the topical formulation is to be applied to the skin. The product should remain on the skin for at least the time needed to produce an effective itching response on the treated skin. The time to onset of the anti-itch effect for any particular composition of the invention will depend on a number of factors, including the nature of the itching of the skin, the area and type of skin being treated, the type and age of the patient and the nature of the composition. In an adult human patient, the time to onset of the anti-itch effect may range from about a few seconds to about an hour or more, typically from about 1 minute to about 20 minutes.

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

The formulations or compositions used in the methods of the invention may have local and / or systemic therapeutic and / or cosmetic effects and may be used in a prophylactic manner, for example, to prevent the formation of pruritus and / or to prevent skin scratching. Such formulations or compositions may be formulated in a manner known to those skilled in the art to provide controlled release, such as rapid release or sustained release, of ibuprofen, flurbiprofen and / or their pharmaceutically acceptable salts or salts.

It will be appreciated that in the topical formulations of the invention described below, the ibuprofen and / or flurbiprofen ingredient may be substituted or supplemented with any pharmaceutically acceptable salt or salts of ibuprofen and / or flurbiprofen that are compatible with the components used in the composition.

Suitable topical compositions of the invention or topical compositions for use in the methods of the invention

Pharmaceutical formulations may contain a matrix in which the ibuprofen and / or flurbiprofen is dispersed by contacting the compound or compounds with the skin and thereby administering the compound or compounds transdermally. Suitable matrices for topical application include local devices such as cataplasms, poultices, patches, or impregnated bandages.

Formulations suitable for transdermal administration may be prepared by admixing ibuprofen and / or flurbiprofen with a carrier for topical administration, for example, mineral oil, petrolatum, light paraffin oil and / or wax (such as paraffin wax and / or beeswax), such as dimethyl sulfoxide and / or propylene glycol. Alternatively, ibuprofen and / or flurbiprofen may be admixed with a pharmaceutically acceptable foam, paste, ointment, lotion, cream, ointment, emulsion and / or gel base; and / or dispersible therein; and / or in the form of a spray. A suitable cream may be formulated by incorporating ibuprofen and / or flurbiprofen in a water-dispersed petrolatum and / or light paraffin oil using a surfactant. A suitable ointment may be formulated by mixing the ibuprofen and / or flurbiprofen with a mineral oil, petrolatum and / or a wax (e.g. paraffin wax and / or beeswax).

A suitable gel can be formulated with ibuprofen and / or flurbiprofen in water

62.339 / BE in admixture with a topical carrier containing a gelling agent such as Carbomer BP.

The topical formulations of the invention preferably contain a pharmaceutically acceptable diluent or carrier, more preferably an aqueous solution, most preferably purified water.

Preferably, the compositions of the present invention also contain a thickening agent, the composition being 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. by weight. The thickening agent may be (hydroxyethyl) cellulose and / or a carboxyvinyl cross-linked polymer (e.g. available from B.F. Goodrich Limited under the tradename Carbopol 980 NF).

The compositions of the invention preferably further comprise a pH adjusting agent, more preferably a basic alkaline 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 in a pharmaceutically and cosmetically acceptable range that does not damage the skin. More preferably, the pH of the composition is between about 5.0 and about 9.0. Subject to the foregoing,

adjusting the pH the agent is preferably based on the amount of trace about Up to 15% by weight, more preferably around µl 0.01 wt from about 12% to about 12% by weight, a Most preferably, from about 0.1% by weight to about 10% by weight;

62.339 / BE. The pH adjusting agent may contain sodium citrate, sodium hydroxide, potassium hydroxide and / or N, N, N ', N'-tetrakis (2-hydroxypropyl) ethylenediamine (commercially available from Quadrol commercially available). ).

The compositions of the invention may also contain a preservative. The preservative is preferably trace

volume up to about 5% by weight of the composition, preferably from about 0.1% to about 3% by weight - up to most preferably about 0.5% by weight

up to about 2% by weight. The preservative may be bromopol, sodium dehydroacetate, poly (hexamethylene biguanide hydrochloride), isothiazolone diazolidinyl urea and / or 2-phenoxyethanol (commercially available as Phenoxetol).

Available under the trade name Nipa).

The compositions of the present invention may further comprise a wetting agent to improve the skin's feel of the composition. Preferably the wetting agent is present in an amount of from about 1% to about 30% by weight of the composition, more preferably from about 5% to about 20% by weight, most preferably from about 7% to about 15% by weight. is present. The wetting agent may contain a glycol, as defined herein, that may be one or more organic compounds, each containing at least two hydroxy groups, preferably adjacent to adjacent atoms. More preferably, the glycol is selected from the group consisting of polyethylene glycol and glycerol

62.339 / BE and / or any mixture thereof.

If 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 denatured ethanol. Preferably, the detergent is present in an amount of from about 5% to about 60% by weight of the composition.

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

The oil phase of the emulsion which may be contained in a composition according to the invention may consist of one or more of the following components and / or any mixture thereof.

hydrocarbon oils (such as paraffin and / or mineral oils);

waxes (such as beeswax and / or paraffin wax);

natural oils (such as sunflower oil, apricot kernel oil, illuminated butter and / or jojoba oil);

silicone oils (such as dimethicone, cyclomethicone and / or cetyldimethicone);

fatty acid esters (such as isopropyl palmitate and / or isopropyl myristate); and fatty alcohols (such as cetyl alcohol and / or stearyl alcohol).

In a preferred oil-in-water emulsion which may be contained in a composition of the invention, the oil phase is comprised of from about 5% to about 30% by weight of the composition, more preferably from about 10% to about 20% by weight. is present.

An emulsifier for use in a composition of the invention may be any known emulsifier for use in water-in-oil or oil-in-water emulsions. Formulations of the present invention which are emulsions may be prepared by using an emulsifier selected from the group consisting of known emulsifiers and / or a mixture of emulsifiers acceptable for use in topical formulations, which may contain one or more of the following ingredients and / or mixtures thereof:

sesquioleate (such as sorbitan sesquioleate (e.g. commercially available from ICI under the tradename Arlacal 83));

ethoxylated esters of derivatives of natural oils (such as polyethoxylated esters of hydrogenated castor oils (for example, commercially available from ICI under the tradename Arlacal 989));

silicone emulsifiers (such as silicone polyols (e.g., commercially available from Th. Goldschmidt AG under the tradename ABIL WS05 and from Dow Coning under the tradename Silicone Fluid 3225C));

fatty acid soaps (such as potassium stearate);

ethoxylated fatty alcohols (e.g. commercially available from ICI under the tradename Brij and Croda under the tradename Cithrol GMS A / S);

sorbitan esters (thus commercially available from Croda under the tradename Crill);

ethoxylated sorbitan esters (commercially available from ICI under the tradename Tween);

62. 339 / BE ethoxylated fatty acid esters (such as ethoxylated stearates (e.g. commercially available from ICI under the tradename Myrj));

ethoxylated mono-, di- and / or triglycerides (such as commercially available from Alfa Chemicals under the tradename Labrafil); and ethoxylated fatty acids (commercially available from Alfa Chemicals under the tradename Tefose).

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

The emulsifier, which may optionally be present in an oil-in-water type emulsion which is part of a composition of the invention, is preferably present in an amount of from about 0.1% to about 20% by weight of the composition.

However, if the composition of the invention is other than an emulsion, an emulsifying ingredient and / or surfactant (e.g., any of the emulsifiers listed above) may still be present (e.g., in the amounts given above) as a surfactant to promote a greater therapeutic effect of the composition. topically applied.

The compositions of the present invention may additionally comprise one or more other ingredients, components and / or any mixture thereof, which are well known to those skilled in the art; these can be selected from:

emulsion stabilizers (such as stearyl alcohols and / or

Cetyl alcohols) and / or emulsion stabilizing salts (such as 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 (such as ethylenediaminetetraacetic acid tetrasodium sodium dihydrate (e.g. commercially available from Rhone-Poulenc under the tradename Sequestene NA4), preferably in trace amounts to about 1% by weight of the composition);

antioxidants (e.g. DL-α-tocopherol acetate and / or butylated hydroxytoluene), preferably in amounts ranging from about 1% by weight to the composition;

emollients (such as mineral oils, poly (methylsiloxane), sweet almond oil, petrolatum jelly, isopropyl myristate and / or fatty acid triglycerides [e.g. lauryl triglyceride, capric / capryl triglyceride, and / or From Huls UK Ltd under the tradename Miglyol 810), preferably from about 0.1% to about 30% by weight of the composition;

wetting agents (e.g., D-panthenol), preferably in amounts ranging from about 1% to about 1% by weight of the composition;

film-forming agents to facilitate spreading onto the skin surface (e.g., alkylated polyvinylpyrrolidone), preferably in a trace amount to about 1% by weight of the composition); and perfuming and / or coloring agents.

62.339 / BE • 4 · 4 ·

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

Example 1% w / w

Ibuprofen5,0

Poly (ethylene glycol) 300 BP (wetting agent) 10.0

2-Phenoxyethanol (Phenoxetol Nipa) 1.0

Carboxy-vinyl cross-linked polymer (Carbopol 980NF) 0.5

Sodium hydroxide BP granules (for pH adjustment) 0.085

Make up to 100 with purified water BP (diluent)

The above ingredients are mixed; This gives an opaque gel composition. The gel formulation of Example 1 was applied to the skin of an ankle of a volunteer who was itchy, scaly, red and inflamed. It was found that the formulation reduced the itching sensation and within a short period of time

62,339 / BE • Scaling of the skin. This surprising effect was independent of any anti-inflammatory, antipyretic, or analgesic response that would have been expected as a result of ibuprofen administration.

A guinea pig suffered from itching to such an extent that the hair fell out of the skin and a penny of red formed on the skin. All of the gel of Example 1 was applied to the wound and repeated daily for one week. During this time, the red spot disappeared and the hair on the affected area began to grow again. The condition of the guinea pig has continued to improve without recession.

Example 2% w / w

S - (+) - Ibuprofen 2.5

Caroboxyvinyl Crosslinked Polymer (Carbopol) 2.0

Denatured ethanol (bleach) 5.0

Sodium hydroxide (pH adjuster) 1.525

2-Phenoxyethanol (Phenoxetol) 1.0

Make up to 100 with purified water (diluent)

The above ingredients are mixed; This gives a pure gel composition which has an anti-itch effect when applied topically as described in Example 1.

Example 3% w / w

Flurbiprofen 2.5

62,339 / BE · «···· · * ·» • * »

Poly (ethylene glycol) (wetting agent) 10.0

2-Phenoxyethanol (Phenoxetol) 1.0

Carboxy-vinyl cross-linked polymer (Carbopol) 0.5

Sodium hydroxide (pH adjuster) 0, 085

Make up to 100 with purified water (diluent)

The above ingredients are mixed; This results in an opaque gel composition having an anti-itch effect when applied topically as described in Example 1.

Example 4% w / w

Flurbiprofen2,5

Carboxyvinyl Crosslinked Polymer (Carbopol) 2.0

Denatured ethanol (bleach) 50.0

Poly (ethylene glycol) (wetting agent) 5.0

Glycerin (wetting agent) 5,0

Make up to 100 with purified water (diluent)

The above ingredients are mixed; This gives a pure gel composition which has an anti-itch effect when applied topically as in Example 1.

Example 5% w / w

Flurbiprofen 10.0

Denatured ethanol (bleach) 40.0

Carboxy-vinyl cross-linked polymer (Carbopol) 2.6

N, N, N'-tetrakis (2-hydroxypropyl) ethylenediamine (Quadrol) 9.0

62 339 / BE

Propylene glycol (wetting agent) 2.0

Ethoxylated fatty alcohol (Brij 92) 2.0

Make up to 100 with purified water (diluent)

The above ingredients are mixed; This gives a pure gel composition which has an anti-itch effect, if any

Topically applied as described in Example 1.

Claims (10)

Use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof as an anti-itching agent or agents for treating itchy skin in animals, characterized in that ibuprofen, flurbiprofen and / or their salt or salts are applied topically to the animal. Use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof according to claim 1, characterized in that when the itching of the skin is triggered by UV-B radiation, the anti-itching agent or agents are other than ibuprofen. also contains. Use of Ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof according to any one of the preceding claims, characterized in that said animal is a human. Use of ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof in the manufacture of a topically applied medicament for the treatment of pruritus of the skin. A method of treating itchy skin in an animal by using a topical pharmaceutical composition comprising ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof as an anesthetic or agents, wherein the composition is applied topically to the animal. 6. The method of treatment according to claim 5, wherein the method of treatment is as follows: that if the itching of the skin is triggered by UV-B radiation, the anti-itching agent (s) also contains ingredients other than ibuprofen. A method of treatment according to any one of claims 5 or 6, wherein said animal is a human. 8. A non-therapeutic method of cosmetic treatment for inhibiting pruritus induced scratching in animals, comprising administering to the animal as an anti-itch agent or agents topical pharmaceuticals containing ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof. employed. 9. A method of cosmetic treatment according to claim 8, wherein said animal is a human. A topical pharmaceutical composition comprising ibuprofen, flurbiprofen and / or one or more pharmaceutically acceptable salts or salts thereof as an anti-itch agent or agent, characterized in that the composition has an anti-itch effect when applied topically, provided that the anti-itch agent is not only flurbiprofen alone or ibuprofen alone.