The present invention relates to the treatment of inflammatory skin conditions, including psoriasis, with a prodrug of 5-fluorouracil. The invention relates to methods for treatment of psoriasis with capecitabine, an oral prodrug of 5-fluorouracil.

SUMMARY OF THE INVENTION

The present invention provides a method for treating inflammatory skin conditions by orally administering an effective amount of a prodrug of 5-FU. The present invention additionally provides a method of treating psoriasis by orally administering an effective amount of an oral prodrug of 5-FU. In a preferred embodiment, the invention provides a method for treating psoriasis by oral administration of capecitabine. According to the invention an effective amount of capecitabine is orally administered to treat psoriasis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method of treating inflammatory skin conditions, particularly psoriasis, by orally administering a prodrug of 5-FU. In a preferred embodiment, the present invention employs oral administration of capecitabine for treating psoriasis.

It has now been unexpectedly discovered that oral administration of 5-FU prodrugs can be used to treat psoriasis in humans. In a preferred embodiment, capecitabine (a 5-FU prodrug) is orally administered to treat psoriasis in humans. The 5-FU prodrugs that have been found to be useful for treatment of psoriasis in humans are capecitabine (N⁴-pentyloxycarbonyl-5′-deoxy-5-fuorocytidine), 5-fluoro-pyrimidinone (5FP), TS-1 (S-1, ftorafur), FdUMP, 1-(2′-oxopropyl)-5FU, and alkyl-carbonyl-5-FU.

The preferred 5-FU prodrug for use in the present invention is capecitabine. Capecitabine is a prodrug of the antimetabolite 5-FU, crosses the gastrointestinal barrier intact, and is rapidly and almost completely absorbed. Surprisingly, this drug, which is responsible for the skin disease known as hand-foot syndrome, is effective as a treatment for another skin disease, psoriasis. The effectiveness of capecitabine for the treatment of psoriasis is especially surprising because hand and foot syndrome (which involves erythema, pain and ulceration) and psoriasis may occur in the same area of the body. As an example, inverse psoriasis occurs in intertriginous areas, which are areas between folds or juxtaposed surfaces of skin. (Stedman's Medical Dictionary, 26^th edition) Intertriginous areas include the skin beneath pendulous breasts and abdominal skin folds. Hand-foot syndrome is known to occur at the intertriginous areas of the bra-line and belt-line. Moreover, pustular psoriasis is known to localize to the palms and soles. (Merck Manual of Diagnosis and Therapy, 17^th edition, section 10 ch. 117).

The use of capecitabine to treat psoriasis is a significant advance because it avoids the serious side effects of 5-FU. Furthermore, capecitabine can be reliably and effectively administered via the oral route. Most adverse events associated with capecitabine administration are reversible and do not require discontinuation of the drug. (Physician's Desk Reference, supra) A benefit of oral prodrugs of 5-FU, and capacitabine particularly, is that patients are more likely to initiate treatment if the active agent can be taken orally rather than undergo the additional pain, expense and inconvenience of IV treatment. Treatment with oral capecitabine does not require hospitalization as does initial IV therapy with 5-FU. (Malet-Martino et al., supra) In addition to the 5-FU specific toxicities, any intravenous catheterization carries the risk of local infection and/or thrombophlebitis. (de Bono J S, Twelves C J, supra).

The 5-FU prodrugs capecitabine (N⁴-pentyloxycarbonyl-5′-deoxy-5-fuorocytidine), 5-fluoro-pyrimidinone (5FP), TS-1 (S-1, ftorafur), FdUMP, 1-(2′-oxopropyl)-5FU, and alkyl-carbonyl-5-FU can be orally administered to treat psoriasis and other inflammatory skin conditions (e.g., keloid (hypertrophic scar), atopic dermatitis, lichen simplex chronicus, prurigo nodularis, Reiter syndrome, pityriasis rubra pilaris, pityriasis rosea, stasis dermatitis, rosacea, acne, lichen planus, scleroderma, seborrheic dermatitis, granuloma annulare, rheumatoid arthritis, dermatomyositis, alopecia greata, lichen planopilaris, vitiligo, and discoid lupus erythematosis) in humans. Therapeutically effective oral doses of 5-FU prodrugs for treating psoriasis and other inflammatory skin conditions in humans in a non-pulse dosing regimen are between 5 and 2500 milligrams per square meter of body surface area per day, a preferred effective amount is between 100 and 1500 milligrams per square meter of body surface area per day and an especially preferred dose is 1250 milligrams per square meter of body surface area per day.

The preferred prodrug, capecitabine, is therapeutically effective for treating psoriasis and other inflammatory skin conditions in humans at doses below 2500 milligrams per square meter of body surface area per day, and capecitabine does not produce a 5-FU like adverse effect profile until dose levels exceed 2500 milligrams per square meter of body surface area per day. Adverse effects experienced at levels in excess of 2500 milligrams per square meter of body surface per day include nausea, vomiting and skin rashes. A therapeutically effective amount is that amount of capecitabine which will relieve or improve to some extent one or more of the symptoms or signs of psoriasis or other inflammatory skin condition.

An effective amount of capecitabine for treating psoriasis or other inflammatory skin condition in a non-pulse dosing regimen is between 100 and 2500 milligrams per square meter of body surface area per day, a preferred effective amount is between 750 and 1500 milligrams per square meter of body surface area per day and an especially preferred dose is 1250 milligrams per square meter of body surface area per day.

Capecitabine (offered under the brand name Xeloda® by Roche Labs, Nutley, N.J. 07110) is commercially available in 150 mg and 500 mg tablets. Xeloda® is indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracyline-containing chemotherapy regimen, or resistant to paclitaxel and for whom further anthracycline therapy is not indicated. (Physician's Desk Reference 2002) Peak plasma concentrations for capecitabine and its two main metabolites occur about 0.5 to 1.5 hours after administration. Plasma concentrations decline exponentially with a half-life of about 0.5 to 1 hour.

An additional dosing regimen is pulse-dosing. In pulse-dosing, an effective amount of a biologically active agent is administered to the patient and then sufficient time is allowed to permit the active agent to clear from the patient's body (i.e. to be metabolized or discharged) prior to the administration of additional doses. The quantity of drug administered to the patient in pulse-dosing may be greater than the dosage administered in a non-pulse-dosing regimen. The quantity, length of administration and interval between doses in pulse-dosing vary according to an individual patient's response to the pulse-dosing regimen.

An effective amount of oral 5-FU prodrug for treating psoriasis or other inflammatory skin condition by pulse dosing is between 5 and 5000 milligrams per square meter of body surface area, a preferred effective amount is between 100 and 3000 milligrams per square meter of body surface area and an especially preferred dose is 1250 milligrams per square meter of body surface area. A preferred pulse-dosing regimen is administration of the effective amount of the 5-FU prodrug daily for one week, an interval of two weeks without administration, repeat the schedule.

A preferred pulse-dosing regimen for treating psoriasis or other inflammatory skin condition is administering oral capecitabine in an effective amount between 100 and 5000 milligrams per square meter of body surface area, a preferred effective amount of between 750 and 3000 milligrams per square meter of body surface area and an especially preferred dose of 1250 milligrams per square meter of body surface area. In the pulse-dose regimen, the effective amount of capecitabine is administered orally each day for one week followed by an interval of one week without administration; the weekly cycle is repeated. Pulse-dose quantity, the period of time during which the effective amount is administered, and interval without dosing are adjusted for patient response and occurrence of adverse effects.

A 5-FU prodrug of the present invention is preferably administered as a pharmaceutical composition in hard shell dosage form such as a pill, tablet, capsule, or caplet. The pharmaceutical composition may be formulated as unit dosage forms, such as tablets, pills, capsules, boluses, powders, granules, elixirs, tinctures, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories. Unit dosage forms may be used for oral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation, transdermal patches, and a lyophilized composition. Preferably the unit dosage form is an oral dosage form, most preferably a solid oral dosage, therefore the preferred dosage forms are tablets, pills, and capsules.

The pharmaceutical composition may contain capecitabine or an enantiomer, diastereomer, N-oxide, crystalline form, hydrate, solvate, active metabolite or pharmaceutically acceptable salt of the compound. The pharmaceutical composition may also include optional additives, such as a pharmaceutically acceptable carrier or diluent, a flavouring, a sweetener, a preservative, a dye, a binder, a suspending agent, a dispersing agent, a colorant, a disintegrator, an excipient, a diluent, a lubricant, an absorption enhancer, a bactericide and the like, a stabiliser, a plasticizer, an edible oil, or any combination of two or more of said additives.

Suitable pharmaceutically acceptable carriers or diluents include, but are not limited to, ethanol, water, glycerol, aloe vera gel, allantoin, glycerine, vitamin-A and E oils, mineral oil, phosphate buffered saline, PPG2 myristyl propionate, magnesium carbonate, potassium phosphate, vegetable oil, animal oil and solketal.

Suitable binders include, but are not limited to, starch, gelatine, natural sugars such as glucose, sucrose and lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, vegetable gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.

Suitable disintegrators include, but are not limited to, starch such as corn starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Suitable lubricants include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

Suitable suspending agents include, but are not limited to, bentonite.

Suitable dispersing and suspending agents include, but are not limited to, synthetic and natural gums such as vegetable gum, tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone and gelatine.

Suitable edible oils include, but are not limited to, cottonseed oil, sesame oil, coconut oil and peanut oil.

Examples of additional additives include, but are not limited to, sorbitol, talc, stearic acid and dicalcium phosphate.

Solid unit dosage forms may be prepared by mixing the active agents of the present invention with a pharmaceutically acceptable carrier and any other desired additives as described above. The mixture is typically mixed until a homogeneous mixture of the active agents of the present invention is obtained and the carrier and any other desired additives are formed, i.e. the active agents are dispersed evenly throughout the composition.

Tablets or pills can be coated or otherwise prepared so as to form a unit dosage form that has delayed and/or sustained action, such as controlled release and delayed release unit dosage forms. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of a layer or envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.

Biodegradable polymers for controlling the release of the active agents include, but are not limited to, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

For liquid dosage forms, the active substances or their physiologically acceptable salts are dissolved, suspended or emulsified, optionally with the usually employed substances such as solubilizers, emulsifiers or other auxiliaries. Solvents for the active combinations and the corresponding physiologically acceptable salts can include water, physiological salt solutions or alcohols, e.g. ethanol, propanediol or glycerol. Additionally, sugar solutions such as glucose or mannitol solutions may be used. A mixture of the various solvents mentioned may be used in the present invention too.

The active agents of the present invention may also be coupled with soluble polymers such as targetable drug carriers. Such polymers include, but are not limited to, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol, and polyethylenoxypolylysine substituted with palmitoyl residues.

A transdermal dosage form also is contemplated by the present invention. Transdermal forms may be a diffusion-driven transdermal system (transdermal patch) using either a fluid reservoir or a drug-in-adhesive matrix system. Other transdermal dosage forms include, but are not limited to, topical gels, lotions, ointments, transmucosal systems and devices, and iontohoretic (electrical diffusion) delivery system. Transdermal dosage forms may be used for timed release and sustained release of the active agents of the present invention.

The total daily dose should be taken as two divided doses approximately 12 hours apart, within 30 minutes of eating. The tablets should be taken with water. (Xeloda™ Patient Package Insert).

The number of daily tablets of a 5-FU prodrug to be taken by a patient for treatment of psoriasis or other inflammatory skin condition is shown in the following dosing table.

The Body Surface Area (BSA) is calculated using a BSA nomogram well known to those skilled in the art and the patient's height and mass. (Mosteller RD. Simplified calculation of body-surface area. NEJM 1987;317:1098). For any given BSA in the first column of Table 1, the total daily dose is disclosed in the second column of the table. The third and fourth columns of Table 1 show, respectively, the number of 150 milligram tablets and the number of 500 milligram tablets to be taken at each administration (morning and evening).

Duration of individual patient treatment will depend on individual response and tolerance. However, treatment with an effective amount of a 5-FU prodrug for 2 to 12 weeks should provide relief from psoriasis and other inflammatory skin conditions in most patients. The dosing regimen may be modified in the event of adverse events. An adverse event includes any adverse change from the patient's pre-treatment condition.
 

Claim 1 of 32 Claims

1. A method for treating an inflammatory skin condition in a patient which consists essentially of orally administering an effective amount of a prodrug of 5-fluorouracil to said patient.

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