WO2010013044A1

WO2010013044A1 - Nalmefene and derivatives thereof for the treatment of skin disorders

Info

Publication number: WO2010013044A1
Application number: PCT/GB2009/050937
Authority: WO
Inventors: John Clements; Alan Rothaul; Elena Lasterra
Original assignee: Serentis Ltd
Current assignee: Serentis Ltd
Priority date: 2008-07-31
Filing date: 2009-07-29
Publication date: 2010-02-04
Anticipated expiration: 2011-01-31
Also published as: GB0814043D0

Abstract

A compound which is nalmefene or of formula (1): wherein R1 is H, C₁ -C₄ alkyl or C₁ -C ₄ alkylcycloalkyl; and X is a counterion of any pharmaceutically acceptable acid; for the treatment of a skin disorder selected from psoriasis, acne, alopecia, bullous pemphigoid, impetigo, vitiligo, rosacea, scarring, burns, seborrhea or seborrheic dermatitis.

Description

NALMΞFENE AND DERIVATIVES THEREOF FOR THE TREATMENT OF SKIN DISORDERS

Field of the Invention

This invention relates to compositions for the prevention or treatment of skin disorders. Background of the Invention

Nalmefene (θ-methylene-δ-desoxy-N-cyclopropylmethyl-M-hydroxy- dihydronormorphine) is a long-acting, orally available, potent opioid antagonist with pure and selective antagonist activity. Nalmefene hydrochloride (REVEX®) is available as a sterile solution for intravenous, intramuscular and subcutaneous administration, indicated for the reversal of opioid drug effects, including respiratory depression.

The use of systemic nalmefene has been proposed for the treatment of a variety of diseases, including autoimmune diseases, such as multiple sclerosis, arthritic and inflammatory diseases and mental, emotional or stress disorders. In addition, nalmefene has been disclosed to treat mast cell-mediated disorders, such as allergic rhinitis, urticaria and atopic dermatitis. US4923875 discloses the utility of topical nalmefene in treating urticaria, various eczemas, and other mast cell-mediated dermatological disorders. Summary of the Invention The present invention is based on the discovery that compositions of nalmefene or peripherally acting analogues of nalmefene are capable of providing relief of skin disorders such as psoriasis, acne, alopecia, bullous pemphigoid, impetigo, vitiligo, rosacea, scarring, burns, seborrhea or seborrheic dermatitis. In another aspect of the invention nalmefene or peripherally acting analogues of nalmefene are useful at delaying and/or preventing the onset of flares in conditions such as psoriasis, acne, rosacea seborrhoea, seborrheic dermatitis or atopic dermatitis. They are also useful at preventing scarring.

Opioid antagonists, even when applied topically, are susceptible to causing unwanted CNS side-effects that would limit their use, particularly in children. These side-effects can be managed by the topical application of nalmefene and peripherally acting analogues of nalmefene when controlled delivery of the compound allows retention in/on the skin and minimizes systemic and ultimately central exposure. This is demonstrated by Franz Cell experiments where certain topical formulations of nalmefene are shown to pass slowly through synthetic and skin membranes. According to the present invention, a skin disorder as described above is treated by the use of nalmefene or a compound of general formula (1):

(1 ) wherein R1 is H, such as in a pharmaceutically active salt of nalmefene itself, or CrC₄ alkyl or CrC₄ alkylcycloalkyl in the preferred peripherally acting analogues; and X is a counterion. Description of Preferred Embodiments Nalmefene has many chiral centres. Any reference herein to nalmefene or peripherally acting analogues should be understood as a reference to any enantiomer or mixture thereof. Any enantiomer may be substantially free of others, e.g. in an enantiomeric excess of at least 80%, preferably at least 90% and more preferably at least 95%. Similarly, any mixture of diastereomers may be substantially free of the other. The form drawn above as (1) is preferred. Nalmefene may be in the form of any pharmaceutically acceptable salt, as described above. Such forms are known to those of ordinary skill in the art. X is preferably a halide but could represent the counterion of any pharmaceutically acceptable acid, including sulphate, methosulphate, phosphate or organic acids such as citrate, succinate, tartarate, fumarate, maleate, acetate, methanesulphonate and the like.

The active agent may be administered by various routes, including parenteral, oral, intraoral, rectal, epicutaneous, transdermal, subcutaneous, intramuscular, intranasal, sublingual, buccal, vaginal, rectal, intradural, intraocular, intrarespiratory, or nasal inhalation and like forms. The amount of active ingredient that is used can be chosen by the skilled person having regard to the usual factors.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The composition may be in immediate or controlled release form.

The topical route may be preferred. For use through this route of delivery the active agent is typically formulated, e.g. with conventional diluents or carriers, or as a dressing or a patch, as a medicament adapted to be delivered by the chosen route. Such formulations may be designed to retard the passage of the compound into the systemic circulation and are chosen according to such considerations as the potency of the drug, the severity of the condition and the route of administration. Topical delivery introduces significant concentrations of nalmefene or the compound of formula (1) into/onto the skin whilst reducing CNS and peripheral side-effects. In this context, a compound of the invention is used at concentrations between 0.1% and 5%, preferably between 0.5% and 2%.

It will often be advantageous to use compounds of the invention in combination with another drug selected from antipruritics, antiinflammatories, antibiotics, salicylic acid, nicotinamide, azelaic acid, a zinc compound, a retinoid, an oral contraceptive or an anti-androgen. Such another drug may also be a local anaesthetic, corticosteroid, calcineurin antagonist or anti-infective. Other suitable combinations may include anti-histamines, including either or both sedating or non-sedating agents, corticosteroids (examples including Cortisol, cortisone, hydrocortisone, dihydrocortisone, fludrocortisone, prednisone, prednisolone, deflazacort, flunisolide, beconase, methylprednisolone, triamcinolone, betamethasone, and dexamethasone), disease modifying antirheumatic drugs (DMARDs) (examples including azulfidine, aurothiomalate, bucillamine, chlorambucil, cyclophosphamide, leflunomide, methotrexate, mizoribine, penicillamine and sulphasalazine), immunosuppressants (examples including azathioprine, cyclosporine and mycophenolate), COX inhibitors (examples including aceclofenac, acemetacin, alcofenac, alminoprofen, aloxipirin, amfenac, aminophenazone, antraphenine, aspirin, azapropazone, benorilate, benoxaprofen, benzydamine, butibufen, celecoxib, chlorthenoxacine, choline salicylate, chlometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole, etodolac, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxylethyl salicylate, ibuprofen, indometacin, indoprofen, ketoprofen, ketorolac, lactyl phenetidin, loxoprofen, mefenamic acid, metamizole, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, oxametacin, phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone, rofecoxib, salicylamide, salsalate, sulindac, suprofen, tiaramide, tinoridine, tolfenamic acid and zomepirac), neutralising antibodies (examples including etanercept and infliximab), antibiotics (examples including doxycycline and minocycline), analgesics (opiate or non opiate such as baclofen), neuropathic pain agents (such as gabapentin or pregabalin), non steroidal antiinflammatory drugs, NMDA antagonists, neuroleptics, anticonvulsants, antispasmodics, anti-depressants or muscle relaxants.

Drugs when used in combination with nalmefene or a compound of formula (1) can be administered either topically or systemically, in the same or a different formulation.

A topical composition of the invention preferably has predetermined control-release characteristics and it is preferably suitable for once or twice daily dosing. Such characteristics can be determined by an objective study such as an in vitro Franz cell experiment.

As indicated above, a topical composition of the invention may comprise conventional components. Preferred components for use in the invention include penetration modifiers, e.g. isopropyl myristate, humectants, preservatives and thickening agents. A preferred topical composition comprises nalmefene in a salt form and has a pH in the range of 3 to 7, preferably 4 to 6. The acidity of the composition ensures that nalmefene remains in the salt form and delays release of drug into the skin and retards transdermal delivery.

The following Examples illustrate the invention. Examples

The following components were formulated:

These formulations were tested in in vitro Franz cell experiments and demonstrated a high and controlled-released dermal load, with limited systemic exposure.

Primary human monocytes are a well established cell model to investigate the effects of compounds on inflammatory cytokine release. An assay was performed to assess the effects of nalmefene and naltrexone on LPS stimulated TNFalpha release in human monocytes. Human primary monocytes were prepared from buffy coats of healthy human blood donors following a standardized procedure. Cells were seeded in 24-well-plates for ELISA measurements. Monocytes were stimulated with LPS (10ng/ml) at 37°C and 5% CO₂ for 24 h. Test compounds were added 30 min prior to LPS treatment. After 24 hours, supernatants were removed, centrifuged and analysed for TNFalpha concentrations by ELISA. No effect on TNFalpha release was observed with naltrexone up to 10 μM. 10μM nalmefene inhibited TNFalpha release by approximately 30%.

Claims

1. A compound which is nalmefene or of formula (1 ):

(1 ) wherein R1 is H, C₁-C₄ alkyl or Ci-C₄ alkylcycloalkyl; and X is a counterion of any pharmaceutically acceptable acid; for the treatment of a skin disorder selected from psoriasis, acne, alopecia, bullous pemphigoid, impetigo, vitiligo, rosacea, scarring, burns, seborrhea or seborrheic dermatitis.

2. A compound according to claim 1 where the skin disorder is psoriasis.

3. A compound according to claim 1 where the skin disorder is rosacea.

4. A compound according to claim 1 where the skin disorder is acne.

5. A compound according to claim 1 for the delay and/or prevention of flares of psoriasis.

6. A compound according to claim 1 for the delay and/or prevention of flares of atopic dermatitis.

7. A compound according to claim 1 for the delay and/or prevention of flares of acne, rosacea, seborrhoea or seborrheic dermatitis.

8. A compound according to claim 1 for the delay and/or prevention of flares of rosacea.

9. A compound according to claim 1 for the prevention of scarring.

10. A compound according to any preceding claim formulated for topical delivery.

11. A compound according to any preceding claim which is nalmefene or a salt of nalmefene.

12. A compound according to any preceding claim, wherein X is halide.

13. A compound according to any preceding claim where the compound is nalmefene methiodide.

14. A compound according to any preceding claim, which is used in combination with one or more agents selected from antipruritics, antiinflammatories, antibiotics, salicylic acid, nicotinamide, azelaic acid, zinc compounds, retinoids, oral contraceptives, anti-androgens, local anaesthetics, corticosteroids, calcineurin antagonists, anti-infective, anti-histamines, disease modifying anti-rheumatic drugs, COX-inhibitors, neutralising antibodies, analgesics, neuropathic pain agents, non steroidal anti-inflammatory drugs, NMDA antagonists, neuroleptics, anticonvulsants, anti-spasmodics, antidepressants or muscle relaxants.