MXPA02001351A - Topical use of anti-muscarinic agents - Google Patents

Abstract

A compound having anti-muscarinic activity, a dipole moment greater than 4D and anti-proliferation activity of at least 50%at 10&mgr;M, e.g. glycopyrrolate, is useful for the treatment of skin conditions such as psoriasis.

Description

TOPICAL USE OF ANTI-MUSCARINIC AGENTS Field of the Invention This invention relates to the treatment of topical conditions using antimuscarinic agents, Background of the Invention Gajewski, Pol. Tyg. Him 25 (47) 1815-6 (1970), describes that the psoriatic skin rash disappeared in the course of atropine therapy. Several drugs similar to quaternary ammonium atropine have been used in the treatment of hyperhidrosis, that is, excessive exudation. These inhibit exudation but generally have no systemic effects. US-A-5185350 discloses substituted pyridinyl amines which are useful as topical anti-inflammatory agents for the treatment of various dermatoses. US-A-5084281 describes the use of cholinergic agents, in combination with a seawater solution or a sea salt solution, for the treatment of persistent neuropathic skin ulcers. WO-A-94/15623 discloses pharmaceutical compositions comprising several components, including urea and hiaurolonic acid, for the treatment of contact dermatitis and other topical conditions. Document OA-98/00119 describes the use of agents that affect the functions of non-acetylcholine neuronal, for the treatment of skin discomforts. It also describes that topically effective muscarinic receptor antagonists, including ipratropium, are useful for the treatment of skin discomforts. Several skin complaints that are described include atopic dermatitis, neurodermatitis, psoriasis and cholinergic urticaria. BRIEF SUMMARY OF THE INVENTION In accordance with the present invention, the conditions of the skin are treated by the topical application of a quaternary ammonium or other compound having antimuscarinic activity, a high dipole moment (greater than 4D) and high antiproliferation activity ( at least 50% inhibition at 10 μM). It may also have high receptor binding activity (half-life for receptor dissociation greater than 0.11 h to Ml). Topical compositions containing such compounds may also be new. Description of the Invention This invention is based at least in part on studies, using the assay described in the following, which show the inhibition of keratinocyte proliferation using antimuscarinic agents. Such agents can be defined by their dipole moment. The dipole moment is related to the polarity of the drug, which in turn is related to the penetration of a given drug through the upper layers of the skin tissue. Ando, J. Pharm. Sci. (1984) 73 (4): 461-467, demonstrated a linear relationship between the flow of drug through the stratified cornea and the dipole moment, and that drugs with a dipole moment greater than 4.0 showed a Limited systemic exposure due to poor passage through the skin to the circulatory system.

The lower polarity of the agents, such as atropine (1,232D) and homatropine (1066D) may be effective in the given assay, for the inhibition of proliferation but have central nervous activity when applied topically. While this in some indications may be an attractive property (eg, motion ailment) for local conditions in which the drug is applied topically, this can give rise to serious side or side effects that limit the use of the drug. Other antimuscarinic agents also show efficacy in the proliferation assay. These agents can be characterized by dipole moments greater than those of atropine, for example, scopolamine (3,946D), revatropathy. (4.168D), ipratropium (13.4 5D), and glycopyrrolate (15.10D). Agents with a high dipole moment are more suitable for topical administration to treat skin conditions. Therefore, this invention relates to the use of antimuscarinic agents for the treatment of skin conditions, especially psoriasis, in which there is a low potential for systemic exposure as defined by a dipole moment greater than 4.0D, and preferably greater than 10D. For use in this invention, suitable antiproliferative antimuscarinic agents have a half-life in human plasma of less than 3 hours. The systemic pharmacological effects characteristic of antimuscarinic agents are caused by high sustained levels of drug in the plasma. This leads to the distribution of the compound to receptors around the body.

For effective therapy of a topically applied antimuscarinic agent in proliferative conditions, a combination of antiproliferative activity (for efficacy) and low plasma life span (to limit side effects) is necessary. Such compounds with a short half-life in plasma include, but are not limited to, glycopyrrolate, ipratropium and tiotropium. Agents for use in this invention preferably also have high binding affinity to the receptor. A long duration of action is extremely desirable for a topically applied drug to treat local conditions. This leads • to low rates of reapplication of medication, which in turn ensures minimal disturbance to the patient's lifestyle and high satisfaction to the patient. patient. Compounds with high binding affinity to the receptor include glycopyrrolate, ipratropium, and tiotropium. Although ipratropium meets the criteria described above, it is not as satisfactory as a treatment of skin conditions when compared to glycopyrrolate and tiotropium. This is not due to its receptor affinity (which is similar to that of glycopyrrolate) but due to its high binding speed to the receptor. Both glycopyrrolate and tiotropium have receptor binding rates that are very attractive for thermal dosing. Barnes, Brtish Journal of Phamacology (1999) 127: 413-420, showed a t1 / 2 adjustment for 96-minute glycopyrrolate compared to 59 minutes for ipratropium in a clinical study of muscarinic activity in the human smooth muscle. This attractive speed can be defined using a test of [N-methyl-3 H] -escopolamine (NMS) broken with tritium; in this experiment, Barnes showed a 60% protection against the binding of [3H] -NMS in 30nM when compared to ipratropium bromide. At the clinical level, glycopyrrolate is known to have a longer duration of action in muscarinic antagonism than ipratropium; see J. Allergy Clin. Immunol. (1988) 82: 115. In addition, in Frey's syndrome, a duration of two days of action of a single application thermal is presented that is common in the use of glycopyrrolate. In addition, Disse et al., Life Sciences (1993) 52 / 5-6: 537-544 compared the dissociation rates of ipratropium and tiotropium. For the muscarinic Ml receptor, the half-life periods were 0.11 h and 14.6 h; for M3, they were 0.26 h and 34.7 h, respectively. The relatively low speed and long half-life for tiotropium are responsible for its very long duration of action on smooth muscle relaxation involving muscarinic antagonism. More particularly, agents suitable for the use of the invention can initially be identified by the Test Protocol described in the following. This' is a time of psoriasis and thus of a proliferative condition of the skin. OR:? The agent for use of the invention preferably has an IC50 value of between 100 μM, more preferably below iC μM, for example, below 1 μM, and much more preferably below 100 nM. Examples of agents that can be used in the invention, as long as they meet the essential criteria, include ambutonium, benzylonium, dibutolin, difermanil, emepromo, glycopyrrolate, isopropamide, lacqueine, mepenzolate, matantelin, oxyphenonium, oxitropium, penthenate, pentimentonium, pipensolate , poldina, tiemonio, tiotropium, triciclamol and tridihexetil. Glycopyrrolate is preferred. These and other compounds for the use of the invention can be provided in the form of a free base or salt. All such forms are within the scope of the invention and in particular organic and inorganic salts are included. For example, the quaternary ammonium compounds can be provided as a halide or other salt. Many anus imuscarinic agents exhibit isomerism, either structural optics (stereoisomerism / regioisomerism). These include glycopyrrolate and tiotropium. The application of a single isomer or a non-stoichiometric mixture of isomers, for example non-racemic mixture, in the case of optical isomers, can optimize the desired antiproliferative activity. Topical formulations and conventional administration techniques can be used. For example, suitable compositions include, but are not limited to, creams, ointments, gels, shampoos, lotions, iontophoresis, patches and emollients. This invention also includes the use of antimuscarinic agents to treat the condition of the skin by topical administration, in which the drug is placed in a formulation system in which the flow of drug through the skin is maintained at a speed such that systemic blood levels are retained at a low level. However, fl. The drug is maintained at a level to effect topical activity on the skin. In this way, antimuscarinic agents can be used, which would otherwise be limited by their side effects. The conditions that can be treated include all forms of psoriasis, including psoriatic arthritis and scalpel arthritis, skin cancer, melanoma, pemphigus, atopic dermatitis, neurodermatitis, eczema, contact dermatitis, acne, leprosy, seborrheic dermatitis, lupus and urticaria . The invention is particularly suitable for the treatment of topical proliferative conditions such as psoriasis. The treatment can be combined with radiological therapy. Alternatively or in addition, the treatment may be combined with a conventional agent, of which examples include steroids, vitamins A, D and their analogues, salicylates, anthralines and coal tar preparations. The amount of the active agent that is used will depend on the usual factors, such as the potency of the agent, the nature and condition of the condition being treated, the condition of the patient, etc. All these factors can be taken into account, and the relevant dose will be determined accordingly, by the person skilled in the art. Human Keratinocyte Assay Protocol Neonatal human epithelial keratinocytes (Biowhittaker) were cultured in defined media (KGM-2 keratinocyte culture medium, Biowhittaker) until confluence. Steps 2-4 are preferred. The cells were placed in a 96-well plate at a density of 1 x 104 / cavity in lOOμl of KGM-2. The cells were allowed to settle at 37 ° C for 48 hours. The medium is removed and the drug is added. Vitamin D3 is included as a standard, and a dose-response analysis to the drug is carried out. Cell proliferation is measured 5 days (or 3 days in the case of ipratropium) after the addition of the drug. This is done using a colorimetric protein-based assay, SRB (Sulforhodamine Blue) and read at an absorbance of 515 nM. The results (tabulated in the following) are presented as% inhibition of control growth (without drug); it will be appreciated that glycopyrrolate is 3 orders of magnitude more active than other drugs tested, and particularly suitable for use as an antiproliferative agent. Atropine 30% (10 μM) Scopolamine 20% (10 μM) Propentelin 35% (10 μM) Glicopirrolatb 50% (10 nM) Vitamin D3 40-80% (10 μM) Ipratropium 20% (10 μM)

Claims (20)

1. CLAIMS Use of a compound having antimuscarinic activity, a dipole moment greater than 4D and antiproliferation activity of at least 50% at 10 μM, for the preparation of a topical mecicamento for use in the treatment of a skin condition.
2. 2. The use according to claim 1, characterized in that the compound has a tV2 setting greater than ipratropium at 30 nM.
3. 3. The use according to claim 1 or claim 2, characterized in that the compound exhibits a half-life period for the dissociation of the receptor a Ml or M3 greater than for ipratropium.
4. 4. The use of compliance with any of the preceding claims, characterized in that the compound exhibits IC50 of less than 1 μM in the assay protocol described herein.
5. 5. The use according to any of the preceding claims, characterized in that the compound exhibits one or more of the characteristics given in any preceding claim, at a level of at least 80% of that for glycopyrrolate or tiotropium.
6. The use according to any of the preceding claims, characterized in that the compound is a quaternary ammonium compound.
7. 7. The use according to any of the preceding claims, characterized in that the compound is selected from ambutonium, benzylonium, dibutoline, difmannanyl, emepronium, glycopyrrolate, isopropamide, laccase. mepenzolate, metantelina, oxyphenonium, pentienato, fentimentonio, pipenzolato, poldina, triemonio, triciclamol and tridihexetilo.
8. The use according to any of the preceding claims, characterized in that the compound exists in more than one isomeric form and is used in the form of an individual isomer or non-stoichiometric mixture of isomers
9. 9. The use according to claim 7 or claim 8, characterized in that the compound is glycopyrrolate
10. 10. The use according to claim 9, characterized in that the compound is SS, RR, RS or SR glycopyrrolate.
11. 11. The use according to claim 5, characterized in that the compound is oxitropium,
12. 12. The use according to claim 5, characterized in that the compound is tiotropium.
13. 13. The use according to claim 12, characterized in that the compound is an isomeric form of tiotropium.
14. 14. The use according to any of the preceding claims, characterized in that the condition is a topical proliferative condition.
15. 15. The use according to any of the preceding claims, characterized in that the condition is selected from psoriasis, atopic dermatitis, neurodermatitis, eczema, contact dermatitis, acne, leprosy, seborrheic dermatitis, lupus and urticaria.
16. 16. The use according to any of claims 1 to 14, characterized in that the condition is a skin cancer, melanoma, scalded psoriasis, psoriatic arthritis or pemphigus.
17. 17. The use according to any of the preceding claims, characterized in that the medicament is a slow release formulation.
18. 18. The use according to any of the preceding claims, characterized in that the medicament is in the form of a cream, ointment, gel, lotion, patch or emollient.
19. 19. The use according to any of claims 1 to 16, characterized in that the medicament is a shampoo.
20. 20. The use according to any of the preceding claims, characterized in that the treatment additionally comprises the use of a compound selected from steroids, vitamins A, D and their analogs, salicylates, anthralines and coal tar preparations. •