Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-03-30
2001-04-24
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S509000
Reexamination Certificate
active
06221915
ABSTRACT:
DESCRIPTION
The present invention relates to the use of nitrate vasodilators, particularly glyceryl trinitrate, capsaicin and capsaicin like compounds as analgesics.
The analgesic properties of topical chilli pepper preparations have been known for sometime. For example, in 1850 the use of such preparations in the treatment of chilblains (Turnbull A., Dublin Med. Press 1850; 95-6.) was reported. It seems that this analgesic effect can be attributed to the capsaicin-containing fraction of the chilli pepper and that this effect is, at least in part, mediated by the ability of capsaicin to reversibly deplete unmyelinated C fibre afferent neurones of sensory neuropeptides, in particular, neuropeptide Substance P (SP) (Rains and Bryson, Drugs and Ageing 1995; 7:317-28; Fitzgerald M., Pain 1983; 15: 109-30.). As Substance P has an important role in central transmission of nociceptive or “pain” signals, its repeated depletion from afferent neurones as a consequence of the repeated application of capsaicin results in a “desensitisation” to pain. Isolated capsaicin has the chemical formula: N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-trans-6-enamide.
An analgesic effect with topical application of capsaicin has been demonstrated in conditions as diverse as post mastectomy pain syndrome (Watson and Evans, Pain 1992; 51: 375-79.), painful diabetic neuropathy Tandan et al., Diabetes Care 1992; 15: 8-13.; The Capsaicin Study Group, Arch Intern Med 1991: 151: 2225-9), post-herpetic neuralgia (Watson et al., Pain 1988, 33: 333-40; Watson et al., Clin. Ther. 1993, 15: 510-26; Bernstein et al., J. Am Acad Dermatol 1989, 21: 265-70.) and pain in Guillian-Barre syndrome (Morganlander et al, Annals of Neurology 1990, 29:199). Capsaicin has also been used in the treatment of osteoarthritis (Deal et al., Clin Ther 1991, 13: 383-95; McCarthy and McCarty, J. Rheumatol 1992, 19: 604-7; Altman et al., Seminars in Arthritis and Rheumatism 1994, 23: 25-33.). The symptoms of osteoarthritis include the destruction of joint architecture and are almost a natural accompaniment of advancing age. Thus, the therapeutic aim in treating this condition is largely to palliate symptoms and to maximise quality of life. Patients suffering from conditions such as osteoarthritis, for which the use of a topical preparation of capsaicin is known to have an effect, generally, will have tried the first line of treatment “over the counter” preparations and will then have progressed to the use of codeine based drugs and anti-inflammatories. However, these available therapeutic agents are limited by side effects such as gastric bleeding with non-steroidal anti-inflammatory agents (Blower et al., Aliment Pharmacol Ther 1997; 11: 283-91.) and analgesic tolerance with codeine based preparations. It is probable, therefore, that capsaicin will have been used in situations where conventional analgesia has either failed to have an effect or has created side effects. It, therefore, would be undesirable for an agent kept in reserve for such a situation to itself be prone to cause side effects which may necessitate termination of treatment prior to a point where analgesia is apparent.
Unfortunately, topical application of capsaicin, especially initially, is associated with burning discomfort at the application site and this prominent side effect compromises the efficacy of the treatment. The Capsaicin Study Group reported that 87 of 138 patients in their study suffered burning discomfort after application of 0.075% capsaicin, while Watson and colleagues (Clinical Therapeutics, 1993, 15:510-26) reported that 9 of 33 patients in their study suffered burning after application of 0.025% capsaicin. This discomfort has lead to patients dropping out of at least one study (Watson et al. Pain 1988; 33: 333-40). The failure of patient drug compliance makes the full potential of this agent to give pain relief hard to gauge.
It would, therefore, be desirable to formulate a cream, ointment or the like for the topical application of capsaicin such that the burning discomfort on application is reduced while the analgesic properties of capsaicin are retained. It would be even more desirable if the formulation that lead to a reduction in burning discomfort could also provide an analgesic effect greater than that obtained by the application of capsaicin alone. Glyceryl trinitrate (GTN) has a long pedigree in the treatment of angina pectoris for which it is administered lingually, sublingually or bucally in the form of chewable tablets. It can also be applied to the skin in the form of a transdermal patch applied to the area in which ischaemic pain is sensed (normally the chest or arms). The predominate effect is rapid vasodilation which may be mediated through the action of GTN on cyclic guanidine monophosphate (cGMP) (Feelisch and Noack, Eur J. Pharmacol 1987; 139: 19-30.). This allows venous pooling of blood with a subsequent reduction in pressure in the ventricles and redistribution of blood to ischaemic regions and, hence, relief from the ischaemic pain.
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the present invention provides a pharmaceutical composition comprising a nitrate vasodilator and a compound of formula I:
the composition being useful in a medical treatment, preferably as an analgesic.
In preferred embodiments, the composition is formulated for topical application at or in the vicinity of a source of pain or discomfort and can further comprise a pharmaceutical carrier rendering it suitable for topical application to the skin. Such carriers are well known to those skilled in the art. Suitable carriers include those employed in Axsain cream available from Bioglan Laboratories Ltd. (purified water, sorbitol solution, isopropyl mysristate, acetyl alcohol, petrolatum (white), benzyl alcohol, glyceryl stearate and PEG-100 stearate (Arlacel 165)) and those employed in the GTN ointment, Percutol (Dominion Pharmaceuticals, UK) (lanolin, white petrolatum, lactose and water). Preferably, pharmaceutical compositions in accordance with the invention are for ameliorating deep seated or internal pain which can be of skeletal or muscular origin, or emanate from a joint. In preferred embodiments, pharmaceutical compositions in accordance with the invention are useful for ameliorating pain associated with arthritis, particularly osteoarthritis.
Where compounds and compositions are said to ameliorate or to be for ameliorating pain or discomfort, it is meant that they are effective to reduce the intensity of pain, or have an analgesic effect, and, although a so described agent is preferably capable of eliminating a particular pain, it need not necessarily be capable of so doing. The term pain is used in a general sense and to encompass pain levels between the merely uncomfortable and the virtually unbearable.
In preferred embodiments of the invention, the nitrate vasodilator is present in an amount sufficient to reduce burning discomfort associated with the application of a compound of formula I to the skin. Preferably, the nitrate vasodilator is present in an amount sufficient to augment an analgesic effect provided by a compound of formula I.
Preferably, the nitrate vasodilator is glyceryl trinitrate; the preferred compound of formula I is capsaicin.
In preferred embodiments, pharmaceutical compositions in accordance with the invention comprise between 0.01 and 0.1%, preferably between 0.015 and 0.075% and, more preferably, between 0.015 and 0.035% capsaicin and between 0.5 and 2.5%, and preferably, between 0.5 and 2% glyceryl trinitrate. Such compositions can be in the form of a cream, jelly, ointment, gel, lotion, paste or for application by a patch.
Other conditions treatable with pharmaceutical compositions in accordance with the invention include post mastectomy pain syndrome, painful diabetic neuropathy and post-herpetic neuralgia.
In a second aspect, the present invention provides anD analgesic treatment comprising sequentially or simultaneously administering a nitrate vasodilator and a compound of formula I
to a patient in need of analg
Criares Theodore J.
Kim Jennifer
Wolf Greenfield & Sacks P.C.
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