Topical clonidine preparation

Details Topical clonidine preparation Topical clonidine preparation

2000-11-10

2003-03-18

Criares, Theodore J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Topical body preparation containing solid synthetic organic...

C514S392000, C514S817000, C514S944000, C514S535000, C514S536000, C514S537000

Reexamination Certificate

active

06534048

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
This invention relates to the relief of sympathetically maintained peripheral neuropathic pain syndromes, and in particular, to the use of gel compositions containing clonidine.
BACKGROUND OF THE INVENTION
Sympathetically maintained peripheral neuropathic pain syndromes of acute or chronic origin can encompass painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), complex regional pain syndrome(CRPS) and like chronic non-malignant neuropathic pain syndromes. Patients with sympathetically maintained peripheral neuropathic pain syndromes typically have stimulus-independent (ongoing) pain and stimulus-dependent pain (hyperalgesia).
Conventional treatments for these pain syndromes include oral administration of tricyclic antidepressants, anti-epileptics, and other miscellaneous neurological agents. Some prior attempts also have been made to treat sympathetically maintained peripheral neuropathic pain syndromes with adrenergic compounds such as clonidine or phentolamine.
Clonidine, in particular, is a potent &agr;
2
-adrenergic partial agonist used primarily for the treatment of hypertension (Jarrott et al., “Clonidine: Understanding its disposition, sites, and mechanism of action”,
Clin. Exp. Pharm. Physiol
., 14, 471-479 (1987)). This drug stimulates &agr;
2
-adrenoceptors in the vasomotor centers, causing a reduction of sympathetic outflow from the central nervous system. Both cardiac output and peripheral resistance are reduced resulting in a decrease in blood pressure. Higher concentrations cause a vasoconstriction by activation of postsynaptic receptors in vascular smooth muscle. However, the significant advantages of the drug are counter balanced by certain troublesome side effects including dryness of the mouth and a discouraging dizziness. Therefore, the blood concentration of clonidine must be controlled within a narrow therapeutic window.
Clonidine and related &agr;
2
-adrenergic agonists have been reported to modify nociception in animal models. See Yaksh, T. L., “Pharmacology of, spinal adrenergic systems which modulate spinal nociceptive processing”,
Pharmacol. Biochem. Behav
., 22, 845-858 (1985); and Nakamura et al., “Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances”,
Eur. J. Pharmacol
., 146, 223-228 (1988). In clinical studies, single doses of epidural clonidine have been reported to relieve post-operative pain (Mendez et al., “Epidural clonidine analgesia after cesarean section”,
Anesthesiology
, 73, 848-852 (1990)), cancer pain (Eisenach et al., “Epidural clonidine analgesia for intractable cancer pain:phase I”,
Anesthesiology
, 71, 647-552 (1989)), and pain due to arachnoiditis (Glynn et al., “A double-blind comparison between epidural morphine and epidural clonidine in patients with chronic non-cancer pain”,
Pain
, 34, 123-128 (1988)).
In a controlled trial of single oral doses of 0.2 milligrams (mg) clonidine in 40 patients with postherpetic neuralgia, observed pain relief was greater than that produced by doses of placebo or 120 mg codeine, but the modest analgesia was accompanied by troublesome levels of sedation and dizziness at the time of peak clonidine levels. (Max et al., “Association of pain relief with drug side effects in postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen and placebo”,
Clin. Pharmacol. Ther
., 43, 363-371 (1988)).
Some attempts have been made to relieve pain, allodynia and hyperalgesia employing transdermal patches containing clonidine, but the effects achieved were restricted to the skin underlying the patch. Hyperalgesia is defined as a leftward shift of the stimulus-response function, such that a lowering of pain threshold or an increase in pain to suprathreshold stimuli or both is observed. The decrease in pain threshold to mechanical or thermal stimuli may be such that lightly stroking the skin evokes pain, a phenomenon sometimes referred to as allodynia.
For example, Davis et al., in “Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain,”
Pain
, 47, 309-318 (1991) reported that delivery of clonidine by transdermal patch relieved sympathetically maintained hyperalgesia in the skin adjacent to the patch . Likewise, Campbell in U.S. Pat. No. 5,447,947 describes hyperalgesia relief with transdermal patches delivering a systemic dose of 0.2 mg and 0.3 mg of clonidine/day (i.e., 30 micrograms/square centimeter patch/day), but the zone of relief was generally limited to the skin area at or adjacent the patch site along with some skin irritation surrounding the patch site and side effects were noted.
In a placebo-controlled cross-over pain trial in patients with painful diabetic neuropathy utilizing clonidine transdermal patches no statistically significant differences between treatments were observed by Zeigler et al., “Transdermal clonidine versus placebo in painful diabetic neuropathy”,
Pain
, 48, 403-408 (1992). In a follow-up placebo controlled pain study in similar patients with painful diabetic neuropathy, transdermal clonidine patches were evaluated using a two-stage enriched enrollment design by Byas-Smith et al., “Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage enriched enrollment design”,
Pain
, 60, 267-274 (1995). Only twelve of forty-one patients (29%) who completed the initial course of treatment were considered clonidine responders. These twelve clonidine responders were then rechallenged in a second placebo controlled study which used the highest dosage available with the transdermal patch system. The pain reduction relative to placebo tended to be modest although statistically significant (p<0.015).
Based on the foregoing attempts it would appear that relatively higher concentrations of clonidine are needed at the painful site. Unfortunately, with the dosage forms utilized, higher doses cannot be given without accompanying undesirable systemic side effects. While clonidine is a desirable potent analgesic drug, it has a narrow therapeutic index.
A desirable treatment for sympathetically maintained peripheral neuropathic pain syndromes, therefore, would be a topical composition of clonidine that could be spread over the entire painful area to deliver targeted high concentrations to the painful site yet affording minimum systemic concentrations.
The present gel composition answers the need for delivering therapeutically effective amounts of clonidine directly to the affected region of patients suffering sympathetically maintained peripheral neuropathic pain syndromes while avoiding undesirable systemic effects.
SUMMARY OF THE INVENTION
Topical aqueous gel compositions containing clonidine are suitable for relieving sympathetically maintained peripheral neuropathic pain. Sympathetically maintained peripheral neuropathic pain is relieved by topically applying, to the affected region of a patient suffering from such pain, a pain relieving amount of an aqueous gel comprising clonidine, and a pharmaceutically acceptable water-gelling agent.
The aqueous gel has a physiologically tolerable pH value. The gels contain clonidine present in an amount in the range of about 0.01 to about 0.5 weight percent based on the weight of the gel. A preferred gel contains clonidine in an amount in the range of about 0.01 to about 0.075 weight percent, based on the weight of the gel.
Preferably, the gelling agent is a carbomer, a glycerin polyacrylate, or a mixture thereof. The gelling agent can provide moisturizing, skin-humectant benefits as well. A preservative, a topical anesthetic and a supplemental skin-humectant also can be present.
Pain relief was achieved with topically applied amounts of clonidine at dosages preferably in the range of about 2 milligrams per day to about 6 milligrams per day.
Advantageously, the topical clonidine gels can be applied and spread over the entire affected region of a patient suffering from a sympathetically maintained peripheral neuropathic pain syndrome, such as from diabetic

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