Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-11-12
2003-07-15
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...
C514S887000, C514S817000, C424S400000
Reexamination Certificate
active
06593370
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a topical capsaicin preparation. Capsaicin, the primary pungent principle in the fruit of capsicum plants, produces marked alterations in the function of a defined subpopulation of unmyelinated sensory afferents, termed C-polimodal nociceptors. Following the initial period of intense burning or stinging pain accompanied by erythema, topical capsaicin application causes insensitivity to further irritation by a variety of noxious stimuli. Accordingly, topical preparations of capsaicin find use as a topical therapy for a variety of cutaneous disorders that involve pain and itching, such as postherpetic neuralgia, diabetic neuropathy, pruritus, psoriasis, cluster headache, postmastectomy pain syndrome, rhinopathy, oral mucositis, cutaneous allergy, detrusor hyperreflexia, loin pain/hematuria syndrome, neck pain, amputation stump pain, reflex sympathetic dystrophy, pain due to skin tumor and arthritis. Martin Hautkappe et al., Review of the Effectiveness of Capsaicin for Painful Cutaneous Disorders and Neural Dysfunction, Clin. J. Pain, 14:97-106, 1998.
Because of intense burning or stinging pain, many patients are not tolerated in the long-term treatment with topical capsaicin and, therefore, have to discontinue the treatment before appearance of analgesic effect of capsaicin through prolonged administration. It was reported that 26 out of 39 (66.7%) patients suffering from postherpetic neuralgia were not tolerated with a 0.025% capsaicin preparation (Zostrix, Gen Derm, USA). With a 0.075% preparation (Zostrix-HP, Gen Derm, USA), 5 out of 16 (31.3 %) and 45 out of 74 (60.8%) patients with postherpetic neuralgia were not tolerated. Peikert, A. et al., Topical 0.025% capsaicin in chronic post-herpetic neuralgia: efficacy,predictors of response and long-term course, J. Neurol. 238:452-456, 1991; Watanabe, A. et al., Efficacy of capsaicin ointment (Zostrix) in the treatment of herpetic pain and postherpetic neuralgia, Pain Clinic 15:709-713, 1994; Bernstein J. E. et al., Topical capsaicin treatment of chronic postherpetic neuralgia, J. Am. Acad. Dermatol. 21: 265-270, 1989; and Watson C. P. N. et al., A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia, Clin. Ther. 15:510-526, 1993.
A need exists for a topical capsaicin preparation which eliminates or substantially ameliorates initial stinging pain caused by capsaicin observed in the administration thereby making the preparation tolerable in long-term administration.
SUMMARY OF THE INVENTION
We have found that the initial stinging pain caused by capsaicin is eliminated or substantially ameliorated by incorporating a large excess of nonionic, amphoteric or cationic surfactants into the topical capsaicin preparation.
Accordingly, the present invention provide a topical preparation comprising (a) an amount of capsaicin effective in long-term or repeated administration to cause insensitivity to painful stimuli associated with painful cutaneous disorders and neural dysfunction, and (b) an amount of a nonionic, amphoteric or cationic surfactant effective to eliminate or substantially ameliorate the initial stinging pain caused by capsaicin, in admixture with a pharmaceutically acceptable carrier for topical administration. Preferably, capsaicin is the sole agent acting on the nervous system contained in the preparation.
The term “substantially ameliorate” as used herein refers to at least 50%, preferably at least 70% and most preferably at least 90% of patients can tolerate the long-term administration of capsaicin to cause insensitivity to painful stimuli. The amount of surfactants to achieve the above effect lies in the range between about 5% and about 20% and preferably in the range between about 9% and 18% by weight of the preparation. When combined with the surfactant, the amount of capsaicin in the topical preparation may be increased to at least about 0.1% by weight although 0.075% of capsaicin has been believed to be maximum.
DETAILED DESCRIPTION
As is known, capsaicin acts on C fibers which serve to transmit the pain impulse to the central nervous system. Initial administration of capsaicin stimulates the C fibers to cause intense burning or stinging pain. Continued administration thereof, however, suppresses the inherent function of these sensory nerve fibers to cause insensitivity to painful and other sensory stimuli.
As a preliminary study, we have tested certain surfactants for the effect on the neuropharmacology of capsaicin.
1. 0.1% capsaicin solutions containing varying amount of polyoxyethylene (60) hydrogenated castor oil were prepared by dissolving 0.1 g of capsaicin and 0, 3, 9 or 18 g of the surfactant in 26.4 ml of ethanol and then diluting with distilled water q.s. to make a total volume of 100 ml.
Each of 0.1% capsaicin solution thus prepared was applied to the hind-limb of rats. One hour after the application, the limb was placed in a water bath warmed at 42° C. and the length of time (in seconds) elapsed until when the rat withdrew the treated limb from the water bath was determined. The results are shown in Table 1.
TABLE 1
Withdrawal latency to thermal stimuli of hind-limb in
rat during sensitization by capsaicin
Surfactant
Withdrawal latency time (sec.)
concentration (%)
Before appln.
One hour after appln.
0
30 ± 0
2.45 ± 0.32
3
30 ± 0
20.29 ± 4.18
9
30 ± 0
30 ± 0
18
30 ± 0
27.28 ± 2.35
As shown in Table 1, application of 0.1% capsaicin solution without polyoxyethylene hydrogenated castor oil remarkably shortened the withdrawal latency compared to the withdrawal latency measured before application of the test solution. The withdrawal latency was slightly shortened at a surfactant concentration of 3% but was not affected significantly at a surfactant concentration of 9% and 18%, respectively.
These results demonstrate that the response of sensory nerves to thermal stimuli during sensitization by capsaicin is suppressed by co-administration of polyoxyethylene hydrogenated castor oil at a concentration of 9% or higher.
2. The effect of polyoxyethylene (60) hydrogenated castor oil on the eye-wiping reflex caused by capsaicin and the desensitization to chemical stimuli was studied according to the eye-wiping method reported by Jancso N. et al., in “Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin”, Br. J. Phamac. Chemother. 31: 138-151, 1967.
When one drop of 0.1% capsaicin solution was applied to the cornea of rats, the animal immediately began to wipe the cornea with front paws and continued the wiping for about 1 minute. The number of this wiping (first wiping) was not virtually affected by the addition of polyoxyethylene hydrogenated castor oil at a concentration of 3%, 9% or 18% to the 0.1% capsaicin solution.
The pretreatment with 0.1% capsaicin solution containing the surfactant at 0%, 3%, 9% or 18% significantly reduced the number of wiping (second wiping) caused by 0.1% capsaicin solution without the surfactant applied 2 hours after the pretreatment. See, Table 2. The pretreatment with the solvent containing the surfactant alone at 0%, 3%, 9% or 18% did not reduce the number of wiping caused by 0.1% capsaicin solution applied 2 hours after the pretreatment. See, Table 3.
TABLE 2
Effect of pretreatment with capsaicin in combination
with polyoxyethylene hydrogenated castor oil at various
concentrations on the eye-wiping reflex caused by capsaicin.
Surfactant
Number of wiping
concentration (%)
First
Second
0
21.5 ± 1.6
9.7 ± 1.6
3
24 ± 2.1
11.5 ± 0.9
9
23.5 ± 1.1
13 ± 0.7
18
22 ± 1.4
11.7 ± 0.6
TABLE 3
Effect of pretreatment with polyoxyethylene hydro-
genated castor oil at various concentrations on the eye-
wiping reflex caused by capsaicin.
Surfactant
Number of wiping
concentration (%)
First
Second
0
5.2 ± 0.7
20.7 ± 1
3
5.3 ± 1&thins
Kawakami Urao
Seto Masahiko
Tamura Takashi
Teratani Yuichi
Yoshimura Masakazu
Criares Theodore J.
Maruishi Pharmaceutical Co., Ltd.
Millen White Zelano & Branigan P.C.
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