Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1997-12-15
2001-05-29
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06239180
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to peripheral neuropathy, and more particularly to treatments of neuropathic pain by use of capsaicin (and/or a capsaicin analog) administered transdermally in high concentration in conjunction with a previously administered anesthetic to the affected areas.
BACKGROUND OF THE INVENTION
Neuropathic pain is thought to occur because of a sensitization in the peripheral and central nervous systems after an initial injury to the peripheral system. Direct injury to the peripheral nerves as well as many systemic diseases including AIDS/HIV, Herpes Zoster, syphilis, diabetes, and various autoimmune diseases, can induce this disorder. Neuropathic pain is typically burning, shooting, and unrelenting in its intensity and can sometimes be more debilitating that the initial injury or the disease process which induced it. Unfortunately, the few remedies that have been reported to alleviate this condition are effective in only a small percentage of patients.
Capsaicin, a pungent substance derived from the plants of the Solanaceae family (hot chili peppers), has long been used as an experimental tool because of its selective action on the small diameter afferent nerve fibers, or C fibers, that are believed to mediate pain. From studies in animals, capsaicin appears to trigger C fiber membrane depolarization by opening cation selective channels for calcium and sodium. Although detailed mechanisms are not yet known, capsaicin mediated effects include: (I) activation of nociceptors in peripheral tissues; (ii) eventual desensitization of peripheral nociceptors to one or more stimulus modalities; (iii) cellular degeneration of sensitive unmyelinated C fiber afferents; (iv) activation of neuronal proteases; (v) blockage of axonal transport; and (vi) the decrease of the absolute number of C fibers without affecting the number of myelinated fibers.
Because of capsaicin's ability to desensitize nociceptors in peripheral tissues, its potential analgesic effects have been assessed in various clinical trials. However, since the capsaicin application itself frequently causes burning pain and hyperalgesia apart from the neuropathic pain being treated, patient compliance has been poor and the drop out rates during clinical trials have exceeded fifty percent. The spontaneous burning pain and heat hyperalgesia are believed to be due to intense activation and temporary sensitization of the peripheral nociceptors at the site of capsaicin application (primary hyperalgesia). Mechanical hyperalgesia evident in areas surrounding the site of topical application appears to originate from central sensitization of dorsal horn neurons involved in pain transmission (secondary hyperalgesia). Because of these side effects, the maximal capsaicin concentration used in previous human studies has usually been limited to 0.075%.
U.S. Pat. No. 5,431,914, issued Jul. 11, 1995, suggests that a topical preparation containing a concentration of capsaicin of about 0.01% to about 0.1% could be used to treat internal organ pathologies. U.S. Pat. No. 5,665,378, issued Sep. 9, 1997, discusses a transdermal therapeutic formulation comprising capsaicin, a non-steroidal anti-inflammatant, and pamadorm (a diuretic agent) where the composition is said to contain from about 0.001-5% by weight capsaicin and to be useful in treating the pain and discomfort associated with menstrual cramps, bloating, and/or muscular pain such as muscular back pain.
Analogs of capsaicin with physiological properties similar to capsaicin are known. For example, resiniferatoxin is described as a capsaicin analog by inventor Blumberg, U.S. Pat. No. 5,290,816, issued Mar. 1, 1994. Inventor Brand in U.S. Pat. No. 4,812,446, issued Mar. 14, 1989, describes capsaicin analogs and methods for their preparation. Further, inventors LaHann et al. in U.S. Pat. No. 4,424,205, issued Jan. 3, 1984, cite Newman, “Natural and Synthetic Pepper-Flavored Substances” published in 1954 as listing pungency of capsaicin-like analogs. Ton et al.,
British Journal of Pharmacology,
10, pp. 175-182 (1955) discuss pharmacological actions of capsaicin and its analogs.
SUMMARY OF THE INVENTION
In one aspect of the present invention, a transdermal delivery system is provided for administration of capsaicin (and/or a capsaicin analog) effective to alleviate the symptoms of peripheral neuropathy for prolonged period of time. Thus, a transdermal kit comprises at least one transdermal device, hereinafter referred to as a patch, which is conveniently applied to the skin to provide the capsaicin formulation. More preferably, the kit has two patches, one of which provides anesthesia and the other the capsaicin formulation. The use of the transdermal drug delivery system produces increased patient compliance. Further, the transdermal delivery of capsaicin is most desirable for reasons of convenience and effectiveness.
In another aspect of the present invention, a therapeutic method comprises administering a suitable anesthetic to a patient suffering neuropathic pain followed by applying a composition including from greater than about 5% to about 10% of capsaicin (and/or a capsaicin analog) by weight to the patient. The anesthetic preferably is administered transdermally. The capsaicin (and/or capsaicin analog) containing composition is administered transdermally and includes a vehicle with skin penetrating properties.
The prior administration of a suitable anesthetic sufficiently desensitizes C fibers to the expected side effects of the subsequent capsaicin application. The administration of the anesthetic together with the subsequent administration of a high concentration of capsaicin appears to alleviate the symptoms of peripheral neuropathy for a prolonged period of time extending several weeks to months.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Practice of the invention prevents the burning pain and hyperalgesia to both heat and touch typically occurring after even the relatively low concentration applications of capsaicin ointment known to the art. Such burning pain is avoided by first administering an anesthetic, so as to cause regional anesthesia in the areas to be treated. Preferred regional anesthetic agents are sodium channel blockers. A variety of sodium channel blocking anesthetics are known and useful, such as Lidocaine, tetracaine, bupivicaine and chloroprocaine.
Effective anesthesia for subsequent capsaicin application can be accomplished by lumbar, epidural catheter, or blockage of the major peripheral nerves of the affected area. However, more preferably the suitable anesthetic is administered transdermally, such as by a patch device to the entire area which will be treated and left in place for a sufficient period of time so as to block C fiber heat transmissions. Such topical agents such as tetracaine (Amethocaine™) or a Eutectic mixture of Lidocaine and Prilocaine (ELMA™) can perform this objective.
When the anesthetic administered has taken effect in providing analgesia, then a composition including capsaicin (and/or a capsaicin analog) is administered, preferably by transdermal application, at least once. This composition preferably is formulated with a vehicle having a skin penetrating and skin absorbing agent. One suitable such vehicle is commercially available as velvachol (Galderma).
The topical application of the capsaicin (and/or capsaicin analog) containing composition delivers the drug through the skin. Because skin is a structurally complex, relatively thick membrane, molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface, then penetrate the viable epidermis, the papillary dermis, and the capillary walls. To be so absorbed, molecules must overcome a different resistance to penetration in the different types of tissue. It is for these reasons that the formulation is prepared so as to increase skin permeability and to increase the permeability in particular of the stratum corneum. Such skin penetrating and absorbin
Jones Dwayne C.
The Regents of the University of California
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