Title:  Iontophoresis disc pain blocker

United States Patent:  6,730,667

Issued:  May 4, 2004

Inventors:  Deagle; William R. (2755 S. Locust St., Suite 107, Denver, CO 80222)

Appl. No.:  995117

Filed:  November 26, 2001

Abstract

Treatment of pain syndromes utilizes a topical polypharmaceutical preparation of phenoxybenzamine, ketamine, gabapentin, nifedipine, carbamazepine, or combinations of them. Other suitable components are blockers of sympathetic alpha 1, 2 and other receptors, NMDA receptor blockers, GABA receptor blockers, AMPA receptor blockers, nitric oxide synthase receptor blockers, calcium channel blockers, ACDP receptor blockers, prostaglandin and leukotriene blockers, substance P blockers, bradykinin and neurotenin as well as other peptide blockers, and TNF alpha blockers. Recommended delivery is by locating a predetermined neurodermal point and locating a gel patch over the predetermined neurodermal point. Iontophoresis then delivers the pharmaceutical agent from the gel patch.

BRIEF SUMMARY OF THE INVENTION

A general object of the invention is to provide a new and improved composition and method of treatment of pain, utilizing topical preparations.

Another object is to provide a composition and method of the type described which provides the desired therapeutic response through topical administration in the form of cream-gel preparation, spray or aerosol, and topical iontophoresis methodology patch.

The invention provides a composition and method of treatment for alleviating pain. A solution of pharmaceuticals including phenoxybenzamine, ketamine, gabapentin, nifedipine, and carbamazepine in PLO carrier or other suitable topical preparation vehicle is applied topically to the painful region of the skin.

The invention is derived from research and observations showing local anesthetic blockade at the Langerhans complex network map of a pain-projected distribution. The mechanisms for pain modulation in the dermis provide a new theory of pain gate and prespinal cord modulation that can block afferent pain perception and the attendant reflex spasm, vasoconstriction, and atrophic and deconditioning effects that can result from a projected neural holographic image.

According to the invention, a method of administering a pharmaceutical agent suited for iontophoretic delivery to a human or animal subject is performed by, first, performing a point locating step by locating on a subject to be treated a preselected neurodermal point for receiving the pharmaceutical agent. Second, a patch application step is performed by applying to the subject, over the preselected neurodermal point, an iontophoretic patch containing the pharmaceutical agent to be administered. Third, a delivery step is performed by applying an electrical potential across the iontophoretic patch and the subject and delivering the pharmaceutical drug from the patch to the subject at the neurodermal point by iontophoresis.

According to another aspect of the invention, a polypharmaceutical composition for treating chronic pain by producing a blockade of the initiation and propagation of the pain stimulus in the Langerhans and other neuroendocrine vascular structures of the superficial and deep dermis is composed of, in combination, at least two pharmaceutical agents selected from the group consisting of an NMDA receptor blocker, a GABA receptor blocker, an AMPA receptor blocker, a nitric oxide synthase receptor blocker, a calcium channel blocker, an ACDP receptor blocker, a prostaglandin blocker, a leukotriene blocker, a substance P blocker, a bradykinin blocker, a neurotenin blocker, a peptide blocker, a TNF alpha blocker, a sympathetic alpha 1 receptor blocker, a sympathetic alpha 2 receptor blocker, and a non-NMDA calcium-channel blocker.

According to still another aspect of the invention, a method of treating pain by producing a blockade of the initiation and propagation of the pain stimulus in the Langerhans and other neuroendocrine vascular structures of the superficial and deep dermis, is performed through an administration step by topically administering to a person in need of such treatment an effective dosage of a combination of at least two pharmaceutical agents selected from the group consisting of an NMDA receptor blocker, a GABA receptor blocker, an AMPA receptor blocker, a nitric oxide synthase receptor blocker, a calcium channel blocker, an ACDP receptor blocker, a prostaglandin blocker, a leukotriene blocker, a substance P blocker, a bradykinin blocker, a neurotenin blocker, a peptide blocker, a TNF alpha blocker, a sympathetic alpha 1 receptor blocker, a sympathetic alpha 2 receptor blocker, and a non-NMDA calcium-channel blocker.

According to a further aspect of the invention, a method of treating pain in a human or animal subject by administering a combination of preselected effective pharmaceutical agents in an suitable dosage to treat a subject in need thereof, is carried out by, first, performing a point locating step by locating a predetermined neurodermal point associated with the pain. Second, the preselected pharmaceutical agents for treating pain are provided in a gel patch suited for delivery by electrically driving charged ions of the pharmaceutical agents from the path and into the subject. Third, an application step is performed by applying the provided gel patch to the predetermined neurodermal point on the subject. Fourth, a delivery step is performed by delivering the selected pharmaceutical agents from the patch to the subject by electrically driving charged ions of the pharmaceutical agents into the subject.

The accompanying drawings, which are incorporated in and forms a part of the specification illustrates preferred embodiments of the present invention, and together with the description, serves to explain the principles of the invention. In the drawings:

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the invention is a method of administering a pharmaceutical drug suited for iontophoretic administration. According to the method, first locate a predetermined neurodermal point selected for its suitability for receiving the pharmaceutical drug. Second, apply an iontophoretic patch to the predetermined point. Third, apply an electrical potential across the patch and the subject to deliver the pharmaceutical drug to the subject by iontophoresis. Related aspects of this invention include the composition and structure of an iontophoretic disc or patch for use in the method.

A second aspect of the invention is a novel composition for treating chronic pain by producing a blockade of the initiation and propagation of the pain stimulus in the Langerhans and other neuroendocrine vascular structures of the superficial and deep dermis.

A third aspect of the invention is a method of treating pain by topically administering the novel composition of pharmaceutical agents, thereby producing a blockade of the initiation and propagation of the pain stimulus in the Langerhans and other neuroendocrine vascular structures of the superficial and deep dermis.

A fourth aspect of the invention is a method of administering the combination of pharmaceutical agents to treat pain, in which the composition is made available in an iontophoretic gel patch that is placed by locating a predetermined neurodermal point associated with the pain. The patch is applied to the predetermined neurodermal point. Iontophoresis delivers the pharmaceuticals by driving charged ions of effective agents into the patient.

When used in the treatment of pain, the compositions, methods, and apparatus of this invention will extinguish the neural hologram of the painful image, topically. The composition is comprised of pharmacologically acceptable salts of active compounds comprised of non-toxic acid addition salts and inorganic acids. Within the United States, "pharmacologically acceptable salts" preferably are those approved for use on humans by the United States Food and Drug Administration (FDA), to the extent such approval currently is required or may be required in the future. FDA approval is desirable in those geographic areas under the jurisdiction of the FDA for the treatment of humans, but it is not a limitation on the scope of the invention.

A unique composition and dosage form have been developed for the topical treatment of refractory neuropathic pain. The composition is a topical pharmaceutical composition for extinguishing the neural hologram of a painful image. The composition is a combination of ingredients that block various released agents that trigger the pain sensation. The released agents are NO (nitric oxide); GABA (gamma amino butyric acid); Ca++ ions via NMDA; ACPD (aminocyclopentane-1,3-dicarboxylate); substance P peptide; AMPA (alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid); and glutamate. Broadly, the blocking agents target the following receptors: sympathetic alpha 1,2; NMDA; GABA; AMPA; nitric oxide synthase; calcium channel; ACPD; prostaglandin and leukotriene; substance P; bradykinin, neurotenin and peptide; and TNF alpha.

Selected components are combined and delivered in a topical vehicle, preferably pluronic lecithin organogel (PLO). Specific components are phenoxybenzamine; ketamine; gabapentin; nifedipine; carbamazepine; and clonidine. Methods of topical application are as cream, gel, ointment, spray or patch, especially by iontophoresis delivering the components through an iontophoretic patch.

A preferred composition consists of three selected active pharmaceutical agents: ketamine HCl USP, gabapentin, and phenoxybenzamine HCl. These three agents are incorporated into pluronic lecithin organogel (PLO) to facilitate transdermal administration.

The concentration by volume of the active pharmaceutical components are preferred to be approximately 2% phenoxbenzamine, 5% ketamine, and 5% gabapentin. The concentration of constituents in percent of solution may be varied for specific types of pain blockade, so as to obtain a desired therapeutic response for a particular patient population. These components are mixed in a controlled environment. Precautionary measures should protect pharmaceutical workers from active ingredients that may become airborne or be topically absorbed. In the United States, OSHA complaint safety procedures should be followed.

The composition includes a pharmaceutically acceptable liquid carrier serving as a vehicle, including a biphasic complex of lecithin and organogel, for molecular egression across the epidermis to the superficial and deep dermis where neuroendocrine vascular structures such as the Langerhans bodies reside. PLO is a phospholipid liposomal micro emulsion used for transdermal drug administration. It has two phases:

(1) Oil Phase: The oil phase is lecithin/isopropyl palmitate solution. Lecithin rearranges the horny layer of the skin. Isopropyl palmitate is a solvent and penetration enhancer. Sorbic acid is a preservative.

(2) Water Phase: The water phase is the pluronic gel. Pluronic f127 NF is a commercial surfactant. Potassium sorbate NF is a preservative. Purified water is a solvent. The active agents are incorporated into the PLO gel and a stable emulsion is formed through sheer force. The concentration of the active agents in the formulation may be adjusted as to obtain the optimal therapeutic response.

A composition of the active agents and carrier is prepared according to the following procedure. First, triturate the ketamine HCl USP, gabapentin, and phenoxybenzamine HCl, together using geometric dilution. Second, solubilize the chemical in purified water, USP. Third, combine the solubilized chemical with the lecithin/isopropyl palmitate solution and mix well. Fourth, add pluronic F127 20% gel in small increments to bring to desired volume. Fifth, mix at high rate of speed in electronic mortar and pestle to form smooth creamy gel.

Once prepared, the solution of pharmaceutical can be administered topically to the region of pain either by the patient or by a heath care provider. The form of dosage for topical administration includes solutions, suspensions or emulsions of the active components in a liquid carrier in the form of cream, gel, ointment, and topical iontophoresis methodology patch technology. Suitable carriers include pluronic lecithin organogel (PLO) or other suitable suspensions or carriers. When the dosage form is a topical cream-gel suspension or topical patch methodology, it may contain preservatives, stabilizers, emulsifiers or suspending agents, wetting agents, salts for osmotic pressure or buffers, as required. When the dosage form is as a pressurized spray or aerosol, the solution is contained in a pressurized container with a liquid propellant such as dichlorodifluroro methane or chlorotrifluoro ethylene. If administered from a pump container, the solution will include a buffer salt solution with preservatives, stabilizers, emulsifiers or suspending agents, wetting agents, and salts for osmotic pressure or buffers, as required.

When the composition is administered in the form of topical gel-cream, spray, or topical iontophoresis gel patch, the time of repeat application will vary from every six to twelve hours for the gel-cream and spray to several days for the topical iontophoresis gel-patch delivery methods. Occlusion with a barrier ointment or physical barrier such as hypoallergenic membrane may also be administered after topical application of the gel-cream or spray to increase efficacy and penetration of the pharmaceutical to active pharmaceutical sites in the dermis.

Claim 1 of 8 Claims

What is claimed is:

1. A topically effective polypharmaceutical composition consisting essentially of a combination of pharmaceutical agents consisting of an effective dosage of phenoxybenzamine, ketamine, and gabapentin carried in a pluronic lecithin organogel as a topical vehicle, wherein said dosage is a therapeutically effective amount for treating chronic pain by producing a blockade of initiation and propagation of the pain stimulus in the Langerhans and other neuroendocrine vascular structures of the superficial and deep dermis.

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