Topical compositions and methods for treating pain

Details Topical compositions and methods for treating pain Topical compositions and methods for treating pain

2001-08-17

2003-10-28

Venkat, Jyothsna (Department: 1615)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S646000, C514S887000, C514S817000, C514S938000, C424S448000

Reexamination Certificate

active

06638981

ABSTRACT:

I. FIELD OF THE INVENTION
The present invention relates to methods for treating or preventing pain via topical formulations that induce a local-anesthetic effect when applied to intact skin. The compositions comprise an antidepressant and a N-methyl-D-aspartate-receptor antagonist.
II. BACKGROUND OF THE INVENTION
Pain results from the noxious stimulation of nerve endings. Nociceptive pain is caused by noxious stimulation of nociceptors (e.g., a needle stick or skin pinch), which then transmit impulses over intact neural pathways to the spinal neurons and then to the brain. Neuropathic pain is caused by damage to neural structures, such as damage to peripheral nerve endings or nociceptors, which become extremely sensitive to stimulation and can generate impulses in the absence of stimulation (e.g., herpes zoster pain after the rash has healed). Peripheral nerve damage can lead to pathological states where there is a reduction in pain threshold (i.e., allodynia), an increased response to noxious stimuli (hyperalgesia), or an increased response duration (persistent pain). GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 529 (Joel G. Hardman et al. eds., 9th ed. 1996); HARRISON'S PRINCIPLES OF INTERNAL MEDICINE 53-58 (Anthony S. Fauci et al. eds., 14th ed. 1998).
In contrast to pain treatment with systemic agents, pain can be treated locally by topically administering a local anesthetic directly to the painful area to block the nociceptive mechanistic pathway. Local anesthetics prevent the generation and conduction of nociceptive nerve impulses. Thus, for example, a local anesthetic can be injected intradermally (non-systemic injection within the skin) or topically applied at the pain area. Advantages of topical local-anesthetic administration over systemic administration of pain relievers include decrease or preclusion of side effects, improved patient compliance, and reversible action (i.e., the action can be reversed by removing the anesthetic from the application site). TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS 33-112 (Tapash K. Ghosh et al. eds., 1997).
A variety of drug classes have local-anesthetic properties and can be administered in topical formulations. Traditional local anesthetics or sodium-channel blockers, such as lidocaine prevent the generation and conduction of nerve impulses by decreasing or preventing the large transient increase in the permeability of excitable membranes to Na+. Other agents with local-anesthetic properties include analgesics, such as non-steroidal anti-inflammatories (“NSAIDs”), see, for example, TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS 87-93 (Tapash K. Ghosh et al. eds., 1997) and opioids, such as morphine. See e.g., U.S. Pat. No. 5,948,389 (issued Sept. 7, 1999); Christoph Stein & Alexander Yassouridis 71 Pain 119 (1997).
N-methyl-D-aspartate (“NMDA”) receptor antagonists, such as ketamine have local-aesthetic properties and topical administration is as an effective neuropathic pain treatment. See, for example, U.S. Pat. No. 5,817,699 (issued Oct. 6, 1998). In another example, topical administration of antidepressant medications, such as amitriptyline, has been reported effective for neuropathic pain treatment. See, for example, U.S. Pat. No. 6,211,171 (issued Apr. 3, 2001); J. Sawynok et al., 82 PAIN 149 (1999). In addition, topical administration of a combination of a tricyclic antidepressant and an NMDA-receptor antagonist is reported to have excellent local-anesthetic properties when topically applied and is useful for treatment of neuropathic pain, U.S. Pat. No. 6,197,830 (issued Mar. 6, 2001).
But even though topical local-anesthetic administration to intact skin is routinely used to treat minor indications, it has not found significant use for treating more severe nociceptive and neuropathic pain because it is difficult to get significant concentrations through the skin barrier. Because of the skin's drug-permeation resistance, as little as about 1 percent and usually no more than about 15 percent of a drug in a topical formulation is bioavailable (TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS 7 (Tapash K. Ghosh et al. eds., 1997)). Another problem with topical administration of pain relievers is stability of the composition. Local-anesthetics emulsion compositions are inherently unstable, and phase separation can occur during shipment and storage. Furthermore, many topical local-anesthetic compositions suffer from oxidative instability. Lecithin compositions are routinely used as bases for topical local-aesthetic compositions, but are highly oxidatively unstable (AM. PHARM. ASSOC., HANDBOOK OF PHARMACEUTICAL EXCIPIENTS 292-294, 292 (Arthur H. Kibbe ed., 3rd ed. 2000)). For example, U.S. Pat. No. 6,197,830 (issued Mar. 6, 2001) describes a lecithin-based composition for topically administering a combination of an NMDA-receptor antagonist and a tricyclic antidepressant and U.S. Pat. No. 5,817,699 (issued Oct. 6, 1998) and U.S. Pat. No. 6,017,961 (issued Jan. 25, 2000) describe topical administration of ketamine in pluronic lecithin organogel.
In sum, topical local-anesthetic administration has advantages over systemic administration of pain relievers. Unfortunately, topical local-anesthetic compositions suffer from instability and poor skin-penetration properties, which limit their use to less severe pain. What are needed are stable topical local-anesthetic compositions with good skin-penetration properties. Particularly, stable, skin-penetrating compositions comprising a combination of an antidepressant and an NMDA-receptor antagonists are needed.
Citation or identification of any reference in the Background section of this application is not an admission that such reference is prior art to the present invention.
III. SUMMARY OF THE INVENTION
The invention provides methods and topical compositions for treating or preventing pain. The compositions of the invention can be topically administered to intact skin to provide a local-anesthetic effect thereby treating or preventing pain, for example, neuropathic pain. In one embodiment, the invention provides stable, skin penetrating compositions for topical administration comprising a combination of an antidepressant and an NMDA-receptor antagonist.
In a second embodiment, the invention provides an emulsion comprising:
(a) an antidepressant or a pharmaceutically acceptable salt thereof;
(b) an NMDA-receptor antagonists or a pharmaceutically acceptable salt thereof;
(c) a lipophilic component;
(d) water; and
(e) a surfactant, wherein the emulsion is an oil-in-water emulsion.
Preferably, the mean oil-droplet size is within the range of about 0.01 microns to about 100 microns, more preferably, within the range of about 0.1 microns to about 10 microns.
In another embodiment, the invention relates to a patch comprising:
(a) an antidepressant or a pharmaceutically acceptable salt thereof;
(b) an NMDA receptor antagonists or a pharmaceutically acceptable salt thereof;
(c) a lipophilic component;
(d) water; and
(e) a surfactant, wherein the emulsion is an oil in water emulsion.
In still another embodiment, the invention provides a method of treating or preventing pain in a mammal comprising topically administering to the skin of a mammal in need thereof an emulsion comprising:
(a) a therapeutically effective amount of an antidepressant or a pharmaceutically acceptable salt thereof;
(b) a therapeutically effective amount of an NMDA-receptor antagonists or a pharmaceutically acceptable salt thereof;
(c) a lipophilic component;
(d) water; and
(e) a surfactant,
wherein the emulsion is an oil-in-water emulsion.
In still another embodiment, the invention relates to a method of inducing local anesthesia in a mammal comprising topically administering to the skin of a mammal in need thereof an emulsion comprising:
(a) a therapeutically effective amount of an antidepressant or a pharmaceutically acceptable salt thereof;
(b) a therapeutically effective amount of an NMDA-receptor antagonists or a pharmaceutically acceptable salt thereof,
(c) a lipophilic component;
(d)

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