Topical compositions comprising opioid analgesic and NMDA antagonist

A technology of opioids and topical drugs, applied in the direction of drug combination, non-central analgesics, active ingredients of heterocyclic compounds, etc., can solve the problem of decreased peripheral efficacy
CN1309562AInactive Publication Date: 2001-08-22MEMORIAL SLOAN KETTERING CANCER CENT
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
MEMORIAL SLOAN KETTERING CANCER CENT
Publication Date
2001-08-22
Estimated Expiration
Not applicable · inactive patent

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Abstract

A topical opioid paradigm was developed to determine analgesic peripheral effects of morphine. Topical morphine as well as peptides such as [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO) produced a potent, dose-dependent analgesia using the radiant heat tailflick assay. The topical drugs potentiated systemic agents, similar to the previously established synergy between peripheral and central sites of action. Local tolerance was rapidly produced by repeated daily topical exposure to morphine. Topical morphine tolerance was effectively blocked by the N-Methyl-D-Aspartate (NMDA) receptors antagonist MK801 and ketamine given either systemically or topically. NMDA receptor antagonists reversed pre-existing morphine tolerance. The activity of topical NMDA antagonists to block local morphine tolerance suggests that peripheral NMDA receptors mediate topical morphine tolerance. Morphine was cross tolerant to [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO), but not to morphine-6 beta -glucuronide, implying different mechanisms of action. These observations have great importance in the design and use of opioids clinically. Topical pharmaceutical compositions comprising an analgesic that functions through an opiate receptor and an NMDA receptor antagonist for producing analgesia without inducing tolerance are described.
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Description

[0001] This application claims priority to Provisional US Application Serial No. 60 / 092,982, filed July 16, 1998, which is incorporated herein by reference in its entirety.

[0002] This invention was made with grants DA07242, DA00220 and CA08748 from The National Institute of Health. field of invention

[0003] The present invention relates to compositions for topical administration of an N-methyl-D-aspartate receptor antagonist alone or in combination with analgesics exerting peripheral analgesic action via opioid receptors, and said topical administration Use of a pharmaceutical composition for the treatment of pain without and / or minimal tolerance to an analgesic. Background of the invention

[0004] Morphine is a strong mu opioid receptor agonist with an important central site of action (Reisine and Pasternak, 1996). Peripheral mechanisms have also been reported and their importance is gradually being understood (Stein et al., 1995; Barber and Gottschlich, 1992; Joris ...

Claims

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