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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

Inactive Publication Date: 2001-08-22
MEMORIAL SLOAN KETTERING CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although we also found that the efficacy of spinal or supraspinal administration remained unchanged after chronic administration of morphine, a marked decrease in peripheral efficacy was seen (Kolesnikov et al., 1996)

Method used

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  • Topical compositions comprising opioid analgesic and NMDA antagonist
  • Topical compositions comprising opioid analgesic and NMDA antagonist
  • Topical compositions comprising opioid analgesic and NMDA antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Materials and methods

[0058] Male Crl:CD-l(ICR)BR mice (25-30 g; Charles River Breeding Laboratories, Bloomington, MA) were housed in a 12-hour light / dark cycle with free access to food and water. Mice were divided into groups of 5 and raised until testing. [ 125 I] NaI (1680 Ci / mmol) was purchased from New England Nuclear (Boston, MA). Morphine, morphine-6β-glucuronide (M6G) and [D-Ala 2 ,MePhe 4 ,Gly(ol) 5 ] Endorphin (DAMGO) was a kind gift from the Research Technologies Branch of National Institute on DrugAbuse (Rockville, MD). MK801 was purchased from Research Biochemicals, Inc. (Natick, MA).

[0059]Systemic administration is administered by subcutaneous (s.c.) injection in the mid-scapular region of the back. As previously reported (Kolesnikov et al., 1996), intracerebroventricular (i.c.v.) and intrathecal administration were performed under mild halothane anesthesia 30 and 15 min before the test, respectively. Injections were performed i.c.v. at a dept...

Embodiment 2

[0063] Topical Morphine and DAMGO Pain Relief

[0064] Our earlier studies demonstrated the potent local analgesic activity of morphine when administered subcutaneously in the tail (Kolesnikov et al., 1996). Morphine is also a strong pain reliever when administered topically. The analgesic response to morphine solution (7.5 mM) gradually increased over time from only 25% after 30 seconds to 50% after 1 minute and 80% after 2 minutes (data not shown). Works very quickly. The analgesic effect can be detected within 1 minute after the mouse tail leaves the opioid solution, and 1 minute is the shortest time detected ( Figure 1a ). However, the duration of the morphine response is relatively short, usually lasting less than 30 minutes. For a fixed exposure time, morphine had a dose-dependent effect ( Figure 1b ;Table 1). In the DMSO solution of μ opioid peptide DAMGO, similar results can also be observed, and its analgesic effect is more than 5 times that of morphine ( Fig...

Embodiment 3

[0072] Analgesic effect of topical morphine-6β-glucuronide

[0073] Morphine-6β-glucuronide (M6G), administered locally by tail subcutaneous injection, was an analgesic but had a 30% ceiling effect at doses of 10 or 30 μg (data not shown). In topical examples, M6G produced a complete analgesic effect with a peak effect immediately after leaving the drug solution ( Figure 1a ), which is similar in potency to morphine ( Figure 1b ;Table 1). Similar to morphine, the proximal tail segment did not produce analgesic effects, and the effects of M6G were easily reversed by systemically administered naloxone ( Figure 2a ). After topical administration, the duration of action of M6G was similar to that of DAMGO and longer than that of morphine ( Figure 1a ). The selective M6G antagonist 3-methoxynaltrexone (3MeONtx) (Brown et al., 1997) also significantly reduced the M6G response ( Figure 2b ). In contrast, the same 3MeONtx dose was not active against the analgesic effects of ...

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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.

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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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/13A61K31/167A61K31/222A61K31/245A61K31/435A61K31/439A61K31/445A61K31/4468A61K31/4535A61K31/485A61K31/675A61K31/706A61K38/00A61K38/33A61K45/06A61P23/02A61P25/04A61P29/00
CPCA61K38/33A61K45/06A61P23/00A61P23/02A61P25/04A61P29/00A61K31/4468A61K31/485
Inventor 尤里·科勒斯尼科夫加夫里尔·W·帕斯特纳克
Owner MEMORIAL SLOAN KETTERING CANCER CENT
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