Composition for the administration of a D1-agonists

Details Composition for the administration of a D1-agonists Composition for the administration of a D1-agonists

1999-12-30

2001-10-30

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S443000

Reexamination Certificate

active

06310089

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the nasal delivery of dopamine agonists and, more particularly, to a composition for the nasal delivery of D1-agonists for the treatment of Parkinson's disease.
DESCRIPTION OF THE RELATED ART
Parkinson's disease is a neurological disorder where there is a progressive loss of dopamine secreting neurons. Dopamine agonists can be used to rectify this loss via interaction with dopamine receptors. There are different families of these receptors, the D1 and D2 families, the D1 family being further subdivided.
Levodopa (L-DOPA or dihydroxypenylalanine) is a well-known and effective treatment for Parkinson's disease. Other drugs for treating the disease include selegiline, bromocriptine and lisuride.
All existing dopaminergic therapies have significant therapeutic properties and are either non-selective or D2-selective. A selective D1 receptor agonist that was acceptable clinically would be most advantageous.
D1 partial agonists, such as SKF 38393 and CY208.243 have been evaluated, but with inconclusive results.
ABT-431 represents a new approach to treating Parkinson's disease that has been shown to be effective in clinical studies when administered by injection. The efficacy compares well with that of oral levodopa. (Brefel et al., Poster Presented at the 7th International Parkinson's Disease Symposium, London, March 1997).
ABT-431 is a mixture of three chemically related hydrochloride salt prodrugs and the hydrochloride salt of the active entity A-86929. The hydrochloride salt of the diacetyl prodrug is termed A-93431.1 and comprises greater than 95% of the mixture. All four compounds making up ABT-431 are rapidly converted to the active form A-86929 in vivo and is then further degraded or metabolised. A-86929 is a selective full agonist of dopamine D1 receptors. A-93431.1 (
FIG. 1
) is (−)-trans9,10-diacetyloxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride. A-86929.1 (
FIG. 2
) is (−)-trans9,10-dihydroxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride.
ABT-431 is also understood to have other effects due to its D1-agonist nature. These include improved cognition in debilitating diseases such as Alzheimer's disease and in the control of substance abuse. The dose of the drug ABT-431 will be selected with such therapeutic applications in mind.
Solid formulations of ABT-431 can be prepared that have acceptable shelf stability. However, when these are given to animals as oral products, the extent of absorption is low as measured by the bioavailability as compared to an intravenous control. Such low and erratic absorption would be unsuitable for the treatment of Parkinson's patients.
It would be advantageous if ABT-431 and similar compounds could be given by a transmucosal route. However, the poor solubility of ABT-431 in water and its inherent instability suggests that transmucosal delivery would be problematical.
BRIEF SUMMARY OF THE INVENTION
The present applicant has developed a new composition for nasal administration comprising a full or partial D1-agonist of the dopamine receptor. The composition may allow for the effective administration of ABT-431 and related compounds via the nasal route for the treatment of Parkinson's disease, cognition and substance abuse.


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