Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-03-14
2001-11-06
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06313176
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel method of administering certain medicaments which surprisingly results in a maximization of the effect on the human body, including the central nervous system receptors, due to the desired medicament and results in minimization of the effect on the human body, including the central nervous system receptors, due to one or more unwanted metabolites from the medicament. Consequently, the invention maximizes therapeutic effects, such as antianxiety, anticonvulsant, anti-Alzheimer's disease, anti-Parkinson's disease, antidepression, antioxidant, and/or hypnotic effects, and minimizes unwanted side effects, such as ataxic, antianxiety, and incoordination effects, of the medicament, due to unwanted metabolites, which effects depend on the specific medicament.
More particularly, the additional information in connection with the instant continuation-in-part patent application involves irreversible enzyme inhibitors, especially the lipid soluble, MAO inhibitor drug deprenyl (which exists as a racemic mixture of levo-deprenyl and dextro-deprenyl), and even more particularly levo-deprenyl, the chemical name of which is L-(−)-N,2-dimethyl-N-2-propynyl phenethyl amine or L-(−)-phenylisopropyl methyl propynyl amine, and also the desired, wanted metabolite of levo-deprenyl, namely L-(−)-desmethyl deprenyl (also known as levo-desmethyl deprenyl and as levo-desmethyl selegiline). Levo-deprenyl is a MAO type B inhibitor, and when in the HCl salt form, is sold as tablets under the trade name selegiline and under the trademarks MOVERGAN®, JUMEX®, and ELDEPRYL®.
When certain medicaments that generate metabolites which are unwanted (the adversive metabolites are increased by gastrointestinal tract absorption and subsequent portal vein entry to the liver for instance when the medicament is orally swallowed), then, in accordance with the present invention, the intraoral administration via the mucous membrane of the mouth, i.e., buccal administration and/or sublingual administration, of such medicaments, i.e., levo-deprenyl and/or levo-desmethyl deprenyl, significantly reduces change of the medicaments into unwanted metabolites.
Also, then, in accordance with the present invention, inhalation administration of such medicaments, i.e., levo-deprenyl and/or levo-desmethyl deprenyl, would avoid the gastrointestinal tract absorption portal vein entry to the liver and thus, will significantly reduce change of the medicaments into unwanted metabolites.
BACKGROUND OF THE INVENTION
The disclosures of all patents mentioned are incorporated by reference.
With respect to intraoral administration, the most pertinent prior art reference known to applicants is U.S. Pat. No. 4,229,447 to Porter which discloses a method of administering certain benzodiazepines sublingually and buccally. Porter specifically mentions the sublingual or buccal administration of diazepam, lorazepam, oxazepam, temazepam and chlorodiazepoxide and describes two generic structures of benzodiazepines that may be administered sublingually or buccally.
The compound shown below is contemplated by the generic structures in Porter. All of the benzodiazepines disclosed and the generic structure described in Porter are BZ
1
-BZ
2
receptor non-specific since they lack the trifluoro ethyl group pendant at the N position of the “B” ring which confers BZ
1
specificity.
Porter's method is based on the rapid buccal or sublingual absorption of selected benzodiazepines to attain effective plasma concentration more rapidly than oral administration. In contrast, while parenteral administration provides a rapid rise of blood levels of the benzodiazepines, parenteral administration is frequently accompanied by pain and irritation at the injection site and may require sterilization of the preparatives and the hypodermic syringes.
Porter points out that the intraoral, i.e., buccal or sublingual administration, of lipid soluble benzodiazepines results in therapeutic levels resembling parenteral administration without some of the problems associated with parenteral administration. Porter's administration technique for benzodiazepines in general builds on a long established knowledge in pharmacology that a drug absorbed in the intraoral route gives rise to more rapid absorption than the same drug swallowed into the stomach. What is not recognized by Porter, however, are concerns with first-pass metabolism which can be avoided either with the sublingual or parenteral route of drug administration of certain benzodiazepines.
Porter does not recognize that first-pass metabolism designates the drug intestinal absorption with subsequent entry directly into the portal blood supply leading to the liver and that the liver in turn rapidly absorbs and metabolizes the drug with its first-pass high concentration through the liver. In addition, some first pass metabolism may occur during the absorption process into the intestine. Thus, large amounts of the drug may never be seen by the systemic circulation or drug effect site. Porter further does not recognize that the more rapid metabolism via the first-pass metabolism route can lead to accelerated desalkylation with formation of high plasma concentrations of an unwanted metabolite.
Thus, applicants' concern with avoiding the degradation of the parent compound and its desired positive effect and avoiding the metabolism of the parent compound to an undesired metabolite is neither recognized nor addressed by Porter, who only addresses the ability of the oral mucous membranes to absorb certain benzodiazepines fast and achieve high plasma levels of these benzodiazepines quickly.
The specific drug for which this phenomenon was demonstrated by Porter was lorazepam which has a simple metabolism that results in it not being metabolized to active compounds. Also, and very significantly, the issue of human nervous system receptor specificity and activation for BZ
1
and BZ
2
type receptors is not recognized by Porter either generally or with reference specifically to trifluorobenzodiazepines.
U.S. Pat. No. 3,694,552 to Hester discloses that 3-(5-phenyl-3H-1,4-benzodiazepine-2-yl)carbazic acid alkyl esters, which are useful as sedatives, hypnotics, tranquilizers, muscle relaxants, and anticonvulsants, can be administered sublingually. Subsequently issued U.S. Pat. No. 4,444,781 to Hester specifically teaches that 8-chloro-1-methanol-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine therapeutic compounds, which are useful as soporifics, can be suitably prepared for sublingual use.
Also, U.S. Pat. No. 4,009,271 to vonBebenburg et al. discloses that 6-aza-3H-1,4-benzodiazepines and 6-aza-1,2-dihydro-3H-1,4-benzodiazepines (which have pharmacodynamic properties including psychosedative and anxiolytic properties as well as antiphlogistic properties) can be administered enterally, parenterally, orally or perlingually.
The chemical formula of nefazodone is 2-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one hydrochloride and it is abbreviated as NEF.
Patients with obsessive compulsive disorder respond to meta-chlorophenylpiperazine (abbreviated as mCPP), an undesirable metabolite of NEF, by becoming much more anxious and obsessional, as reported by Zohar et al. in “Serotonergic Responsivity in Obsessive Compulsive Disorder: Comparison of Patients and Healthy Controls”,
Arch. Gen. Psychiatry
, Vol. 44, pp. 946-951 (1987). The peak in the anxiousness and obsessional behaviors is observed within 3 hours of mCPP administration and the duration of the worsening ranges from several hours to as much as 48 hours. Much more significantly, mCPP induced a high rate of emergence of entirely new obsessions or the reoccurrence of obsessions that had not been present in the patients for several months. Patients also reported being more depressed and dysphoric.
More specifically, Zohar et al. administered 0.5 mg/kg of mCPP orally to subjects in eliciting their obsessional symp
Ellinwood, Jr. Everett J.
Gupta Samir K.
Fay Zohreh
Jenkins and Wilson P.A.
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