Transdermally administered dextromethorphan as antitussive...

Details Transdermally administered dextromethorphan as antitussive... Transdermally administered dextromethorphan as antitussive...

1998-10-23

2002-01-01

Dodson, Shelley A. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C424S443000, C424S444000, C514S289000, C514S850000

Reexamination Certificate

active

06335030

ABSTRACT:

FIELD OF INVENTION
This invention relates to the use of dextromethorphan, optionally encompassing salts, prodrugs and metabolites thereof, for the manufacturing of a medicament to be administered transdermally for achieving an antitussive effect and to methods of treating diseases being treatable with antitussive agents by transdermal administration of dextromethorphan, optionally encompassing salts, prodrugs and metabolites thereof.
BACKGROUND
Dextromethorphan, (+)-3-methoxy-17-methyl-9a,13a,14a-morphinan, is a synthetic opioid. Normally the hydrobromide of dextromethorphan is used pharmacologically, although other salts are not excluded. The preparation of (+)-3-methoxy-17-methyl-9a,13a,14a-morphinan was disclosed in U.S. Pat. No. 2,676,177 (SCHNIDER ET AL) and in Häfliger et al., Helv. Chil. Acta 39, 1956: 2053.
Clinically, in connection with tussometri dextromethorphan has shown a significant effect on reducing coughing frequency as well as intensity compared to placebo at a dosage of 40 mg perorally, an effect of the same order of magnitude as 60 mg codeine, see Mathys, Schweiz Med Wschr 1985;115: 307-11. However dextromethorphan has not shown any antitussive effect upon inhalation of 1-30 mg. Also demethylated metabolites, including dextrorphan, have shown cough suppressing effects, see Martindale, The Pharmaceutical Press, London, 1993: 746.
Dextromethorphan is a safe drug as concluded by Bem J. L., Peck R., Drug safety, 1992 (7): 190-199. Dextromethorphan has fewer side-effects than the other antitussive agents codeine and noscapine.
Dextromethorphan is rapidly converted in the liver into inter alia dextrorphan, which also has a clinical activity, see above, however on other receptors than dextromethorphan. Pharmacokinetic studies have shown that populations can be divided into two main groups based on their ability to metabolize dextromethorphan, the so called poor metabolizers and the extensive metabolizers, see e.g. J.-C Duché et al., “Dextromethorphan O-demethylation and dextrorphan glucoronidation in a French population”, Int J. of Clin Pharm, Therapy and Tox, 1993; 31(8):392-98, J. S. Marinac et al., “Dextromethorphan Polymorphic Hepatic Oxidation (CYP2D6) in Healthy Black American Adult Subjects”. Therapeutic Drug Monitoring, Raven Press New York, 1995; 17:120-124, and Chen et al., “Dextromethorphan: pharmacogenetics, and a pilot study to determine its disposition and antitussive effect in poor and extensive metabolisers”, Eur. J. Pharmacol 1990; 183(4):1573-74. Around 10% of the population are slow metabolizers of dextromethorphan and therefore more easily have side-effects, most often being fairly mild, such as drowsiness, confused speech, nausea and dizziness, although serious in case of overdosing, such as excitation, confusion and respiratory depression. The clinical implications of these findings are that different dosing regimes should be used for the individual patients. As this difference is related to the first-pass metabolism in the liver it is highly advantageous to avoid the first pass passage of the drug.
As metabolism following transdermal delivery of a drug is of much lesser extent than after oral delivery of the drug it is highly desirable to deliver dextromethorphan through the transdermal route.
When administered perorally dextromethorphan undergoes an extensive first-pass metabolism, i.e. the oral bioavailability is low meaning that fairly high doses need to be given. Absolute bioavailabilities have been reported as low as 3.8% in dogs, see Barnhart J. W., Massad E. N., “Determination of dextromethorphan in serum by gas chromatography”, J.
Chromatography 1979, 163: 390-395. Other reported values are 7% and 18%, see Dixon et al., Res. Commun. Chem. Pathol. Pharmacol., 1978;22:243).
The half-life of dextromethorphan is around 4-6 hours, which means that the plasma concentration-varies substantially during day and night unless dextromethorphan is delivered frequently, by peroral administration at least 3-4 times daily. Even then the sleeping pattern of the patient will be disturbed by cough attacks as the antitussive effect will not remain through a whole night. The sleeping pattern disturbance, as well as the other adverse effects mentioned above, are removed or reduced with the present invention being transdermally administered dextromethorphan as antitussive agent. The above transdermal administration can be used for human beings as well as animals.
PRIOR ART
Transdermal administration of dextromethorphan, but not as antitussive agent, is known, e.g. from U.S. Pat. No. 5,260,066 (CARLTON ET AL.) for cryogel bandages. Here dextromethorphan is administered only to sites of trauma, column 2, lines 59-60, whereas in the present invention dextromethorphan is only administered to intact skin. Further U.S. Pat. No. 5,260,066 just mentions dextromethorphan in a long listing of drugs. There are no examples showing administration of dextromethorphan. Further U.S. Pat. No. 5,260,066 does not even mention that an antitussive effect should be achieved. Supposedly this is not what is desired upon administration to sites of trauma
WO 91/15261 (MEDTRONIC) concerns iontophoretic devices which depend upon the physical activity of the patient and just mentions dextramethorphan on page 4, line 32-33, as a drug which could possibly be administered via said devices. Buth there are no examples showing that this is at all possible with said devices. Dextromethorphan is further not mentioned in the claims. Thus, WO 91/15261 simply concerns a very special device, requiring measurement of patient activity (page 4, lines 24-25, which means an activity sensor (page 11, lines 10-17). This is a non-useful device for administering dextromethorphan as the administration takes place once the patient starts coughing—which is too late. Thus, WO 91/15261 is in all respects an irrelevant and non-enabling reference. WO 91/15261 corresponds to U.S. Pat. No. 5,213,568 (LATTIN ET AL.) which thus also is a non-relevant reference.
WO 95/05416 (CYGNUS THERAPEUTIC SYSTEMS) discloses mucoadhesive devices for administration of drugs, inter alia dextromethorphan, to a body cavity, specifically to the oral cavity. It does not relate to transdermal administration.
U.S. Pat. No. 4,783,450 (FAWZI ET AL.), corresponding to WO 88/07871 (WARNER LAMBERT) discloses the use of lecithin for enhancing transdermal penetration. U.S. Pat. No. 4,645,502 (GRACE ET AL.) discloses a specific system for transdermal delivery of highly ionized fat insoluble drugs. WO 93/07902 (RICHARDSON-VICKS, INC.) discloses compositions for topical application comprising a drug and a non-ionic polyacrylamide. WO 93/07903 (RICHARDSON-VICKS, INC.) discloses compositions for topical application comprising a drug and a high molecular weight cationic polymer. EP 0 351 897 (THE PROCTER & GAMBLE COMPANY) discloses pharmaceutical compositions comprising a drug, a fatty acid and an alkane diol. EP 0 349 763 (BRISTOL-MYERS COMPANY) discloses a composition for trans-dermal administration comprising a drug and an imidazole derivative as penetration enhancer. U.S. Pat. No. 4,888,354 (CHANG ET AL.) discloses compositions for topical administration of drugs present in both free and acid addition salt form. U.S. Pat. No. 4,557,934 (COOPER) discloses topical compositions comprising a drug and 1-dodecyl-azacycloheptan-2-one as penetration enhancing agent In all these patent documents dextromethorphan is just mentioned in lengthy listings of drugs which theoretically might be included in the claimed compositions.
Anyhow there are nowhere in the above patent documents any examples of formulations including dextromethorphan as an antitussive agent. Thus use of transdermally administered dextromethorphan as an antitussive agent has neither been contemplated nor shown.
The only non-patent literature reference relating to transdermal delivery of dextromethorphan being known to the applicant is Mahjour et al., J. Controlled Release 14 (3); 1990:243-252. The contents thereof essentially corresponds to the above mentioned patent U.S. Pat. No

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