Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-01-26
1997-10-07
Jarvis, William R.A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514456, 514320, 514397, 514385, 514422, A61K 31505, A61K 3135, A61K 31445, A61K 31415, A61K 3140
Patent
active
056748710
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based upon PCT Application Serial No. PCT/EP 94/02764, filed Aug. 19, 1994, which claims priority from European Patent Application Serial No. 93.202.523.2, filed on Aug. 27, 1993.
The present invention relates to the iontophoretic delivery to a patient, more in particular to a migraine patient, of a compound of formula (I) as shown hereinunder. The invention also relates to a device for the iontophoretic delivery of a compound of formula (I), as well as to a composition comprising a compound of formula (I), which can be applied in a device for iontophoretic delivery.
Although in general, oral administration of a drug is considered as most convenient, this route poses particular problems when administering a drug, more in particular an anti-migraine drug, to patients suffering from a migraine attack. Migraine patients often feel nauseous, sometimes resulting in violent vomiting, thus hampering the oral administration of the anti-migraine drug. The successful oral delivery of some anti-migraine substances is also impeded by its susceptibility to degradation by the acid environment of the stomach and by the digestive activity of several enzymes in the gastrointestinal tract. Other disadvantages of the oral route are the often poor absorption due to gastroparesis and the extensive first-pass elimination in the liver (the hepatic first-pass effect), whereby a compound is transformed in the liver into a metabolite more prone for excretion. Along with convenient administration, it is essential for an effective treatment of a migraine attack that the activity of the drug sets on immediately, or at least very rapidly, after administration and that the effect lasts long enough. Hence a means of directly inserting the drug into the bloodstream should be a method of choice for the administration of an anti-migraine drug. An obvious way of doing so is by injecting a solution of the drug either intravenously or subcutaneously. However, the consequent pain, risk of infection, the complex procedures of self-administration and potential for low patient compliance make such parenteral administration undesirable.
Transdermal delivery is an attractive alternative because: (a) it avoids gastrointestinal degradation and the hepatic first-pass effect; (b) it lends itself to a controlled and/or sustained release; (c) it allows for convenient and simple self-administration and encourages patient compliance, since a transdermal formulation would be easy to apply or to remove.
Traditional transdermal drug delivery systems are based on the transport of drugs into the skin by diffusion through the outermost layer of the epidermis, i.e. the stratum corneum. The number of solutes which can be delivered by this route are limited due to the excellent barrier properties of the said stratum corneum. Hence, attainment of a therapeutically effective level is therefore difficult without some form of facilitation. One means of facilitation is the delivery of the drug by electrokinetic action, more in particular by iontophoretic action. The principle of iontophoresis is that ionized (or polar) drug molecules can be driven into the skin if an appropriate electrical potential is applied across the skin. Iontophoresis may be due solely to electromigration, i.e. the movement of ionized drug molecules across an electrical field per se, or it may be due to a combined effect of electromigration and electroosmosis. The latter is a transdermal flux of liquid solvent containing the drug by the presence of an electrical field.
The problem to be solved is to find or develop compounds and compositions, which have the desired anti-migraine activity and which are susceptible for said convenient iontophoretic delivery.
Recently, it was discovered that the compounds of formula (I) show 5HT.sub.1-like agonistic activity and, more in particular, anti-migraine activity. Unexpectedly it has been found that these compounds of formula (I) can be delivered via iontophoretic action. Said compounds are dihydrob
REFERENCES:
patent: 5541180 (1996-07-01), Van Lommen et al.
Lambert et al., "The Spinal Cord Processing of Input from the Superior Sagittal Sinus; Pathway and Modulation by Ergot Alkaloids", Brain Research, vol. 597, No. 2, 1992, pp. 321-330.
De Beukelaar Frank Maria Jozef
Mesens Jean Louis
Van Reet Gustaaf
Janssen Pharmaceutica N. V.
Jarvis William R.A.
Metz Charles J.
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