Method for transdermal administration of GP IIb/IIIa antagonist

Details Method for transdermal administration of GP IIb/IIIa antagonist Method for transdermal administration of GP IIb/IIIa antagonist

1999-04-14

2001-11-27

Bockelman, Mark (Department: 3762)

Surgery

Means for introducing or removing material from body for...

Treating material introduced into or removed from body...

C604S020000

Reexamination Certificate

active

06322550

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a method for transdermal administration of a GP IIb/IIIa antagonist by iontophoresis, comprising plural electric current application steps, progressively reduced in current density.
BACKGROUND ART
In recent years a variety of compounds designed to produce antithrombotic effects through the inhibition of platelet aggregation by competitive antagonism against GP IIb/IIIa, one of the platelet receptors, have been synthesized for possible application to the prophylaxis and therapy of (1) angina pectoris, (2) unstable angina and (3) reobstruction and restenosis of coronary arteries after PTCA (percutaneous transluminal coronary angioplasty) or coronary thrombolysis, among other applications. Particularly among GP IIb/IIIa antagonists comprising 2-piperazinone-1-acetic acid derivatives, compounds having high anti-platelet aggregation activity have been discovered (e.g. JP-A-25285/1994, JP-A-316059). However, generally the following three problems have been pointed out with GP IIb/IIIa antagonist in common. The first problem is that the serum concentration threshold causing a prolongation of bleeding time, a side effect, is so close to the effective serum concentration range producing the main pharmacological efficacy that the serum concentration of the drug must be somehow controlled so that the main effect may be isolated from the side effect. The second problem is that therapeutic efficacy is not shown without maintenance of pharmacologically effective serum concentration for a long term (e.g. about not less than 3 days, preferably about 3 to 100 days, more preferably about 7 to 100, further more preferably about 7 to 30 days, most preferably about 7 to 14 days), in view of the operation mechanism of GP IIb/IIIa antagonists. The third problem is that because of the high hydrophilicity and poor mucosal penetration efficiency of those compounds, their application by the oral route, which is of convenience in self-administration, cannot be expected so that generally intravenous infusion, which is feasible only on an inpatient basis, has so far been the exclusive method of administration which is safe and effective.
The first and second problems suggest that the preferred serum concentration pattern of any GP IIb/IIIa antagonist is such that the drug reaches its therapeutically effective concentration range quickly and maintains that concentration range for a long time.
With regard to the third problem, nasal administration or transpulmonary administration, together with an absorption promoter, may be considered possible as a method enabling self-administration but is not satisfactory in that a transient excessive elevation of serum concentration in an initial phase following administration, which is observed with those administration methods in common, contributes to side effects. Transdermal administration may be mentioned as another method permitting self-administration but, as far as the conventional transdermal delivery system is concerned, the absorbability of those highly water-soluble compounds is generally very low even when they are formulated with an absorption promoter and other additives so that it cannot be considered to be a realistically useful method of administration. Supposing that the necessary absorption could be attained by some means or other, the absorption lag time would be too long (generally after application, it takes about a few hours for the drug to enter the circulation), thus failing to provide an ideal mode of administration.
Meanwhile, iontophoresis as a means for assisted transdermal absorption of drugs, by which the drugs are forced to penetrate the skin under the influence of an electrical energy, has been known for many years [Journal of Controlled Release, 18, 1992, pp.213-220; Advanced Drug Delivery Review, 9, 1992, p.119; Pharmaceutical Research, 3, 1986, pp.318-326]. This system is based on the principle that when a positively charged water-soluble compound, for instance, is incorporated in an anode patch to be affixed to the skin and an electric current is applied, the positively charged compound is forced, by electrical repulsion, to penetrate the stratum corneum of the skin, which is inherently impermeable, and get absorbed systemically. This system is currently applied to the self-administration of basic peptides such as calcitonin and parathyroid hormone and many techniques for efficient transdermal penetration have also been proposed (JP-A-16535/1994 and JP-A-103494/1997). Regarding the transdermal administration of a GP IIb/IIIa antagonist by iontophoresis, relevant disclosures can be found in WO 97/49382, WO 97/48395, WO 97/49382, JP-A-103494/1997 and JP-A-56827/1997. However, no sufficient studies have been undertaken on the optimum conditions of electrical current application for the administration of a GP IIb/IIIa antagonist by iontophoresis.


REFERENCES:
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patent: WO97/49382 (1997-12-01), None
patent: WO97/48395 (1997-12-01), None
patent: WO97/48444 (1997-12-01), None

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