United States Patent:  5,990,179

Assignee:  ALZA Corporation (Palo Alto, CA)

Filed:  April 28, 1995

A composition suitable for transdermal electrotransport delivery of an agent through a body surface comprises a free acid/base form of an agent to be delivered by transdermal electrotransport, and a salt form of the agent, and optionally a permeation enhancer. Methods of enhancing transdermal electrotransport delivery and of forming a composition for the enhancement of transdermal electrotransport drug delivery, and a transdermal electrotransport delivery device (10) utilizing the compositions of the invention are disclosed.

DISCLOSURE OF THE INVENTION

The present invention provides a composition and method of adjusting or setting the pH of a donor solution of an electrotransport device to a level at which the permselectivity of the skin is maximized without undesirably introducing substantial amounts of competing ions to the donor solution. In the case of an anodic donor solution, the solution pH is preferably in the range of about 6 to 9, and more preferably in the range of about 7.5 to 8 in order to maximize transdermal electrotransport flux. In order to raise the pH of an anodic donor solution of an acid addition salt of a base drug to the desired range, the base drug itself is added to the salt solution instead of adding a conventional base (eg, NaOH or KOH) which would introduce competing cations (eg, Na⁺ or K⁺) into the donor reservoir. The base drug acts as a proton acceptor which thereby raises the pH of the donor solution without introducing competing ions. Of course, the protonated base drug will have a net positive charge but it is not considered "competing" since it is chemically identical to the drug being delivered by electrotransport. The relative amounts of base drug and drug salt added to the solution will vary depending upon the particular drug salt in solution, the desired concentration of the drug in the solution, the pK of the drug salt and the final desired pH of the donor solution. Those skilled in the art can determine the appropriate relative amounts of base drug and drug salt by routine experimentation following the specific descriptions hereinafter.

In the case of a cathodic donor solution, the solution pH is preferably in the range of about 3 to 6, and more preferably in the range of about 3.5 to 5 in order to maximize transdermal electrotransport flux. In order to lower the pH of a donor solution of a salt of an acid drug to this desired range, the acid drug itself is added to the salt solution instead of a conventional acid (eg, HCl or H₂ SO₄) which would introduce competing anions (eg, Cl^- or SO₄ ^-2) into the donor reservoir. The acid drug acts as a proton donor which thereby lowers the pH of the donor solution without introducing competing ions. Of course, once the proton is donated, the remaining "counter" ion will have a net negative charge but it is not considered "competing" since it is chemically identical to the drug being delivered by electrotransport. The relative amounts of acid drug and drug salt added to the solution will vary depending upon the particular drug salt in solution, the desired concentration of the drug in the solution, the pK of the drug salt and the final desired pH of the donor solution. Those skilled in the art can determine the appropriate relative amounts of acid drug and drug salt by routine experimentation following the specific descriptions hereinafter.

The invention also contemplates an electrotransport delivery device comprising donor and counter electrodes wherein the donor reservoir contains the composition of the invention.

Claim 1 of 18 Claims

1. An anodic donor reservoir composition comprising:

a solution of the acid addition salt of a base therapeutic agent wherein the pH of said solution has been adjusted to within a predetermined range by the addition of base therapeutic agent and wherein the water content is at least about 44.3 wt %.

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