The invention relates to a transdermal system for the administration of at least two substances through the skin with the aid of an electric current.
Transdermal systems are generally used to administer a substance, for example a therapeutically active substance or mixture of substances, through the skin of a living organism without the need for clear penetration of the outer layer of the skin--the stratum corneum--and possibly also underlying layers of skin, by mechanical means using a device such as, for example, an injection needle. Transdermal systems are accordingly normally classed as being non-invasive dosage forms.
The great interest in transdermal systems stems from the fact that that dosage form has distinct advantages over other conventional dosage forms. In the case of oral administration undesired side effects frequently occur as a result of incompatibilities in the gastrointestinal tract or the liver. Also, orally administered substances are frequently decomposed or so modified in the gastrointestinal tract or the liver that the desired therapeutic effect does not occur ("first pass" effect). Other forms of parenteral administration, such as, for example, intravenous, subcutaneous or intramuscular injections, involve penetration of the skin or of layers of the skin and are therefore associated by the patient with a sensation of pain. In addition, local inflammation or infection may occur as a result of the partial damage to the skin. Especially in the case of long-term therapy requiring regular injections of the substance or infusions over prolonged periods--often a plurality of times a day--the patient is frequently subjected to a high level of discomfort. This has, among other things, an adverse effect on the co-operation of the patient in adhering to the medically necessary dosage scheme.
Since transdermal systems are not subject to those limitations they are today, especially in the form of one typical example, that is to say the transdermal patch, numbered among the current dosage forms that enjoy widespread usage. Transdermal systems may be divided roughly into passive and active systems. In passive systems the substance to be administered diffuses from a reservoir through the skin. In active systems an additional force promotes the transport of substance through the skin. Especially preferred for that purpose are electric fields, which generate a flow of current through the skin. The administration of a therapeutically active substance through the skin with the aid of an electric current is generally referred to as iontophoresis.
Typically, the iontophoretic systems used today comprise at least two electrodes, one of which forms a contact with the reservoir containing the substance. The other electrode, often referred to as the neutral electrode, is applied directly to the skin and serves to close the circuit via the body. On connection to a source of electrical energy, a current then flows through the skin and transports the substance into the body. In such active systems this is usually accompanied by a passive transport of substance.
A disadvantage of the passive transdermal systems customary today is that the process of diffusion by way of the natural channels of the skin (sebaceous and sweat glands, inter- and trans-cellular transport paths, hair follicles) proceeds very slowly. It is accordingly difficult using a passive transdermal system to administer a substance through the stratum corneum at a dosage rate that is high enough to achieve the desired therapeutic effect. The dosage rate is the amount of substance administered through the skin per unit of time.
Compared with passive transdermal systems, active systems, especially iontophoretic systems, usually enable higher dosage rates to be achieved. An additional advantage of the latter systems is that with them it is possible in a simple manner to influence and alter the dosage rate in a controlled manner. By regulation of the current as the active control element in the administration it is possible, for example, to adapt the dosage rate to the individual requirements of the patient. In addition, therapeutically expedient dosage schemes are feasible, for example it is possible to alternate phases of higher dosage rates with phases of low dosage rates.
In addition, iontophoretic systems have the advantage that the substance to be administered is, as it were, available "on demand". The administration of the substance can be started or stopped by simple activation or deactivation of the electric current flow.
There are, of course, physiologically determined limitations to the current intensities that can be used in iontophoretic systems, since too strong an electric current may result, for example, in burns or other kinds of irritation to the skin. There is therefore a need to control or increase the dosage rate by a means other than merely by way of the intensity of the electric current. One possible method of controlling or altering the dosage rate comprises administering the therapeutically active substance together with a preparation that has an effect on the blood flow in the capillaries of the skin. Such a method is disclosed, for example, in EP-A-0 448 300. In that method, first of all a composition is produced that comprises a vessel-manipulating preparation in addition to the therapeutically active substance. The joint iontophoretic administration is then carried out with that composition. If the vessel-manipulating preparation is one that dilates the vessels, then the blood flow through the capillaries of the skin is increased, resulting in a higher dosage rate of the therapeutically active substance. If the vessel-manipulating preparation is one that contracts the vessels, then the blood flow through the capillaries is reduced, resulting in a depot effect of the therapeutically active substance. Since the vessel-manipulating preparation and the therapeutically active substance are administered together, this process is referred to as "co-iontophoresis".
It is often desirable, for reasons other than for the purpose of controlling the dosage rate, to administer more than one substance iontophoretically using a transdermal system. For example different substances may have different therapeutic effects, or one substance may reduce the undesired side effects of the other substance.
A problem with the transdermal administration of a plurality of substances using currently known iontophoretic systems, however, is that the substances, which are usually contained in the reservoir in the form of different ions, may enter into competition with one another during the iontophoresis; this means that the transport of the charge associated with the current flow is effected by means of a plurality of different charge carriers. This results in it being difficult to control the dosage rates of those substances individually. Reference is expressly made to the problem of competition also in EP-A-0 448 300 which, however, describes only the co-iontophoresis of a therapeutically active substance and a vessel-manipulating preparation. In the case of co-iontophoresis of a vessel-dilating preparation, for example, as the concentration of the vessel-dilating preparation increases, first of all an increase in the dosage rate of the therapeutically active substance is observed, but this is followed by a decrease as the concentration of the vessel-dilating preparation increases further. Consequently, it is necessary first to spend a great deal of time in determining an optimum composition of the therapeutically active substance and the vessel-manipulating preparation in order that the two substances will have the desired effect during co-iontophoresis.