Blister containing a transdermal therapeutic system and a single dose form of administration

This application a 371 of PCT/EP99/04614 filed Jul. 2, 1999.

The invention relates to a dosage form for medicinal active ingredients in blister form, which makes it possible to administer simultaneously a transdermal therapeutic system (TTS) and at least one single-dose active ingredient.

It is customary in hormone replacement therapy to combine administration of the basic hormone with administration of another hormone in order to avoid side effects. This applies, for example, to oestradiol administration, which takes place with administration of a gestagen. Since long-term, continuous administration of the basic hormone is desired, a suitable administration form has proved to be the transdermal therapeutic system (TTS), with which the active ingredient is delivered to the skin in controlled manner via a defined contact area of an active ingredient reservoir. The system preferably comprises a pressure-sensitive adhesive. If discontinuous concomitant medication with another hormone is desired, this usually takes place in tablet form. The tablets are normally stored separately and can be manipulated in accordance with the administration schedule only with difficulty. This type of dosage forms is thus extremely unfavourable for patient compliance.

It was therefore an object of the invention, for compliance reasons, to create a suitable packaging procedure for simultaneous administration of medicinal active ingredients via the transdermal and non-transdermal route. This was intended to ensure that the patient is aided, by an appropriate design of packaging, in implementing where possible intake of single doses at defined times.

The achievement of the object has now been found in a blister form which, besides the TTS, contains at least one single-dose active ingredient form. The TTS is packed individually in a blister but may also be fixed to the dosage form in another way, such as, for example, by means of the pressure-sensitive adhesive contact area. Accommodation in a blister is also the method of choice for the single-dose active ingredient form, which is preferably a tablet, it also being possible, of course, to conceive other attachment mechanisms.

Joining together several blister forms has proved advantageous for longer-term administration. This means for the patient that his administration regimen is fixed accurately and unambiguously for weeks. The series of blister forms may perfectly well include those which have no single-dose active ingredient form, if required for therapeutic reasons.

The single-dose active ingredient form is usually designed for non-transdermal administration. Otherwise, care must be taken that bolus-like release is ensured. Besides or in place of systemic active ingredients it is possible for the single-dose active ingredient form also to contain preparations for topical pretreatment and/or after-treatment of the TTS administration area. These preparations may, for example, improve the skin permeability of the active ingredient from the TTS or prevent or even reverse harmful skin changes after administration of the TTS. Last but not least, the single-dose active ingredient form may also contain one or more TTS active ingredients in order to cover the TTS lag time or generate an additional plasma peak required by the circadian rhythm.

The following example, illustrated by FIG. 1, summarizes the compliance-ensuring aspects of the novel dosage form with the aid of a unit composed of eight TTS 1 to 8 , which is provided for a treatment period of 28 days. 9 indicates the single-dose active ingredient forms, none of which are contained in 1 - 4 .

The following table reflects the course of administration for an oestrogen/gestagen treatment:

A gestagen-free treatment period of 14 days is followed by provision of a gestagen administration for each day of the TTS administration (alternating three and four days) in the last two weeks.

As the example illustrates, the invention provides a reliable means for permanently improving the compliance of patients on TTS administration with an additional single-dose active ingredient form.

The compliance can be increased by joining several blister forms together or labelling the individual blisters in the required sequence of use.