Title:  Transdermal absorption of active substances from subcooled melts

United States Patent:  6,344,211

Assignee:  LTS Lohmann Therapie-Systeme GmbH (Neuwied, DE)

Filed:  November 21, 2000

Foreign Application Priority Data:  Dec 24, 1994[DE] (44 46 600)

A pharmaceutical product for the release of medicinal agents to the skin having absorption-increasing auxiliary agents is characterized in that the auxiliary material forms subcooled melts.

Description of the Invention

The present invention relates to the transdermal application of medicinal agents with the aid of inactive ingredients forming sub-cooled melts. Applying pharmaceuticals transdermally undoubtedly is very advantageous, but the limited quantity of medicinal substance that can be absorbed by the skin frequently is a disadvantage. With introducing the therapy by means of transdermal application there have therefore been attempts to increase the pharmaceuticals' capability of penetrating through the skin. The development of penetration enhancers added to drugs for dermal application is regarded as one approach. These substances change subjacent skin structures, at least for a short period; in unfavorable cases they may result in undesired side effects. These side effects are the less marked, the better the penetration enhancers are tolerated physiologically.

A neat approach of increasing the absorption of medicinal agents through the skin is the manufacture of matrix systems. Owing to the concentration gradient the dissolved portion of the active substance diffuses out of the system into the skin first. At the same time, the portion of active substance which is contained in the system in suspended form starts to dissolve. The dissolution rate of the active substance in the system is the factor determining the rate of active substance release. Experiments have shown that dodecanol promotes penetration and is physiologically acceptable. Since its melting point amounts to about 24^oC. dodecanol is solid at normal room temperature. The solid state makes it more difficult to deliver dodecanol out of a matrix. This deficiency restricts the use of dodecanol in polymeric matrices because the release rate of a substance from polymer matrices is the higher, easier it can diffuse, in as the matrix. This does not only apply to dodecanol, but also to other penetration enhancers which are solid at room temperature.

Accordingly it is the object of the present invention to improve the release of auxiliary agents which are solid at room temperature from a matrix.

Most surprisingly, this object has been achieved according to the present invention by a pharmaceutical product as defined herein. Compounds forming subcooled melts are understood to mean those whose melting point is above room temperature but which, after a melting process, remain in the liquid state during cooling to room temperature.

The term drug is known to the skilled artisan. Ointments representing gels of plastic deformability as well as pastes which may be characterized as ointments having a high solids content are suitable for the application to the skin or mucous membranes (e.g. nose, eye).

A transdermal therapeutic system (TTS) is to be understood according to Zaffaroni as "a medicinal substance-containing device or administration form continuously releasing one or several medicinal agents at a predetermined rate over a predetermined period of time to a fixed place of application" (quoted according to Heilmann, therapeutische Systeme--Konzept und Realisation programmierter Arzneiverabreichung, 4th edition, Ferdinand Enke Verlag, Stuttgart 1984, page 26). In the present case the place of application is the skin.

The structure of transdermal systems is known to the skilled artisan. Patents describing the basic design include, for example, DE 3315272, DE 3843239, U.S. Pat. No. 3,598,122.

When a transdermal therapeutic system is applied on the skin of a patient, the medicinal agent is to be released to take a topical or systemic effect in the patient. Administration forms of this kind have already been used in therapy. In most cases they have a layered structure; in the simplest case they consist of a backing layer, a self-adhesive active substance reservoir, and a removable protective layer to be removed prior to application. In the present case, an auxiliary agent must be introduced that increases the absorption of medicinal agents by the skin, is solid at room temperature, and forms subcooled melts, for example, dodecanol or levulic acid.

Substances are used as medicinal agents which--when applied on the skin either without or with an absorption filter--produce a local or systemic effect.

Substances having a local action include, for example, antiperspirants, fungicides, bactericides, and bacteriostatics.

Substances having a systemic action include, for example, antibiotics, hormones, antipyretics, antidiabetic agents, coronary vasodilators, cardio-active glycosides, analgesics, spasmolytics, antihypertensives, psychotropic drugs, migraine analgesics, corticoids, contraceptives, antirheumatics, anticholinergics, sympathicolytics, sympathicomimetics, vasodilators, anticoagulants, and antiarrhythmics. This listing is incomplete.

The delivery of pilocarpine base and ephedrine base from polymer matrices can also be increased, provided that they are present in subcooled melts. Owing to their heat-sensitivity, however, it is impossible to subject these medicinal substances to a melting process.

Claim 1 of 6 Claims

What is claimed is:

1. A method of releasing a pharmaceutical agent for effecting a topical or systemic effect in a patient from a transdermal therapeutic system having a layered structure and comprising at least one substance selected from the group of pharmaceutical agents producing a local or systemic effect and at least one auxiliary agent which increases the penetration of said pharmaceutical agents and has a melting point above room temperature, which comprises:

a) in a first step preparing said transdermal therapeutic system by using an auxiliary agent which has been melted and afterwards allowed to form a subcooled melt by cooling it down to room temperature, and

b) in a second step applying the transdermal therapeutic system as prepared in the first step on the skin of said patient.

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