Title:  Transdermally administrable medicament with ACE inhibitors

United States Patent:  6,303,141

Assignee:  Hexal AG (DE)

Filed:  September 29, 1999

Foreign Application Priority Data:  Mar 31, 1995[DE] (195 12 181)

The invention relates to a transdermal system containing at least one angiotensin-converting enzyme inhibitor.

Description of the Invention

The long-term therapy of hypertension with angiotensin-converting enzyme inhibitors (ACE inhibitors) has an increasingly wide scope. Together with good tolerability, ACE inhibitors are known for their reliable activity. The first substance of the ACE inhibitor class, captopril, is a very hydrophilic substance which is active in unmodified form. The oral bioavailability of captopril is approximately 70%. More recent ACE inhibitors, such as enalapril, are metabolized from their precursor during passage through the liver into the active component enalaprilate, that is to say the acid form. Like enalapril, the ACE inhibitors ramipril, cilacapril, trandolapril, benazepril or fosinopril are lipophilic prodrugs of the actual active form of the dicarboxylic acid. As a result of the esterification of one carboxyl group of the respective ACE inhibitor in each case, the substance becomes more lipophilic and thereby more favourable for oral absorption. The oral bioavailability of these prodrugs, however, is always lower than that of captopril. It is, for example, 28% for benazepril and about 40 to 60% for trandolapril. Now it is a known fact that substances having low bioavailability are very dependent on the respective metabolization capacity of the patients. This means that the resulting plasma levels are subject to a very high variation. The high variation in the blood levels of ACE inhibitors or their active forms leads, however, to uncertain courses of action. In order to make the action of ACE inhibitors independent of the metabolic condition of the patients, a pharmaceutical form which makes possible a reliable, reproducible systemic supply of the active compounds would be desirable. The transdermal administration of active compounds leads to a circumvention of the hepatic first-pass metabolism and thus to an elimination of the metabolization variations of the liver. If it was now possible to make ACE inhibitors in the form of their prodrugs or their active forms systemically available transdermally, a more reliable steady action could be achievable.

WO-A1-9 323 019 has already disclosed a transdermal reservoir system containing an ACE inhibitor and

(a) an impermeable covering layer (backing layer),

(b) a layer-like element having a hollow space,

(c) a means controlling the release of active compound (claim 1) and

(e) a covering layer (release liner) which can be torn off based on paper (page 12 lines 7/8).

Transdermal systems containing an ACE inhibitor are furthermore described in EP-A2-0 439 430 (reservoir TTS) and EP-A2-0 468 875 (matrix TTS), according to EP-A2-0 468 875 silicone elastomers being used as matrix material.

The object of the present invention is to provide a system for the transdermal supply of ACE inhibitors, in particular of ramipril, trandolapril and/or their therapeutically active salts, which is improved compared with the prior art.

In particular, it is an object of the invention to provide a system for the transdermal supply of ACE inhibitors, with which an activity of up to approximately one week can be achieved, such that for approximately one week a continuous release of active compound and a therapeutically effective plasma level can be achieved, for example of more than 0.5 ng of trandolapril/ml.

To do this, according to the invention a transdermal system having a matrix based on polyisobutylene or butyl rubber and containing at least one ACE inhibitor is provided. According to the invention, it was surprisingly found that lipophilic ACE inhibitors or their active forms, which can only permeate the human skin with difficulty, can penetrate the skin easily with the aid of a transdermally administrable medicament having a polyisobutylene matrix or butyl rubber matrix and produce a reliable, continuous blood level.

According to the invention, a release rate of the active compound from, for example, a polymer matrix, of 0.01 to 0.1 mg of active compound/cm² of 24 h and, in particular, 0.025 to 0.050 mg of active compound/cm² of 24 h can be achieved, such that a transdermal system according to the invention offers a plasma concentration of active compound in a therapeutically active amount. For example, for trandolapril a therapeutically active concentration in the blood of more than approximately 0.5 ng/ml can be achieved.

The person skilled in the art is familiar with suitable polyisobutylene or butyl rubber matrices; cf., for example, Higgins et al. in Satas, Handbook of Pressure Sensitive Adhesive Technology, 14:374 etc., Butyl Rubber and Polyisobutylene; Van Nostrand Reinhold, New York.

In the transdermal system according to the invention, the ACE inhibitor can be present in a concentration of at least 5% by weight and in particular in a concentration of 10 to 20% by weight (based on the matrix).

The ACE inhibitor can be employed here as a prodrug or as an active form.

Examples of ACE inhibitors which may be mentioned are ramipril, trandolapril and/or their active forms (acid forms) and also their therapeutically active salts.

The transdermal system according to the invention can include a permeation promoter, for example 2-octyldodecanol (Eutanol G).

Different forms of the transdermal systems according to the invention can be used, for example membrane- or matrix-controlled systems.

Thus, the transdermal system according to the invention can be a patch having a reservoir (patch of the reservoir type).

According to a specific embodiment, a patch of this type having a reservoir can be characterized by

(a) an impermeable covering layer (backing foil),

(b) a layer-like element having a hollow space,

(c) a microporous or semi-permeable membrane,

(d) a self-adhesive layer (adhesive layer) and

(e) if appropriate a covering layer (release liner) which can be torn off.

In this case, the layer-like element having a hollow space can be formed by the covering layer and the membrane.

The microporous or semi-permeable membrane can consist of an inert polymer, for example polypropylene, polyvinyl acetate or silicone.

According to a further specific embodiment of the invention the patch of the reservoir type can be characterized by

(a) an impermeable covering layer (backing foil),

(b) an open-pore foam, a closed-pore foam, a fabric-like layer or a web-like layer as a reservoir,

(c) if the layer according to (b) is not self-adhesive, a self-adhesive layer (adhesive layer) and

(d) if appropriate a covering layer (release liner) which can be torn off.

The reservoir can thus be formed, for example by a hollow space or in another manner. The reservoir is in this case filled with the active compound/mixture of the auxiliaries. For accommodating the active compound in the reservoir, reference may be made to the prior art for reservoir systems. After tearing off the covering film (protective film) and sticking the patch on the skin, the active compound with the auxiliaries permeates (through the membrane provided if appropriate) through the covering layer into the skin.

If a membrane is provided, depending on the pore width, it can have an action controlling the release of the active compound or alternatively no influence on the release of active compound from the system.

If the reservoir is provided by an open-pore foam, a closed-pore foam, a fabric-like layer or a web-like layer, the active compound/mixture of the auxiliaries are present in absorbed or finely divided form. In this case, a microporous or semi-permeable membrane can be absent, and the layer forming the reservoir can be self-adhesive or (if that is not the case) can carry a self-adhesive layer (adhesive layer).

According to a specific embodiment, the transdermal system according to the invention can be characterized by

(a) an impermeable covering layer (backing foil),

(b) a matrix layer for the active compound,

(c) (if the layer according to (b) is not self-adhesive) an active compound-permeable contact adhesive layer and

(d) if appropriate a covering layer (release liner) which can be torn off.

The matrix used according to the invention can be a self-adhesive polyisobutylene adhesive.

Claim 1 of 22 Claims

What is claimed is:

1. A passive sustained release transdermal drug delivery system, comprising:

a matrix comprising polyisobutylene, butylene rubber, or mixtures thereof, and an angiotensin-converting enzyme inhibitor which comprises at least one of ramipril or trandolapril.

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