IE63878B1 - Transdermal therapeutical system comprising norpseudoephedrine as active component - Google Patents

Abstract

The invention relates to a transdermal therapeutic system for applying an active substance to the skin and consisting of a backing layer impermeable to the active substance, a reservoir layer and, if appropriate, a detachable protective layer, the reservoir layer being adhesive and containing 10-90% by weight of polymer material, 0-30% by weight of softener and 0.1-20% by weight of a norpseudoephedrine.

Description

The present invention relates to a transdermal therapeutical t system comprising norpseudoephedrine as active component.

The amphetamines, the chemical group many of the antiadi10 pogenics belong to, were discovered as early as in the nineteen thirties, however were prescribed only as remedy against fatigue. Even later, it was recognized that these pharmaceuticals had another therapeutically useful effect they reduce the sensation of hunger. It was achieved by systematic synthesis of the pharmaceutical to develop substances which emphasize the reduction of the feeling of hunger, while neglecting the stimulating component. Nevertheless, the following aspects have to be considered in the application of such antiadipogenics: - They must not be combined with certain other medicines (neither with alcohol) - Drug habituation and drug addiction have to be observed - Intravenous injections are to be avoided due to the danger > of induction of blood level peaks.

Legislation as well as the pharmaceutical industry take into account these facts, on the one hand in that 'liquid drugs are sold only on prescription while the solid ones are OTC-pharmaceuticals, and, on the other hand, in that due to the development of orally adminstrable controlled release drugs the dosage of the antiadipogenics may be reduced, the blood levels, however, may be kept constant. Since, nowadays, the medical profession is of the opinion that the administration form contributes to the addiction to a substance (a constant blood level is by far more favourable as the rapid change of blood level peaks with overdose and intervals with undersupply), it is obvious to develop controlled release drugs which create an even better constant concentration level than the oral ones are able to provide. Since, although the common oral forms of controlled release drugs are a masterly achievement of galenic technology, which under in-vitro-conditions, i.e. in artificial gastric or intestinal juices, create optimum release, they cannot guarantee constant blood levels, since the resorption of drug substance from the gastrointestinal tract is considerably influenced by the evacuation time of the stomach which is retarded by the ingestion of food as a function of the volume and the composition of the nourishment. Furthermore, pH-value shifs in the stomach occur during the ingestion and the diffusion effective gradients decrease due to mixing of the gastric juice with the chyme. The significance of the pH-value conditions within the stomach for the gastral resorption is underlined by tests in which the gastric juice was alkalized. It was proved in aminal tests that after alkalization of the stomach content with NaHCO3 to pH : 8.0, the resorption from the stomach was reduced in the case of weak acids corresponding to the pKa-value and increased in the case of weak bases. Since amphetamines are bases of medium strength (pKa-value D-norpseudoephedrine : 8.9), the effect of the pH-value depending resorption is not distinctive, but it should not be neglected at all. ' The use of so-called therapeutical systems is suitable for the creation of an active substance concentration which is as constant as possible; said therapeutical systems are defined as a drug containing device or administration form, respectively, which continuously releases a drug or several 3' drugs at a predefined rate over a predetermined period of time onto a defined place of application (cf. Heilmann, Therapeutische Systeme, 4th edition, Enke publishers, Stuttgart 1984, page 26). An oral therapeutical system, e.g., as described in EP 0 237 159, however, is no solution to the problem described, since bases of medium strength better dissolve in acidic gastric juice than in neutral gastric juice. Thus the release becomes pH-value dependent.

In US-PS 4,292,301 the transdermal release of ephedrine from a non-adhesive polymeric matrix has been described, however, the ephedrine exhibits only a weak efficiency as antiadipogenic.

Thus it is the object of the present invention to provide norpseudoephedrine as antiadipogenic or an agent, respectively, in a form with which a by far improved, constant active substance level in contrast to the oral form of controlled release drugs is achieved, in order to overcome the disadvantages of the prior art.

According to the present invention this object is surprisingly achieved by a transdermal therapeutical system which releases an antiadipogenic to the skin comprising a backing layer which is imDermeable to active substances, a reservoir layer, and optionally a removable protective layer, and which’ is characterized in that the reservoir layer is pressure-sensitive adhesive and comprises 10-90%-wt polymeric material, 0-30%-wt softener, and 0.1-20%-wt norpseudoephedrine.

This solution is surprising all the more, since norpseudoephedrine has to be applied in daily dosages, and this normally cannot be achieved in acceptable ranges by transdermal therapeutical systems.

In this connection, the backing layer which is impermeable to active substances may consist of flexible or non-flexible material. Substances suitable for the production are polymeric foils or metal foils, such as aluminium foils which can be used alone or coated with a polymeric substrate. Textile fabrics may be used as well, if the components of the reservoir, due to their physical properties, cannot penetrate through the fabrics. In a preferred embodiment the backing layer is a nonwoven fabric from a foil vapourized with aluminium.

The reservoir layer consists of a polymeric matrix and the active substance, whereby the polymeric matrix guarantees the coherence of the system. The matrix consists of a basic polymer and optionally of common additives. The selection of the basic polymer depends on the chemical and physical properties of the active substance used. Examples for polymers are rubber, rubber-like synthetic homopolymers, copolymers or block polymers, polyacrylic acid esters and their copolymers, polyurethanes, and silicones. In principle all polymers are suitable which are used in the production of pressure-sensitive adhesives and which are physiologically acceptable. It is particularly preferred to use those polymers consisting of block copolymers on the basis of styrene and 1,3-dienes, polyisobutylenes, polymers of acrylate and/or methacrylate. In particular, linear styrene-isoprene block copolymers are used from the group of block copolymers on the basis of styrene and 1,3-dienes.

Acrylate-copolymers of 2-ethylhexylacrylate, vinyl acetate, and acrylic acid with or without titane chelate ester are preferred as polymers on acrylate basis. Copolymers on the basis of dimethylaminoethyl methacrylates and neutral meth5 acrylic acid esters are preferred as methacrylates. As esters of hydrogenated colophonium its methyl and glyceryl esters are particularly preferred.

The kind of possible additive depends on the polymer used and the active substance: According to their function they can be divided into softeners, tackifiers, stabilizers, carriers, diffusion and penetration regulating additives or fillers. Suitable physiologically acceptable substances are known to the man skilled in the art. The reservoir layer has such a self-adhesiveness that a constant contact to the skin is guaranteed.

Examples for suitable softeners are diesters of dicarboxylic acids, such as di-n-butyl adipate and triglycerides, particularly medium chain triglycerides of the caprylic/capric acid of coconut oil. Further examples for suitable softeners are glycerol, propanediol (1,2) etc.

The removable protective layer, which is in contact with the reservoir layer and is removed prior to application, for example consists of the same materials as are used for the production of the backing layer, provided that they are rendered removable, for example by way of a silicone treatment. Further detachable protective layers, e.g., are polytetrafluoroethylene, treated paper, cellophane, polyvinyl chloride, etc. If the laminate according to the present * invention is cut into suitable sizes (plasters) prior to applying the protective layer, the dimensions of the protective layer to be applied may have overlapping ends, so that they may be removed from the plaster more easily.

According to the present invention, norpseudoephedrine is used as antiadipogenic, since it exhibits the lowest ten6 dency to dependence of all antiadipogenics.

The transdermal therapeutical system according to the present invention is produced in that the active substance together with the components of the pressure-sensitive reservoir layer, optionally in solution, are homogeneously admixed and coated onto the backing layer which is impermeable to the active substance, then optionally the solvent or solvents is/are removed. Subsequently, the adhesive layer is provided with a suitable protective layer.

The invention is illustrated but not limited by the following examples; Preparation - Example 1: 4.3 g n-heptane and 15.7 g butanone are mixed. 4.0 g norpseudoephedrine, free base, is dissolved therein. After complete dissolution of the active substance there is added by portions 23.5 g of a glyceryl ester of completely hydrogenated colophonium, 15.5 g of a linear styrene-butadiene-styrene block copolymer, 3.9 g methyl ester of hydrogenated colophonium and 3.1 g triglycerides of the caprylic/capric acid of coconut oil (medium chain triglycerides DAB 8 (= The German Pharmacopeia, 1978). Under elimination of light it is stirred up to complete dissolution (approximately 8 hours) and the solution obtained is coated onto a aluminized and siliconized polyethylene foil with a 300pm coating knife.

After removal of the solvent by drying at 50°C in the drying channel for 25 minutes, the adhesive film is covered with a polyester foil of 15μ. Sizes of 16cm2 and 50cm2, respectively, are punched with an adequate cutting tool and the edges are separated off. The diagram of the in-vitro-release is shown in figure 1. It shows the controlled active substance release from a 16 cm2 plaster in. physiological saline. Furthermore, a healthy volunteer wore a 50 cm2 plaster for 12 hours, which contains 52 mg norpseudoephedrine, free base, having an area weight of 130 g/m2. After removal of the system the residual content was determined at approximately 17 mg, so that approximately 35 mg/50 cm2 have been diffused through human skin within 12 hours.

Thus, the therapeutically required value has been surpassed.

Preparation - Example 2: g butanone and 15 g ethylacetate are mixed. 10.0 g norpseudoephedrine, free base, is dissolved therein. After complete dissolution of the active substance there is added by portions 17.5 g of a glyceryl ester of completely hydrogenated colophonium and 22.5 g of a linear styrene-butadiene-styrene block copolymer. Under elimination of light it is stirred up to complete dissolution (approximately 8 hours) and the solution obtained is coated onto a aluminized and siliconized polyethylene foil (thickness: 100 pm) with a 350pm coating knife.

After removal of the solvent by drying at 50"C in the drying channel for 25 minutes, the adhesive film is covered with a polyethylene foil (thickness: 15pm). Sizes of 16cm2 are punched with an adequate cutting tool and the edges are separated off. The diagram of the in-vitro-release is shown in figure 2. It shows the controlled release of the active substance from a 16 cm2 plaster in physiological saline. Furthermore, the in-vitro penetration was determined with excised mice skin. It amounts to 9.8 mg/16 cm2 x 24 h and thus lies in the range of example 1 without the addition of a softener.

Claims (15)

1. A transdermal therapeutical system for the administration of an antiadipogenic to the skin comprising a backing layer which is 10 impermeable to the active substance, a reservoir layer, and optionally a removable protective layer, characterized in that the reservoir layer is pressure-sensitive adhesive and comprises 10-90% by weight polymeric material, 0-30% by weight softener and, as active substance, 0.1-20% by weight norpseudoephedrine, the active substance being present in 15 homogeneous mixture with the components of the pressure-sensitive adhesive reservoir layer.

2. The transdermal therapeutical system according to claim 1, characterized in that the polymeric material is selected from the group 20 consisting of block copolymers on the basis of styrene and 1,3-dienes, polyisobutylenes, polymers on the basis of acrylate and/or methacrylate, and esters of hydrogenated colophonium.

3. The transdermal therapeutical system according to claim 2, 25 characterized in that the polymeric material comprises linear styrene-isoprene block copolymer.

4. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises linear 30 styrene-butadiene block copolymer.

5. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises self-crosslinking acrylate copolymer of 2-ethylhexyl acrylate, vinyl 35 acetate, acrylic acid, and titanium chelate ester.

6. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises non-self-crosslinking acrylate copolymers of 2-ethylhexyl acrylate, vinyl acetate, and acrylic acid.

7. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises as polymer on the basis of methacrylates a copolymer of dimethylaminoethyl methacrylate and neutral methacrylic acid esters.

8. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises as ester of the hydrogenated colophonium the methylesters thereof.

9. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises as ester of the hydrogenated colophonium the glyceryl esters thereof.

10. The transdermal therapeutical system according to claim 1, characterized in that the softeners are selected from the group consisting of vicinal alcohols and esters.

11. The transdermal therapeutical system according to claim 10, characterized in that it comprises propanediol-1,2 as softener.

12. The transdermal therapeutical system according to claim 10, characterized in that it comprises di-n-butyl adipate as softener.

13. The transdermal therapeutical system according to claim 10, characterized in that it comprises triglycerides as softener.

14. The transdermal therapeutical system according to claim 10, characterized in that it comprises glycerol as softener

15. A transdermal therapeutical system according to claim 1 substantially as hereinbefore described. TOMKINS & CO.