WO1997004758A1

WO1997004758A1 - Pharmaceutical preparation for percutaneous absorbtion

Info

Publication number: WO1997004758A1
Application number: PCT/IE1996/000048
Authority: WO
Inventors: William Byrne; Dermot Mccafferty
Original assignee: Cal International Limited
Priority date: 1995-07-27
Filing date: 1996-07-26
Publication date: 1997-02-13
Also published as: AU6709096A

Abstract

A transdermal patch comprises a backing, an adhesive for applying the patch, and a liner which is released to apply the patch. The adhesive contains both aspirin and an isosorbide mononitrate to achieve both anti-anginal and platelet washing properties.

Description

"Pharmaceutical Preparation for Percutaneous Absorbtion"

The invention relates to a transdermal patch.

Isosorbide nitrates are dilators of arterial and venous smooth muscle. The dilation on the venous system maintains or increases coronary artery flow while simultaneously reducing the oxygen requirement of the heart muscle. Patients with coronary artery narrowing frequently suffer from angina pectoris. The ability of the isosorbide mono nitrates (isosorbide-5-nitrate and isosorbide-2-nitrate) to function as vasodilators, in the manner described above, has lead to their extensive use in the prophylaxis of angina pectoris.

Nitrates have been formulated in many different ways to provide clinical relief of angina. For example, glyceryl trinitrate has been formulated as a sublingual tablet, spray and as a transdermal patch. Modified-release oral preparations (tablets and capsules) have also been made using the longer-acting nitrates, isosorbide dinitrate and isosorbide mononitrate. However, to best knowledge, there are no commercially available transdermal products containing these longer-acting nitrates.

Aspirin alters the balance between TXA₂ which promotes aggregation and prostacyclin (PGI₂) which inhibits it. Aspirin inactivates cyclo-oxygenase, acting mainly by irreversibly acetylating the active site on the enzyme, COX-1. This reduces both TXA₂ synthesis in platelets and prostacyclin synthesis in endothelium. Vascular endothelial cells can synthesise new enzymes whereas platelets cannot. After administration of Aspirin, TXA₂ synthesis does not recover until the affected cohort of platelets is replaced. This process typically takes 7 - 10 days. Also, inhibition of the cyclo-oxygenase of the vascular endothelium requires higher concentrations of aspirin than does platelet cyclo-oxygenase. Therefore low doses of aspirin decrease the synthesis of thro boxane A₂ without drastically reducing prostacyclin synthesis. Clinical trials have now demonstrated the efficacy of aspirin treatment regimes for acute myocardial infarction, in reducing the incidence of reinfarction following recovery and in preventing occlusive vascular disease in individuals at particular risk.

Thus, it is now generally accepted that low-dose acetylsalicyclic acid (aspirin) can be beneficial as an anti-platelet agent. However, the oral delivery of aspirin may cause mucosal irritation, and bleeding, in susceptible individuals. Therefore, an alternative route of administration for aspirin would obviate these unwanted gastrointestinal side-effects.

According to the invention there is provided a transdermal patch comprising :-

a backing;

an adhesive for applying the patch; and

a liner which is released to apply the patch,

characterised in that

the adhesive contains a pharmaceutical product having anti-anginal and platelet washing properties.

In one aspect, the invention provides a transdermal patch for sustained transdermal administration of a pharmaceutical product having anti-anginal and platelet washing properties to a patient in need of such properties comprising a backing, an adhesive for applying the patch, in which a pharmaceutical product having anti-anginal and platelet washing properties is incorporated in the adhesive on an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

The invention also provides the use of a pharmaceutical product having anti-anginal and platelet washing properties for preparing a transdermal patch comprising a backing, an adhesive for applying the patch, and a liner which is released to apply the patch, in which the pharmaceutical product is incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

The invention further provides a method for achieving a platelet washing and anti-anginal effect in a patient comprising the step of applying a transdermal patch comprising a backing, an adhesive for applying the patch, and a liner which is released to apply the patch to the patient's skin, a pharmaceutical product having anti- anginal and platelet washing properties being incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

In a particularly preferred embodiment of the invention the pharmaceutical product comprises a first pharmaceutical having antianginal properties and a second pharmaceutical having platelet washing properties.

Preferably the first pharmaceutical is Aspirin. Preferably the second pharmaceutical is an organic nitrate, especially a long acting nitrate. In a particularly preferred embodiment of the invention the nitrate is isosorbide mononitrate, especially isosorbide 2- mononitrate or isosorbide-5-mononitrate. The nitrate may also be isosorbide dinitrate.

In a preferred embodiment of the invention the first pharmaceutical and the second pharmaceutical are incorporated into the adhesive. Preferably the adhesive is a pressure sensitive adhesive, based, for example, on acrylic acid copolymers.

In one embodiment of the invention, the adhesive is applied to the release liner. Typically, the release liner is a fluoro-polymeric-coated polyester.

Preferably, the backing comprises a backing layer attached to the adhesive. Alternatively, the liner is a siliconised release liner. Typically the backing layer comprises aluminised polyester. In one case the aluminised polyester is sputter coated onto the adhesive.

In another embodiment of the invention the patch includes a penetration enhancer to promote the diffusion of the pharmaceutically active product.

The invention also provides a method for producing a transdermal patch comprising the steps of incorporating a pharmaceutically active product having antianginal and platelet washing properties into an adhesive,

coating the adhesive onto a release liner, and

applying a backing layer.

According to another aspect, the invention provides a method for achieving an anti-anginal effect and for reducing platelet aggregation in a patient comprising the step of applying to a patient a transdermal patch of the invention .

The purpose of the present invention is to provide a once daily treatment for the prophylaxis of angina in combination with an anti-platelet effect. To achieve this isosorbide mononitrate and aspirinate are delivered transdermally for up to a 24 hour period in an amount sufficient to provide therapeutic efficacy. Due to the comparatively long half-life of isosorbide mononitrate it may be preferable to leave the isosorbide mononitrate aspirinate transdermal patch in contact with skin for a period of time less than 24 hours. Although circulating concentrations of isosorbide mononitrate would decrease it is likely that there would be sufficient residual plasma levels of the compound to prevent pre-dose rebound due to the comparatively long half-life of isosorbide mononitrate.

The invention will be more clearly understood from the following description thereof given by way of example only with reference to the accompanying drawing which is a diagrammatic cross sectional view of a transdermal patch according to the invention.

Referring to the drawing, there is illustrated a transdermal patch according to the invention comprising a pressure sensitive adhesive layer (b) into which the pharmaceutically active product is incorporated, a release liner (c) and a backing (a).

The drug has been incorporated directly into a pressure- sensitive adhesive such as, but not limited to, acrylic acid copolymers (b) . This mixture can then be cast, rolled or knife-coated onto a suitable release-liner such as, but not limited to, a fluoropolymeric-coated polyester (c) . A backing-layer such as, but not limited to, a sputter-coated aluminised polyester (to prevent drug strike though) can then be attached (a). The release- liner (c) is removed before the drug containing adhesive is presented to the skin. Unusually, this patch has been designed so that skin acts as the rate-determining membrane to drug diffusion. The advantage of this system is that this will provide the most efficient delivery of drug through the skin. This, in turn, will provide the smallest unit area of skin for drug delivery and hence the smallest patch size. This is an important consideration given the possible daily amounts of drug required by the transdermal route.

A further advantage of the invention is that aspirin can be delivered directly into the system thus avoiding first pass metabolism. Furthermore, delivering Aspirin transdermally will also prevent its known adverse side- effects on the gastrointestinal tract in some patients.

A further aspect of this invention is the use of various penetration enhancers to promote the diffusion of isosorbide mononitrate and aspirin through the skin to the systemic circulation. The advantage of this is in reducing the size (area) of the patch required to deliver a specific amount of the drugs to the systemic circulation. Examples of such penetration enhancers include, but is not limited to, propylene glycol, oleic acid, isopropyl myristate, dimethylsulphoxide, ethanol, and/or limonene.

A variety of suitable matrices may be used as a drug reservoir. These include the above mentioned acrylate co- polymers, polyisobutylenes and silicon-based adhesives. Other excipients present in the formulation may include plasticisers such as diethylphthalate, dibutylphthalate and/or glycerol. Example 1

A transdermal system for isosorbide mononitrate and aspirin was prepared as follows. A pressure sensitive adhesive solution (PSA) was prepared using DURO-TAK 387- 2054 dissolved in ethyl acetate. 108 mg of isosorbide mononitrate and 102 mg of aspirin were dissolved in 20 g of PSA and cast onto a siliconised polyester release liner using a 10 x 10 cm template. The film was oven dried after which an aluminium sputter-coated polyester backing layer was attached to the exposed, drug-containing, adhesive film (dry weight 5 g) . Thereafter, 1 cm² sections were cut from the laminate and examined for drug release using silicone-based (Silescol) sheeting in a Franz cell

(Fig. 2).

Patches (5 x 5 cm²) were also applied to 5 human volunteers for a 24 hour period. Thereafter, the patches were removed and extracted for remaining ISMN and aspirin. It can be seen from Fig. 3 that, typically, 20 - 30% of ISMN had been absorbed from the patches within a 24 hour period and that, typically, 30 - 40% of aspirin had been absorbed from the patches within a 24 hour period.

DURO-TAK are a range of adhesives available from National Starch.

Silescol is manufactured by Esco Rubber and is available from Bibby Sterilin.

The invention is not limited to the embodiments hereinbefore described which may be varied in detail.

Claims

1. A transdermal patch comprising :-

a backing;

an adhesive for applying the patch; and

a liner which is released to apply the patch,

characterised in that

2. A transdermal patch as claimed in claim 1 wherein the pharmaceutical product comprises a first pharmaceutical having antianginal properties and a second pharmaceutical having platelet washing properties.

3. A transdermal patch as claimed in claim 2 wherein the second pharmaceutical is Aspirin.

4. A transdermal patch as claimed in claim 2 or 3 wherein the first pharmaceutical is an organic nitrate.

5. A transdermal patch as claimed in claim 4 wherein the organic nitrate is a long acting nitrate.

6. A transdermal patch as claimed in claim 5 wherein the organic nitrate is isosorbide mononitrate.

7. A transdermal patch as claimed in claim 5 wherein the organic nitrate is isosorbide dinitrate.

8. A transdermal patch as claimed in claim 5 wherein the organic nitrate is isosorbide-2-nitrate.

9. A transdermal patch as claimed in claim 5 wherein the organic nitrate is isosorbide-5-nitrate.

10. A transdermal patch as claimed in any of claims 2 to 9 wherein the first pharmaceutical and the second pharmaceutical are incorporated into the adhesive.

11. A transdermal patch as claimed in any preceding claim wherein the adhesive is a pressure sensitive adhesive.

12. A transdermal patch as claimed in claim 11 wherein the adhesive is based on acrylic acid copolymers.

13. A transdermal patch as claimed in any preceding claim wherein the adhesive is applied to the release liner.

14. A transdermal patch as claimed in any preceding claim wherein the release liner is a fluoro-polymeric-coated polyester.

15. A transdermal patch as claimed in any of claims 1 to 14 wherein the liner is a siliconised release liner.

16. A transdermal patch as claimed in any preceding claim wherein the backing comprises a backing layer attached to the adhesive.

17. A transdermal patch as claimed in any preceding claim wherein the backing layer comprises aluminised polyester.

18. A transdermal patch as claimed in claim 17 wherein the aluminised polyester is sputter coated onto the adhesive.

19. A transdermal patch as claimed in any of claims 2 to 18 including a penetration enhancer to promote the diffusion of the first and/or second pharmaceutical.

20. A transdermal patch as claimed in claim 19 wherein the penetration enhancer is selected from one or more of propylene glycol, oleic acid, isopropyl myristate, dimethylsulphoxide, ethanol or limonene.

21. A transdermal patch substantially as hereinbefore described with reference to the example and drawings.

22. A method for producing a transdermal patch comprising the steps of incorporating a first pharmaceutical having antianginal properties and a second pharmaceutical having platelet washing properties into an adhesive; coating the adhesive onto a release liner; and applying a backing layer.

23. A method for producing a transdermal patch substantially as hereinbefore described with reference to the example and drawing.

24. A transdermal patch whenever produced by a method as claimed in claim 22 or 23.

25. A method for achieving an anti-anginal effect and for reducing platelet aggregation in a patient comprising the step of applying to a patient a transdermal patch as claimed in any of claims 1 to 21 or 24.

26. A method for achieving an anti-anginal effect and for reducing platelet aggregation in a patient substantially as hereinbefore described with reference to the examples and drawings.

27. A transdermal patch for sustained transdermal administration of a pharmaceutical product having anti-anginal and platelet washing properties to a patient in need of such properties comprising a backing, an adhesive for applying the patch, in which a pharmaceutical product having anti-anginal and platelet washing properties is incorporated in the adhesive on an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

28. Use of a pharmaceutical product having anti-anginal and platelet washing properties for preparing a transdermal patch comprising a backing, an adhesive for applying the patch, and a liner which is released to apply the patch, in which the pharmaceutical product is incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

29. A method for achieving a platelet washing and anti¬ anginal effect in a patient comprising the step of applying a transdermal patch comprising a backing, an adhesive for applying the patch, and a liner which is released to apply the patch to the patient's skin, a pharmaceutical product having anti-anginal and platelet washing properties being incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.