WO1997004757A1

WO1997004757A1 - Transdermal nitrate formulation

Info

Publication number: WO1997004757A1
Application number: PCT/IE1996/000047
Authority: WO
Inventors: William Byrne; Dermot Mccafferty
Original assignee: Cal International Ltd
Current assignee: Cal International Ltd
Priority date: 1995-07-27
Filing date: 1996-07-26
Publication date: 1997-02-13
Anticipated expiration: 1998-01-27
Also published as: AU6708996A

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 an isosorbide mononitrate aspirinate as a pharmaceutically active product to achieve antianginal and platelet washing properties.

Description

-Transdermal Nitrate Formulation"

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.

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 enzymeε 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 thromboxane 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.

The preparation of isosorbide mononitrate aspirinates used in the transdermal patches of the invention are described below.

EXAMPLE A

Preparation of isosorbide-5-nitrate-2-aspirinate

Acetylsalicoyl chloride (1.52 g, 7.6 mmol) is dissolved in dry dichloromethane (20 cm³). Triethyl amine (1.52 g, 2.1 cm³, 15 mmol) is added followed by isosorbide-5-nitrate (1.43 g, 7.5 mmol). The mixture is εtirred under an atmosphere of Nitrogen for 2 h. The reaction mixture is filtered, washed with water (2 x 20 cm³), sat. aq. εodium bicarbonate (2 x 20 cm³) and dried (Na₂S0₄). The volatiles are removed on a rotary evaporator and the residue triturated with diethyl ether to give a yellow solid which crystallises from ethanol to give compound 1 as a white crystalline solid (1.55 g, 58%). The product has the following physical-chemical properties :

appearance white solid

crystal habit tabular/prismatic

melting point 85-85-5°C at 1.5⁰C/min

optical rotation [α]_D= +935 (22.0°C, 1.01% in Dichloromethane

[αJ_D= + 102.0 (22.5°C, 1.0% in Ethanol)

(recorded on an optical activity LTD AA10 Automatic Polarimeter)

EXAMPLE B

Preparation of isosorbide-2-nitrate-5-aspirinate

Acetylsalicoyl chloride (1.52 g, 7.6 mmol) is dissolved in dry dichloromethane (20 cm³). Triethyl amine (1.52 g, 2.1 cm³, 15 mmol) is added followed by iεoεorbide-2-nitrate (1.43 g, 7.5 mmol). The mixture iε εtirred under an atmoεphere of Nitrogen for 3 h. The reaction mixture is then filtered, washed with water (2 x 20 cm³), sat. aq. sodium bicarbonate (2 x 20 cm³) and dried (Na₂S0-.) . The volatiles are removed on a rotary evaporator and the residue triturated with diethyl ether to give a yellow solid. This material crystallises from ethanol to give the compounds 2 as a white crystalline solid (1.8 g, 65%).

The compound has the following physical chemical properties :

appearance white solid

crystal habit tabular/prismatic melting point 90.5-92.0°C at 4o3C7min

IR(KBr) 855. 1085. 1128, 1134, 1195, 1292, 1275, 1255, 1639, 1727. 1769 cm^"1;

¹H NMR (300 MHz., CDC1₃), δ ppm 2.35 (3H, s, OC(O)Me), 3.94 (4H,m), 4.6 (IH, d, j5Hz.), 4.94 (IH, t, .|5.3Hz.), 5.38 (IH, m), 7.1 (IH, . ArH), 7.35 (IH, m, ArH), 7.6 (IH, m, ArH), 7.62 (IH, m, ArH).

¹³C NMR (75.5 MHz; CDC1₃), 20.9, 70.8, 71.4, 74.0, 76.6, 77.0, 81.1, 84.5, 85.9, 122.5.123.9, 126.1, 131.9, 134.3, 150.7, 163.6, 169.6.

Solubility Properties

Isosorbide mononitrate aspirinate is soluble in aqueous buffers of interest in the range 75 μg/ml to 140 μg/ml at room temperature. The drug was found to be most soluble in solvents with polarity indices in the range 4.0 to 6.0. The drug was soluble in oils to a low degree. Acetone (polarity index 5.1) was a good solvent (>200 mg of drug per ml). Acetonitrile (polarity index 5.8) was also found to be a good solvent for the drug, reinforcing the choice of acetonitrile as the organic component of the HPLC mobile phase.

In Vitro Hydrolysis Properties

Isosorbide mononitrate aspirinate exhibits the hydrolysis properties shown in Fig. 1 which illustrates the kinetics of ISMNA in buffered solutions, using real time analysis at pH 7.45.

Method

Three glass ampoules are taken and 250ul of ISMN-ASP (2.0ug/ul) were pippetted into each of the ampoules, followed by 4.75 mis of the buffer at pH 7.45. The 4 ( a )

ampoules were then placed in a water bath and removed at the appropriate time. When a set of samples were removed from the bath they were filtered with preheated apparatus and diluted 1:3 with aqueous mobile phase. The samples are then analysed by the method " Analytical method used for the examination of IsoSorbide MonoNitrate Aspirinate (ISMN-ASP)". The amounts calculated by the millenium software are then used to plot the kinetic graph. The graph shows the change ISMNA undergoes over the time period examined, and the evolution of the components that it degrades into. The graph shows concentration of these components in the ampoules expressed in umol/ml vs the time of sampling expressed in Hours.

It is clear from the graph that the isosorbide mononitrate aspirinate (ISMNA) hydrolyses into Isosorbide-mono-Nitrate (ISMN), Salicyclic Acid (Sal Acid), and Aspirin compounds known to express platelet washing and anti-anginal activities .

- 5 -

Stability of the Substance;

The dry substance is stable for three months at 40.0°C as demonstrated by Figs. 3 and 2, which shows the week 12 stability εample chromatogram and a blank chromatogram overplayed. The baεeline iε amplified so that degradation products, if present, could be seen.

A product of the present invention contains an aspirinate ester of an iεosorbide mono nitrate. The applicants demonstrate that in vitro hydrolysis of this ester occurs to give the components described above whose activity is complementary.

A product applicable to the invention, may be named as isosorbide-5-nitrate-2-aspirinate, or 2-(2-acetoxy- benzoyl)-isosorbide-5-nitrate, or 2-acetylsalicycloxy-l, 4:3, 6-dianhydro-D-glucitol-5-nitrate 1.

The product may also comprise isoεorbide-2-nitrate-5- aspirinate, or 5-(2-acetoxybenzoyl)-isoεorbide-2-nitrate, or 5-acetylsalicyloxy-l , 4 : 3, 6-dianhydro-D-glucitol-2- nitrate 2. - 6 -

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,

characteriεed in that

the adheεive containε an iεoεorbide mononitrate aεpirinate as a pharmaceutically active product having antianginal and platelet washing properties.

In one aspect, the invention provides a transdermal patch for sustained transdermal adminiεtration of an iεosorbide mononitrate aεpirinate to a patient in need of antianginal and platelet washing properties comprising a backing, an adhesive for applying the patch, in which an isosorbide mononitrate aspirinate is incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

In a further aspect, the invention provides use of an isosorbide mononitrate aspirinate 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 isosorbide mononitrate aspirinate is incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

The invention also provides a method for achieving a platelet washing and antianginal effect in a patient comprising the step of applying a transdermal patch - 7 -

compriεing a backing, an adhesive for applying the patch and a liner which is releaεed to apply the patch to the patient's skin, isosorbide mononitrate aspirinate being incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

The pharmaceutically active product may be isosorbide-5- nitrate-2-aspirinateorisosorbide-2-nitrate-5-aεpirinate.

Preferably the adheεive iε a preεsure εenεitive adhesive, baεed, for example, on acrylic acid copolymerε.

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. The liner may be a siliconiεed release liner. Typically the backing layer compriseε aluminised polyester. In one case the aluminised polyester iε 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 provideε a method for producing a tranεdermal patch comprising the stepε 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.

Alternatively, the invention provides a method for - 8 -

achieving an anti-platelet effect and for reducing platelet aggregation in a patient comprising the step of applying 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 aspirinate is 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 Fig. 4 which is a diagrammatic cross sectional view of a transdermal patch according to the invention.

Referring to Fig. 4, 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 - 9 -

aε, but not limited to, a fluoropolymeric-coated polyeεter (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 εkin. Unusually, this patch has been designed εo that εkin actε as the rate-determining membrane to drug diffusion. The advantage of this syεtem iε that this will provide the most efficient delivery of drug through the skin. This, in turn, will provide the εmallest 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 this invention iε that aspirin can be delivered systematically, in the form of isosorbide mononitrate aspirinate, thus avoiding first-pass metabolism.

A further aspect of this invention is the use of various penetration enhancers to promote the diffusion of isoεorbide mononitrate aεpirinate through the εkin to the systemic circulation. This would also reduce the εize (area) of patch required to deliver a given amount of drug to the systemic circulation. In vitro studies have indicated that it is possible to greatly increase drug penetration. 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 silicone-based adhesiveε. Other excipients present in the formulation may include plasticisers such aε diethylphthalate, dibutylphthalate, and/or glycerol. - 10 -

Example 1

A transdermal delivery system for isosorbide mononitrate aspirinate was prepared as follows. A pressure sensitive adhesive solution (PSA), was prepared using DURO-TAK 387- 2054 dissolved in ethyl acetate. Solid polymer content was 7.5% w/w. 200 mg of isosorbide mononitrate aspirinate was dissolved in 20 g of PSA and cast onto a fluoropolymer coated white 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. The dry weight was 5 g. Thereafter, 1 cm² sections were cut from the laminate and examined for drug release using silicone-based (Silescol) sheeting in a modified Franz cell (Fig. 5). Similar experiments were undertaken using porcine skin (Fig. 6) and human stratum corneum (Fig. 7).

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

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

Example 2

The same procedure was used as for Example 1 except 400 mg of isosorbide mononitrate aspirinate were used. Drug release profiles are also shown in Figs. 5 - 6.

Example 3

The same procedure was used as for Example 1 except 800 mg of isosorbide mononitrate aspirinate were used. Drug - 11 -

release profiles are shown in Figs. 5 - 6.

Example 4

The same procedure was used as for Example 1 except 20 g of PSA solution was employed. The drug release profile is shown in Fig. 8.

Example 5

The same procedure was used as for Example 1 except that a siliconised release liner, Hostaphan RN 100 was used.

Example 6

The same procedure was used as for Example 1 except that 880 mg of propylene glycol was included. The drug release characteristics are shown in Fig. 9.

Example 7

The same procedure was used as for Example 1 except that 680 mg of limonene was included. The drug release characteristics are shown in Fig. 9.

Example 8

The same procedure was used as for Example 1 except that

440 mg of propylene glycol and 340 mg of limonene was included. The drug release characteristics are shown in Fig. 9.

Example 9

The same procedure was used as for Example 1 except that 3 . 5 g of DURO-TAK 387-2054 was used . The drug release - 12 -

characteristics are shown in Fig. 10.

Example 10

The same procedure was used as for Example 1 except that 5 g of DURO-TAK 387-2054 was used. The drug release characteristics are shown in Fig. 10.

Example 11

The same procedure was used as for Example 1 except that 5 g of DURO-TAK 387-2516 was used. The drug release characteristics are shown in Fig. 10.

Example 12

The same procedure was used as for Example 1 except that 7.5 g of DURO-TAK 387-2516 was used. The drug release characteristics are shown in Fig. 10.

In vivo Studies

Patch samples of 91cm² containing 2 mg/cm² of isosorbide mononitrate aspirinate were prepared as outlined in Example 1 and applied to eight human volunteers for a 24 hour period (volunteer 5 withdrew from the study after 10 hours due to development of a headache). Blood samples were taken at 0, 24 and 96 hours. Platelet aggregation behaviour, thromboxane B2 and isosorbide mononitrate plasma concentrations were all determined. The percentage reduction in platelet aggregation is shown in Fig. 11 and thromboxane B2 plasma concentrations are shown in Fig. 12. [Initial isosorbide mononitrate plasma concentrations are in the low 5 to 30 mg ml^"1 level]. - 13 -

It will be noted that there was a marked reduction in platelet aggregation even after a 24 hour application. It was also surprising that this reduction in platelet aggregation was evident, in some cases more pronounced, even upon completion of the study at 96 hours (Fig. 12). In general, as shown in Fig. 11, thromboxane plasma concentrations correlated well with platelet aggregation data.

Hplc analysis of the compound after four months stability at 40°C indicated that the compound had not degraded and nor could any degradation production be seen.

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

Claims

- 14 -C AIMS

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

the adhesive contains an isosorbide mononitrate aspirinate as a pharmaceutically active product having antianginal and platelet waεhing propertieε.

2. A transdermal patch as claimed in claim 1 wherein the adheεive contains isosorbide-5-mononitrate-2- aspirinate.

3. A transdermal patch as claimed in claim 1 wherein the adhesive contains isoεorbide-2-mononitrate-5- aεpirinate.

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

5. A transdermal patch as claimed in claim 4 wherein the adhesive is based on acrylate acid copolymers.

6. A transdermal patch as claimed in any preceding claim wherein the adhesive is applied to the release liner. - 15 -

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

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

9. A transdermal patch as claimed in any of claims 1 to 6 wherein the liner is a siliconised releaεe liner.

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

11. A transdermal patch as claimed in claim 10 wherein the aluminised polyester is sputter coated onto the adhesive.

12. A transdermal patch as claimed in any preceding claim including a penetration enhancer to promote the diffusion of the pharmaceutically active product.

13. A transdermal patch as claimed in claim 12 wherein the penetration enhancer is selected from one or more of: propylene glycol, oleic acid, isopropyl myristate, dimethylsulphoxide, ethanol or limonene.

14. A transdermal patch subεtantially aε hereinbefore deεcribed with reference to the examples and drawings. - 16 -

15. A method for producing a transdermal patch comprising the steps of incorporating an isoεorbide mononitrate aεpirinate aε 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.

16. A method as claimed in claim 15 wherein the isosorbide mononitrate aspirinate is iεosorbide- 5-mononitrate-2-aspirinate.

17. A method as claimed in claim 15 wherein the isosorbide mononitrate aspirinate is isoεorbide- 2-mononitrate-5-aspirinate.

18. A method for producing a transdermal patch subεtantially aε hereinbefore deεcribed with reference to the examples and drawings.

19. A transdermal patch whenever produced by a method as claimed in any of claims 15 to 18.

20. 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 14 or 19.

21. A method for achieving an anti-platelet effect and for reducing platelet aggregation in a patient substantially as hereinbefore described with reference to the examples and drawings. - 17 -

22. A transdermal patch for sustained transdermal administration of an isosorbide mononitrate aspirinate to a patient in need of antianginal and platelet washing properties comprising a backing, an adhesive for applying the patch, in which an isoεorbide mononitrate aεpirinate is incorporated in the adheεive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

23. Use of an iεosorbide mononitrate aspirinate 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 iεosorbide mononitrate aspirinate is incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

24. A method for achieving a platelet washing and antianginal 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, isoεorbide mononitrate aspirinate being incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plaεma levelε.