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WO1997004757A1 - Formulation transdermique a base de nitrate - Google Patents

Formulation transdermique a base de nitrate Download PDF

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Publication number
WO1997004757A1
WO1997004757A1 PCT/IE1996/000047 IE9600047W WO9704757A1 WO 1997004757 A1 WO1997004757 A1 WO 1997004757A1 IE 9600047 W IE9600047 W IE 9600047W WO 9704757 A1 WO9704757 A1 WO 9704757A1
Authority
WO
WIPO (PCT)
Prior art keywords
adhesive
transdermal patch
patch
mononitrate
aspirinate
Prior art date
Application number
PCT/IE1996/000047
Other languages
English (en)
Inventor
William Byrne
Dermot Mccafferty
Original Assignee
Cal International Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cal International Limited filed Critical Cal International Limited
Priority to AU67089/96A priority Critical patent/AU6708996A/en
Publication of WO1997004757A1 publication Critical patent/WO1997004757A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates

Definitions

  • 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.
  • glyceryl trinitrate has been formulated as a sublingual tablet, spray and as a transdermal patch.
  • Modified-release oral preparations have also been made using the longer-acting nitrates, isosorbide dinitrate and isosorbide mononitrate.
  • Aspirin alters the balance between TXA 2 which promotes aggregation and prostacyclin (PGI 2 ) which inhibits it. Aspirin inactivates cyclo-oxygenase, acting mainly by irreversibly acetylating the active site on the enzyme, COX-1. This reduces both TXA 2 synthesis in platelets and prostacyclin synthesis in endothelium. Vascular endothelial cells can synthesise new enzyme ⁇ whereas platelets cannot. After administration of Aspirin, TXA 2 synthesis does not recover until the affected cohort of platelets is replaced. This process typically takes 7 - 10 days.
  • acetylsalicyclic acid can be beneficial as an anti-platelet agent.
  • aspirin acetylsalicyclic acid
  • 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.
  • Acetylsalicoyl chloride (1.52 g, 7.6 mmol) is dissolved in dry dichloromethane (20 cm 3 ). Triethyl amine (1.52 g, 2.1 cm 3 , 15 mmol) is added followed by isosorbide-5-nitrate (1.43 g, 7.5 mmol). The mixture is ⁇ tirred under an atmosphere of Nitrogen for 2 h. The reaction mixture is filtered, washed with water (2 x 20 cm 3 ), sat. aq. ⁇ odium bicarbonate (2 x 20 cm 3 ) and dried (Na 2 S0 4 ).
  • 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 :
  • Acetylsalicoyl chloride (1.52 g, 7.6 mmol) is dissolved in dry dichloromethane (20 cm 3 ). Triethyl amine (1.52 g, 2.1 cm 3 , 15 mmol) is added followed by i ⁇ o ⁇ orbide-2-nitrate (1.43 g, 7.5 mmol). The mixture i ⁇ ⁇ tirred under an atmo ⁇ phere of Nitrogen for 3 h. The reaction mixture is then filtered, washed with water (2 x 20 cm 3 ), sat. aq. sodium bicarbonate (2 x 20 cm 3 ) and dried (Na 2 S0-.) . 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 :
  • Isosorbide mononitrate aspirinate is soluble in aqueous buffers of interest in the range 75 ⁇ g/ml to 140 ⁇ g/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.
  • 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.
  • 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.
  • ISMN-ASP IsoSorbide MonoNitrate Aspirinate
  • ISMNA isosorbide mononitrate aspirinate
  • 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 ⁇ ample chromatogram and a blank chromatogram overplayed.
  • a product of the present invention contains an aspirinate ester of an i ⁇ osorbide 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 iso ⁇ orbide-2-nitrate-5- aspirinate, or 5-(2-acetoxybenzoyl)-iso ⁇ orbide-2-nitrate, or 5-acetylsalicyloxy-l , 4 : 3, 6-dianhydro-D-glucitol-2- nitrate 2. - 6 -
  • transdermal patch comprising :-
  • the adhe ⁇ ive contain ⁇ an i ⁇ o ⁇ orbide mononitrate a ⁇ pirinate as a pharmaceutically active product having antianginal and platelet washing properties.
  • the invention provides a transdermal patch for sustained transdermal admini ⁇ tration of an i ⁇ osorbide mononitrate a ⁇ pirinate 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.
  • 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 -
  • a backing for applying the patch and a liner which is relea ⁇ ed 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-a ⁇ pirinate.
  • the adhesive is applied to the release liner.
  • the release liner is a fluoro-polymeric-coated polyester.
  • the backing comprises a backing layer attached to the adhesive.
  • the liner may be a siliconi ⁇ ed release liner.
  • the backing layer comprise ⁇ aluminised polyester. In one case the aluminised polyester i ⁇ sputter coated onto the adhesive.
  • the patch in another embodiment of the invention includes a penetration enhancer to promote the diffusion of the pharmaceutically active product.
  • the invention also provide ⁇ a method for producing a tran ⁇ dermal patch comprising the step ⁇ of incorporating a pharmaceutically active product having antianginal and platelet washing properties into an adhesive,
  • the invention provides a method for - 8 -
  • 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.
  • 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.
  • Fig. 4 is a diagrammatic cross sectional view of a transdermal patch according to the invention.
  • a transdermal patch 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) .
  • 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 -
  • a ⁇ but not limited to, a fluoropolymeric-coated polye ⁇ ter (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 ⁇ kin.
  • this patch has been designed ⁇ o that ⁇ kin act ⁇ as the rate-determining membrane to drug diffusion.
  • the advantage of this sy ⁇ tem i ⁇ that this will provide the most efficient delivery of drug through the skin. This, in turn, will provide the ⁇ mallest 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 i ⁇ 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 iso ⁇ orbide mononitrate a ⁇ pirinate through the ⁇ kin to the systemic circulation. This would also reduce the ⁇ ize (area) of patch required to deliver a given amount of drug to the systemic circulation.
  • penetration enhancers include, but is not limited to, propylene glycol, oleic acid, isopropyl myristate, dimethylsulphoxide, ethanol, and/or limonene.
  • Suitable matrices may be used as a drug reservoir. These include the above mentioned acrylate co ⁇ polymers, polyisobutylenes and silicone-based adhesive ⁇ . Other excipients present in the formulation may include plasticisers such a ⁇ diethylphthalate, dibutylphthalate, and/or glycerol. - 10 -
  • 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.
  • 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 1 The same procedure was used as for Example 1 except 800 mg of isosorbide mononitrate aspirinate were used.
  • Example 1 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 2 The same procedure was used as for Example 1 except that a siliconised release liner, Hostaphan RN 100 was used.
  • Example 2 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 1 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 2 The same procedure was used as for Example 1 except that 3 . 5 g of DURO-TAK 387-2054 was used .
  • Example 2 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 2 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 2 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.
  • Patch samples of 91cm 2 containing 2 mg/cm 2 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 -

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Ce timbre transdermique comprend une couche support, un adhésif destiné à l'application du timbre ainsi qu'un papier isolant que l'on détache pour appliquer le timbre. L'adhésif contient un aspirinate mononitrate d'isosorbide en tant que principe actif sur le plan pharmacologique, destiné à exercer une action antiangineuse et de lavage de plaquettes.
PCT/IE1996/000047 1995-07-27 1996-07-26 Formulation transdermique a base de nitrate WO1997004757A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU67089/96A AU6708996A (en) 1995-07-27 1996-07-26 Transdermal nitrate formulation

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IE950575 1995-07-27
IE950575 1995-07-27
IE960366 1996-05-27
IE960366 1996-05-27

Publications (1)

Publication Number Publication Date
WO1997004757A1 true WO1997004757A1 (fr) 1997-02-13

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IE1996/000047 WO1997004757A1 (fr) 1995-07-27 1996-07-26 Formulation transdermique a base de nitrate

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AU (1) AU6708996A (fr)
WO (1) WO1997004757A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017673A1 (fr) * 1996-10-21 1998-04-30 Cal International Limited Esters d'aspirinate d'isosorbide
CN112190569A (zh) * 2020-07-27 2021-01-08 珠海润都制药股份有限公司 一种经皮吸收型贴剂及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4241128A1 (en) * 1991-12-20 1993-06-24 Lohmann Therapie Syst Lts Transdermal aspirin dosage forms - for antithrombotic therapy or cancer prophylaxis
WO1994003421A2 (fr) * 1992-07-30 1994-02-17 Cal International Limited Esters et combinaisons d'un nitrate organique et d'un salicylate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4241128A1 (en) * 1991-12-20 1993-06-24 Lohmann Therapie Syst Lts Transdermal aspirin dosage forms - for antithrombotic therapy or cancer prophylaxis
WO1994003421A2 (fr) * 1992-07-30 1994-02-17 Cal International Limited Esters et combinaisons d'un nitrate organique et d'un salicylate

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017673A1 (fr) * 1996-10-21 1998-04-30 Cal International Limited Esters d'aspirinate d'isosorbide
CN112190569A (zh) * 2020-07-27 2021-01-08 珠海润都制药股份有限公司 一种经皮吸收型贴剂及其制备方法

Also Published As

Publication number Publication date
AU6708996A (en) 1997-02-26

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