WO2008128280A1

WO2008128280A1 - Method and system for transdermal administration of volatile active

Info

Publication number: WO2008128280A1
Application number: PCT/AU2008/000537
Authority: WO
Inventors: Adam Watkinson; Barrie Charles Finnin; Nina Frances Wilkins
Original assignee: Acrux Dds Pty Ltd
Priority date: 2007-04-20
Filing date: 2008-04-18
Publication date: 2008-10-30

Abstract

This invention relates to a method of transdermal administration of a volatile active agent, preferably selected from Nicotine and Selegiline, comprising applying a solution, preferably as a spray, containing the volatile active dissolved in a volatile solvent in a concentration in the range of from 0.5 to 25% by weight to an area of skin without occlusion of the applied solution.

Description

METHOD AND SYSTEM FOR TRANSDERMAL ADMINISTRATION OF VOLATILE ACTIVE

Field [0001] This invention relates generally to a system and method for treating conditions responsive to volatile active agents. In a particularly preferred embodiment the invention relates to transdermal administration of nicotine to effect smoking cessation and transdermal administration of selegiline for treatment or prophylaxis of Parkinson's disease and related disorders.

Background

[0002] The use of volatile low molecular weight drugs, which are generally liquid at or about room temperatures, such as nicotine and selegiline [levorotatory form of phenyl isopropylmethylpropynylamine,N,-dimethyl-N-2- propynylbenzene-ethanamine], also known in treating human beings or other animals is well known in the art. For example, WO 91/185592 describes the use of selegiline for treating Parkinson's disease and increasing the life- expectancy of human beings. U.S. Patent No. 5,192,808 describes the use of selegiline in the treatment of Cushing's disease in humans and animals. U.S. Patent No. 5,242,950 describes the use of a transdermal patch containing selegiline for macular degeneration. U.S. Patent No. 4,868,218 describes the transdermal application of selegiline in the treatment of depression. Nicotine and nitroglycerine are drugs, normally liquid at or about room temperatures, for which there is considerable art on transdermal use.

[0003] Nicotine is a principal component of tobacco, and the most pharmacologically active. It is physically addictive, making it extremely difficult for a smoker to quit. Smoking a cigarette delivers nicotine vapors to the lungs, where nicotine is rapidly absorbed through the arteries and delivered to the brain. Nicotine interacts with nicotinic cholinergic receptors in the brain to induce the release of neurotransmitters and produce an immediate reward-the "rush" that smokers experience-that is associated with a rapid rise in blood level. [0004] Most reported rapid on-set systems, such as those described above, use drugs having the salt form of the drug which is less volatile and has a much higher boiling point than the free-base form of the drug. Transdermal drug delivery systems use the free-base form of the drug, all suffer from the loss of the drug during manufacture of the transdermal system. This loss is due to the volatile nature of the drug during the drying stage in the production of cast systems. European patent application 593,807 describes a transdermal system that attempts to solve the problem of liquid drug loss. However, this transdermal system requires the use of multilayers of polymeric adhesive which contributes toward increased cost and complexity.

[0005] Another related problem with liquid, low molecular weight drugs is the plasticizing effect that the drug has on the polymer matrix in the transdermal drug delivery system. Namely, the low molecular weight base form of the drug has an excessive plasticizing effect on the polymer, resulting in a composition that is "leggy or gummy." This renders the composition unsuitable for adhesion to the epidermis.

[0006] PCT Pub. No. WO 96/40085 describes transdermal matrix patches for administering drugs such as selegiline, nitroglycerin and nicotine that are liquid at normal room temperature. The publication suggests making a monolithic matrix of the drug in an adhesive by mixing one or more polymeric adhesives, preferably polyacrylate and polysiloxane, and the drug in a volatile solvent, casting the mixture, and evaporating the solvent. The publication lists as examples of volatile solvents isopropanol, ethanol, xylene, toluene, hexane, cyclohexane, heptane, ethyl acetate and butyl acetate.

[0007] There are also a number of commercially available nicotine replacement therapies that deliver nicotine to the systemic circulation via absorption through mucosal membranes or the skin. These include nicotine- containing chewing gum, sachets, transdermal patches, capsules, tablets, lozenges, nasal sprays and oral inhalation devices. [0008] Nicotine delivery via inhalation offers the benefit of addressing the psychological component of cigarette smoking in addition to the physiological dependence on nicotine. Nicotine inhalation systems release nicotine as a vapor (see U.S. Pat. Nos. 5,167,242; 5,400,808; 5,501 ,236; 4,800,903; 4,284,089; 4,917,120; 4,793,366), aerosol (see U.S. Pat. Nos. 5,894,841 ;

5,834,01 1 ) or dry powder (see U.S. Pat. No. 5,746,227) when air is inhaled through the inhaler. A droplet ejection device (U.S. Pat. No. 5,894,841 ) has also been described that delivers a controlled dose of nicotine via inhalation.

These systems deliver low doses of nicotine to the mouth and throat, where nicotine is absorbed through the mucosal membranes into the circulation.

[0009] Currently available nicotine replacement therapies, such as transdermal where absorption occurs slowly, provide a low, steady-state blood level of nicotine to the patient without the early nicotine concentration spike that occurs due to immediate, arterial delivery of nicotine to the brain. It is believed by some that the relatively high recividism rate of those quitting smoking may be due to the lack of "rush" experienced by the subject using these therapies. However, by maintaining the steady state blood levels in this manner, it is believed to reduce the severity of nicotine withdrawal symptoms effectively and thus allows the smoker to abstain from smoking more easily.

[00010] US Patent 6299900 describes a non-occlusive transdermal composition which contains an active which may be selected from a wide range of options, a penetration enhancer which is preferably a sunscreen ester and volatile solvent. Although the system is generally very effective we have found that relatively speaking the administration of volatile active agents is less effective than via patches. Patches have the advantage of protecting the volatile active from being lost from the skin surface.

[00011] The problems faced in obtaining effective transdermal administration with non occlusive systems are demonstrated in paper by Zorin et al [In Vitro Test of Nicotine's Permeability through Human Skin Ann. Occup. Hyg. 43;6; 405-413 1999]. Zorin et al examine the absorption of nicotine from a range of solvents including water, acetic acid/water and ethanol. Examination of solutions using a Franz cell led the authors to conclude that the flux of nicotine across the skin is remarkably low for ethanol and much poorer than for water. Indeed the flux is significantly less than necessary to achieve useful therapeutic blood levels. Indeed, extrapolation from the flux of nicotine in ethanolic solutions described in Zorin et al to the area of skin required to deliver a therapeutic dose of the drug through the skin, yields application areas of between 100 and 230 cm². These areas of skin are impractical for commercial use.

Summary

[00012] The invention provides a method of transdermal administration of a volatile active agent, preferably selected from Nicotine and Selegiline, comprising applying a solution containing the volatile active dissolved in a volatile solvent in a concentration in the range of from 0.5 to 25% by weight to an area of skin without occlusion of the applied solution. Preferably, the solution is applied by means of a spray, however the invention may equally work where the solution is applied as an aerosol, a roll-on or by any other spreading device.

[00013] The spray is typically allowed to dry without occlusion such as with a patch plaster or other applied physical barrier.

[00014] In a further aspect the invention provides a system for non-occlusive transdermal delivery of a volatile active, preferably selected from Nicotine and Selegiline, to an area of skin comprising a container; within the container a solution containing the volatile active dissolved in a volatile solvent in a concentration in the range of from 0.5 to 25% by weight; an applicator nozzle for delivering a spray of the solution onto the skin; and preferably a nozzle housing about the nozzle (and optionally also housing the container); and preferably a spacer extending from the housing for placement against the skin to stabilize the nozzle in spaced relationship to the area of skin.

[00015] In another aspect we provide a method of reducing a craving for cigarettes in a smoker comprising administering to an area of skin of the smoker a metered dose spray of a composition comprising in the range of from

5 to 25% (preferably from 10 to 20% and most preferably from 12 to 18%) by weight of nicotine in a volatile solvent (preferably selected from ethanol, isopropanol and mixtures thereof) wherein the metered dose contains in the range of from 0.9 to 22.5 mg of nicotine and wherein the spray is preferably allowed to dry without occlusion such as with a patch plaster or other applied physical barrier.

[00016] In onother aspect we provide method of treatment or prophylaxis of Parkinson's disease comprising administering to an area of skin of the subject suffering or in need of prophylaxis against Parkinson's disease a metered dose spray of a composition comprising in the range of from 0.5 to 10% (preferably from 3 to 10% and most preferably from 4 to 8%) by weight of selegiline in a volatile solvent (preferably selected from ethanol, isopropanol and mixtures thereof) wherein the metered dose contains in the range of from 0.45 to 20 mg of Selegiline, preferably from 2.7 to 9 mg and most preferably from 3.6 to 7.2 mg selegiline.

[00017] In yet another aspect we further provide the use of a volatile active and (particularly nicotine or selegiline) and a volatile solvent (particularly ethanol, isopropanol or a mixture thereof) in manufacture of a medicament composition for treatment of a disease (preferably selected from smoking addiction and Parkinson's disease) in a subject by application of a unit dose spray comprising from 0.45 to 22.5 mg to an area of skin of the subject wherein the composition comprises the volatile active dissolved in a volatile solvent in a concentration in the range of from 5 to 25% by weight of the composition.

Detailed Description

Definitions

[00018] The term skin is used to refer to the organ of the integumentary system made up of multiple layers of epithelial tissues that guard underlying muscles and organs. The term skin as used herein does not include mucous membranes (or mucosae).

[00019] The term mucous membranes (or mucosae; singular: mucosa) refers to the linings of mostly endodermal origin, covered in epithelium, and are involved in absorption and secretion. The term "mucous membrane" refers generally to any of the mucous membranes in the body such as the oral cavity and respiratory system. Thus, buccal, sub lingual, gingival, palatal, throat and lung absorption are not the included in the reference to transdermal administration.

[00020] The term "non-occlusive" is used herein in its broadest sense to refer to not trapping or closing the skin to the atmosphere by means of a patch device, fixed reservoir, application chamber, tape, bandage, sticking plaster, or the like which remains on the skin at the site of application for a prolonged length of time.

[00021] The term "stratum corneum" is used herein in its broadest sense to refer to the outer layer of the skin, which is comprised of (approximately 15) layers of terminally differentiated keratinocytes made primarily of the proteinaceous material keratin arranged in a ^'brick and mortar^' fashion with the mortar being comprised of a lipid matrix made primarily from cholesterol, ceramides and long chain fatty acids. The stratum corneum creates the rate- limiting barrier for diffusion of the active agent across the skin.

[00022] The term "propellant" is used to refer to materials which are aerosol spray propellants and generally have a boiling point lower than room temperature. Propellants are not considered as part of the volatile solvent in compositions of the invention and amounts based on the weight of the spray composition do not include propellants or materials which have a boiling point below 25⁰C.

[00023] The term "volatile active agent" refers to pharmaceutically active agents that are liquid at or below the skin temperature of 32^QC, and suffer from significant loss due to evaporation during product manufacture and from the dosage form during storage or product use.

[00024] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[00025] The active agents used in the method and system of the invention are volatile low molecular weight drugs of less than 500 Daltons, which are generally liquid at skin temperature (32^QC) in the free base form. Nicotine and selegiline are preferred examples of such active agents and nicotine is the most preferred active agent.

[00026] The composition of the invention contains a solution of the active agent in a volatile solvent. The active agent is present in an amount of from 0.5 to 25% by weight of the composition. Where the active agent is nicotine, the composition may comprise nicotine in an amount from 5 to 25% by weight and preferably from 10 to 20% by weight and most preferably from 12 to 18% by weight of the composition. Where the active agent is selegiline, the composition may comprise selegiline in an amount from 0.5 to 10% by weight and preferably from 3 to 10% by weight and most preferably from 4 to 8% by weight of the composition.

[00027] We have found that delivery of this composition, preferably as a fine spray, to the skin allows sustained uptake of the active into the bloodstream and thus maintain levels sufficient for example to reduce the severity of nicotine withdrawal symptoms effectively and allow smokers to modify their behavior. The key benefits of transdermal drug delivery versus oral delivery are well-known and include avoidance of the first pass effect, drug deactivation by digestion in the gut; the delivery of sustained dose over a longer period of time versus repeated dosing several times a day; and the avoidance of the systemic drug "peaks and troughs" associated with oral delivery. In addition to those advantages, the present invention eliminates the key detrimental issues associated with patch and gel/cream-based technologies. For the patch, the main generic issue is localised irritation or inflammation. For the gel/cream the key issues are accurate dosage and "messiness". The system of the present invention is fast drying, quickly absorbed, non-irritating to the skin, invisible after application and will not fall off during use.

[00028] Furthermore, we have found that this composition and dosage form is particularly useful since the manufacturing process provides significant advantages when using volatile active agents. In contrast to other dosage forms, this particular composition requires no heating during manufacture, and thus will not suffer from the loss of volatile active agent, resulting in reduced manufacturing site contamination, a more stable composition and ultimately cost savings.

[00029] The preferred delivery of the active as a spray or mist of the solution over an area of skin allows the problems of poor delivery from alcohol reported by Zorin et al to be addressed. Preferably the system of the invention is a metered dose system adapted to apply a dose of from about 0.45 to about 22.5 mg of active per unit dose. Where the active agent is nicotine, the dose applied will more preferably be from about 0.9 to about 18 mg of nicotine per unit dose and most preferably from 10.9 to 16.2 mg of nicotine per unit dose. Where the active agent is selegiline, the dose applied will more preferably be from about 2.7 to about 9 mg of selegiline per unit dose and most preferably from about 3.6 to about 7.2 mg of selegiline per unit dose. The system will typically apply the dose over an area of skin of at least 5 cm², preferably via a metered dose spray, and generally no more than about 100 cm². Preferably, the dose will be applied over an area of skin of at least 20 cm².

[00030] The solution used in the method of the invention will typically contain no more than 10% by weight of components other than volatile solvent and active, more preferably no more than 5% of other components still more preferably less than 1 % and most preferably is essentially free of other components. It is particularly preferred that the composition is free of dermal penetration enhancers such as those referred to in US Patent 6299900.

[00031] The solution comprises a volatile solvent. Preferably the volatile solvent is present in an amount of from 75 to 99% by weight of the total composition; where the active agent is selegiline the volatile solvent is most preferably present in the mount of from 80 to 96% and where the active agent is nicotine the volatile solvent is most preferably about 80 to 90% by weight of the total solution.

[00032] Examples of volatile solvents include ethanol, isopropanol, ethyl acetate, chloroform and acetone. The most preferred volatile solvents are ethanol and isopropanol. In some instances propellants such as hydrofluorocarbons, hydrocarbons, hydrochlorofluorocarbons and their mixtures may be used in aerosol delivery of the compositions. Examples of suitable propellants include hydrofluorocarbons, hydrocarbons hydrochlorofluorocarbons and mixtures of two or more thereof. The most preferred propellants are HFC134a and mixtures thereof.

[00033] In a further aspect the invention provides a system for non-occlusive transdermal delivery of a volatile active, preferably selected from Nicotine and Selegiline, to an area of skin comprising a container; within the container a solution containing the volatile active dissolved in a volatile solvent in a concentration in the range of from 0.5 to 25% by weight; an applicator nozzle for delivering a spray of the solution onto the skin; and preferably a nozzle housing about the nozzle (and optionally also housing the container); and preferably a spacer extending from the housing for placement against the skin to stabilize the nozzle in spaced relationship to the area of skin.

[00034] The system of the invention may be in the form of an aerosol in a pressurized container with a propellant such as hydrofluorocarbons, hydrocarbons, hydrochlorofluorocarbons and their mixtures. Alternatively the container may be pressurized by priming to build pressure prior to the solution being dispensed or the container may be provided with a pump spray. In yet another option the system may comprise a pump pack for delivery of a spray from a container via a spray nozzle.

[00035] The system of the invention preferably uses a spacer such as the shroud extending from the housing for placement against the skin to stabilize the nozzle in spaced relationship to the area of skin. The shroud preferably provides spacing from the skin of at least 1 cm and more preferably at least 2 cm and generally not more than 8cm and preferably not more than 5 cm.

[00036] One example of a preferred system in accordance with the invention utilizes a pump spray dispensing device of the type described in US Patent 6978945 the contents of which are herein incorporated by reference.

[00037] BRIEF DESCRIPTION OF THE DRAWINGS [00038] Embodiments of the present invention are described in detail in the following detailed description which refers to the accompanying drawings. The drawings, however, are merely illustrative of how the present invention might be put into effect, so that the specific form and arrangement of the various features as shown is not to be understood as limiting on the invention. [00039] FIG. 1 is a side, elevational view of one form of dispensing device incorporating one embodiment of the present invention; [00040] FIG. 2 is a rear, elevational view of the device shown by FIG. 1 ; [00041] FIG. 3 is a side, elevational, cross-sectional view taken along line MINI of FIG. 2; [00042] FIG. 4 is a front, perspective, exploded view of the device shown by FIG. 3;

[00043] FIG. 5 is a side, elevational, cross-sectional view of the device shown in FIG. 3, but with a dust cap positioned over the outlet of the device; [00044] FIG. 6 is a side, elevational view of the device shown in FIG. 5; [00045] FIG. 7 is a graph showing the in-vitro human skin penetration of nicotine from formulations in isopropylalcohol.

[00046] FIG. 8 is a graph showing the in-vitro human skin penetration of selegiline from formulations in IPA. [00047] The example of the dispensing device containing a composition for use in the inventioni is shown in the accompanying drawings and includes a hollow body 2 having a chamber 3 (FIG. 3) for receiving a substance capsule 4, which may be replaceable in some circumstances. The contents (the substance) of the capsule 4 will be selected to suit the intended use of the device 1. In the example shown, the capsule 4 includes a substance container 5 and a manually operable pump 6 (FIG. 3) for dispensing a metered quantity of the substance. Other arrangements could be adopted, such as an aerosol- type dispenser, in which event a suitable control valve (not shown) would be provided within the upper part, or some other convenient part, of the capsule 4.

[00048] The substance stored in the container 5 includes selegiline or nicotine in a volatile solvent (preferably ethanol, isopropanol or a mixture of the two) in an amount of from 0.5 to 25% (preferably from 10 to 20% and most preferably from 12 to 18% where the active agent is nicotine; and preferably from 3 to 10% and most preferably from 4 to 8% where the active agent is selegiline) by weight of the solution. The solution composition contains no more than 1 % (and is preferably essentially free) of other components such as penetration enhancers, adhesives and film formers. The total volume of liquid in the system will depend on the number of doses required, the concentration of the active and the volume dispersed and is typically in the range of from 1 to 50ml.

[00049] However the solution of volatile active is driven to emerge from the device, it is preferably applied to a target area at relatively low volume levels. By way of example, the substance may be deposited in the range of 1 to 10 microliters per square centimeter of the target area.

[00050] As shown by FIG. 4, the body 2 may be formed of two separable parts 2a and 2b. Those parts combine to form the chamber 3 when they are connected together as shown by FIGS. 1 and 6, and any suitable means may be adopted to releasably connect the two parts 2a and 2b. In the arrangement shown, pins 7 provided on the part 2a are adapted to fit within complementary holes 8 provided in the part 2b (FIG. 4). The pins 7 and the holes 8 cooperate in a manner such as to resist inadvertent separation of the parts 2a and 2b.

[00051] In the particular arrangement shown, an actuator button 9 is movably mounted on the body 2 so as to be accessible at the upper end of the body 2 (FIGS. 1 , 5 and 6). The button 9 cooperates with the pump 6 in a manner such that depression of the button 9 causes operation of the pump 6. When the pump 6 is operated, a quantity of the volatile active solution is withdrawn from the container 5 and is expelled through an outlet nozzle 10 associated with the pump 6, possibly in the form of a spray. In the arrangement shown, the button 9 locates over the outlet nozzle 10 and has an opening 1 1 aligned with the outlet passage 12 of the nozzle 10 so as to allow egress of the substance being dispensed. The pump 6 operates in a known manner to pressurize the contents of the volatile active solution container 5, and thereby force a metered quantity of the solution to be expelled through the nozzle 10.

[00052] A shroud 13, preferably of substantially conical form, may be connected to the side of the body 2 adjacent the nozzle 10. The shroud 13 is arranged to surround the spray of volatile active solution emerging from the nozzle 10, and may serve to confine that spray so that all or most of the substance is deposited on the intended target area. In that regard, the shroud 13 is preferably non-vented as hereinbefore defined. The shroud 13 may also function as a distance regulator. That is, the distance between the nozzle 10 and the outer edge 14 of the shroud 13 may substantially correspond to the ideal distance over which the substance should be sprayed on to the target area. Such distance regulation may be particularly useful in circumstance where the device is being used for transdermal application of a substance.

[00053] As shown in FIGS. 5 and 6, a protective cap 15 may be removably attached to the outer end of the shroud 13 so as to close the open mouth 16 (FIG. 3) of the shroud 13. The cap 15 is removed when the pump 6 is to be operated, and is replaced when the pump 6 is not in use. Any suitable means may be employed to enable releasable attachment of the cap 15. One option is to provide for snap engagement between the cap 15 and the shroud 13. By way of example, a circumferential rib 17 or lugs formed on an inner surface of a side wall 21 of the cap 15 may snap engage with an external circumferential rib 19 formed on the shroud 13 (FIG. 3).

[00054] In the arrangement shown by FIGS. 4 to 6, the dispensing device 1 is provided with means for closing the nozzle 10 when the device is not in use. Any suitable means may be used for that purpose. In the arrangement shown by FIGS. 4, 5 and 6, however, the nozzle closure means includes a member 20 attached to the end wall 21 of the cap 15. Preferably, as shown, the member 20 is in the form of an elongated stem extending axially of the cap 15 in the same direction as the side wall 21. The length of the member 20 is such as to enable the outer terminal end 22 to engage around and/or within the outlet of the nozzle 10 when the cap 15 is properly in place on the shroud 13.

[00055] The system of the invention preferably comprises a shroud defining an exit space from said hollow body for receiving said substance emerging from said outlet passage and the end of which is placed against the area of skin to define the administration area within the perimeter of the shroud.

[00056] The system of the invention may be adapted as a fixed dose or may be adapted to allow the user to modify the dose to be delivered.

[00057] The system may provide a metered dose of the solution of active. It is preferred that the unit dose delivered by the system of the invention is in the range of from 0.45 to 22.5 mg of volatile active particularly for nicotine or selegiline.

[00058] In a further aspect the invention provides a method of reducing a craving for cigarettes in a smoker comprising administering to an area of skin of the smoker a metered dose spray of a composition comprising in the range of from 5 to 25% (preferably from 10 to 20% and most preferably from 12 to 18%) by weight of nicotine in a volatile solvent (preferably selected from ethanol, isopropanol and mixtures thereof) wherein the metered dose contains in the range of from 0.9 to 22.5mg of nicotine, preferably from 5 to 18mg of nicotine and most preferably from 10.8 to 16.2 mg of nicotine.

[00059] The spray is preferably allowed to dry without occlusion such as with a patch plaster or other artificial applied physical barrier.

[00060] The invention may comprise administration of one or more metered doses during a day and preferably at least two sets of metered doses each set providing one or more metered dose spray applications and providing a total dosage in the range of from 10 to 32.5 mg of nicotine and spaced at least four hours and more preferably at least eight hours apart.

[00061] The invention further provides a method of treatment or prophylaxis of Parkinson's disease comprising administering to an area of skin of the subject suffering or in need of prophylaxis against Parkinson's disease a metered dose spray of a composition comprising in the range of from 0.5 to 10% (preferably from 3 to 10% and most preferably from 4 to 8%) by weight of selegiline in a volatile solvent (preferably selected from ethanol, isopropanol and mixtures thereof) wherein the metered dose contains in the range of from 0.45 to 20 mg of selegiline, preferably from 2.7 to 9 mg of selegiline and most preferably from 3.6 to 7.2 mg of selegiline. The spray is preferably allowed to dry without occlusion such as with a patch plaster or other applied physical barrier.

[00062] The invention may comprise administration of one or more metered doses during a day and preferably only one metered dose per day, providing a single metered dose spray application and providing a total dosage in the range of from 0.45 to 15 mg of selegiline.

[00063] In yet a further aspect the invention provides the use of a volatile active and (particularly nicotine or selegiline) and a volatile solvent (particularly ethanol, isopropanol or a mixture thereof) in manufacture of a medicament composition for treatment of a disease (preferably selected from smoking addiction and Parkinson's disease) in a subject by application of a unit dose spray comprising from 0.45 to 22.5 mg to an area of skin of the subject wherein the composition comprises the volatile active dissolved in a volatile solvent in a concentration in the range of from 0.5 to 25% by weight of the composition.

[00064] The invention will now be described with reference to the following examples and accompanying drawings. The examples and drawings are not to be construed as limiting the invention in any way. They are included to further illustrate the present invention and advantages thereof.

Examples

Example 1

[00065] This example examines the transdermal administration of Nicotine from a spray solution in a volatile alcohol.

[00066] Compositions were prepared containing 1 1.1 and 16.7% nicotine in isopropanol by dissolving the appropriate amount of nicotine in the alcohol.

[00067] In-vitro diffusion experiments were performed using Franz type static diffusion cells, using human epidermis maintained at 32^QC. The nicotine formulations were added to each Franz cell at a finite dose of 3.6μl/cm². Samples were collected at appropriate time points and analysed by high performance liquid chromatography (HPLC). The results of the study are shown in FIG. 7.

[00068] The results indicate that these formulations will deliver 4.4, 6.8 and 13.6 mg of nicotine systemically if applied to human skin at time zero and time 8 hours after application. The formulations may be modified to provide doses of 5, 10 and 15 mg for use clinically by using concentrations of about 12.6 % and 18.4% nicotine.

[00069] Useful regimens for assisting smoking cessation may include: • 1 spray of a 12.6% nicotine/I PA from a 20cm² metered dose system at t=0 and t = 8 hours

• 2 sprays of a 12.6% nicotine/IPA from a 20cm² metered dose system at t=0 and t = 8 hours • 2 sprays of a 18.4% nicotine/IPA from a 20cm² metered dose system at t=0 and t = 8 hours OR

• 1 spray of a 12.6% nicotine/IPA from a 20cm² metered dose system at t=0 and t = 8 hours • 2 sprays of a 12.6% nicotine/IPA from a 20cm² metered dose system at t=0 and t = 8 hours

• 3 sprays of a 12.6% nicotine/IPA from a 20cm² metered dose system at t=0 and t = 8 hours

[00070] The most preferred anatomical application site is the inner forearm although a range of anatomical sites may be used such as the thigh, abdomen, outer arm, buttocks etc.

[00071] The administration may thus be made to provide 5, 10 and 15 mg of nicotine per 16 hours. These equate to the current delivery from single applications of transdermal patches. It may be preferred to apply the formulations twice a day at time zero hours and then eight hours later or when cigarette craving dictated other regimens in accordance with the known blood level effects of nicotine.

[00072] The differing doses can be achieved using formulations containing increasing amounts of nicotine.

Example 2

[00073] This Example examines the transdermal administration of Selegiline from a spray solution in a volatile alcohol. [00074] Selegiline is used as a treatment for Parkinson's disease as a monotherapy or in combination with levodopa. The therapeutic daily dose of selegiline varies depending on the route of administration. Oral tablets are dosed at 5-10 mg per day whilst an orally dissolving formulation is dosed at 1.25 -2.5 mg.

[00075] The systemic dose for transdermal administration may be approximately 0.45 mg per spray with the applied number of sprays being one or two per day at a single dosing time or a single spray per day utilizing two different concentrations i.e. the daily systemic dose is 0.5 or 1 mg.

[00076] Formulations containing 10, 15 and 20% selegiline were prepared by dissolving the requisite amount of the drug in isopropyl alcohol.

[00077] All formulations used selegiline freebase in isopropyl alcohol but other solvents (e.g. ethanol, ethyl acetate, acetone etc) could also be used.

[00078] In-vitro diffusion experiments were performed using Franz type static diffusion cells, using human epidermis maintained at 32^QC. The selegiline formulations were added to each Franz cell at a finite dose of 3.6μl/cm². Samples were collected at appropriate time points and analysed by high performance liquid chromatography (HPLC). The results are shown in FIG. 8.

[00079] The pattern of delivery observed in FIG. 8 is actually quite unexpected and advantageous because there is no need to sustain delivery for the full 24 hour since selegiline is an irreversible inhibitor of monoamine oxidase (MAO) type B. Therefore sustained blood levels over a 24 hour period are not required and those delivered by a single dose of a profile such as that shown in FIG. 8 will rise and fall during that period.

[00080] The following compositions may be delivered from a metered dose spray system such as that described in US Patent 6978945.

• 1 spray of a 4% selegiline/IPA from a 20cm² metered dose system = 0.5 mg per day • 2 sprays of a 4% selegiline/1 PA from a 20cm² metered dose system

1 mg per day

OR

1 spray of a 4% selegiline/IPA from a 20cm metered dose system 0.5 mg per day

• 1 spray of a 8% selegiline/IPA from a 20cm² metered dose system 1 mg per day

Example 3

[00081] A phase I, open label, two way cross-over study to determine the pharmacokinetics of nicotine following application of various nicotine spray formulations versus a commercially available nicotine patch (5mg).

Study Design

[00082] The primary objective of this study was to determine and compare the pharmacokinetics of three different formulations of Nicotine Spray with a commercially available 5mg per 16 h transdermal patch.

[00083] Sixteen healthy male volunteers, who had smoked between 1 and 99 cigarettes (or equivalent) over their lifetime, were recruited into this open label, two-way cross over pharmacokinetic study. The subjects were randomised to receive a dose of two out of four study treatments, over two dosing periods (Period 1 and Period 2, which were separated by a 7-day washout period). The study treatments are described in Table 1.

Table 1 : Study Treatments Investigated During a Human Clinical Trial

• The second dose of Nicotine Spray (applied at t = 8 h) was applied to a site on the abdomen that was adjacent to the original site dosed at t = 0 h. Results

Table 2: Mean ± SD Nicotine and Cotinine Pharmacokinetic Parameters Calculated For Study Treatments A, B, C and D. Values in brackets represent 5 the range between subjects.

[00084] As demonstrated by the data shown in Table 2, all of the nicotine spray formulations investigated exhibited similar pharmacokinetic properties. In relation to the onset of maximal nicotine plasma concentrations (t_max) from the various formulations investigated, it is noteworthy that the t_max values calculated for each of the spray study treatments appeared to be ~ 2 h shorter than that derived for the commercially available patch.

Claims

1. A method of transdermal administration of a volatile active agent, selected from Nicotine and Selegiline, comprising applying a spray of a solution containing the volatile active dissolved in a volatile solvent in a concentration in the range of from 0.5 to 25% by weight to an area of skin without occlusion of the applied solution.

2. A method of transdermal administration according to claim 1 wherein the spray composition used in the method of the invention contains no more than 5% by weight of components other than volatile solvent and active.

3. A method of transdermal administration according to claim 1 or claim 2 wherein the spray composition is free of dermal penetration enhancers.

4. A method according to any one of the previous claims wherein the active agent is nicotine.

5. A method according to any one claims 1 to 3 wherein the active agent is selegiline.

6. A method according to claim 4 wherein the spray composition comprises nicotine in an amount from 5 to 25% by weight of the composition.

7. A method according to claim 4 wherein the spray composition comprises nicotine in an amount from 12 to 18% by weight of the spray composition.

8. A method according to claim 5 wherein the spray composition comprises selegiline in an amount from 0.5 to 10% by weight of the composition.

9. A method according to any one of the previous claims wherein the spray is a metered dose of from about 0.45 to about 22.5 mg of active per unit dose.

10. A method according to claim 4 wherein the spray is a metered dose of from about 0.9 to about 22.5 mg of nicotine per unit dose.

1 1. A method according to claim 5 wherein the spray is a metered dose of from about 0.45 to about 20 mg of selegiline per unit dose.

12. A method according to any one of the previous claims wherein the spray is applied over an area of skin of at least 20 cm² to no more than 100cm².

13. A method according to any one of the previous claims wherein the solvent is present in an amount of from 75 to 96% by weight of the total spray composition.

14. A method according to any one of the previous claims wherein the volatile solvent is selected from the group consisting of ethanol, isopropanol, ethyl acetate and acetone.

15. A method according to claim 14 wherein the composition further comprises a propellant selected from the group consisting of hydrofluorocarbons, hydrochlorocarbons, hydrochlorofluorocarbons and mixtures thereof.

16. A system for non-occlusive transdermal delivery of a volatile active, selected from Nicotine and Selegiline, to an area of skin comprising a container; within the container a solution containing the volatile active dissolved in a volatile solvent in a concentration in the range of from 0.5 to 25% by weight; and an applicator nozzle for delivering a spray of the solution from the container onto the skin.

17. A system for non-occlusive transdermal delivery of a volatile active according to claim 15 further comprising a nozzle housing about the nozzle (and optionally also housing the container); and a spacer arm extending from the housing for placement against the skin to stabilize the nozzle in spaced relationship to the area of skin.

18. A system for non-occlusive transdermal delivery of a volatile active according to claim 16 or claim17 wherein the system applies from about 0.45 to about 22.5 mg of active per unit dose.

19. A system for non-occlusive transdermal delivery of a volatile active according to any one of claims 16 to 18 wherein the spray is applied over an area of skin of from 20 cm² to no more than 100cm².

20. A system for non-occlusive transdermal delivery of a volatile active according to any one of claims 16 to 19 wherein the spray composition contains no more than 5% by weight of components other than volatile solvent and active.

21. A system for non-occlusive transdermal delivery of a volatile active according to any one of claims 16 to 20 wherein the spray composition is free of dermal penetration enhancers.

22. A system for non-occlusive transdermal delivery of a volatile active according to any one of claims 16 to 21 wherein the active agent is nicotine.

23. A system for non-occlusive transdermal delivery of a volatile according to any one of claims 16 to 21 wherein the active agent is selegiline.

24. A system for non-occlusive transdermal delivery of a volatile according to claim 22 wherein the spray composition comprises nicotine in an amount from 5 to 25% by weight of the composition.

25. A system for non-occlusive transdermal delivery of a volatile according to claim 23 wherein the spray composition comprises selegiline in an amount from 0.5 to 10% by weight of the composition.

26. A system for non-occlusive transdermal delivery of a volatile active according to any one of claims 16 to 25 wherein the volatile solvent is present in an amount of from 75 to 96% by weight of the total spray solution.

27. A system for non-occlusive transdermal delivery of a volatile active according to any one of claims 16 to 26 wherein the volatile solvent is selected from the group consisting of ethanol, isopropanol, ethyl acetate and acetone.

28. A system for non-occlusive transdermal delivery of a volatile active according to any one of claims 16 to 27 wherein the volatile solvents are selected from the group consisting of ethanol and isopropanol.

29. A system for non-occlusive transdermal delivery of a volatile active according to any one of claims 16 to 28 wherein the container is provided with a pump spray.

30. A system for non-occlusive transdermal delivery of a volatile active according to any one of claims 17 to 29 wherein the spacer is a shroud extending from the housing for placement against the skin to stabilize the nozzle in spaced relationship to the area of skin.

31. A system for non-occlusive transdermal delivery of a volatile active according to claim 29 wherein the spacer provides a spacing of the nozzle from the skin of from 1 cm to not more than 5 cm.

32. A method of reducing a craving for cigarettes in a smoker comprising administering to an area of skin of the smoker a metered dose spray of a composition comprising in the range of from 5 to 25% by weight of nicotine in a volatile solvent selected from ethanol, isopropanol and mixtures thereof wherein the metered dose contains in the range of from 0.9 to 22.5 mg of nicotine and wherein the spray is allowed to dry without occlusion with a physical barrier.

33. A method of reducing a craving for cigarettes in a smoker according to claim 32 comprising administration of at least two sets of metered doses each set providing one or more metered dose spray applications and providing a total dosage in the range of from 10 to 32.5 mg of nicotine and and at least two sets being spaced at least six hours apart.

34. A method of treatment or prophylaxis of Parkinson's disease comprising administering to an area of skin of the subject suffering or in need of prophylaxis against Parkinson's disease a metered dose spray of a composition comprising in the range of from 0.5 to 10% by weight of selegiline in a volatile solvent selected from ethanol, isopropanol and mixtures thereof wherein the metered dose contains in the range of from 0.45 to 20 mg of Selegiline.

35. A method of treatment or prophylaxis of Parkinson's disease according to claim 34 wherein the spray is allowed to dry without occlusion such as with a patch plaster or other applied physical barrier.

36. A method of treatment or prophylaxis of Parkinson's disease according to claim 34 wherein a single metered dose is applied per a day each metered dose spray application providing a dosage in the range of from 0.5 to 15 mg of selegiline.

37. The use of a volatile active selected from nicotine or selegiline and a volatile solvent selected from ethanol, isopropanol or a mixture thereof in manufacture of a medicament composition for treatment or inhibition of a disease selected from smoking addiction and Parkinson's disease in a subject by application of a unit dose spray comprising from 0.45 to 22.5 mg to an area of skin of the subject wherein the composition comprises the volatile active dissolved in a volatile solvent in a concentration in the range of from 5 to 25% by weight of the composition.