[go: up one dir, main page]

EP1534241A1 - Transdermal aerosol compositions - Google Patents

Transdermal aerosol compositions

Info

Publication number
EP1534241A1
EP1534241A1 EP03732114A EP03732114A EP1534241A1 EP 1534241 A1 EP1534241 A1 EP 1534241A1 EP 03732114 A EP03732114 A EP 03732114A EP 03732114 A EP03732114 A EP 03732114A EP 1534241 A1 EP1534241 A1 EP 1534241A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
composition according
skin
agent
penetration enhancer
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP03732114A
Other languages
German (de)
French (fr)
Inventor
Igor Gonda
Timothy Matthias Morgan
Nina Frances Wilkins
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Acrux DDS Pty Ltd
Original Assignee
Acrux DDS Pty Ltd
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 Acrux DDS Pty Ltd filed Critical Acrux DDS Pty Ltd
Publication of EP1534241A1 publication Critical patent/EP1534241A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to transdermal aerosol compositions for topical application, a spray device for transdermal delivery of aerosol compositions and to a method of transdermal delivery of therapeutic agents.
  • Transdermal delivery of therapeutic agents offers several inherent clinical and patient advantages over traditional oral tablet and capsule formulations, especially for drugs that:
  • transdermal drug delivery has received increased attention because it not only provides a relatively simple dosage regime but it also provides a relatively slow and controlled route for release of a physiologically active agent into the systemic circulation.
  • transdermal drug delivery is complicated by the fact that the skin behaves as a natural barrier and therefore transport of agents through the skin is a complex mechanism.
  • the skin consists of two principle parts, a relatively thin outermost layer (the 'epidermis') and a thicker inner region (the 'dermis').
  • the outermost layer of the epidermis (the 'stratum corneum') consists of flattened dead cells which are filled with keratin.
  • the region between the flattened dead cells of the stratum corneum is filled with lipids which form lamellar phases that are responsible for the natural barrier properties of the skin.
  • the agent For effective transdermal delivery of a physiologically active agent that is applied to the surface of the skin ('topical application'), the agent must be partitioned firstly from the vehicle into the stratum corneum, it must typically then be diffused within the stratum corneum before being partitioned from the stratum corneum to the viable epidermis, dermis and into the bloodstream.
  • physiologically active agents can be formulated with incorporation of one or more drug penetration enhancers.
  • aqueous ethanol can be used as a vehicle in formulations for topical application.
  • Ethanol can act as a penetration enhancer that can increase the flux of an active agent across the skin due to a solvent drag effect (Berner et al., 1989, J. Pharm. Sci, 78(5), 402- 406).
  • Octyl salicylate and AzoneTM are further examples of penetration enhancers that have been shown to improve percutaneous absorption (U.S Patent Number 6299900).
  • PCT/AU00/01419 describes a propellant free spray on skin patch composition, which forms a flexible porous skin patch to improve wound healing and drug administration, however the composition is limited to water soluble compounds.
  • transdermal aerosol drug delivery system has the potential to overcome the limitations of existing transdermal drug delivery devices, such as transdermal patches.
  • the potential to avoid skin irritation offers a significant advantage over existing patch and nasal delivery methods, both of which have been shown to cause application site reactions in up to 50% of patients using these types of dosage forms (Lopes et al., 2001 , Maturitas 38, S31 -39).
  • U.S Patent No. 6325990 relates to a film forming composition for spraying on the skin comprising a physiological active, a polysiloxane adhesive, an absorption promoter, a solvent, a volatile silicone and a propellant.
  • a physiological active a physiological active
  • a polysiloxane adhesive an absorption promoter
  • a solvent a volatile silicone
  • a propellant a propellant
  • the adhesive In transdermal systems where both a drug and an enhancer are incorporated, it is important that the enhancer is released at a rate that will result in an optimal effect upon drug permeation through the skin. Therefore, in a film-forming system, the adhesive must show effective permeability for the drug and the enhancer, defined by the delivery profile of the drug under consideration. If the solubility of either the drug or the enhancer is not optimised, then the permeation profile will be affected (Venkatraman ⁇ t al., 1998). Drug-in-adhesive systems are more recent second-generation systems wherein the drug is dispersed in the adhesive itself. The saturated solubility for many compounds in adhesives is low, thus the tendency for the drug to precipitate is even greater, leading to stability issues. (Kotiyan et al., 2001).
  • Liquid excipients (including the drug) will 'plasticise' the adhesive to some degree; which would lead to an undesirable residue on the skin. This "plasticised” residue is often sticky, collecting dirt and lint, and is therefore cosmetically unacceptable.
  • the present invention arises from the inventor's studies of finite dose formulations which contain penetration enhancers that enhance the percutaneous absorption of a therapeutic agent.
  • the present invention arises, at least in part, from the realisation that an improvement in percutaneous delivery can be achieved by the appropriate selection of a hydrofluorocarbon propellant dissolved in a lower alcohol such as ethanol or isopropyl alcohol or a combination thereof, and which can also exist as a single-phase solution with the penetration enhancer of choice.
  • the aerosol composition may initially contain water in an amount up to 50% w/v preferably up to 10% w/v water, and more preferably may initially contain up to 5% w/v water without impacting upon the capacity of the volatile vehicle to dissolve the desired amount of the therapeutic agent and penetration enhancer used in said metered-dose transdermal aerosol compositions in their most preferred form as single-phase solutions.
  • the present invention provides a composition including:
  • a volatile pharmaceutically acceptable solvent comprising a lower alcohol and a hydrofluorocarbon propellant, and optionally up to 50% w/v water wherein the physiologically active agent, dermal penetration enhancer, volatile pharmaceutically acceptable solvent and propellant combine to preferably form a single-phase solution.
  • compositions with a relatively higher water content of up to 50% w/v water may be used in a topical vehicle that can be applied to irritated skin, broken skin or mucous membranes, wherein the composition may exist as a single phase solution, emulsion or micro-emulsion in which the active agent and/or penetration are either completely dissolved within one of the aforementioned vehicle phases or are alternatively dispersed within one of these vehicle phases, or a combination thereof, such as the physiologically active agent being dissolved in the composition and the dermal penetration enhancer being dispersed in the same composition.
  • compositions comprising water in an amount of up to 10% w/v are preferred.
  • composition of the present invention may overcome at least some of the disadvantages of the composition described in the aforementioned U.S Patent No. 6325990, which can result in a two phase solution or emulsion, as opposed to the single phase solution of the present invention.
  • the present invention also provides a metered dose spray applicator containing the above composition for transdermal administration.
  • the present invention further provides a method of treatment of a subject with a physiologically active agent comprising applying a transdermal composition as hereinbefore described to an area of skin of a subject.
  • a physiologically active agent comprising applying a transdermal composition as hereinbefore described to an area of skin of a subject.
  • the composition of the invention comprises a hydrofluorocarbon propellant.
  • the hydrofluorocarbon propellant is preferably a hydrofluoroalkane such as HFC-134a or HFC 127.
  • the most preferred hydrofluorocarbon propellant is HFC-134a.
  • HFC-134a is particularly advantageous in compositions to be administered transdermally as compositions of the invention applied to the skin , with HFC-134a produce more saturation of the drug when compared with other propellants such as dimethyl ether.
  • HFC-134a rapidly providing high saturation of the active and penetration enhancer on the skin increases partitioning of the drug and penetration enhancer into the skin rapidly providing a reservoir of active and penetration enhancer within the skin.
  • incorporation of HFC-134a provides for a faster drying time which allows the physiological active and the penetration enhancer to form an amorphous deposit upon evaporation of the volatile carrier.
  • the volatile solvent evaporates and the composition becomes touch dry within 2 minutes, more preferably within 1 minute, leaving no residue or film on the skin.
  • the amount of propellant in the composition of the invention is preferably 15 to 50% v/v and more preferably 20 to 40% v/v.
  • composition of the invention contains a penetration enhancer.
  • penetration enhancers for use in the composition of the invention are sunscreen esters of formula (I):
  • R 1 is hydrogen, lower alcohol, lower alkoxy, halide, hydroxy or NR 3 R 4 ;
  • R 2 is a C 8 to C-18 alkyl
  • R 3 and R 4 are each independently hydrogen, lower alkyl or R 3 and R 4 together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclic ring
  • n is 0 or 1
  • q is 1 or 2 wherein when n is 0 and R1 is NR 3 R 4 , the NR 3 N 4 is para-substitued.
  • sunscreen esters are those selected from the group consisting of C 8 to C ⁇ 8 alkylcinnamate, C 8 to C ⁇ 8 alkylmethoxycinnamate, C 8 to C ⁇ s alkyl salicylate and mixtures thereof. More preferably the penetration enhancers are selected from padimate O and octyl salicylate.
  • the amount of penetration enhancer present in the composition of the invention is preferably in the range of 0.1 to 10% w/v and more preferably 2 to 8% w/v.
  • the composition of the invention contains a lower alcohol, preferably ethanol, propanol (including isomers thereof) or a mixture thereof.
  • the volatile solvent comprises at least 60% w/v of one or more lower alcohols. More preferably the volatile solvent component consists essentially of an ethanol, isopropanol or mixture thereof. It is present in an amount sufficient to provide a single phase with the penetration enhancer and propellant. Typically the alcohol will be present in an amount of from 40 to 80% v/v and more preferably 50 to 70% v/v.
  • the choice of solvent used in a composition can be selected on the basis of the desired transdermal delivery profile as measured by percutaneous penetration in order to achieve the desired pharmacological effect. Combinations of volatile solvents could be used to obtain the desired pharmacological effect; for example on a weight basis:
  • the composition of the invention may contain water.
  • the decision on whether water is to be present and the amount of water will depend on the active physiological agent and its stability and interaction with water and whether the composition is to be applied to irritated skin, broken skin or mucous membranes. In some instances water may be a useful solvent whereas in other circumstances instability of the active in the presence of water may dictate that water be omitted. Indeed in some cases special precautions against the presence of water such as the use of desiccants may be desirable.
  • composition of the invention includes a physiologically active agent.
  • suitable physiologically active agents include steroid, hormone derivative, non-steroidal anti-inflammatory drug, opioid analgesic, antinauseant, antioestrogen, aromatase inhibitor, 5-alpha reductase inhibitor, anxiolytic, prostaglandin, anti-viral drug, anti-migraine compound, antihypertensive agent, anti-malarial compound, bronchodilator, anti-depressant, anti-alzheimer's agent, neuroleptic and antipsychotic agent, anticholinergic agent, anti-parkinson's agent antiandrogen or anorectic agent.
  • the preferred physiologically acceptable agents include testosterone, oestradiol, ethinyloestradiol, levonorgestrel, progesterone, norethisterone acetate, ibuprofen, ketoprofen, flurbiprofen, naproxen, diclofenac, fentanyl, buprenorphine, scopolamine, prochlorperazine, metochlopramide, ondansetron, tamoxifen, epitiostanol, exemestane, oxybutynin, darifenacin, tolterodine, ropinirole, granisetron, rivastigmine, buspirone, rizatriptin, zolmitriptan, lacidipine, tropisetron, olanzapine and methyl phenidate, 4-hydroxy- androstenedione and its derivatives, finasteride, dutasteride, turosteride, LY
  • physiologically acceptable agents include apomorphine, oxybutynin, ropinirole, fentanyl, granisetron, rivastigmine, buspirone, rizatriptin, zolmitriptan, lacidipine, tropisetron, olanzapine and methyl phenidate or a pharmaceutically acceptable salt or derivative of any one of the aforementioned.
  • One aspect of the invention provides a metered dose spray applicator containing a composition for transdermal administration.
  • the composition of the invention will generally be retained under pressure within the container so that a significant proportion of the propellant is in liquid form.
  • the spray applicator may comprise a nozzle and means for providing a metered dose of spray from the nozzle.
  • the spray applicator may further comprise spacing means for spacing the application nozzle at a predetermined distance from the skin of the subject onto which the spray is to be delivered.
  • An aerosol composition for transdermal delivery of an analgesic was prepared from the following composition.
  • An aerosol composition for transdermal delivery of an anti-cholinergic drug was prepared as a single phase solution from the composition described below.
  • composition for transdermal delivery of an anti-anxiety drug to the skin was prepared as a single phase solution from the following composition:
  • An aerosol composition for transdermal delivery of an anti-Parkinson agent was prepared as a single phase solution from the composition described below.
  • Example 7 is described with reference to the attached drawing.
  • Figure 1 is a graph showing skin penetration of buspirone over time.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Dispersion Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Psychology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention provides a pharmaceutical composition for transdermal delivery comprising: one or more physiologically active agents; one or more dermal penetration enhancers; a pharmaceutically acceptable carrier comprising a volatile solvent; and a hydrofluorocarbon propellent; wherein the carrier and penetration enhancers combine to provide a single-phase solution of the one or more physiologically active agents.

Description

TRANSDERMAL AEROSOL COMPOSITIONS
Field of the Invention
The present invention relates to transdermal aerosol compositions for topical application, a spray device for transdermal delivery of aerosol compositions and to a method of transdermal delivery of therapeutic agents.
Background of the Invention
Conventional means for administering therapeutic agents ('active agents') to a human or animal are usually limited to some degree by biological, chemical, and physical barriers. Examples of physical barriers are the skin and various organ membranes that must be traversed before the agent reaches a target. Chemical barriers include pH variations, lipid bi-layers, and degrading enzymes. Both biologically and chemically active agents are particularly vulnerable to such barriers.
Transdermal delivery of therapeutic agents offers several inherent clinical and patient advantages over traditional oral tablet and capsule formulations, especially for drugs that:
- cannot safely be given orally, for example because of irritant effects on the gastrointestinal tract
- undergo extensive so-called 'first-pass' metabolism and are thus substantially inactivated in the liver immediately after oral administration
- are poorly absorbed or poorly bioavailable after oral administration
- are best delivered in small, consistent quantities over a long period, rather than in 'spikes', which may be associated with side-effects.
Administration of physiologically active agents through the skin ('transdermal drug delivery') has received increased attention because it not only provides a relatively simple dosage regime but it also provides a relatively slow and controlled route for release of a physiologically active agent into the systemic circulation. However, transdermal drug delivery is complicated by the fact that the skin behaves as a natural barrier and therefore transport of agents through the skin is a complex mechanism.
Structurally, the skin consists of two principle parts, a relatively thin outermost layer (the 'epidermis') and a thicker inner region (the 'dermis'). The outermost layer of the epidermis (the 'stratum corneum') consists of flattened dead cells which are filled with keratin. The region between the flattened dead cells of the stratum corneum is filled with lipids which form lamellar phases that are responsible for the natural barrier properties of the skin.
For effective transdermal delivery of a physiologically active agent that is applied to the surface of the skin ('topical application'), the agent must be partitioned firstly from the vehicle into the stratum corneum, it must typically then be diffused within the stratum corneum before being partitioned from the stratum corneum to the viable epidermis, dermis and into the bloodstream.
To overcome some of the problems with transdermal delivery that are associated with transport across the dermal layers ('percutaneous absorption'), physiologically active agents can be formulated with incorporation of one or more drug penetration enhancers. For example, aqueous ethanol can be used as a vehicle in formulations for topical application. Ethanol can act as a penetration enhancer that can increase the flux of an active agent across the skin due to a solvent drag effect (Berner et al., 1989, J. Pharm. Sci, 78(5), 402- 406). Octyl para-methoxycinnamate (Padimate O), Octyl salicylate and Azone™ are further examples of penetration enhancers that have been shown to improve percutaneous absorption (U.S Patent Number 6299900).
PCT/AU00/01419 describes a propellant free spray on skin patch composition, which forms a flexible porous skin patch to improve wound healing and drug administration, however the composition is limited to water soluble compounds.
The use of a transdermal aerosol drug delivery system has the potential to overcome the limitations of existing transdermal drug delivery devices, such as transdermal patches. In particular, the potential to avoid skin irritation (Morgan et al., 1998, J. Pharm. Sci. 87, 1226-28) offers a significant advantage over existing patch and nasal delivery methods, both of which have been shown to cause application site reactions in up to 50% of patients using these types of dosage forms (Lopes et al., 2001 , Maturitas 38, S31 -39).
U.S Patent No. 6325990 relates to a film forming composition for spraying on the skin comprising a physiological active, a polysiloxane adhesive, an absorption promoter, a solvent, a volatile silicone and a propellant. We have found that this invention suffers from a number of disadvantages.
In transdermal systems where both a drug and an enhancer are incorporated, it is important that the enhancer is released at a rate that will result in an optimal effect upon drug permeation through the skin. Therefore, in a film-forming system, the adhesive must show effective permeability for the drug and the enhancer, defined by the delivery profile of the drug under consideration. If the solubility of either the drug or the enhancer is not optimised, then the permeation profile will be affected (Venkatraman θt al., 1998). Drug-in-adhesive systems are more recent second-generation systems wherein the drug is dispersed in the adhesive itself. The saturated solubility for many compounds in adhesives is low, thus the tendency for the drug to precipitate is even greater, leading to stability issues. (Kotiyan et al., 2001).
Liquid excipients (including the drug) will 'plasticise' the adhesive to some degree; which would lead to an undesirable residue on the skin. This "plasticised" residue is often sticky, collecting dirt and lint, and is therefore cosmetically unacceptable.
There is a need for an effective transdermal composition which can be easily applied to the skin and which provides effective transdermal administration.
Not surprisingly, it has been found that to date there is no metered dose transdermal aerosol composition that improves percutaneous delivery, by the appropriate selection propellant and solvent, existing as a single-phase solution, with a penetration enhancer of choice and without leaving a residue or film.
No admission is made that any reference, including any patent or patent document, cited in this specification constitutes prior art. In particular, it will be understood that, unless otherwise stated, reference to any document herein does not constitute an admission that any of these documents forms part of the common general knowledge in the art in Australia or in any other country. The discussion of the references states what their authors assert, and the applicant reserves the right to challenge the accuracy and pertinency of any of the documents cited herein.
Summary of the Invention
The present invention arises from the inventor's studies of finite dose formulations which contain penetration enhancers that enhance the percutaneous absorption of a therapeutic agent.
The present invention arises, at least in part, from the realisation that an improvement in percutaneous delivery can be achieved by the appropriate selection of a hydrofluorocarbon propellant dissolved in a lower alcohol such as ethanol or isopropyl alcohol or a combination thereof, and which can also exist as a single-phase solution with the penetration enhancer of choice. Additionally, the aerosol composition may initially contain water in an amount up to 50% w/v preferably up to 10% w/v water, and more preferably may initially contain up to 5% w/v water without impacting upon the capacity of the volatile vehicle to dissolve the desired amount of the therapeutic agent and penetration enhancer used in said metered-dose transdermal aerosol compositions in their most preferred form as single-phase solutions.
Accordingly, in a first form the present invention provides a composition including:
- one or more physiologically active agents;
- one or more dermal penetration enhancers; and
- a volatile pharmaceutically acceptable solvent comprising a lower alcohol and a hydrofluorocarbon propellant, and optionally up to 50% w/v water wherein the physiologically active agent, dermal penetration enhancer, volatile pharmaceutically acceptable solvent and propellant combine to preferably form a single-phase solution. Compositions with a relatively higher water content of up to 50% w/v water may be used in a topical vehicle that can be applied to irritated skin, broken skin or mucous membranes, wherein the composition may exist as a single phase solution, emulsion or micro-emulsion in which the active agent and/or penetration are either completely dissolved within one of the aforementioned vehicle phases or are alternatively dispersed within one of these vehicle phases, or a combination thereof, such as the physiologically active agent being dissolved in the composition and the dermal penetration enhancer being dispersed in the same composition.
Compositions comprising water in an amount of up to 10% w/v are preferred.
The composition of the present invention may overcome at least some of the disadvantages of the composition described in the aforementioned U.S Patent No. 6325990, which can result in a two phase solution or emulsion, as opposed to the single phase solution of the present invention.
Water uptake in polysiloxane systems such as the one described in U.S Patent No. 6325990 is a challenging issue due to the irreversible changes to the polymer properties that water brings about. For example, it has been shown that entrance of water induces both a swelling of the system and a break in the adhesive bonding capability (Cabanelas, et ah, 2003). Any absorption of water during storage of compositions such as the one described in U.S. Patent No. 6325990 may result in a change in the physical properties of the vehicle phase separation, leading to a decrease in the leaving tendency of the physiological active and subsequent decline in percutaneous penetration and/or a need to shake the container holding the vehicle prior to its application to the skin.
The present invention also provides a metered dose spray applicator containing the above composition for transdermal administration.
The present invention further provides a method of treatment of a subject with a physiologically active agent comprising applying a transdermal composition as hereinbefore described to an area of skin of a subject. Detailed description of the preferred embodiment
The composition of the invention comprises a hydrofluorocarbon propellant. The hydrofluorocarbon propellant is preferably a hydrofluoroalkane such as HFC-134a or HFC 127. The most preferred hydrofluorocarbon propellant is HFC-134a.
We have found that HFC-134a is particularly advantageous in compositions to be administered transdermally as compositions of the invention applied to the skin, with HFC-134a produce more saturation of the drug when compared with other propellants such as dimethyl ether. We have found that rapidly providing high saturation of the active and penetration enhancer on the skin increases partitioning of the drug and penetration enhancer into the skin rapidly providing a reservoir of active and penetration enhancer within the skin. In addition, we have found that incorporation of HFC-134a provides for a faster drying time which allows the physiological active and the penetration enhancer to form an amorphous deposit upon evaporation of the volatile carrier. Upon delivery of the composition to the skin, it is preferable that the volatile solvent evaporates and the composition becomes touch dry within 2 minutes, more preferably within 1 minute, leaving no residue or film on the skin.
The amount of propellant in the composition of the invention is preferably 15 to 50% v/v and more preferably 20 to 40% v/v.
The composition of the invention contains a penetration enhancer. The preferred penetration enhancers for use in the composition of the invention are sunscreen esters of formula (I):
(I) wherein
R1 is hydrogen, lower alcohol, lower alkoxy, halide, hydroxy or NR3R4;
R2 is a C8 to C-18 alkyl, R3 and R4 are each independently hydrogen, lower alkyl or R3 and R4 together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclic ring; n is 0 or 1 , q is 1 or 2, wherein when n is 0 and R1 is NR3R4, the NR3N4 is para-substitued.
Particularly preferred sunscreen esters are those selected from the group consisting of C8 to Cι8 alkylcinnamate, C8 to Cι8 alkylmethoxycinnamate, C8 to Cιs alkyl salicylate and mixtures thereof. More preferably the penetration enhancers are selected from padimate O and octyl salicylate.
The amount of penetration enhancer present in the composition of the invention is preferably in the range of 0.1 to 10% w/v and more preferably 2 to 8% w/v.
The composition of the invention contains a lower alcohol, preferably ethanol, propanol (including isomers thereof) or a mixture thereof. Preferably the volatile solvent comprises at least 60% w/v of one or more lower alcohols. More preferably the volatile solvent component consists essentially of an ethanol, isopropanol or mixture thereof. It is present in an amount sufficient to provide a single phase with the penetration enhancer and propellant. Typically the alcohol will be present in an amount of from 40 to 80% v/v and more preferably 50 to 70% v/v.
The choice of solvent used in a composition can be selected on the basis of the desired transdermal delivery profile as measured by percutaneous penetration in order to achieve the desired pharmacological effect. Combinations of volatile solvents could be used to obtain the desired pharmacological effect; for example on a weight basis:
or a mixture thereof. The composition of the invention may contain water. The decision on whether water is to be present and the amount of water will depend on the active physiological agent and its stability and interaction with water and whether the composition is to be applied to irritated skin, broken skin or mucous membranes. In some instances water may be a useful solvent whereas in other circumstances instability of the active in the presence of water may dictate that water be omitted. Indeed in some cases special precautions against the presence of water such as the use of desiccants may be desirable.
The composition of the invention includes a physiologically active agent. Examples of suitable physiologically active agents include steroid, hormone derivative, non-steroidal anti-inflammatory drug, opioid analgesic, antinauseant, antioestrogen, aromatase inhibitor, 5-alpha reductase inhibitor, anxiolytic, prostaglandin, anti-viral drug, anti-migraine compound, antihypertensive agent, anti-malarial compound, bronchodilator, anti-depressant, anti-alzheimer's agent, neuroleptic and antipsychotic agent, anticholinergic agent, anti-parkinson's agent antiandrogen or anorectic agent.
The preferred physiologically acceptable agents include testosterone, oestradiol, ethinyloestradiol, levonorgestrel, progesterone, norethisterone acetate, ibuprofen, ketoprofen, flurbiprofen, naproxen, diclofenac, fentanyl, buprenorphine, scopolamine, prochlorperazine, metochlopramide, ondansetron, tamoxifen, epitiostanol, exemestane, oxybutynin, darifenacin, tolterodine, ropinirole, granisetron, rivastigmine, buspirone, rizatriptin, zolmitriptan, lacidipine, tropisetron, olanzapine and methyl phenidate, 4-hydroxy- androstenedione and its derivatives, finasteride, dutasteride, turosteride, LY191704, MK-386, alprazolam, alprostadil, prostacylcin and its derivatives, melatonin, n-docosanol, tromantadine, lipophilic pro-drugs of acyclovir, low molecular weight heparin, enoxaparin, sumatriptan, amlodipine, nitrendipine, primaquine, minoxidi, minoxidil pro-drugs, pilocarpine, salbutamol, terbutaline, salmeterol, ibogaine, bupropian, rolipram, tacrine, fluphenazine, haloperidol, N- 0923, cyproterone acetate, MENT (7-methyl-19-testosterone), or mazindol or an pharmaceutically acceptable salt or derivative of any one of the aforementioned. Examples of suitable anticholinergic agents include oxybutynin, darifenacin and tolterodine.
More preferably the physiologically acceptable agents include apomorphine, oxybutynin, ropinirole, fentanyl, granisetron, rivastigmine, buspirone, rizatriptin, zolmitriptan, lacidipine, tropisetron, olanzapine and methyl phenidate or a pharmaceutically acceptable salt or derivative of any one of the aforementioned.
One aspect of the invention provides a metered dose spray applicator containing a composition for transdermal administration. The composition of the invention will generally be retained under pressure within the container so that a significant proportion of the propellant is in liquid form. The spray applicator may comprise a nozzle and means for providing a metered dose of spray from the nozzle. The spray applicator may further comprise spacing means for spacing the application nozzle at a predetermined distance from the skin of the subject onto which the spray is to be delivered.
The invention will now be described with reference to the following examples. It is to be understood that the examples are provided by way of illustration of the invention and that they are in no way limiting to the scope of the invention.
Example 1
An aerosol composition for transdermal delivery of an analgesic was prepared from the following composition.
Example 2
An aerosol composition for transdermal delivery of a non-steroidal anti- inflammatory drug was prepared as a single phase solution, using the following components:
Example 3
An aerosol composition for transdermal delivery of an anti-cholinergic drug was prepared as a single phase solution from the composition described below.
Example 4
An aerosol composition for transdermal delivery of an anti-anxiety drug to the skin was prepared as a single phase solution from the following composition:
Example 5
An aerosol composition for transdermal delivery of an anti-Parkinson agent was prepared as a single phase solution from the composition described below.
Example 6
Example 7 Example 7 is described with reference to the attached drawing. In the drawing Figure 1 is a graph showing skin penetration of buspirone over time.
The use of an HFC propellant in a composition will produce a single phase solution with better drug saturation when compared with other propellants. By providing high saturation of the active and penetration enhancer on the skin, a amorphous deposit of drug within the stratum corneum can be achieved. As a result an increase in the penetration of a drug across the skin can be expected as shown in Figure 1. Finally, it is to be understood that various other modifications and/or alterations may be made without departing from the spirit of the present invention as outlined herein.

Claims

1. A pharmaceutical composition for transdermal delivery comprising;
• one or more physiologically active agents;
• one or more dermal penetration enhancers;
• a pharmaceutically acceptable carrier comprising a volatile solvent; and
• a hydrofluorocarbon propellent;
wherein the carrier and penetration enhancers combine to provide a single-phase solution of the one or more physiologically active agents.
2. A pharmaceutical composition according to claim 1 wherein the volatile solvent has a vapour pressure above 35 mmHg at atmospheric pressure and a temperature of 32°C.
3. A composition according to claim 1 substantially free of adhesives for forming a film on the skin.
4. A composition according to claim 1 wherein said composition maintains a drying time of less than 2 minutes, more preferably less than 1 minute.
5. A pharmaceutical composition according to claim 1 wherein said propellent is a selected from HFC-134a, HFC-127 and mixtures thereof.
6. A composition according to claim 4 wherein said propellent is HFC-134a.
7. A pharmaceutical composition according to claim 1 wherein the hydrofluorocarbon propellant is from 15% to 50% by volume of the total pharmaceutical composition.
8. A pharmaceutical composition according to claim 7 wherein the propellant is from 20 to 40% by volume of the composition.
9. A pharmaceutical composition according to claim 1 wherein the penetration enhancer comprises one or more sunscreen esters.
10. A pharmaceutical composition according to claim 9 wherein the one or more sunscreen esters has the formula (I):
(I) wherein
R1 is hydrogen, lower alcohol, lower alkoxy, halide, hydroxy or NR3R4; R2 is a C8 to Cιβ alkyl,
R3 and R4 are each independently hydrogen, lower alkyl or R3 and R4 together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclic ring; n is 0 or 1 , q is 1 or 2, wherein when n is 0 and R1 is NR3R4, the NR3N4 is para-substitued
11. A pharmaceutical composition according to claim 10 wherein the one or more sunscreen esters is selected from the group consisting of C8 to C-ι8 alkylcinnamate, C8 to C-ι8 alkylmethoxycinnamate, C8 to C-ι8 alkyl salicylate and mixtures thereof.
12. A pharmaceutical composition according to claim 11 wherein the penetration enhancer is octyl salicylate.
13. A pharmaceutical composition according to claim 11 wherein the penetration enhancer is padimate-o.
14. A pharmaceutical composition according to claim 9 wherein the composition comprises from 0.1% to 10% by weight of dermal penetration enhancer.
15. A composition according to claim 14 wherein the composition comprises from 2% to 8% by weight of dermal penetration enhancer.
16. A pharmaceutical composition according to claim 1 wherein the solvent comprises acetone, a lower alcohol or mixtures thereof.
17. A pharmaceutical composition according to claim 1 wherein the solvent comprises chloroform, a lower alcohol or mixtures thereof.
18. A pharmaceutical composition according to claim 1 wherein the solvent comprises ethanol, propanol or a mixture thereof, providing a single phase of penetration enhancer and propellent.
19. A pharmaceutical composition according to claim 16 wherein the solvent is present in from 40% to 80% by volume of the total pharmaceutical composition.
20. A pharmaceutical composition according to claim 17 wherein the solvent is present in from 50% to 70% by volume of the total pharmaceutical composition.
21. A pharmaceutical composition according to claim 1 comprising one or more physiologically active agents selected from the group consisting of steroid, hormone derivative, non-steroidal anti-inflammatory drug, opioid analgesic, antinauseant, antioestrogen, aromatase inhibitor, 5-alpha reductase inhibitor, anxiolytic, prostaglandin, anti-viral drug, anti-migraine compound, antihypertensive agent, anti-malarial compound, bronchodilator anti-depressant, anti-Alzheimer's agent, anticholinergic agent, neuroleptic and antipsychotic agent, anti-Parkinson's agent, antiandrogen and anoretic agent.
22. A pharmaceutical composition according to claim 21 wherein the one or more physiologically acceptable agents is selected from the group consisting of testosterone, oestradiol, ethinyloestradiol, levonorgestrel, progesterone, norethisterone acetate, ibuprofen, ketoprofen, flurbiprofen, naproxen, diclofenac, fentanyl, buprenorphjne, scopolamine, prochlorperazine, metochlopramide, ondansetron, tamoxifen, epitiostanol, exemestane, darifenacin, 4-hydroxy-androstenedione and it's derivatives, finasteride, dutasteride, turosteride, LY191704, MK-386, alprazolam, alprostadil, prostacyclin and it's derivatives, melatonin, n- docosanol, tromantadine, lipophilic pro-drugs of acyclovir, low molecular weight heparin, enoxaparin, sumatriptan, amlodipine, nitrendipine, primaquine, minoxidiland it's pro-drugs, pilocarpine, salbutamol, terbutaline, sameterol, ibogaine, bupropian, rolipram, tacrine, fluphenazine, haloperidol, N-0923, cyproterone acetate, MENT (7- methyl-19-testosterone), or mazindol or a pharmaceutically acceptable salt or derivative of any one of the aforementioned. More preferably, the physiological agents include apomorphine, oxybutynin, fentanyl, ropinirole, granisetron, rivastigmine, buspirone, rizatriptin, zolmitriptan, lacidipine, tropisetron, olanzapine and methyl phenidate or a pharmaceutically acceptable salt or derivative of any one of the aforementioned.
23. A pharmaceutical composition according to claim 1 wherein the composition is contained in a chamber of a spray applicator device comprising a valve for delivering the composition from the chamber, a nozzle for dispersing the composition as an aerosol and means for providing a metered dose of aerosol from the nozzle said composition being retained under pressure within the chamber so as to maintain said propellent in a liquid form.
24. An aerosol applicator device for delivering the composition of claim 23 wherein the applicator device comprises a spacer for placement against the skin of the subject onto which the spray is to be delivered, whereby the skin is in the field of spray of the aerosol from the nozzle and spaced from the nozzle.
EP03732114A 2002-06-25 2003-06-24 Transdermal aerosol compositions Withdrawn EP1534241A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AUPS3171A AUPS317102A0 (en) 2002-06-25 2002-06-25 Transdermal aerosol compositions
AUPS317102 2002-06-25
PCT/AU2003/000784 WO2004000275A1 (en) 2002-06-25 2003-06-24 Transdermal aerosol compositions

Publications (1)

Publication Number Publication Date
EP1534241A1 true EP1534241A1 (en) 2005-06-01

Family

ID=3836730

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03732114A Withdrawn EP1534241A1 (en) 2002-06-25 2003-06-24 Transdermal aerosol compositions

Country Status (9)

Country Link
EP (1) EP1534241A1 (en)
JP (1) JP2005533795A (en)
KR (1) KR20050071373A (en)
AU (1) AUPS317102A0 (en)
BR (1) BR0312004A (en)
CA (1) CA2490325A1 (en)
EA (1) EA007351B1 (en)
NZ (1) NZ537435A (en)
WO (1) WO2004000275A1 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2489865C (en) * 2002-06-25 2012-05-08 Acrux Dds Pty Ltd Transdermal delivery rate control using amorphous pharmaceutical compositions
WO2005049026A1 (en) * 2003-11-19 2005-06-02 Acrux Dds Pty Ltd Method and composition for treatment or prophylaxis of amyloidosis disorders
US20060263421A1 (en) 2005-05-18 2006-11-23 Abeille Pharmaceuticals Inc Transdermal Method and Patch for Nausea
CN101883556B (en) * 2007-11-02 2013-05-29 艾克若克斯Dds有限公司 Transdermal delivery systems for hormones and steroids
BR112013020604A2 (en) * 2011-02-15 2016-10-18 Lilly Co Eli methods for controlling pain in horses using a fentanyl transdermal solution
WO2012112348A1 (en) * 2011-02-15 2012-08-23 Eli Lilly And Company Methods for controlling pain in canines using a transdermal solution of fentanyl
GB2571696B (en) 2017-10-09 2020-05-27 Compass Pathways Ltd Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced
US12459965B2 (en) 2017-10-09 2025-11-04 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
AU2020258086A1 (en) 2019-04-17 2021-11-11 Compass Pathfinder Limited Methods of treating neurocognitive disorders, chronic pain and reducing inflammation

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5082866A (en) * 1988-06-01 1992-01-21 Odontex, Inc. Biodegradable absorption enhancers
AUPN814496A0 (en) * 1996-02-19 1996-03-14 Monash University Dermal penetration enhancer
US6004969A (en) * 1996-04-15 1999-12-21 National Science Council Transdermal delivery of buprenorphine preparations
EP1150661B1 (en) * 1999-02-05 2003-10-22 Cipla Ltd. Topical sprays comprising a film forming composition
IN191090B (en) * 2000-08-29 2003-09-20 Ranbanx Lab Ltd

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004000275A1 *

Also Published As

Publication number Publication date
NZ537435A (en) 2006-02-24
JP2005533795A (en) 2005-11-10
EA200500082A1 (en) 2005-06-30
BR0312004A (en) 2005-03-29
AUPS317102A0 (en) 2002-07-18
KR20050071373A (en) 2005-07-07
WO2004000275A1 (en) 2003-12-31
CA2490325A1 (en) 2003-12-31
EA007351B1 (en) 2006-10-27

Similar Documents

Publication Publication Date Title
US20050186141A1 (en) Transdermal aerosol compositions
US8784878B2 (en) Transdermal delivery rate control using amorphous pharmaceutical compositions
EP1674068B1 (en) Dermal penetration enhancers and drug delivery systems involving same
KR101662186B1 (en) Transdermal delivery system
TWI277418B (en) Enhanced drug delivery in transdermal systems
US20070280972A1 (en) Adhesive solid gel-forming formulations for dermal drug delivery
US20070196323A1 (en) Polyvinyl alcohol-containing compositions and methods for dermal delivery of drugs
WO2004000275A1 (en) Transdermal aerosol compositions
WO2004064841A1 (en) Formulation and methods for the treatment of thrombocythemia
US20050181032A1 (en) Metastable pharmaceutical compositions
US20090075963A1 (en) Transdermal hormone spray
JP2005533795A5 (en)
AU2003238543B2 (en) Transdermal aerosol compositions
AU2003240299B2 (en) Metastable pharmaceutical compositions
JPH06184000A (en) Percutaneous absorption promoter comprising @(3754/24)-)-isopregol
JP2010248250A (en) Metastable pharmaceutical composition
HK1087355B (en) Dermal penetration enhancers and drug delivery systems involving same
HK1077192B (en) Transdermal delivery rate control using amorphous pharmaceutical compositions
HK1075844B (en) Formulation and methods for the treatment of thrombocythemia

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20050111

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

DAX Request for extension of the european patent (deleted)
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1074995

Country of ref document: HK

RIN1 Information on inventor provided before grant (corrected)

Inventor name: WILKINS, NINA, FRANCES

Inventor name: MORGAN, TIMOTHY, MATTHIAS

Inventor name: GONDA, IGOR

18W Application withdrawn

Effective date: 20090814

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

R18W Application withdrawn (corrected)

Effective date: 20090817

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1074995

Country of ref document: HK