Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• • 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
• • 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
  • 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
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • 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
  • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • 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
  • A61P25/06—Antimigraine agents
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/26—Androgens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• the present invention relates to compositions for the transdermal delivery of physiologically active agents, to uses of those compositions, and to methods for the transdermal delivery of physiologically active agents.
• 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).
• Padimate O, Octyl salicylate (US Patent no 6,299,900) and AzoneTM are further examples of penetration enhancers that have been shown to improve percutaneous absorption.
• compositions that form in-situ have previously found use as biodegradable in situ forming film dressings (US Patent no. 5,792,469) for the formation of barrier surfaces for open dermal wounds.
• amorphous compositions for advanced drug delivery systems has been largely restricted to solid-state drug delivery systems such as; oral capsules an example of which is an amorphous paroxetine composition disclosed in WO 99/16440; or drug-in-adhesive, hot-melt type transdermal patches such as those disclosed in US Patent no. 5,662,923, US Patent no. 4,409,206, US Patent no. 6,264,980 and WO 95/18603.
• These existing amorphous delivery systems suffer from the particular disadvantage of being prone to poor stability during storage over their shelf-life which makes them particularly difficult to design and develop and in many instances has led to variability in drug release and/or dramatic changes in physical appearance (e.g.
• transient formation of an amorphous pharmaceutical composition could occur from existing alcohol-based volatile:non-volatile vehicles such as those disclosed in a dual-phase carrier system that uses benzyl alcohol as the dermal penetration enhancer (US Patent no. 4,820,724), or those acetone-based volatile: non-volatile vehicles using DMSO, DMAC as penetration enhancers (Feldmann, R. J.; Maibach, H. I. Percutaneous penetration of 14C hydrocortisone in man. II. Effect of certain bases and pre-treatments. Arch. Derm. 1966, 94, 649-651).
• alcohol-based volatile:non-volatile vehicles such as those disclosed in a dual-phase carrier system that uses benzyl alcohol as the dermal penetration enhancer (US Patent no. 4,820,724), or those acetone-based volatile: non-volatile vehicles using DMSO, DMAC as penetration enhancers (Feldmann, R. J.; Maibach, H. I. Percutaneous penetration of 14C hydrocor
• thermodynamic-based enhancement for improving percutaneous absorption
• a stable, in-situ forming amorphous pharmaceutical composition for release rate control within the skin are not foreseen by existing delivery systems which rely upon the control of release rate through the modification of the drug reservoir that resides above the skin such as that described for transdermal matrices that reside above the skin of the host and which are directed at deliberately modifying the profile of the transdermal drug delivery, such examples being described in US Patent no 5,091 ,186 titled Biphasic transdermal drug delivery device, or US Patent no. 5,613,958, titled Transdermal delivery systems for the modulated administration of drugs or WO 93/00058, titled Solubility parameter based drug delivery system and methods for altering drug saturation concentration.
• the present invention arises from the inventor's studies of penetration enhancers and in particular from the realisation that, for finite dose formulations, any enhancement in percutaneous absorption of a physiologically active agent is likely to result from one or more of:
• the present invention arises, at least in part, from the realisation that an increase and/or control in the stratum corneum to viable epidermis partition coefficient (c) may be achieved by deliberately forming an amorphous drug in situ so that the drug has increased water solubility within the viable epidermis.
• an increase and/or control in the stratum corneum to viable epidermis partition coefficient (c) may be achieved by deliberately forming an amorphous drug in situ so that the drug has increased water solubility within the viable epidermis.
• the present inventor's have found that some combinations of physiologically active agent and penetration enhancer form an amorphous solid in situ when they are applied topically and that these combinations can be used for controlling the extent and/or profile of transdermal release of a physiologically active agent.
• the present invention provides a composition including:
• a volatile carrier comprising a pharmaceutically acceptable solvent wherein the physiologically active agent and the dermal penetration enhancer form an amorphous deposit upon evaporation of the volatile carrier for the purpose of controlling the extent and/or profile of transdermal release of a physiologically active agent.
• Amorphous deposits that are formed using compositions of the present invention can be distinguished from solid precipitate (e.g. salt derivative of a drug) or crystalline polymorphs because the amorphous deposit is formed in-situ in the skin upon evaporation of the volatile carrier. In this way, the physiologically active agent is able to rapidly partition out of the stratum corneum and into the viable epidermis.
• solid precipitate e.g. salt derivative of a drug
• crystalline polymorphs because the amorphous deposit is formed in-situ in the skin upon evaporation of the volatile carrier.
• the physiologically active agent is able to rapidly partition out of the stratum corneum and into the viable epidermis.
• the formation of crystalline deposits in the skin typically leads to a higher propensity toward skin irritation and a decrease in percutaneous absorption efficiency (due to the need for greater energy to dissolve the crystal prior to diffusional transport). This problem increases in significance for higher melting point crystalline deposits.
• compositions of the present invention may also be more acceptable to consumers than other topical compositions because amorphous deposits have good skin feel and touch when the deposit is rubbed into the skin.
• the composition of the invention may also provide lower irritancy than some other delivery systems such as benzyl alcohol sprays, because the relatively low volume and type of volatile and non-volatile excipients used to deliver the active agent results in lower levels of irritation of the skin.
• the composition of the present invention may avoid problems with crystallisation and/or supersaturation that are encountered with existing amorphous compositions such as amorphous type transdermal patches. This is able to be overcome because in the present invention the amorphous deposit is formed in-situ.
• the invention further provides an aerosol composition for transdermal delivery of a physiologically active agent comprising: one or more physiologically active agents; one or more dermal penetration enhancers; and a volatile carrier comprising a volatile pharmaceutically acceptable solvent wherein topical application of the composition causes the physiologically active agent and dermal penetration enhancer to form an amorphous deposit on evaporation of the volatile carrier for the purpose of controlling the extent and/or profile of transdermal release of a physiologically active agent.
• the invention provides a pharmaceutical composition wherein the carrier comprises a hydrofluorocarbon propellant wherein topical application of the composition as an aerosol provides an amorphous deposit on evaporation of the volatile carrier, wherein the hydrofluorocarbon propellant is HFC-134a.
• the invention provides an aerosol applicator device for transdermal administration of physiologically active agent, the aerosol applicator comprising a chamber for containing an aerosol composition, a valve for delivering the aerosol composition and means for providing a metered dose of spray from the nozzle.
• the aerosol applicator may further comprise spacing means for spacing the applicator nozzle at a predetermined distance from the skin of the subject on which the spray is to be delivered.
• compositions of the present invention may avoid a disadvantage associated with spray nozzle blockage that is experienced with existing film-forming sprays or aerosols.
• the present invention provides a method of delivering an amorphous drug formulation to a host, the method including the steps of applying a topical spray composition containing one or more physiologically active agents, one or more dermal penetration enhancers, and a volatile pharmaceutically acceptable solvent to the skin of the host so that the volatile solvent evaporates to form an amorphous deposit containing the active agent and the dermal penetration enhancer.
• amorphous means substantially non-crystalline. It will be appreciated that, unless specified otherwise, the term amorphous includes within its scope a phase that does display some crystallinity. Amorphous for the purpose of the present invention therefore includes a phase in which only part of the deposit is in an amorphous phase. However, provided at least some of the deposit is in the amorphous phase the composition will provide the benefits of the present invention. In practice, it is preferred that at least 10% of the deposit is in the amorphous phase.
• the methods which may be used to assess the formation of amorphous compositions in potential compositions are Differential Scanning Calorimetry (DCS) and Brightfield microscopy. We have found that these techniques, as described herein in the examples, allow the propensity of composition to form amorphous residues in-situ to be readily determined.
• DCS Differential Scanning Calorimetry
• Brightfield microscopy We have found that these techniques, as described herein in the examples, allow the propensity of composition to form a
• physiologically active agent and dermal penetration enhancer of the present invention is limited functionally to those that together form an amorphous deposit. For this reason it is preferred that both the active agent and the dermal penetration enhancer are non-volatile relative to the volatile solvent so that upon application of the composition to the skin of the host, only the volatile solvent evaporates at physiological temperatures.
• the physiologically active agent may be selected from a range of lipophilic physiologically active agents with a molecular weight less than 600 Daltons and a melting point less than 200 degrees Celcius.
• suitable physiologically active agents includes, but is not limited to: apomorphine, butorphanol, oxybutynin, ropinirole, rivastigmine, buspirone, rizatriptin, tolterodine, zolmitriptan, lacidipine, tropisetron, olanzapine and methyl phenidate or a pharmaceutically acceptable salt or derivative of any one of the aforementioned.
• the physiologically active agent has a molecular weight less than 400 Daltons and a melting point less than 200 degrees Celcius.
• the dermal penetration enhancer may be selected from the classes of enhancers that are lipophilic non-volatile liquids whose vapour pressure is below 10mm Hg at atmospheric pressure and normal skin temperature of 32 degrees Celsius.
• the dermal penetration enhancer has a molecular weight within the range of 200 to 400 Daltons.
• the preferred enhancers for use in accordance with the invention may be identified by their balance of organic and inorganic properties.
• the organic and inorganic values for each penetration enhancer for use in accordance with the invention may be determined by the method described by Fujita in "Production of organic compounds by a Conceptional Diagram” Chem. Pharm. Bull (Tokyo) 2:163 (1954). Whereby area 1 and area 2 possess different physicochemical properties, with area 1 being solvent based enhancers.
• the preferred penetration enhancers are taken from the area 2 of the conceptional diagram proposed by Hori et al J. Pharm. Pharmacol (1990) 42: 71-72.
• the preferred area spans an inorganic value of from about 0 to about 200 and an organic value of about 200 to about 400.
• the preferred dermal penetration enhancers includes: fatty acids, fatty acid esters, fatty alcohols, glycols and glycol esters, 1 ,3-dioxolanes and 1 ,3- dioxanes, macrocyclic ketones containing at least 12 carbon atoms, oxazolidinones and oxazolidinone derivatives, alkyl-2-(N,N-disubstituted amino)-alkanoate esters, (N,N-disubstituted amino)-alkanol alkanoates, and mixtures thereof.
• the dermal penetration enhancer is selected from the list including oleic acid, oleyl alcohol, cyclopentadecanone (CPE- 218TM), sorbitan monooleate, glycerol monooleate, propylene glycol monolaurate, polyethylene glycol monolaurate, 2-n-nonyl 1 ,3-dioxolane (SEPATM), dodecyl 2-(N,N-dimethylamino)-propionate (DDAIP) or its salt derivatives, 2-ethylhexyl 2-ethylhexanoate, isopropyl myristate, dimethyl isosorbide, 4-decyloxazolidinon-2-one (SR-38TM,TCPI, Inc.), 3-methyl-4- decyloxazolidinon-2-one, and mixtures thereof.
• the volatile solvent has a vapour pressure above 35mm Hg at atmospheric pressure and normal skin temperature of 32 degrees Celsius.
• the mole ratio of physiologically active agent to dermal penetration enhancer may be between 1 :100 and 100:1. More preferably the mole ratio is between 1 :20 and 20:1. Most preferably the mole ratio is 1 :1.
• the composition is a topical spray composition that contains the physiologically active agent, the drug penetration enhancer and the volatile solvent and the method includes the step of spraying the composition onto the skin of the host to form the amorphous deposit containing the physiologically active substance.
• the amorphous deposit is preferably formed in the epidermis of the host, or has a shortened residence time in the viable epidermis or dermis of the host.
• 'viable epidermis' is meant the water rich tissue below the stratum corneum.
• Figure 3 Bar chart showing the melting point of a number of buspirone compositions
• Figure 4 Graph showing the cumulative amount of buspirone diffused through human epidermis with time from a control containing buspirone and compositions containing different proportions of buspirone and 2-n-nonyl 1 ,3-dioxolane penetration enhancer;
• Figure 5 Graph showing the cumulative amount of buspirone diffused through human epidermis with time from a control containing buspirone and a compositions containing buspirone and octyl salicylate penetration enhancer;
• Figure 7 Graph showing the cumulative amount of fentanyl diffused through human epidermis with time from a control containing fentanyl and a compositions containing fentanyl and octyl salicylate penetration enhancer;
• Figure 8 Graph showing the cumulative amount of fentanyl diffused through human epidermis following application of a transdermal spray composition (95% ethanol) containing fentanyl (5%) and octyl salicylate (5%, OS) penetration enhancer and a further composition containing fentanyl (5%) and cyclopentadecanolide (5%, CPDL) penetration enhancer.
• Figure 9 Graph showing the cumulative amount of granisetron diffused through human epidermis with time from a control containing granisetron and a compositions containing granisetron and octyl salicylate penetration enhancer.
• Figure 10 Graph showing the cumulative amount of granisetron diffused through human epidermis with time from a control containing granisetron and a composition containing granisetron and padimate O penetration enhancer.
• Figure 11 Graph showing the cumulative amount of testosterone delivered with time for compositions of the invention providing a zero order or first order delivery rate using two different dermal penetration enhancers (Padimate O or Octyl salicylate);
• Figure 12 Graph showing the plasma concentrations of free testosterone in postmenopausal women at steady state from a transdermal spray composition containing octyl salicylate (ACROSS ® ) as the dermal penetration enhancer.
• ACROSS ® octyl salicylate
• FIG 13 Graph showing the plasma concentrations of buspirone in healthy human volunteers at steady state and from a single dose using a transdermal spray composition containing octyl salicylate (ACROSS ® ) as the dermal penetration enhancer; compared with a single dose of oral buspirone (Buspar) at an oral dose of 15mg in the same subjects (crossover study design).
• ACROSS ® octyl salicylate
• Buspar oral buspirone
• a benefit of the present invention is that the composition is stable, which means that it is not prone to supersaturation or crystallisation during its pharmaceutical shelf life. This may be contrasted with transdermal patches in which crystallisation of the active agent has presented a problem in the past.
• the composition of the present invention can be held in a primary container during the shelf life without encountering shelf-life problems of the prior art transdermal patches.
• composition of the present invention may contain from about 0.1% to about 10% of the physiologically active agent, from about 0.1% to about 10% of the dermal penetration enhancer, and from about 85% to about 99.8% of the volatile solvent by weight.
• the dermal penetration enhancer is non-irritating to the skin of a recipient.
• terpenes, benzyl alcohol and other solvent based enhancers may not be suitable for use in the compositions of the present invention because they irritate the skin by penetrating into the viable regions of the skin in appreciable quantities.
• the vehicle may have additional pharmaceutical excipients, for example gelling agents, such as carbopol and cellulose derivatives.
• gelling agents such as carbopol and cellulose derivatives.
• the release rate profile of the physiologically active agent from the amorphous deposit into the systemic circulation may be deliberately modified to adjust the delivery profile of the physiologically active agent within the systemic circulation to achieve a desired therapeutic effect.
• a zero order release rate profile is achieved by forming an amorphous deposit that has a higher proportion of dermal penetration enhancer relative to the physiologically active agent and/or alternatively selecting a dermal penetration enhancer or combination of dermal penetration enhancers for which the physiologically active agent has a higher saturated solubility.
• the absolute amount of physiologically active agent can also be increased in the skin reservoir so as to reduce the extent of the plateau in the release rate profile toward the latter half of the dosage interval.
• the relative amount of crystalline to amorphous deposit may also be modified to achieve the desired release rate profile.
• the release rate profile of the physiologically active agent from the amorphous deposit into the systemic circulation preferably approaches zero order in nature so as to reduce the ratio of maximum concentration (C max ) to the average concentration (C avg ) for the physiologically active agent over the dosage interval. In this way it is possible to reduce potential side effects associated with elevated C ma ⁇ to C aV g ratios. For example C max to C avg ratios less than 2 and more preferably less than 1.5.
• a first order release rate profile can be achieved by selecting a dermal penetration enhancer or combination of dermal penetration enhancers in which the physiologically active agent has a lower saturated solubility thus increasing the leaving tendency of the physiologically active agent from the amorphous deposit, and increasing the initial burst of physiologically active agent across the skin.
• the absolute amount of physiologically active agent per unit area can also be reduced in the skin reservoir so as to increase the extent of the plateau in the release rate profile toward the latter half of the dosage interval.
• the relative amount of crystalline to amorphous deposit may also be modified to achieve the desired release rate profile.
• the release rate profile of the physiologically active agent from the amorphous deposit into the systemic circulation is substantially first order in nature so as to increase the ratio of C max to C avg and decrease the time for maximum systemic concentration (t max ) for the physiologically active agent over the dosage interval.
• t max maximum systemic concentration
• the method of in vitro diffusion of various physiologically active agents across human skin was used in accordance with the invention to assess the effect of addition of the various dermal penetration enhancers on transdermal drug delivery.
• the methods of Differential Scanning Calorimetry (DSC) and Brightfield Microscopy were used in accordance with the invention to assess whether or not a composition is amorphous after evaporation of the volatile liquid and where necessary the extent of amorphous material present.
• DSC is used to determine changes in physicochemical properties of compounds in combination with a dermal penetration enhancer after volatile liquid evaporation. This enables determination of the optimum ratio of drug to enhancer, which results in an altered amorphous form to enhance percutaneous absorption (i.e. enhance transdermal drug delivery).
• amorphous nature of a mixture of compounds is evident in a depressed melting point of the mixture of compounds relative to the melting point of any of the individual components of the mixture.
• a decrease in peak height and heat of enthalpy along with a broadening of the melting transition temperature are also characteristics inherent of amorphous compounds.
• mole ratio mixtures of the physiologically active agent and dermal penetration enhancer shown were prepared in 95% ethanol as per the compositions shown.
• a 10 ⁇ l aluminium micro DSC pan was placed in a 50 ⁇ l DSC aluminium pan, and 5 ⁇ l aliquots of each formulation were pipetted into the 10 ⁇ l DSC pan.
• the volatile liquid (95% ethanol) was allowed to evaporate and further aliquots were re-applied until a sufficient quantified residue of physiologically active agent and dermal penetration enhancer remained.
• the pans were maintained at ambient temperature and 33% relative humidity for 24 hours (which simulated a typical in-use daily dosage interval), after which the pans were covered and hermetically sealed. DSC was then performed under a stream of nitrogen, at 10 Q C per minute, within the temperature range that was drug dependent.
• Briqhtfield Microscopy Brightfield microscopy was used to determine the crystallisation/amorphous solid potential of various physiologically active agents in combination with a dermal penetration enhancer after volatile liquid (95% ethanol) evaporation. This enables a determination of the optimum ratio of drug to enhancer in conjunction with DSC.
• Figure 1 shows the organic and inorganic values for typical penetration enhancers that can be used in accordance with the invention (determined by the method described by Fujita in "Production of organic compounds by a Conceptional Diagram” Chem. Pharm. Bull. Tokyo 1954 2:163).
• Area 1 being solvent based dermal penetration enhancers which are prone to irritate the skin or evaporate off it when using non-occlusive percutaneous or transdermal drug delivery systems.
• the preferred penetration enhancers are taken from the area 2 of the conceptional diagram (as originally proposed by Hori et al J. Pharm. Pharmacol 1990 42: 71-72).
• the preferred area spans an inorganic value of from about 0 to about 200 and an organic value of about 200 to about 400.
• Example 2 Example 2
• compositions of the invention formed by the combination of buspirone with a range of penetration enhancers having a range of organic and inorganic characteristics.
• the physicochemical properties of buspirone are shown in the following table:
• the penetration enhancers examined in this example were 2-n-nonyl, 1 ,3- dioxolane (SEPA), dodecyl 2-(N,N-dimethylamino)-propionate (DDAIP) and cylclopentadecanone (CPL).
• SEPA 2-n-nonyl, 1 ,3- dioxolane
• DDAIP dodecyl 2-(N,N-dimethylamino)-propionate
• CPL cylclopentadecanone
• FIG. 1 there is shown a plot of inorganic index against organic index for potential penetration enhancers.
• the organic and inorganic values are determined according to the procedure of Fujita A Chem. Pharm. Bull (Tokyo) 2:173 (1954).
• the compounds 2-n-nonyl, 1 ,3-dioxolane, dodecyl 2-(N,N- dimethylamino)-propionate (DDAIP) and cylclopentadecanone demonstrate a range of organic, inorganic index in Area 2 generally defining organic index between 0 and 200 and an organic index between 200 and 400.
• DDAIP dodecyl 2-(N,N- dimethylamino)-propionate
• cylclopentadecanone demonstrate a range of organic, inorganic index in Area 2 generally defining organic index between 0 and 200 and an organic index between 200 and 400.
• Test Formulations All enhancer containing (test) formulations were prepared as 1 :1 and 4:1 mole ratios of drug:enhancer unless stated.
• IPM Isopropyl myristate
• Buspirone 2-n-nonyl, 1 ,3-dioxolane (SEPA)
• Buspirone Laurocapram (AzoneTM, AZ)
• DSC profiles were determined for the control and test formulations pure buspirone and buspirone with several particular enhancers with a mole ratio of 1 :1. Solvent evaporation, for each formulation, resulted in a melting point reduction.
• Figure 2 demonstrates characteristics inherent of amorphous compounds, for example the decrease in melting point, ⁇ H and peak height, and the broadening of the melting transition temperature.
• DSC analysis of buspirone with each enhancer, at mole ratio of 1 :1 and 4:1 showed a reduction in melting point, with buspirone:azone 1 :1 ratio remaining as an oil thus presenting no melting point (Figure 3).
• Figure 3 also shows the inability of the solvent based enhancer (2-ethyl acetate) to reliably reduce the melting point of buspirone. This disadvantage combined with its propensity to irritate the skin is why solvent based enhancers are not preferred for the non-occlusive transdermal delivery system of this invention.
• Buspirone diffusion through human skin confirms an increase in buspirone permeability at the 1 :1 mole ratio with 2-n-nonyl, 1 ,3-dioxolane of 2.6.
• the 4:1 ratio demonstrated no significant enhancement (Table 2, Figure 4).
• Table 2 Summary of Mean Cumulative Amount penetrated across human epidermis at 24 hours (Q 24h ) ( ⁇ g/cm 2 ) for various formulations.
• Figure 5 shows the cumulative amount of buspirone diffused across human epidermis with time from a control containing buspirone in volatile liquid (95% ethanol) and a composition containing buspirone and octyl salicylate penetration enhancer in the same volatile liquid. Addition of the octyl salicylate to the transdermal spray formulation caused a significant marked increase in the amount of buspirone diffusing across the skin over 24 hours (p ⁇ 0.05).
• Example 4 The amorphous deposit formed in situ by the compositions of Examples 2 and 3 result in an enhanced delivery of buspirone across the skin.
• the delivery profile across the skin for these enhanced amorphous compositions can be either a zero order delivery profile or a first order delivery profile, whichever of these situations is desired for the particular pharmacological therapy.
• the composition without the enhancer shows poor penetration enhancement of buspirone across the skin and consequent low amounts of drug penetrating across the skin.
• Figure 6a depicts the diffusion profile that may be obtained by transdermal zero and first order administration of buspirone in accordance with the invention and figure 6b shows the approximated plasma concentration profile that would correspond to each delivery rate profile shown in figure 6a.
• the diffusion profiles of amorphous deposits investigated confirm an increase in the delivery of the active across the skin.
• the rate of delivery may be modified to suit the desired pharmacological therapy by either changing the dermal penetration enhancer used in the composition or by changing the ratio of drug to enhancer in the composition.
• Figures 7 and 8 demonstrate the ability to modify the fentanyl delivery rate by changing penetration enhancer. Therefore, the leaving tendency may be modified to suit the desired delivery rate.
• a stable zero order delivery rate in the case of fentanyl would be desirable for the treatment of chronic pain.
• Figure 9 and 10 demonstrates the ability the ability to modify the granisetron delivery rate by changing penetration enhancer and/or the ratio of drug to enhancer in the composition.
• the drug to enhancer ratio was varied to modulate the delivery rate of testosterone in vitro using transdermal spray vehicles. Varying concentrations of testosterone (Tes) and the dermal penetration enhancers octyl salicylate (Osal) or padimate O (PadO) were applied to shed snake skin in vitro from a finite vehicle volume (5 ⁇ l/cm 2 ) designed to mimic in vivo dosing. The rate and extent of drug permeation was modelled to a single compartment model with a first-order rate constant (Kubota, K. J. Pharm. Sci. 1991 , 80, 502-504).
• the in vitro diffusion model allowed accurate and rapid characterisation of the diffusion profiles using three parameters alone, total % absorbed ⁇ A, units ⁇ g), rate constant ( , units h "1 ) and lagtime (/, units h). Varying Tes to Osal ratio changed A and / significantly (p ⁇ .001) and increased Tes loading in a PadO formulation resulted in zero-order delivery in vitro over 48 h as shown in Figure 11 (suggesting the drug solubility in the enhancer plays a role in drug release). For practical formulation development purposes a simple compartmental diffusion model can be used to optimise the drug to enhancer ratio in order to modulate drug permeation across the skin.
• the plasma concentrations of free testosterone were determined in postmenopausal women at steady state from a transdermal spray composition containing testosterone 5% w/v and octyl salicylate 8% w/v in 95% ethanol. A zero-order delivery profile was obtained and is shown in Figure 12.
• Figure 13 shows the results for a pharmacokinetic study in 6 normal healthy male volunteers which studied a single transdermal spray dose followed by washout period; then a single oral dose of buspirone 15mg (3 x 5mg tablets; BuSpar) was given followed by washout period after which the volunteers received multiple transdermal doses once daily until steady state was achieved.
• the daily transdermal dosage applied was 4 x 91 ⁇ l sprays of the buspirone metered-dose transdermal spray (MDTS®) containing 4% w/v buspirone and 5% w/v octyl salicylate applied to the forearm.
• MDTS® buspirone metered-dose transdermal spray
• the mean half-life was 2 hours and mean tmax was 0.9 hours.
• the mean Cavg was 0.15 ng/ml and mean Cmax was 1.3ng/ml_, with the calculated ratio of Cmax to Cavg having a value of 8.7.
• the mean Cavg was 0.32 ng/ml and mean Cmax was 0.49ng/ml_, with the calculated ratio of Cmax to Cavg having a value of 1.5 and a mean tmax of 9.3 hours.
• buspirone composition of this example could be expected to have particular advantages for the use in humans or animals for the treatment of general anxiety disorders and attention deficit hyperactivity disorder whereupon the stable zero order transdermal delivery of the drug and avoidance of a high Cmax concentration provided by the invention would beneficially result in a reduction in side effects such as gastrointestinal disturbances, drowsiness, impaired driving or motor ability and/or impaired cognitive function.

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