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 . thus 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 . the 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 . preferably , the dermal penetration enhancer is non - irritating to the skin of a recipient . thus , 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 . optionally , the vehicle may have additional pharmaceutical excipients , for example 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 . in this way , the leaving tendency of the physiologically active agent from the amorphous deposit is modified and the initial burst of physiologically active agent across the skin is limited . 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 max to c avg ratios . for example c max to c avg ratios less than 2 and more preferably less than 1 . 5 . conversely 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 . preferably , 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 . in this way it is possible to decrease the time to onset of therapeutic response or increase the therapeutic response after a single dose interval . for example c max to c avg ratios greater than 1 . 5 and more preferably greater than 2 and t max less than 4 to 6 hours and more preferably less than 2 to 3 hours . 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 . 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 . in vitro diffusion experiments were performed using stainless steel flow - through diffusion cells , using human epidermis maintained at 32 ° c . the receptor solution consisted of either 10 % ethanol in 0 . 002 % sodium azide . the non - occlusive composition was added to each of four cells at a finite dose of 5 μl per cell . samples were collected at appropriate time points and analysed by reverse - phase high performance liquid chromatography ( rp - hplc ). 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 ). the 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 . in addition , 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 . firstly , 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 μl aluminium micro dsc pan was placed in a 50 μl dsc aluminium pan , and 5 μl aliquots of each formulation were pipetted into the 10 μl 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 ° c . per minute , within the temperature range that was drug dependent . 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 . 5 μl aliquots of each formulation were pipetted onto a clean , glass slide at 32 ° c ./ ambient relative humidity . after evaporation of the volatile liquid vehicle ( 95 % v / v ethanol ), the slide was viewed under a leica wild microscope , linked to spot diagnostics camera , at 1 and 24 hours . the nature of the mixture remaining after 24 hours is assessed and the proportion by volume of amorphous material may be visually estimated . fig1 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 . this example examines 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 : m . wt ( da ) logp m . pt (° c .) buspirone 385 . 51 2 . 63 103 . 5 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 ). referring to fig1 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 . all formulations were prepared by accurately weighing the appropriate amount of physiological active and penetration enhancer into a volumetric flask and made up to volume with ethanol ( 95 % v / v ). all enhancer containing ( test ) formulations were prepared as 1 : 1 and 4 : 1 mole ratios of drug : enhancer unless stated . buspirone : isopropyl myristate ( ipm ) buspirone : dodecyl 2 -( n , n - dimethylamino )- propionate ( ddaip ) buspirone : 2 - n - nonyl , 1 , 3 - dioxolane ( sepa ) buspirone : laurocapram ( azone ™, az ) buspirone : myristic acid ( ma ) buspirone : 2 - ethyl acetate ( ea ) 2 - ethyl acetate ( ea ) which has a molecular weight of 88 . 1da and boiling point of 77 . 1 ° c . is included as an example of a solvent based dermal penetration enhancer which is not preferred for use in this invention because it is prone to irritate the skin or evaporate off it when using non - occlusive percutaneous or transdermal drug delivery systems . 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 . fig2 demonstrates characteristics inherent of amorphous compounds , for example the decrease in melting point , δh 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 ( fig3 ). fig3 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 . microscopy of each binary mixture confirmed the part - amorphous state of buspirone . in most cases an unevenly spread oily film was observed , with occasional few small crystals present or some compositions with some needle shaped crystals protruding . diffusion experiments ( table 2 ) were performed on various 95 % ethanol formulations containing buspirone and 2 - n - nonyl , 1 , 3 - dioxolane ; buspirone diffusion through human skin ( epidermis ) confirms an increase in buspirone permeability at the 1 : 1 mole ratio with 2 - n - nonyl , 1 , 3 - dioxolane of 2 . 6 . however , the 4 : 1 ratio demonstrated no significant enhancement ( table 2 , fig4 ). fig5 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 & lt ; 0 . 05 ). 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 . fig6 a depicts the diffusion profile that may be obtained by transdermal zero and first order administration of buspirone in accordance with the invention and fig6 b shows the approximated plasma concentration profile that would correspond to each delivery rate profile shown in fig6 a . 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 . fig7 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 . fig9 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 μl / 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 μg ), rate constant ( α , units h − 1 ) and lagtime ( i , units h ). varying tes to osal ratio changed a and i significantly ( p & lt ; 0 . 001 ) and increased tes loading in a pado formulation resulted in zero - order delivery in vitro over 48 h as shown in fig1 ( 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 fig1 . fig1 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 15 mg ( 3 × 5 mg 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 × 91 μl sprays of the buspirone metered - dose transdermal spray ( mdts ®) containing 4 % w / v buspirone and 5 % w / v octyl salicylate applied to the forearm . for a single dose of the oral buspirone tablet ( 15 mg ) 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 . 3 ng / ml , with the calculated ratio of cmax to cavg having a value of 8 . 7 . in contrast , following once - daily dosing of the buspirone transdermal spray of the invention the mean cavg was 0 . 32 ng / ml and mean cmax was 0 . 49 ng / ml , with the calculated ratio of cmax to cavg having a value of 1 . 5 and a mean t max of 9 . 3 hours . the 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 .
a pharmaceutical composition for transdermal delivery comprising one or more physiologically active agents ; one or more dermal penetration enhancers ; and a volatile pharmaceutically acceptable carrier comprising a volatile solvent ; and wherein the physiologically active agent and dermal penetration enhancer form an amorphous deposit upon evaporation of the volatile carrier , said amorphous deposit forming a reservoir within the stratum corneum ; and wherein the composition has a release rate profile of physiologically active agent so as to provide a ratio of the maximum concentration to the average concentration for the physiologically active agent over the dosage interval within the range of 1 to 10 .