Transdermal delivery rate control using amorphous pharmaceutical compositions

Abstract

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 (A) wherein the composition has a release rate profile of physiologically active agent so as to provide a ratio of the maximum concentration (C max ) to the average concentration (C avg ) for the physiologically active agent over the dosage interval within the range of 1 to 10.

1 . 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 (C max ) to the average concentration (C avg ) for the physiologically active agent over the dosage interval within the range of 1 to 10. 
   
   
       2 . A pharmaceutical composition according to  claim 1  wherein the ratio (C max ) to (C avg ) is in the range of from 1 to 5. 
   
   
       3 . A pharmaceutical composition according to  claim 1  wherein the composition provides a substantially zero order or substantially first order release rate profile of the physiologically active agent over the dosage interval whichever is desirable for the therapeutic effect of the physiologically active agent. 
   
   
       4 . The transdermal drug delivery system according to  claim 1 , wherein the composition provides a zero order release rate profile of the physiologically active agent so as to reduce the ratio of the maximum concentration (C max ) to the average concentration (C avg ) to a value less than 2 for the physiologically active agent over the dosage interval in order to reduce potential side effects associated with elevated C max  to C avg  ratios. 
   
   
       5 . The transdermal drug delivery system according to  claim 1 , wherein the composition provides a zero order release rate profile of the physiologically active agent so as to reduce the ratio of the maximum concentration (C max ) to the average concentration (C avg ) to a value less than 1.5 for the physiologically active agent over the dosage interval in order to reduce potential side effects associated with elevated C max  to C avg  ratios. 
   
   
       6 . The transdermal drug delivery system according to  claim 1 , wherein the composition provides a first order release rate profile of the physiologically active agent so as to increase the ratio of C max  to C avg  to a value greater than 1.5 and decrease the time for maximum systemic concentration (t max ) to less than 6 hours for the physiologically active agent over the dosage interval in order to decrease the time to onset of therapeutic response or increase the therapeutic response after a single dose interval. 
   
   
       7 . The transdermal drug delivery system according to  claim 1 , wherein the composition provides a first order release rate profile of the physiologically active agent so as to increase the ratio of C max  to C avg  to a value greater than 2 and decrease the time for maximum systemic concentration (t max ) to less than 3 hours for the physiologically active agent over the dosage interval in order to decrease the time to onset of therapeutic response or increase the therapeutic response after a single dose interval. 
   
   
       8 . The transdermal drug delivery system according to  claim 1 , wherein the physiologically active agent is a steroid, hormone derivative, opioid analgesic, thrombolytic, antinauseant, anxiolytic, anti-migraine compound, antihypertensive agent, anti-malarial compound, bronchodilator, anti-depressant, anti-Alzheimer's agent, neuroleptic and antipsychotic agent, anti-Parkinson's agent, anticholinergic, antiandrogen or anoretic agent. 
   
   
       9 . The transdermal drug delivery system according to  claim 1 , wherein the physiologically active agent is testosterone, oestradiol, ethinyloestradiol, nestorone, levonorgestrel, lacidipine, norethisterone acetate, buspirone, fentanyl, buprenorphine, ropinirole, scopolamine, granisetron, amlodipine, oxybutynin, rivastigmine, rizatriptan, primaquine, fluoxetine, paroxetine, tacrine, N-0923 and mazindol. 
   
   
       10 . A pharmaceutical composition according to  claim 1  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. 
   
   
       11 . A pharmaceutical composition according to  claim 10  wherein the hydrofluorocarbon propellant is HFC-134a. 
   
   
       12 . A pharmaceutical composition according to  claim 10  wherein the volatile solvent and propellant provide a single phase solution of the active agent. 
   
   
       13 . A pharmaceutical composition according to  claim 1  wherein the composition comprises from 0.1% to 10% of physiologically active agent; from 0.1 to 10% by weight of dermal penetration enhancer and from 85% to 99.8% by weight of volatile carrier. 
   
   
       14 . A pharmaceutical composition according to  claim 10  wherein the hydrofluorocarbon propellant is from 15 to 50% by volume of the total pharmaceutical composition. 
   
   
       15 . A pharmaceutical composition according to  claim 1  wherein the physiologically active agent component comprise a molecular weight of less than 600 Daltons and a melting point less than 200° C. 
   
   
       16 . A pharmaceutical composition according to  claim 1  wherein the penetration enhancer has an organic nature value of from 200 to 400 and an inorganic nature value of from 0 to 200. 
   
   
       17 . A pharmaceutical composition according to  claim 1  wherein the dermal penetration enhancer is a lipophilic liquid having a vapour pressure below 10 mmHg at atmospheric pressure and a temperature of 32° C. and a molecular weight in the range of from 200 go 400 Daltons. 
   
   
       18 . A pharmaceutical composition according to  claim 1  wherein the penetration enhancer comprises one or more compounds selected from the groups consisting of 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, most preferably the dermal penetration enhancer is selected from the list including oleic acid, oleyl alcohol, cyclopentadecanone, sorbitan monooleate, glycerol monooleate, propyle glycol monolaurate, polyethylene glycol monolaurate, 2-n-nonyl 1,3-dioxolane, dodecyl 2-(N,N-dimethylamino)-propionate or its salt derivatives, 2-ethylhexyl 2-ethylhexanoate, isopropyl myristate, dimethyl isosorbide, 4-decyloxazolidinon-2-one, 3-methyl-4-decyloxazolidinon-2-one, and mixtures thereof. 
   
   
       19 . A pharmaceutical composition according to  claim 1  wherein the solvent comprises ethanol, isopropanol or a mixture thereof. 
   
   
       20 . A pharmaceutical composition according to  claim 1  wherein the molar ratio of the physiologically active agent compound and the dermal penetration enhancer is from 1:20 to 20:1. 
   
   
       21 . 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. 
   
   
       22 . An aerosol applicator device as defined in  claim 21  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. 
   
   
       23 . A method of treatment to provide enhanced percutaneous absorption of a physiologically active substance, the method comprising the step of applying a spray of a pharmaceutical composition according to  claim 1  to the skin of a subject to form an amorphous deposit of the active agent and penetrating enhancer upon evaporation of the volatile solvent whereby partitioning of the physiologically active agent from the stratum corneum to the viable epidermis is enhanced. 
   
   
       24 . A method of treatment to provide a substantially zero order release rate profile of the physiologically active agent, the method comprising applying a spray of a pharmaceutical composition according to  claim 1  to the skin of a subject wherein the potential side effects associated with elevated maximum bloodstream concentrations of the active (Cmax) over the dosage interval are reduced, whilst still maintaining effective average bloodstream concentrations of the active (Cavg). 
   
   
       25 . A method of treatment to provide a substantially first order release rate profile of the physiologically active agent, the method comprising applying a spray of a pharmaceutical composition according to  claim 1  to the skin of a subject wherein the time to onset of a therapeutic response to the active or an increase in the therapeutic response to the active is achieved by a decrease in the time to maximum concentration of the active in the bloodstream (tmax) and by an increase in the ratio of Cmax to C avg over the dosage interval.