Transdermal delivery rate control using amorphous pharmaceutical compositions

Abstract

A pharmaceutical composition for transdermal delivery comprisingone or more physiologically active agents;one or more dermal penetration enhancers; anda 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 (Cmax) to the average concentration (Cavg) for the physiologically active agent over the dosage interval within the range of 1 to 10.

Description

FIELD OF THE INVENTION[0001]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.BACKGROUND OF THE INVENTION[0002]There is a constant need for methods for the safe and effective administration of physiologically active agents. For many medications it is important that the administration regime is as simple and non-invasive as possible in order to maintain a high level of compliance by a patient. Oral administration is one administration regime that is commonly used because it is a relatively simple regime to follow. However, the oral administration route is also complicated because of complications associated with gastrointestinal irritation and with drug metabolism in the liver.[0003]Administration of physiologically active agents through the skin (‘transdermal drug delivery’) has received increased attention because it ...

AI Technical Summary

Benefits of technology

[0023]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. To put the invention into practice 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.

[0027]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. In contrast we have found that 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.

[0028]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.

[0029]In addition to providing improved percutaneous absorption efficiency, 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. Also, 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.

[0036]In addition, the use of compositions of the present invention may avoid a disadvantage associated with spray nozzle blockage that is experienced with existing film-forming sprays or aerosols.

Problems solved by technology

However, the oral administration route is also complicated because of complications associated with gastrointestinal irritation and with drug metabolism in the liver.

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.

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. crystallization and supersaturation in drug-in-adhesive transdermal patch delivery systems).

These existing volatile:non-volatile delivery systems suffer from the limitations of using water soluble dermal penetration enhancers that have poor substantivity for the skin and thus are unreliable in maintaining a stable amorphous composition within the skin over the delivery period due to their propensity to wash out of the skin.

Further, these prior art systems are prone to irritate the skin due to the solvent nature of the penetration enhancers used within such prior art systems (which results in significant penetration of the enhancer into the viable epidermis).

While these methods have all aimed at improvements in percutaneous absorption none have solved the problem of forming a stable amorphous composition capable of controlling the extent and / or profile of transdermal release of a physiologically active agent from within the skin whilst avoiding the skin irritation seen with prior art systems and compositions.

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