Dermal penetration enhancers and drug delivery systems involving same

Abstract

The invention relates to a method for treatment or prophylaxis of a disease or condition in an animal comprising administering to a mucosal membrane of said animal in need of such treatment a therapeutically effective amount of a drug delivery system comprising at least one physiologically active agent or prodrug thereof and at least one penetration enhancer selected from safe ester sunscreens.

Description

[0001] This application is a continuation in part application Ser. No based on 09 / 910,780 filed on Jul. 24, 2001.FIELD OF THE INVENTION [0002] The present invention relates to percutaneous or transdermal drug delivery. More specifically, the invention relates to a topical absorption / penetration enhancing agent for use in the delivery of a physiologically active agent to an animal, including a human. The invention also relates to a system for the non-occlusive delivery to an animal of a physiologically active agent across a dermal surface or mucosal membrane of the animal. Transdermal drug formulations of the present invention may be used for local application or systemic delivery. BACKGROUND OF THE INVENTION [0003] The prevention or treatment of local or topical disease states or conditions of the skin has traditionally used simple non-occlusive delivery systems. These drug delivery systems usually include a volatile and / or non-volatile medium whereby a composition of the drug and m...

AI Technical Summary

Benefits of technology

"The present invention provides a transdermal drug delivery system that includes a physiologically active agent or prodrug and a safe skin-tolerant ester sunscreen as a dermal penetration enhancer. The use of a safe skin-tolerant ester sunscreen as a dermal penetration enhancer improves the delivery of the active ingredients through the skin. The dermal penetration enhancers are preferably esters of formula (i) and more preferably long chain alkyl para-aminobenzoate, long chain alkyl dimethyl-para-aminobenzoate, long chain alkyl cinnamate, long chain alkyl methoxycinnamate, or long chain alkyl salicylate. The technical effect of this invention is to provide a safer and more effective way to deliver drugs through the skin."

Problems solved by technology

The limitation with this type of delivery system is that systemic drugs are generally not suitable for this type of administration.

Some major problems with the current state of the art relate to a lack of efficacy of systemic drugs because of the low drug flux across the skin, as observed for drugs such as testosterone, amlodipine, fentanyl, buprenorphine and many others.

Other drugs, such as glyceryl trinitrate, Nitrobid™ (a drug for the treatment of angina), are difficult to deliver by these systems due to the inability to adequately control the rate of drug delivery, or the requirement for a very large application area.

Other problems with the poor dermal penetration of drugs is that the drug can be easily washed off or transferred to clothes, other surfaces or other animals.

Transdermal formulations are however limited.

For example polar drugs tend to penetrate the skin too slowly.

Since most drugs are of a polar nature this limitation is significant, as is the fact that many drugs cause irritation at the site of topical application.

The prolonged length of time required for transfer of the drug and excipients from the patch into the skin can and often does result in local skin irritation.

The irritation is caused by prolonged contact on the skin by the drug, volatiles, vehicle excipients, or the adhesive used to attach the patch device to the skin.

The occlusive nature of the patch device also restricts the natural ability of the skin to “breathe”, increasing the risk of irritation.

The problem with most known dermal penetration enhancers is that they are often toxic, irritating or allergenic.

However, difficulties remain with such dermal enhancers because the problem of irritation at the site of application has not been overcome.

The most critical problem with these compounds however is their toxicity.

If a compound when used as a dermal enhancer is toxic, irritating or allergenic, then that compound is unsuitable for application to the animal body.

Dimethyl sulfoxide and dimethyl acetamide are not clinically acceptable for these reasons.

Although Deet and Azone® have lower reported toxicities, their toxicity is still such that they are not widely used.

However, topical vehicles relying on supersaturation, have the major limitation of formulation instability, both prior to and during application to the skin.

As such, they are of limited clinical value within a non-occlusive volatile:non-volatile delivery vehicle, because as soon as the formulation comes into contact with a person's clothing or the like, the drug often precipitates; hence the formulation is no longer supersaturated and any enhanced percutaneous absorption ceases.

However, the applied drug formulations stabilised with polymers formed an appreciable surface mass on the skin which remained there over a prolonged duration of many hours, not a few minutes.

So while Kondo advocated the use of a metered spray to deliver these formulations, in reality it would be impossible to obtain a non-occlusive delivery system with a short application time and still maintain a clinically useful transdermal penetration enhancement.

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