Skin permeation enhancer compositions comprising glycerol monolaurate and ...

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SKIN PERMEATION ENHANCER
COMPOSITIONS COMPRISING GLYCEROL
MONOLAURATE AND LAURYL ACETATE

RELATED APPLICATIONS 5

This application is a continuation-in-part of Ser. No. 08/481,549, now U.S. Pat. No. 5,785,991, filed Jun. 7,1995, assigned to ALZA Corporation, for which the benefit of the earlier filing date is claimed.

TECHNICAL FIELD

This invention relates to the transdermal delivery of agents or other biologically active agents and more particularly to methods and compositions for enhancing the per- 15 cutaneous absorption of agents or other agents when incorporated in transdermal agent delivery systems or devices. More particularly, this invention relates to the transdermal delivery of agents utilizing a novel dual permeation enhancer comprising glycerol monolaurate and lauryl 20 acetate.

DESCRIPTION OF TERMS

As used herein, the term "transdermal" means percutaneous delivery of an agent through skin or mucosal tissue into 25 the circulation by topical application.

As used herein, the term "therapeutically effective" amount or rate refers to the amount or rate of agent or active agent needed to achieve a desired therapeutic result. 30

As used herein, the phrase "predetermined area of skin" refers to a defined area of intact unbroken skin or mucosal tissue. That area is usually in the range of about 5 cm2 to about 100 cm2.

As used herein, the term "monoglyceride" refers to a 35 monoglyceride of a fatty acid or a mixture of monoglycerides of fatty acids, or mixtures thereof with other materials in which the monoglyceride component comprises at least 50% by weight, and includes, for example, glycerol monolaurate, glycerol monooleate, and glycerol monoli- 40 noleate.

As used herein, "glycerol monolaurate" refers to glycerol monolaurate itself or a mixture of glycerides wherein glycerol monolaurate is present in the greatest amount.

As used herein, "glycerol monooleate" refers to glycerol monooleate itself or a mixture of glycerides wherein glycerol monooleate is present in the greatest amount.

As used herein, "glycerol monolinoleate" refers to glycerol monolinoleate itself or a mixture of glycerides wherein 5Q glycerol monolinoleate is present in the greatest amount.

As used herein, the phrase "water absorbing polymer" refers to a hydrophilic polymer being able to absorb water and includes, but is not limited to, polyvinyl pyrrolidones, polyvinyl alcohol, and polyaminoacrylates. 55

BACKGROUND ART

The transdermal route of parenteral delivery of drugs provides many advantages, and transdermal systems for delivering a wide variety of drugs or other beneficial agents 60 are described in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731, 683; 3,797,494; 4,286,592; 4,314,557; 4,379,454; 4,435, 180; 4,559,222; 4,568,343; 4,573,999; 4,588,580; 4,645, 502; 4,704,282; 4,816,258; 4,849,226; 4,908,027; 4,943, 435; and 5,004,610, for example, all of which are 65 incorporated herein by reference. In many cases, agents which would appear to be ideal candidates for transdermal

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delivery are found to have such low permeability through intact skin that they cannot be delivered in therapeutically effective amounts from reasonably sized devices.

In an effort to increase skin permeability so that agents can be delivered in therapeutically effective amounts at therapeutically effective rates, it has been proposed to pretreat the skin with various chemicals or to concurrently deliver the agent in the presence of a permeation enhancer. Various materials have been suggested for this, as described in. U.S. Pat. Nos. 3,472,931; 3,527,864; 3,896,238; 3,903, 256; 3,952,099; 4,046,886; 4,130,643; 4,130,667; 4,299, 826; 4,335,115; 4,343,798; 4,379,454; 4,405,616; 4,746, 515; 4,788,062; 4,820,720; 4,863,738; 4,863,970; and 5,378,730; British Pat. No. 1,011,949; and Idson, "Percutaneous Absorption," J. Pharm. Sci. (1975) 64:901-924.

To be considered useful, a permeation enhancer should have the ability to enhance the permeability of the skin for at least one and preferably a significant number of agents. More importantly, it should be able to enhance the skin permeability such that the agent delivery rate from a reasonably sized system (preferably 5-50 cm2) is at therapeutic levels. Additionally, the enhancer when applied to the skin surface, should be non-toxic, non-irritating on prolonged exposure and under occlusion, and non-sensitizing on repeated exposure. Preferably, it should be odorless and capable of delivering agents without producing burning or tingling sensations.

It is often difficult to predict which compounds will work as permeation enhancers and which permeation enhancers will work for particular agents. In systemic drug delivery applications, a compound that enhances the permeability of one agent or a family of agents may not necessarily enhance the permeability of another agent or family of agents. Therefore, the usefulness of a particular compound as a permeation enhancer must be analyzed carefully.

U.S. Pat. No. 4,954,487 and European Patent Application 0 043 738 disclose pharmaceutical compositions containing a penetrating vehicle consisting essentially of a C1-C4 diol compound and a cell envelope disordering compound. Lauryl acetate is disclosed as a suitable cell envelope disordering compound.

U.S. Pat. No. 5,026,556 discloses a composition for the transdermal delivery of buprenorphine comprising an amount of buprenorphine in a carrier comprising a polar solvent material selected from the group consisting of C3-C4 diols, C3-C6 triols, and mixtures thereof; and a polar lipid material selected from the group consisting of fatty alcohol esters, fatty acid esters, and mixtures thereof. Lauryl acetate is disclosed as a suitable polar lipid material.

U.S. Pat. No. 5,149,538 discloses the transdermal delivery of an opioid. Preferred permeation enhancers are saturated and unsaturated fatty alcohols, fatty alcohol esters, or fatty acids having 8-18 carbon atoms. All of the aforementioned patents are incorporated herein in their entirety by reference.

While it is known in the art to combine permeation enhancers, this invention utilizes a novel combination of dodecyl acetate (lauryl acetate) and glycerol monolaurate (GML), and the combined effect is a significant and surprising improvement over use of GML or lauryl acetate alone.

DISCLOSURE OF THE INVENTION

It has been found that GML, known to enhance agent permeation in vitro, does not exhibit a good in vitro/in vivo correlation. Results derived from in vivo testing using GML as a permeation enhancer have not been found to be as consistent as the results from in vitro tests. Cosolvents such