United States Patent:   6,001,390

Assignee:  Alza Corporation (Palo Alto, CA)

Filed:  December 18, 1996

Composition of matter for application to a body surface or membrane to administer pergolide by permeation through the body surface or membrane, the composition comprising pergolide to be administered, at a therapeutically effective rate, alone or in combination with a permeation enhancer or mixture. Also disclosed are drug delivery devices containing the pergolide or pergolide and enhancer composition and methods for the transdermal administration of the pergolide and pergolide/enhancer composition.

SUMMARY OF THE INVENTION

It is unexpected that pergolide would be delivered through the skin at meaningful therapeutic rates either as a base or salt because, as its chemical name 8-[(methylthiolmethyl]-6-propylergoline monomethanesulfonate)] indicates, it has a complex chemical structure which does not lend itself to readily permeate through biological membranes such as the skin. Furthermore, it is even more unexpected that transdermal dosage forms provided with a pharmaceutically acceptable salt form of pergolide would result in a greater pergolide flux through skin than dosage forms provided with pergolide free base. Nonetheless, according to this invention, it has been discovered that pergolide can be safely and efficaciously administered transdermally to provide, among other things, treatment for Parkinson's Disease, with a reduced incidence of side effects and improved individual compliance. In addition, the present invention provides methods for the transdermal delivery of pergolide and delivery systems for effecting the same, which are suitable for the administration of pergolide continuously through a body surface or membrane to achieve and maintain therapeutic blood plasma levels of pergolide in an individual. A particularly advantageous aspect of this invention is the ability to maintain substantially constant blood plasma levels of pergolide in an individual over extended periods of time.

Surprisingly, the inventors have discovered that transdermal dosage forms provided with a pharmaceutically acceptable salt form of pergolide result in a greater pergolide flux through skin than dosage forms provided with pergolide free base. This is contrary to findings of a substantial amount of the prior art wherein for a majority of agents which have been tested for transdermal administration, it is recognized in the art that the permeability of the skin to the unioinized form of the drug is generally substantially greater than that of the ionized form. A preferred embodiment is therefore directed to providing the reservoir of a transdermal delivery device with a pharmaceutically acceptable salt of pergolide, preferably pergolide mesylate, together with a permeation enhancer.

As used herein, the term "transdermal" intends percutaneous and transmucosal administration, i.e., passage of pergolide through intact unbroken skin or mucosal tissue into the systemic circulation.

As used herein, the term "pergolide" intends not only the basic form of pergolide but also pharmaceutically acceptable salt forms of pergolide.

As used herein the term "salt" intends, but is not limited to, pharmaceutically acceptable salts such as chlorides, acetates, sulfates, phosphates, and mesylates.

As used herein, the term "pergolide therapy" intends all medical conditions for which pergolide is or will be indicated, including, without limitation, as a psychic energizer and in the treatment of Parkinson's Disease, migraine, allergic responses, urticaria, hypertension, endometritis, and other conditions associated with dopaminergic agonists.

As used herein, the term "individual" intends a living mammal and includes, without limitation, humans and other primates, livestock and sports animals such as cattle, pigs and horses, and pets such as cats and dogs.

As used herein, the term "therapeutic blood plasma level" intends the level of pergolide in blood plasma that achieves a therapeutic effect and is typically within the range of about 100 pg/mL-2000 pg/mL.

As used herein, the term "therapeutically effective rate" intends a rate of pergolide delivery effective to achieve therapeutic blood plasma levels of pergolide in an individual during the administration period.

As used herein, the phrase "sustained time period" or "administration period" intends at least about 8 hours and will typically intend a period in the range of about one to about seven days.

As used herein, the phrase "predetermined area of skin" intends a defined area of intact unbroken skin or mucosal tissue. That area will usually be in the range of about 1 cm.sup.2 to about 100 cm.sup.2.

As used herein, the term "permeation enhance" intends an agent or a mixture of agents which increases the permeability of the skin to pergolide.

As used herein, the term "permeation enhancement" intends an increase in the permeability of skin to pergolide in the presence of a permeation enhancer as compared to permeability of skin to pergolide in the absence of a permeation enhancer.

The present invention relates to compositions, devices and methods for the transdermal administration of pergolide in the treatment of Parkinson's Disease, among other things. According to the present invention, it has been found that pergolide may be safely and efficaciously administered transdermally through a body surface or membrane at a therapeutically effective rate for a predetermined, sustained time period in order to provide an effective therapeutic result. Another aspect of the present invention is directed to the transdermal administration of pergolide together with a suitable permeation enhancer or mixture of enhancers.

The system of the invention comprises a carrier or matrix adapted to be placed in pergolide- and permeation enhancer- transmitting relation to the selected skin or other body site. The carrier or matrix contains sufficient amounts of pergolide and a permeation enhancer to continuously coadminister pergolide at a therapeutically effective rate to the site together with the permeation enhancer during the administration period.

Claim 1 of 30 Claims

1. A composition of matter for delivering pergolide through the skin or mucosa by permeation through the skin or mucosa, the composition comprising an amount of a pharmaceutically acceptable salt of pergolide and a permeation-enhancing amount of a permeation enhancer comprising a monoglyceride or mixture of monoglycerides of a fatty acid and an alkyl laurate in a carrier effective to permit sustained release of pergolide over an administration period in order to deliver about 1.5-8 mg/day of pergolide at a flux greater than about 1 .mu.g/cm.sup.2 .multidot.hr and achieve therapeutically effective blood plasma levels of pergolide in a patient over a substantial portion of said administration period.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.