Novel formulations for the administration of fluoxetine

Abstract

Composition of matter for application to a body surface or membrane to administer fluoxetine by permeation through the body surface or membrane, the composition comprising fluoxetine to be administered, at a therapeutically effective rate, alone or in combination with a permeation enhancer or mixture. A preferred embodiment is directed to the transdermal administration of fluoxetine at reduced skin irritation levels wherein fluoxetine, preferably provided as fluoxetine acetate, is coadministered with a corticosteroid such as hydrocortisone. Also disclosed are drug delivery devices containing the fluoxetine or fluoxetine and enhancer composition and methods for the transdermal administration of the fluoxetine and fluoxetine / enhancer composition.

Description

RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application Nos. 60 / 021,727, filed on Jul. 15, 1996 and 60 / 038,425 filed Feb. 19, 1997.FIELD OF INVENTION [0002] This invention relates to sustained release formulations for the safe and efficacious administration of fluoxetine for, among other things, the treatment of depression. More particularly, the invention relates to novel methods, compositions, and devices for transdermally administering fluoxetine to a subject through a body surface or membrane over a sustained time period. A preferred embodiment is directed to the transdermal administration of fluoxetine at reduced skin irritation levels. BACKGROUND OF THE INVENTION [0003] Fluoxetine, (±)-N-methyl-γ-[4-(trifluoromethyl)-phenoxy]benzenepropanamine, is one of the 3-aryloxy-3-phenylpropylamine compounds described in U.S. Pat. No. 4,314,081. Additionally, U.S. Pat. No. 4,626,549 discloses a method of blocking the uptake of monoamines such as se...

AI Technical Summary

Benefits of technology

[0051] Another aspect of this invention is to provide compositions, devices, and methods for transdermally administering fluoxetine at reduced skin irritation levels.

[0052] Another aspect of this invention is to improve patient compliance of patients in need of fluoxetine therapy by providing compositions, devices, and methods for the transdermal administration of fluoxetine at a therapeutically effective rate.

[0054] According to this invention, it has been discovered that fluoxetine can be safely and efficaciously administered transdermally at a therapeutically effective rate to provide, among other things, treatment for depression, when administered alone or when coadministered with a suitable permeation enhancer. A preferred embodiment is directed to transdermally administering a therapeutically effective amount of fluoxetine at reduced skin irritation levels wherein fluoxetine is coadministered from a transdermal drug delivery device containing a pharmaceutically acceptable salt of fluoxetine, an anti-irritant, and a permeation enhancer in order to provide systemic administration of fluoxetine.

Problems solved by technology

This assumption, however, has not been proven true.

The failure of the transdermal route to fulfill the initial expectations of its potential as an administrative portal was primarily due to the incredible variety of properties with which nature has endowed the skin to permit it to perform its function as the primary barrier to prevent the ingress of foreign substances into the body.

If large amounts of the agent are bound in the skin, significant delays in the onset of therapeutic effect (“lag time”) will be observed together with corresponding delays and termination of effect upon removal of the device.

The potential also exists for toxic quantities of potent agents to be contained within the skin beneath the device.

Agents that are highly permeable may also be highly bound causing a lag time sufficiently long as to render them unsuitable for their intended use.

The skin reacts to many topically applied substances, particularly those maintained under occlusion, by blistering or reddening accompanied by unpleasant burning, itching, and stinging sensations.

Animal models, however, often produce both false positives and false negatives.

If the latter occurs, the individual will be unable to take the drug by any route of administration.

Animal models, however, produce both false positives and false negatives.

Constant blood levels may not produce the desired therapeutic effects.

For example, a therapeutic effect may only be observed at peak blood concentration obtained from bolus dosing but the peak blood or plasma concentration cannot be maintained because of side effects associated therewith.

Also, continuous administration of many agents produces tolerance that may require either some agent-free interval or continually increasing and therefore potentially hazardous doses of the agent.

Although a certain degree of potency is required for transdermally administered agent to be effective, it is also possible for an agent to be too potent.

Because of normal inter-individual variations and skin permeability, it may not be possible to precisely control whether a individual is receiving 1 μg / hr or 2 μg / hr, for example.

For a highly potent agent, a 1 μg / hr administration may be totally ineffective and a 2 μg / hr rate fatal.

Thus, the therapeutic index of an agent, which is the ratio of toxic blood concentration to the therapeutic blood concentration, becomes extremely significant.

Thus, although first-pass metabolism that occurs after an orally administered agent enters the blood stream can be avoided, skin metabolism, which occurs before the agent enters the bloodstream, cannot be avoided.

There are undoubtedly others, some of which have not yet been recognized, and, in order for an agent to be suitable for transdermal administration, it must possess the right combination of all these characteristics, a combination of which, as illustrated by the very few drugs that are now suitable for administration from transdermal delivery devices, is quite rare and unpredictable.

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