Controlled Release Delivery System for Nasal Applications and Method of Treatment

Abstract

This invention relates to a gel formulation for nasal administration of a controlled release formulation of hormones to the systemic circulation and / or to the brain. The special lipophilic or partly lipophilic system of the invention leads to higher bioavailability of the active ingredient caused by sustained serum levels in plasma but also leads to a more favorable serum level profile. The special lipophilic or partly lipophilic system also allows for the modulation of brain functioning. The invention also relates to the nasal administration of steroid hormones for treatment of female sexual dysfunction (FSD) or female arousal disorder.

Description

[0001] The present application is a continuation-in-part of U.S. patent application Ser. No. 10 / 772,964 filed Feb. 4, 2004, which is hereby incorporated by reference.FIELD OF THE INVENTION [0002] The invention relates generally to a formulation for the controlled release of hormones to the systemic circulation and / or to the brain (by bypassing the blood-brain barrier) after nasal application and for the modulation of brain functioning. More specifically, the invention relates to the treatment of neuroendocrinologic disorders, such as Female Sexual Disorder (FSD) by nasally administering a formulation comprising a hormone drug. BACKGROUND [0003] A growing body of evidence suggests a modulatory role of brain-acting compounds, such as neurosteroids (e.g., androgens, progestins) or neurotransmitters in the regulation of disorders influenced by receptors in the brain, such as depression, Parkinson's disease, Alzheimer's, or even loss of libido. [0004] Considerable importance has been pla...

AI Technical Summary

Benefits of technology

[0019] The inventor has surprisingly found that the incorporation of various hormone drugs, such as sexual hormones, into a special lipophilic or partly lipophilic system not only leads to a higher bioavailability in general caused by sustained serum levels in plasma but also to a more favorable serum level profile. In an especially important aspect, the lipophilic or partly lipohilic system of the invention allows hormones to cross the blood-brain-barrier in such a way as to achieve efficacy in medicines for disorders of the central nervous system (CNS).

[0021] While not wishing to be bound by theory, it is believed that nasal administration of the formulation of the invention may be able to recruit selective actions of a molecule which, in turn, may provide new clinical applications. Of particular interest is the use of formulations to modulate brain functioning. Application of the formulation of the invention to the nose results in surprising and different action of compounds to the brain as compared to what is seen with conventional formulations. While not wishing to be bound by theory, it is believed that this effect is due to new, possibly also non-genomic, mechanisms that are made available by the gel formulation of the invention.

Problems solved by technology

However, the underlying mechanisms of action are still poorly understood.

Much of the confusion about the wide range of effects and side effects is due to various non-genomic actions.

However, there is very little knowledge of the possible differential relevance of a molecule's non-genomic actions in different cell types.

However, maintaining constant in vivo therapeutic drug concentrations for an extended period of time has been problematic.

The rapid mucociliary clearance of a therapeutic agent from the site of deposition and the presence of enzymes in the nasal cavity (that may cause degradation of the therapeutic agent) result in a short time span available for absorption.

Due to this fact, the short half-life of sexual steroids, and the limited possibilities for formulating nasal application forms with sustained release, the use of sexual steroids in clinical practice has been limited because hormone replacement therapy, in general, is a long-term application.

It should be noted, however, that this speed is not necessary or desirable because sex hormone replacement is not an emergency therapy.

However, because Ko et al. did not take blood samples before application, it is not possible to evaluate the differences in the decrease of serum levels, although from a graph it seems that after intravenous application (hydroalcoholic solution) the level shows the longest elimination half time.

In practice, however, such an emulsion is not suitable for nasal application because of the droplet size (approximately 430 nm).

Again, this speed is not necessary for sex hormone replacement therapy and is not desirable in view of the short elimination half-life of hormones.

However, high protein-binding also presents a problem because only the unbound fraction is biologically active.

Previous research has shown that sublingual application of testosterone undecanoate results in a very fast and high testosterone peak that triggers sexual arousal.

Apperloo et al. found an acute and prolonged rise in testosterone and free testosterone above physiological levels with a peak at 5.5 hours is not sufficient to influence the female sexual response.

Thus, these application forms probably lack a sufficient CNS effect.

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