Controlled release delivery system for nasal applications

Abstract

This invention relates to a pernasally administrable preparation for the controlled release of sexual hormones to the systemic circulation, in particular to a formulation which enables its active ingredient to be absorbed in a sustained manner providing a better bioavailability at very low doses and longer duration of action.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a formulation for the controlled release of sexual hormones to the systemic circulation after nasal application. DESCRIPTION OF THE RELATED ART [0002] Nasal drug delivery offers many advantages that include rapid adsorption due to abundant capillary vessels, fast onset of action, avoidance of hepatic first-pass metabolism, utility for chronic medication and ease of administration. [0003] It is known that, in contrast to large and / or ionized molecules, lipophilic pharmaceutical compounds having a sufficiently low molecular weight in general are readily adsorbed by the mucous membrane of the nose. For such drugs it is possible to obtain pharmacokinetic profiles similar to those obtained after intravenous injection. [0004] However, maintaining constant in vivo therapeutic drug concentrations for an extended period of time has been problematic because of the rapid mucociliary clearance of the therapeutic agent from the site ...

AI Technical Summary

Benefits of technology

[0018] The inventor made intensive studies of various sexual hormone drug formulations and, as a result, surprisingly found that the incorporation of the drug 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 favourable serum level profile.

Problems solved by technology

However, maintaining constant in vivo therapeutic drug concentrations for an extended period of time has been problematic because of the rapid mucociliary clearance of the therapeutic agent from the site of deposition resulting in a short span of time available for absorption and of the presence of enzymes that may cause degradation in the nasal cavity.

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

It must be mentioned that this speed is not necessary / desirable because sex hormone replacement is not an emergency therapy.

It is difficult to discuss these results because Ko did not take blood samples before application and thus 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 because the droplet size (430 nm) is not acceptable for nasal application.

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

Apart from the “liberation / adsorption” problem shown above, in connection with sexual hormones and bioavailability, nearly exclusively the crucial liver metabolism and the short half-life are discussed, although a problem is also the high protein-binding.

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