Modulation of solubility, stability, absorption, metabolism, and pharmacokinetic profile of lipophilic drugs by sterols

Abstract

A formulation for drug delivery, providing enhanced modulation of solubility, stability, absorption, metabolism, and/or pharmacokinetic profile of a lipophilic therapeutic agent by formulation with sterols and/or sterol esters, resulting in higher bioavailability of a therapeutic agent administered to a subject in need of such therapeutic agent. The formulation contains a therapeutic agent and a sterol or sterol ester, and can, optionally, further contain a solubilizer and/or an enhancing agent. Also described are pharmaceutical compositions containing the formulations and methods of making and methods of using the formulations and pharmaceutical compositions. Formulations of the disclosure can be constituted to minimize the synthesis of dihydrotestosterone when the therapeutic agent includes testosterone or testosterone esters.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of priority of U.S. Provisional Patent Application No. 61 / 291,769, titled “MODULATION OF SOLUBILITY, STABILITY, ABSORPTION, METABOLISM, AND PHARMACOKINETIC PROFILE OF LIPOPHILIC DRUGS BY STEROLS” and filed on Dec. 31, 2009. The disclosure of the foregoing application is hereby incorporated herein by reference in its entirety, for all purposes.FIELD OF THE INVENTION[0002]The present invention relates to formulations for administration of a therapeutic agent, where the formulation contains one or more therapeutic agents, administered with a sterol and, optionally, a solubilizer and an enhancer, where the formulations provide modulation to one or more of: solubility, stability, absorption, metabolism, and pharmacokinetic profile of the therapeutic agent when administered to a subject. The invention also relates to methods of making and methods of using the formulations.DESCRIPTION OF THE RELATED ART[0003]D...

AI Technical Summary

Benefits of technology

[0029]In a still further aspect, the invention provides a method of enhancing biological absorption or metabolic stability of one or more poorly soluble therapeutic agents, the method comprising administering: a) a phytosterol or phytosterol ester; b) a non-sterol solubilizing agent; c) an enhancing agent; and d) at least one lipophilic, poorly water soluble therapeutic agent in a composition, wherein the composition is effective to enhance biological absorption or metabolic stability of at least one therapeutic agent, as compared to correspondingly administered therapeutic agent in the absence of a) a phytosterol or phytosterol ester, b) a non-sterol solubilizing agent and c) an enhancing agent.

[0030]In yet another aspect, the invention provides a method of treating a condition, comprising administering: a) at least one lipophilic, poorly water soluble therapeutic agent; b) a phytosterol or phytosterol ester; c) a non-sterol solubilizing agent effective for solubilization of the at least one therapeutic agent; and d) an enhancing agent effective to enhance the biological absorption and / or metabolic stability of the at least one therapeutic agent.

[0031]In still another aspect, the invention provides a method for maintaining or controlling physiological levels of testosterone and DHT in a subject in need of testosterone replacement, the method comprising administering: a) one or more therapeutic agents selected from testosterone, testosterone esters and combinations thereof, in a formulation selected from immediate release, sustained release, and combinations thereof; b) a phytosterol or phytosterol ester; c) a non-sterol solubilizing agent effective for solubilization of the testosterone or testosterone ester; and d) an enhancing agent effective to enhance the biological absorption and / or metabolic stability of the one or more therapeutic agents; wherein the method is effective to deliver the one or more therapeutic agents to the subject to achieve in the subject a testosterone level of about 300 ng / dL to about 1100 ng / dL and a DHT level of about 30 ng / dL to about 300 ng / dL.

Problems solved by technology

This may result in a lowered systemic bioavailability of the drug as the drug is metabolized.

Poor water solubility is a significant obstacle for drug absorption.

Approximately 40% of drugs worldwide are insoluble in water and therefore, are difficult to formulate.

First, poor water solubility can limit the type of formulation available to a bioactive compound.

Second, poorly soluble compounds are likely to have limited bioavailability because once in the body, they do not remain in solution at the site of action.

This results in lower absorption and reduced efficacy.

However, higher doses can potentially lead to increased side effects.

The particle size reduction technologies often fail to overcome bioavailability limitations and result in a large food effect, i.e., much higher exposure in a fed state than in a fasted state, which can lead to greater sensitivity of the pharmacokinetic profile to the fat content of meals and the timing of food administration.

These conventional dissolution enhancement and transient solubilization technologies do not improve the transport across the unstirred water (or boundary) layer (UWL), which separates the bulk fluid phase of the small intestine lumen from the brush border membrane of enterocytes.

For many poorly soluble drugs, this transport across the UWL represents the dominant rate-limiting step for drug absorption.

Oral, and transdermal administration is particularly challenging because testosterone is metabolized by 5-alpha reductase enzyme in the skin or GI brush-border layer to dihydrotestosterone resulting in supraphysiological levels of DHT.

A regimen involving such a large number of separate administrations is not very suitable for the practical use of TU as an acceptable hormone replacement therapy (HRT) product, and even less practical for the use of male contraception.

So many separate administrations of the drug give rise to varying serum levels and gastrointestinal side effects.

These effects can make long-term replacement therapy difficult (A. M. Matsumoto: Hormonal therapy of male hypogonadism, Endocrinol. Metab. Clin. North Am.

Drawbacks of the aforementioned therapies are as follows: 1) the therapies can have a too short effect on the systemic testosterone level, with a rapid decrease in the level shortly after an increase resulting from an oral administration; 2) the therapies' lack of individual time control of the testosterone action (in the case of i.m. injection of testosterone esters) due to the inability to change the constantly set testosterone level over a long period of time (days to weeks to months); 3) the presence of a significant food effect upon oral administration; 4) the elevation of DHT levels above physiological normal levels due to the metabolism of testosterone and its esters in organs with high 5-α-reductase activity and 5) where the therapies are in gel form, they may be hazardous to children or others, e.g., where a third party comes in contact with the skin after topical administration.

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