Phosphocholine linked prodrug derivatives

Abstract

Disclosed are compounds of general formula (I) that function as prodrugs, thereby increasing bioavailabilities of the linked therapeutic agents, wherein the LINKER is (i) substituted or unsubstituted alkyl, (ii) substituted or unsubstituted alkenyl, (iii) substituted or unsubstituted alkanoyl, (iv) substituted or unsubstituted alkenoyl wherein the double bond is cis, and (v) (ortho or para) carbonyl-substituted aryl; and wherein the substituent is each an independent group or linked together thereby forming a ring; and wherein X is one or more substituted or unsubstituted group containing one or more O, N, or S atom and wherein the substituent is each an independent group or linked together thereby forming a ring; and wherein the therapeutic agent is an alcohol-containing water-insoluble steroids or another alcohol containing compounds and methods to prepare such compounds.

Description

FIELD OF THE INVENTION [0001] The present invention is directed to a novel class of phosphocholine-linked derivatives which not only increase water solubility, but also function as true prodrugs, allow phosphocholines or phosphocholine congeners to be attached to a variety of functional groups on the therapeutic agent, and have the potential on being able to control the rate of release of the pharmaceutical agent. BACKGROUND OF THE INVENTION [0002] Conventional means for delivering pharmaceutical and therapeutic agents to mammals often are severely limited by chemical and physical properties of the agent, such as aqueous solubility. For example, oral delivery of many biologically-active agents would be the route of choice if not for poor bioavailability due to the limited dissolution of the active agent and subsequent absorption. [0003] Water insoluble therapeutic agents are particularly difficult to administer parenterally. Formulations often require inclusion of a variety of emuls...

AI Technical Summary

Benefits of technology

[0007] In another aspect, the present invention provides a method for increasing the bioavailability of a pharmaceutical agent, comprising the steps of derivatizing the agent with one or more linker moieties, producing an intermediate, recovering and coupling the intermediate with phosphocholine or a phosphocholine-congener to the linkers, producing a final derivative and administering the final derivative to a mammal, wherein the agent in derivative form is significantly more soluble in aqueous media than the agent in non-derivatized form.

Problems solved by technology

Conventional means for delivering pharmaceutical and therapeutic agents to mammals often are severely limited by chemical and physical properties of the agent, such as aqueous solubility.

Water insoluble therapeutic agents are particularly difficult to administer parenterally.

But CREMOPHOR®, which is poly(oxyethylene)-40-castor oil, can result in hypotension, dyspnea, angioedema, or generalized urticaria.

This emulsion contains soy bean oil, glycerol, and egg phosphatide that create a microbial contamination problem with the current formulation of propofol, which can result in life-threatening illness or death from fever, infection or sepsis.

This is especially problematic for post-operative or intensive care unit (ICU) patients.

Although U.S. Pat. No. 5,714,120 discloses a method to minimize microbial contamination by the addition of a preservative, this formulation is not an antimicrobial preserved product by USP standards and extrinsic contamination remains problematic.

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