AU2002316582A1

AU2002316582A1 - Oral administration of 6-hydroxy-oxymorphone for use as an analgesic

Info

Publication number: AU2002316582A1
Application number: AU2002316582A
Authority: AU
Inventors: Huai-Hung Kao; David Lee; Troy Mccall; Richard Smith-Carliss
Original assignee: Endo Pharmaceuticals Inc
Current assignee: Endo Pharmaceuticals Inc
Priority date: 2001-07-06
Filing date: 2002-07-03
Publication date: 2003-05-22
Anticipated expiration: 2022-07-03

Description

ORAL ADMINISTRATION OF 6-HYDROXY-OXYMORPHONE FOR USE AS AN ANALGESIC

This application relates to provisional patent application serial nos. 60/329,445 filed October 15, 2001, .60/329,432 filed October 15, 2001, 60/303,357 filed July 6, 2001, and 60/329,444 filed October 15, 2001.

Background Field of Invention

The invention relates to methods for alleviating pain. More particularly, the invention relates to methods for alleviating pain by administering 6-hydroxy oxymorphone. Most particularly, the invention relates to methods of inducing analgesia by increasing blood plasma levels of 6-hydroxy oxymoφhone through oral administration of a pharmaceutical composition containing 6-hydroxy oxymoφhone.

Summary of the Invention

The present invention provides methods of treating pain by administering a pharmaceutical composition comprising 6-hydroxy oxymoφhone in an amount sufficient to induce analgesia. In one embodiment, the pharmaceutical composition is administered orally. Any known or later developed method of oral delivery may be used. To achieve the desired analgesic effect, blood plasma levels of 6-hydroxy oxymoφhone are raised to at least about 0.2 ng/mL. Most preferably blood plasma levels of 6-hydroxy oxymoφhone of at least about 0.3 ng/mL during treatment. Methods for administering compositions comprising 6-hydroxy oxymoφhone, and one or more carriers, diluents, and excipients in an amount sufficient to induce analgesia are also provided.

Brief Description of the Drawings

Fig. 1 is a pharmacokinetic profile for 6-hydroxy oxymoφhone with PID scores. Fig. 2 is a pharmacokinetic profile for oxymoφhone with PID scores. Fig. 3 is a pharmacokinetic profile for 6-hydroxy oxymoφhone with categorical pain scores.

Fig. 4 is a pharmacokinetic profile for oxymoφhone with categorical pain scores. Detailed Description

The methods described herein provide for the administration of a pharmaceutical composition containing 6-hydroxy oxymoφhone as an active ingredient. In a preferred embodiment the preferred composition comprises 6-hydroxy oxymoφhone alone (excepting, of course, carriers, diluents, and other excipients). In other preferred embodiments, 6-hydroxy oxymoφhone may be combined with other opioids or other pharmaceutical agents. For example, another preferred embodiment provides compositions comprising both 6-hydroxy oxymoφhone and its parent, oxymoφhone.

In two separate studies, blood plasma levels and indications of pain relief were recorded over a 12 hour period after. Figs. 1-4 show graphical representation of the data combining the two studies such that the effect of blood plasma levels of oxymoφhone and its metabolite , 6-hydroxy oxymoφhone on pain can be evaluated.

The administration of oxymoφhone yields blood plasma levels of oxymoφhone and all of its metabolites, 6-hydroxy oxymoφhone. Oxymoφhone levels peak within 2 hours, fall slightly, and plateau. Interestingly, the level spikes again at 4-6 hours from administration. After this time, oxymoφhone levels again drop and eventually fall to levels near the earlier plateau.

Like oxymoφhone, 6-hydroxy oxymoφhone blood plasma levels peak within 2 hours after administration. After the initial peak, however, a more or less steady decline in the 6-hydroxy oxymoφhones plasma levels is observed.

Comparing these levels to the pain profiles, a correlation between the 6-hydroxy oxymoφhone blood plasma levels and pain relief can be seen. The pain levels nearly mirror the 6-hydroxy oxymoφhone levels, with substantial rises in relief near the spikes associated with 6-hydroxy oxymoφhone blood levels. Thus, pain relief can be achieved through administration of 6-hydroxy oxymoφhone alone.

In addition to the pharmacokinetic studies, binding studies have been conducted to compare the binding affinity of 6-hydroxy oxymoφhone to that of oxymoφhone. The results are reported in TABLE 1. These results clearly indicate that 6-hydroxy oxymoφhone has great binding affinity for the δ, K, and μ receptor cites, comparable to the binding affinity of its parent. The inventors believe that by virtue of this binding affinity, 6-hydroxy oxymoφhone has similar analgesic effects to its parent, oxymoφhone.

TABLE 1: ASSAY REPORT

Accordingly, methods of administering the metabolite, 6-hydroxy oxymoφhone, directly have been developed. It is believed that the β isomer has greater efficacy in the treatment of pain, but this disclosure is not limited to use of that isomer alone. Pharmaceutical compositions containing either 6-α-hydroxy oxymoφhone, 6-β-hydroxy oxymoφhone, or mixtures thereof can be used in the invention.

Formulation as a suspension, syrup, or other liquid, tablet, capsule, liquid-filled gel cap, or other solid or semi-solid means may be used. The composition may alternately be in the form of a time release formulation, including timed, suspended and extended release formulations. Regardless of the formulation, an amount of 6-hydroxy oxymoφhone sufficient to induce analgesia will be supplied to the patient. Blood plasma levels of 6-hydroxy oxymoφhone must be raised to levels sufficient to induce the desired level of analgesia. The amount administered will be dependent upon normal criteria such as patient weight, intensity of pain, and other factors. Based on the pharmacokinetic studies, blood plasma levels around at least 0.2 ng mL will provide some analgesia. The upper plasma level limit will be ultimately established by safety concerns. Over-dosing of any opioid, including 6-hydroxy oxymoφhone, may lead to respiratory failure and other undesirable side effects and can even result in death. Preferably, the blood plasma level of 6-hydroxy oxymoφhone will be raised to at least 0.3 ng/mL. Subsequent doses may be required to maintain these blood levels.

The preferred administration is of 6-hydroxy oxymoφhone with appropriate carriers and excipients as will be readily apparent to those skilled in the art. The resulting blood plasma in these preferred administrations will therefore be substantially free of oxymoφhone.

The above description encompasses some preferred embodiments of the invention. This disclosure is merely illustrative in nature and is not intended to limit the following claims.

Claims

CLAIMSWhat is claimed is:

1. A method of treating pain comprising the step of: administering to a patient a pharmaceutical composition comprising 6-hydroxy oxymoφhone in an amount sufficient to induce analgesia.

2. The method of claim 1 wherein said pharmaceutical composition is administered orally.

3. The method of claim 2 wherein said pharmaceutical composition is administered in a form selected from a liquid formulation, syrup, suspension, solid formulation, tablet, capsule, liquid-filled gel cap, and a semi-solid formulation.

4. The method of claim 1 wherein said administration is sufficient to raise bipod plasma levels of 6-hydroxy oxymoφhone to at least about 0.2 ng/mL.

5. The method of claim 1 wherein said administration is sufficient to raise blood plasma levels of 6-hydroxy oxymoφhone to at least about 0.3 ng/mL.

6. A method of treating pain comprising the step of: orally administering to a patient a pharmaceutical composition comprising 6- hydroxy oxymoφhone, and one or more carriers, diluents, and excipients in an amount sufficient to induce analgesia.

7. A method of treating pain comprising the step of: orally administering to a patient a pharmaceutical composition comprising 6- hydroxy oxymoφhone and oxymoφhone in an amount sufficient to induce analgesia.

8. A pharmaceutical composition comprising 6-hydroxy oxymoφhone in a formulation for oral delivery to animals including hormone.