Novel Alpha-Hydroxy Carboxylic Acid And Derivatives And Other GRAS-Based Prodrugs Of Oxymorphone And Uses Thereof
a technology of which is applied in the field of new alpha-hydroxy carboxylic acid and derivatives and other gras-based prodrugs of oxymorphone and uses thereof, can solve the problems of reducing the bioavailability of oxymorphone, reducing the potential of oxymorphone, and reducing the potential of overdos
Inactive Publication Date: 2018-09-06
3ST RES LLC
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- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Benefits of technology
[0012]Provided are pharmaceutical compounds, compositions, and methods of using such compounds and compositions. Also provided are methods of using chemical moieties that are generally recognized as safe (GRAS), which are attached to the opioid oxymorphone. These chemical moieties are monomers, homo- and hetero-oligomers of alpha-hydroxy carboxylic acids, and their chemical derivatives. The compounds may provide a substantial decrease in the potential of oxymorphone to cause overdose or to be abused. In some embodiments the oxymorphone prodrug conjugates provide therapeutic activity which is similar to that of unmodified oxymorphone when delivered at typical dosage ranges. However, when delivered at higher doses the potential for overdose is reduced as compared to conventional non-conjugated oxymorphone due to decreased bioavailability of the oxymorphone, especially when taken by non-approved oral routes. Additionally, the prodrugs may be designed to provide fast or slow release of oxymorphone depending on its standard use for chronic or acute pain.
Problems solved by technology
Proper medical treatment of pain remains a challenge for patients and healthcare professionals.
However, misuse and abuse of opioids are widespread social and medical problems that may deter physicians from prescribing these useful drugs.
In addition, accidental and intentional overdose with prescription and / or over-the-counter (OTC) drugs is a serious health problem that is associated with thousands of fatalities every year.
Opioid overdose is a significant and growing problem associated with drug abuse, but overdoses also occur accidentally (e.g., when a child obtains and ingests an opioid), or intentionally (e.g., when related to suicide attempts).
Accidental overdose can also commonly occur when unusually potent batches of illicit opioids are ingested by drug addicts or other abusers.
Opioid abuse is an increasing problem, and oxymorphone has become one of the most widely abused drugs.
Moreover, crushing and intranasally snorting the extended release form of oxymorphone (known by the brand name as Opana-ER®), results in rapid drug release and absorption, which results in high peak blood concentrations that produce a quick “high” but can also precipitate a fatal overdose.
Poor oral bioavailability results in variable blood levels, and consequently variable patient response—a highly undesirable feature in the treatment of pain where rapid and reliable relief is desired.
However, such methods, as well as conventional controlled-release formulations, are often ineffective and can be circumvented.
Although typically used for the relief of moderate to moderately severe pain, oxymorphone can also produce drug dependence of the morphine type.
Moreover, the rapidity of ester hydrolysis within the gut or through first-pass metabolism in the liver has further limited the utility of this approach.
However, in the 20 years since ester conjugates were first reported, no such prodrugs have been approved as marketed products, which suggest that this approach has not been successful.
The compounds may provide a substantial decrease in the potential of oxymorphone to cause overdose or to be abused.
However, when delivered at higher doses the potential for overdose is reduced as compared to conventional non-conjugated oxymorphone due to decreased bioavailability of the oxymorphone, especially when taken by non-approved oral routes.
Method used
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Experimental program
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embodiment 1
[0068]An oxymorphone prodrug of the following formula where the prodrug moiety X is attached covalently to the oxymorphone molecule via the 6 position ketone enolate oxygen as the enolate ester,
or a pharmaceutically acceptable salt thereof.
embodiment 2
[0069]An oxymorphone prodrug of the following formula where the prodrug moiety X is attached covalently to the oxymorphone molecule via the 6 position ketone enolate oxygen as the enolate ester, and the prodrug moiety Y is attached covalently to the oxymorphone molecule via the 14 position hydroxyl oxygen as the alcohol ester,
or a pharmaceutically acceptable salt thereof.
embodiment 3
[0070]The oxymorphone prodrug of embodiment 2, wherein X and Y are the same or different.
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Abstract
The invention describes pharmaceutical compounds and compositions comprised of a ligand attached to the opioid oxymorphone, in a manner that substantially decreases or deters the potential for opioid abuse, addiction, illicit and illegal use, and overdose. When delivered at the proper dosage, the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent.
Description
CROSS REFERENCE TO RELATED APPLICATIONS[0001]This is a continuation of U.S. application Ser. No. 14 / 956,143, filed Dec. 1, 2015, which claims the benefit of U.S. Provisional Application No. 62 / 153,157, filed Apr. 27, 2015.FIELD OF INVENTION[0002]The present invention relates to pharmaceutical compounds, compositions, and methods of using chemical moieties that are generally recognized as safe (GRAS) and that are attached to the opioid, oxymorphone. These chemical moieties are monomers, as well as homo- and hetero-oligomers, of alpha-hydroxy carboxylic acids and their chemical derivatives. These inventions provide a variety of beneficial effects, particularly a substantial decrease in the potential of oxymorphone to cause overdose or to be abused. Some embodiments of the invention provide therapeutic activity similar to that of unmodified oxymorphone at typical dosage; however, the risk of overdose from higher doses is reduced due to decreased bioavailability of oxymorphone. Overdose...
Claims
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IPC IPC(8): A61K31/485A61K47/54A61K9/00
CPCA61K9/0053A61K47/542A61K31/485A61P25/36A61K47/543
InventorTHOTTATHIL, JOHN K.
Owner3ST RES LLC