Compositions and methods for ameliorating pain
Inventors
Bazan, Nicolas • BAZAN, Hernan • Alvarez-Builla, Julio • Paul, Dennis • BURGOS, Carolina
Assignees
Alcala De Henares, University of • South Rampart Pharma LLC • Louisiana State University
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Publication Number
US-11458142-B2
Publication Date
2022-10-04
Expiration Date
Abstract
This invention is directed to compositions, methods and kits that can be used for the treatment or amelioration of pain.
Core Innovation
The invention relates to analgesic compositions of formula (I) and pharmaceutically acceptable salts, including substituted acetaminophen (ApAP)/saccharin-derived analgesic analogs, saccharin derivatives, and N-substituted amide analogs. The compounds are defined by specific substituent selections for R, R1, and R2, or by related saccharin-derived and N-substituted amide analog series such as SRP6D/SRP6R, SRP6n-SRP6x, and SCP-1 and analogs.
The disclosure addresses analgesia and antipyresis efficacy together with hepatotoxicity risk associated with cytochrome P450 metabolism and formation of the toxic NAPQI metabolite. The compounds are presented as novel ApAP analogs designed around the objective of retaining analgesia and antipyretic effects while reducing hepatotoxicity, improving solubility, and avoiding metabolism to NAPQI.
The description also includes pharmacological evaluation in acetic-acid induced abdominal writhing and tail-flick assays, yeast-induced hyperthermia and LPS-induced fever models, in vitro hepatocyte studies using HepaRG cells and primary human hepatocytes with LDH and GSH readouts, and in vivo liver function testing using ALT, AST, and ALP. The document further includes saccharin derivative construction, conversion to a saccharin-derivative compound, formation of N-substituted amide analogs, pharmaceutically acceptable salts, pharmaceutical carriers, routes of administration, and controlled-release formulations.
Claims Coverage
The provided claim coverage centers on an analgesic composition defined by formula (I) with specific definitions for R, R1, and R2, including pharmaceutically acceptable salts. The coverage also includes dependent-claim themes directed to therapeutic use, administration routes, pain types, and safety-related constraints.
Analgesic composition of formula (I)
An analgesic composition of formula (I) wherein R, R1, and R2 are selected from defined substituent sets including amine/heteroatom-containing substituents, alkyl, haloalkyl, halobenzyl, phenyl, cycloalkane, H, OH, CH3, CH2CH3, and related substituted groups, with pharmaceutically acceptable salts included.
Palliation of pain via administration of a therapeutically effective amount
A method that administers a therapeutically effective amount of the composition to palliate, alleviate, prevent, delay, and/or reduce incidence of pain.
Pain types covered by the method
The method applies to neuropathic pain and nociceptive pain, including post-surgical pain, post- and/or traumatic pain, dental pain, ophthalmic pain, and arthritic pain.
Route-selective administration of the composition
The composition is administered orally, parenterally, transdermally, or nasally.
Concentration range for administration
The composition is administered at a concentration of about 10 μM to about 10 mM.
Reduced risk of hepatotoxicity
The composition reduces the risk of hepatotoxicity by at least about 20%.
Metabolic constraint not metabolized to NAPQI
The composition is not metabolized to NAPQI.
Claim coverage is grounded in an analgesic composition defined by formula (I) with tightly specified substituent sets for R, R1, and R2, and pharmaceutically acceptable salts. The provided claim-related summaries also indicate dependent-claim themes involving pain treatment, administration concepts, and safety or metabolism constraints.
Stated Advantages
Analgesia comparable to acetaminophen (ApAP).
Non-narcotic analgesic activity.
Antipyretic activity.
Reduced hepatotoxicity risk.
Not metabolized to NAPQI.
Comparable analgesic and antipyretic effects to acetaminophen (ApAP).
Reduced hepatotoxicity, including higher GSH and lower LDH compared with ApAP.
Improved liver function markers (ALT, AST, and ALP) compared with ApAP.
More favorable cytochrome P450 metabolism/inhibition profiles compared with ApAP.
Reduced formation of the toxic NAPQI metabolite compared with ApAP.
Improved solubility.
Avoidance of metabolism to NAPQI.
Retains analgesia.
Reduced hepatotoxicity (at least about 20% risk reduction, as stated in dependent claim content).
Documented Applications
Treating, alleviating, preventing, delaying, and palliating pain.
Treating neuropathic pain and nociceptive pain, including post-surgical, post- and/or traumatic, dental, ophthalmic, and arthritic pain.
Use in veterinary pain.
Use alone or with a second active ingredient, including opioid and/or NSAID co-administration.
Medical kit uses.
Analgesia evaluation using in vivo acetic-acid induced abdominal writhing and tail-flick assays.
Antipyresis/antipyretic evaluation using yeast-induced hyperthermia and LPS-induced fever models.
Hepatotoxicity and liver function evaluation using in vitro hepatocyte studies (HepaRG cells and primary human hepatocytes) and in vivo liver function testing using ALT, AST, and ALP.
Cytochrome P450-related metabolism evaluation using screening and metabolite analysis focused on reduced formation of NAPQI.
Palliation or alleviation of pain including neuropathic pain, nociceptive pain, dental pain, ophthalmic pain, arthritic pain, and post-surgical/post-traumatic pain, including combinations.
Use in combination therapy with an opioid and/or an NSAID.
Controlled-release formulations and pharmaceutical carriers/routes of administration.
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