Patent Publication Number: US-2021186923-A1

Title: Therapeutic formulations and uses thereof

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation-in-part application of U.S. application Ser. No. 16/100,035 filed Aug. 9, 2018, now pending; which claims the benefit under 35 U.S.C. § 119(e) to U.S. Application Ser. No. 62/594,399 filed Dec. 4, 2017 and to U.S. Application Ser. No. 62/543,215 filed Aug. 9, 2017, both now expired. This application also claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Application Ser. No. 62/929,631 filed Nov. 1, 2019, now pending. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application. 
    
    
     BACKGROUND OF THE INVENTION 
     Field of the Invention 
     The invention relates generally to therapeutic formulations and more specifically to formulations including a selective cyclooxygenase-2 (COX-2) inhibitor (coxib) and optionally buprenorphine. 
     Background Information 
     Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2 enzymes and have been commonly used in veterinary medicine for the treatment of inflammation and pain, (COX is the commonly accepted abbreviation for cyclooxygenase the enzyme that produces prostaglandins from arachidonic acid). While the specificity for which COX isoform a given NSAID inhibits varies depending on the details of the particular assay employed and their chemical structure, as a class all NSAIDs inhibit both COX-1 and COX-2 enzymes. Among the numerous chemotypes of NSAID drugs, the propionic acid derivatives are the most common. 
     COX-2-selective inhibitors (coxibs) developed in the 2000s supplanted traditional NSAIDs in some settings by virtue of their comparable efficacy with improved gastrointestinal safety. Several COX-2 inhibitors are available for treatment of pain and inflammation in companion animals. However, it is particularly desirable to have a coxib formulation which can be safely provided with long-lasting results. 
     SUMMARY OF THE INVENTION 
     The present invention is based on the seminal discovery of compositions containing a coxib and optionally buprenorphine to provide prolonged treatment of pain and inflammatory disorders in mammals. 
     As such, provided herein are compositions containing a coxib and optionally buprenorphine. 
     In one aspect, the composition is formulated as an injectable including: 
     (a) at least about 0.5% w/w and up to 50% w/w (and all concentrations in between) of a coxib; and 
     (b) a solvent, wherein the composition is formulated for subcutaneous administration. 
     In embodiments the injectable composition includes: 
     (c) a solvent optionally including at least 0.1% and up to about 85% of one or more excipients (e.g., polyethylene glycol, “PEG” and/or propylene glycol); 
     (d) optionally up to 25% w/w of at least one optional excipient (e.g., ethanol), preservative, penetration enhancer and/or viscosity reducer; and 
     (e) optionally up to 10% w/w of at least one anti-oxidant. 
     In another aspect, the composition is formulated in a topical dosage form including: 
     (a) at least about 0.5% w/w and up to 50% w/w (and all concentrations in between) of a coxib; and 
     (b) a solvent, wherein the composition is formulated for topical administration. 
     In embodiments the topical composition includes: 
     (c) a solvent optionally including at least 1.0% and up to about 99.5% of one or more excipients (e.g., propylene glycol); 
     (d) optionally up to 75% w/w of at least one penetration enhancer (e.g., propylene carbonate and/or n-methyl pyrrolidone); 
     (e) optionally up to 25% w/w of at least one optional solvent and/or penetration enhancer (e.g., ethanol and/or n-methyl pyrrolidone); and 
     (f) optionally up to 10% w/w of at least one anti-oxidant. 
     In another aspect, the composition is formulated in an oral dosage form including: 
     (a) at least about 0.5% w/w and up to 90% w/w (and all concentrations in between) of a coxib; 
     (b) optionally up to about 99.5% of a suitable pharmaceutical carrier (e.g., lactose monohydrate and/or microcrystalline cellulose); and 
     (c) optionally flavoring(s), binder(s), disintegrate(s), lubricant(s) and/or glidant(s). 
     In embodiments, the composition is formulated for oral delivery as a liquid. For example, the composition is formulated for oral delivery as a liquid suspension, colloid, emulsion, or homogeneous solution. In various embodiments, the oral composition is non-aqueous and sterile. 
     In various embodiments, the formulations of the invention (e.g., oral, injectable and topical) include one or more coxibs, such as mavacoxib, or a chromene coxib (as described further herein), such as PAH-100 as shown in Formula (I) or Formula (II): 
     
       
         
         
             
             
         
       
     
     or isomers or pharmaceutically acceptable salts thereof. 
     In various embodiments, the formulations of the invention (e.g., oral, injectable and topical) include one or more compounds of Formula (III): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof, wherein: 
     X is O, S, or N; 
     Y is a bond, —CO—, —SO 2 —, or —CH 2 —; 
     R 1 , R 2 , R 3 , R 4 , and R 5  are each independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, aryl, —CN, —OR 6 , —NR 7 R 8 , —SR 6 , —SOR 9 , —SO 2 R 9 , —COR 6 , —OCOR 6 , —COOR 6 , —NR 6 COR 6 , —CONR 7 R 8 , —NR 6 SO 2 R 9 , —SO 2 NR 7 R 8 , —NR 6 CONR 7 R 8 , —NR 6 COOR 9  or —NR 6 SO 2 NR 7 R 8 ; 
     R 6  is H, C 1 -C 8  alkyl or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; 
     R 7  and R 8  are each independently H, aryl, C 1 -C 6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3 -C 8  cycloalkyl, or are taken together with the nitrogen atom to form a 3- to 8-membered heterocyclic ring containing 1-4 nitrogen atoms or 1 nitrogen and 1 oxygen atom, said heterocyclic ring being optionally substituted by one or more halo atoms, C 1 -C 6  alkyl optionally substituted by one or more halo atoms, or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; 
     R 9  is H, C 1 -C 8  alkyl or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; and 
     aryl is phenyl or naphthyl, said phenyl and naphthyl being optionally substituted with 1-5 substituents selected from C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, halo, —CN, —OR 6 , —NR 7 R 8 , —SR 6 , —SOR 9 , —SO 2 R 9 , —COR 6 , —OCOR 6 , —COOR 6 , —NR 6 COR 6 , —CONR 7 R 8 , —NR 6 SO 2 R 9 , —SO 2 NR 7 R 8 , —NR 6 CONR 7 R 8 , —NR 6 COOR 9  and —NR 6 SO 2 NR 7 R 8 . 
     In some embodiments, the formulations include a coxib and optionally buprenorphine and/or one or more NSAIDS. 
     Further provided herein is a pharmaceutical composition for use in treating a disease or disorder in a mammalian subject, the composition including one or more compounds of Formula (III): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof, wherein: 
     X is O, S, or N; 
     Y is a bond, —CO—, —SO 2 —, or —CH 2 —; 
     R 1 , R 2 , R 3 , R 4 , and R 5  are each independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, aryl, —CN, —OR 6 , —NR 7 R 8 , —SR 6 , —SOR 9 , —SO 2 R 9 , —COR 6 , —OCOR 6 , —COOR 6 , —NR 6 COR 6 , —CONR 7 R 8 , —NR 6 SO 2 R 9 , —SO 2 NR 7 R 8 , —NR 6 CONR 7 R 8 , —NR 6 COOR 9  or —NR 6 SO 2 NR 7 R 8 ; 
     R 6  is H, C 1 -C 8  alkyl or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; 
     R 7  and R 8  are each independently H, aryl, C 1 -C 6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3 -C 8  cycloalkyl, or are taken together with the nitrogen atom to form a 3- to 8-membered heterocyclic ring containing 1-4 nitrogen atoms or 1 nitrogen and 1 oxygen atom, said heterocyclic ring being optionally substituted by one or more halo atoms, C 1 -C 6  alkyl optionally substituted by one or more halo atoms, or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; 
     R 9  is H, C 1 -C 8  alkyl or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; and 
     aryl is phenyl or naphthyl, said phenyl and naphthyl being optionally substituted with 1-5 substituents selected from C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, halo, —CN, —OR 6 , —NR 7 R 8 , —SR 6 , —SOR 9 , —SO 2 R 9 , —COR 6 , —OCOR 6 , —COOR 6 , —NR 6 COR 6 , —CONR 7 R 8 , —NR 6 SO 2 R 9 , —SO 2 NR 7 R 8 , —NR 6 CONR 7 R 8 , —NR 6 COOR 9  and —NR 6 SO 2 NR 7 R 8 . 
     Also provided herein is a method of treating a disease or disorder (e.g., pain or an inflammatory disorder) in a subject by administering a formulation of the invention to the subject. Surprisingly, a clinically effective amount of the coxib when provided in a formulation of the invention is present in the blood stream of the subject for at least 96, 120, 144 or 168 hours after administration. In various embodiments, buprenorphine is administered along with the coxib, either in a single formulation or in a separate formulation that is co-administered along with the coxib. In a particularly preferred embodiment, a formulation of the invention is delivered to a companion animal such as a cat or dog. 
     Also provided herein is a method of treating a disease or disorder (e.g., pain or an inflammatory disorder) in a subject by administering a compound of the disclosure to the subject. For example, administering to the subject a compound of Formula (III): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof, wherein: 
     X is O, S, or N; 
     Y is a bond, —CO—, —SO 2 —, or —CH 2 —; 
     R 1 , R 2 , R 3 , R 4 , and R 5  are each independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, aryl, —CN, —OR 6 , —NR 7 R 8 , —SR 6 , —SOR 9 , —SO 2 R 9 , —COR 6 , —OCOR 6 , —COOR 6 , —NR 6 COR 6 , —CONR 7 R 8 , —NR 6 SO 2 R 9 , —SO 2 NR 7 R 8 , —NR 6 CONR 7 R 8 , —NR 6 COOR 9  or —NR 6 SO 2 NR 7 R 8 ; 
     R 6  is H, C 1 -C 8  alkyl or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; 
     R 7  and R 8  are each independently H, aryl, C 1 -C 6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3 -C 8  cycloalkyl, or are taken together with the nitrogen atom to form a 3- to 8-membered heterocyclic ring containing 1-4 nitrogen atoms or 1 nitrogen and 1 oxygen atom, said heterocyclic ring being optionally substituted by one or more halo atoms, C 1 -C 6  alkyl optionally substituted by one or more halo atoms, or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; 
     R 9  is H, C 1 -C 8  alkyl or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; and 
     aryl is phenyl or naphthyl, said phenyl and naphthyl being optionally substituted with 1-5 substituents selected from C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, halo, —CN, —OR 6 , —NR 7 R 8 , —SR 6 , —SOR 9 , —SO 2 R 9 , —COR 6 , —OCOR 6 , —COOR 6 , —NR 6 COR 6 , —CONR 7 R 8 , —NR 6 SO 2 R 9 , —SO 2 NR 7 R 8 , —NR 6 CONR 7 R 8 , —NR 6 COOR 9  and —NR 6 SO 2 NR 7 R 8 . 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  is a graph showing pharmacokinetic (PK) curves for oral, subcutaneous injectable and topical formulations of the disclosure administered to a mammal via their respective routes of administration in embodiments of the invention. 
         FIG. 2  is a graph showing plasma concentrations for formulations of the disclosure administered to subjects in embodiments of the invention. 
         FIG. 3  is a graph showing plasma concentrations for formulations of the disclosure administered to subjects in embodiments of the invention. 
         FIG. 4  is a graph showing plasma concentrations for formulations of the disclosure administered to subjects in embodiments of the invention. 
         FIG. 5  is a graph showing plasma concentrations for formulations of the disclosure administered to subjects in embodiments of the invention. 
         FIG. 6  is a graph showing plasma concentrations for formulations of the disclosure administered to subjects in embodiments of the invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The following terms, definitions and abbreviations apply. Abbreviations used herein have their conventional meaning within the chemical and biological arts. 
     As used herein, a “patient” or “subject” refers to either a human or non-human mammalian animal. Non-human animals include any non-human mammalian animals. Such non-human animals may include, but are not limited to rodents, non-human primates (e.g., monkey and apes), ungulates, ovines, bovines, ruminants, lagomorphs, porcines, caprines, equines, canines, felines, murines, and the like. In certain embodiments of the invention, the animals are mammals. In the context of the disclosure, the term “subject” generally refers to an individual who will receive or who has received treatment described below (e.g., administration of a composition of the disclosure, and optionally one or more additional therapeutic agents). 
     The term “therapeutically effective amount” means the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a patient or tissue that is being sought by the researcher, veterinarian, medical doctor or other clinician. 
     By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. 
     The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the disclosure or pharmaceutical composition to the subject in need of treatment. 
     The disclosure provides pharmaceutical compositions comprising at least one coxib in an amount effective for treating a disorder, such as pain or inflammation, and a pharmaceutically acceptable vehicle or diluent. As used herein the term “coxib” refers to a selective cyclooxygenase-2 (COX-2) inhibitor or “COX-2 inhibitor”. 
     In embodiments, the coxib may be any coxib known in the art, for example, an in now was limiting, mavacoxib, rofecoxib, celecoxib, cimicoxib, deracoxib, firocoxib, robenacoxib, valdecoxib, parecoxib, etoricoxib or any combination thereof. 
     In some embodiments, the coxib is mavacoxib, a non-steroidal anti-inflammatory drug (NSAID) of the coxib class (ATCvet Code QM01AH92). Mavacoxib—4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide is used in the treatment of chronic pain and inflammation associated with osteoarthritis in canines. It is a specific inhibitor of the inducible form of cyclooxygenase. 
     In some embodiments, the coxib is a “chromene coxib” and is referred to herein as PAH-100. The coxib PAH-100 is a member of a structural class of COX-2 selective inhibitors. As used herein, PAH-100 refers of a compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof, or a compound of Formula 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     Particular isomers or pharmaceutically acceptable salts of PAH-100 for use in compositions of the invention include Tris(hydroxymethyl)aminomethane (±)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate, (±)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, Tris(hydroxymethyl)aminomethane (R)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate, (R)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, Tris(hydroxymethyl)aminomethane (S)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate, and (S)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid. 
     In embodiments, PAH-100 may be a racemic mixture, for example a mixture of Tris(hydroxymethyl)aminomethane (R)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate and Tris(hydroxymethyl)aminomethane (S)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate, or a mixture of (R)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid and (S)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid. 
     A key structural feature of PAH-100 is the presence of a benzopyran (also known as chromene) moiety having the following structure: 
     
       
         
         
             
             
         
       
     
     Chromene coxibs are selective COX-2 inhibitors based on this very unique central chemical ring system. Unlike NSAIDs and other COX-2 inhibitors, PAH-100 does not possess a propionic acid moiety or a sulfone or sulfonamide group. The presence of a carboxylic acid endows PAH-100 with an unexpected and advantageous degree of aqueous solubility allowing for rapid oral absorption. In addition, PAH-100 has a relatively long duration of action in vivo making for a more convenient dosing regimen. The inventors have also discovered that mavacoxib, while being of a different structural claim than PAH-100 exhibits pharmacokinetic characteristics comparable to PAH-100. As such, both compounds are uniquely suitable for use in the compositions of the invention. 
     In embodiments, the coxib is a compound of Formula (III): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof, wherein: 
     X is O, S, or N; 
     Y is a bond, —CO—, —SO 2 —, or —CH 2 —; 
     R 1 , R 2 , R 3 , R 4 , and R 5  are each independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, aryl, —CN, —OR 6 , —NR 7 R 8 , —SR 6 , —SOR 9 , —SO 2 R 9 , —COR 6 , —OCOR 6 , —COOR 6 , —NR 6 COR 6 , —CONR 7 R 8 , —NR 6 SO 2 R 9 , —SO 2 NR 7 R 8 , —NR 6 CONR 7 R 8 , —NR 6 COOR 9  or —NR 6 SO 2 NR 7 R 8 ; 
     R 6  is H, C 1 -C 8  alkyl or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; 
     R 7  and R 8  are each independently H, aryl, C 1 -C 6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3 -C 8  cycloalkyl, or are taken together with the nitrogen atom to form a 3- to 8-membered heterocyclic ring containing 1-4 nitrogen atoms or 1 nitrogen and 1 oxygen atom, said heterocyclic ring being optionally substituted by one or more halo atoms, C 1 -C 6  alkyl optionally substituted by one or more halo atoms, or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; 
     R 9  is H, C 1 -C 8  alkyl or C 3 -C 8  cycloalkyl optionally substituted by one or more halo atoms; and 
     aryl is phenyl or naphthyl, said phenyl and naphthyl being optionally substituted with 1-5 substituents selected from C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, halo, —CN, —OR 6 , —NR 7 R 8 , —SR 6 , —SOR 9 , —SO 2 R 9 , —COR 6 , —OCOR 6 , —COOR 6 , —NR 6 COR 6 , —CONR 7 R 8 , —NR 6 SO 2 R 9 , —SO 2 NR 7 R 8 , —NR 6 CONR 7 R 8 , —NR 6 COOR 9  and —NR 6 SO 2 NR 7 R 8 . 
     In embodiments, the coxib is a compound of Formula (IV): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (V): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (VI): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (VII): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (VIII): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (IX): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (X): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (XI): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (XII): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (XIII): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof, wherein: 
     X is O, S, or N; 
     Y is a bond, —CO—, —SO2—, or —CH2-; 
     R1, R2, R3, R4, and R5 are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, aryl, —CN, —OR6, —NR7R8, —SR6, —SOR9, —SO2R9, —COR6, —OCOR6, —COOR6, —NR6COR6, —CONR7R8, —NR6SO2R9, —SO2NR7R8, —NR6CONR7R8, —NR6COOR9 or —NR6SO2NR7R8; 
     R6 is H, C1-C8 alkyl or C3-C8 cycloalkyl optionally substituted by one or more halo atoms; 
     R7 and R8 are each independently H, aryl, C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-C8 cycloalkyl, or are taken together with the nitrogen atom to form a 3- to 8-membered heterocyclic ring containing 1-4 nitrogen atoms or 1 nitrogen and 1 oxygen atom, said heterocyclic ring being optionally substituted by one or more halo atoms, C1-C6 alkyl optionally substituted by one or more halo atoms, or C3-C8 cycloalkyl optionally substituted by one or more halo atoms; 
     R9 is H, C1-C8 alkyl or C3-C8 cycloalkyl optionally substituted by one or more halo atoms; and 
     aryl is phenyl or naphthyl, said phenyl and naphthyl being optionally substituted with 1-5 substituents selected from C1-C6 alkyl, C3-C8 cycloalkyl, halo, —CN, —OR6, —NR7R8, —SR6, —SOR9, —SO2R9, —COR6, —OCOR6, —COOR6, —NR6COR6, —CONR7R8, —NR6SO2R9, —SO2NR7R8, —NR6CONR7R8, —NR6COOR9 and —NR6SO2NR7R8. 
     In embodiments, the coxib is a compound of Formula (XIV): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (XV): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (XVI): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (XVII): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (XVIII): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments the coxib is a compound of Formula XIX): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (XX): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (XXI): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is a compound of Formula (XXII): 
     
       
         
         
             
             
         
       
     
     or an isomer or pharmaceutically acceptable salt thereof. 
     In embodiments, the coxib is selected from the following compounds: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In embodiments, the coxib is: 
     
       
         
         
             
             
         
       
     
     In embodiments, the coxib is: 
     
       
         
         
             
             
         
       
     
     The compositions of the disclosure may contain therapeutic agents in addition to a coxib and may be formulated, for example, by employing solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation. 
     Additional excipients which are contemplated for use in the practice of the disclosure are those available to those of ordinary skill in the art, for example, those found in the United States Pharmacopeia Vol. XXII and National Formulary Vol. XVII, U.S. Pharmacopeia Convention, Inc., Rockville, Md. (1989) as well as updates thereto, such as United States Pharmacopeia Vol. XL and National Formulary Vol. XXXV, U.S. Pharmacopeia Convention, Inc., Rockville, Md., the relevant contents of which are incorporated herein by reference. In addition, polymorphs, hydrates, and solvates of the compounds are included in the disclosure, with hydrates being particularly preferred. It should be noted that while the hydrate molecules will contribute water to the pharmaceutical composition, it is most preferred that no other water source be included. 
     Also, while the coxibs may be in their hydrated form, no water is added to the composition during or after mixture. As such, the compositions described herein are substantially non-aqueous, for example, the compositions have less than about 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.5 or 0.1% w/w of an aqueous substance, such as water. 
     The disclosed pharmaceutical compositions could be administered by any suitable means, for example, orally, sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, intrathecal, or intracisternal injection or infusion techniques (e.g., as sterile injectable non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. Preferably, however, the administration will be by injection, topically or orally. 
     The pharmaceutical compositions of the present invention are for the administration of a coxib either alone or in combination with other agents, for example, anti-inflammatories, analgesics, antibiotics, anti-fungals, anti-virals and other pharmaceutically active components, although the compositions are therapeutically effective when a coxib is the sole active agent present. 
     In embodiments, the compositions may include coxib and an analgesic, such as buprenorphine. Buprenorphine is a synthetic opioid drug that is about 30 times more potent than morphine. 
     In embodiments, the compositions may include include a coxib and one or more additional NSAIDS. As used herein, the term “NSAID” refers to a class of therapeutic compounds with analgesic, anti-inflammatory, and anti-pyretic properties. NSAIDs reduce inflammation by blocking cyclooxygenase. NSAIDs may be classified based on their chemical structure or mechanism of action. Non-limiting examples of NSAIDs include a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclooxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX-1) inhibitor, and a selective cyclooxygenase 2 (COX-2) inhibitor. A NSAID may be a profen. Examples of a suitable salicylate derivative NSAID include, without limitation, Acetylsalicylic acid (asprin), Diflunisal, Hydroxylethyl Salicylate, and Salsalate. Examples of a suitable p-amino phenol derivative NSAID include, without limitation, Paracetamol and Phenacetin. Examples of a suitable propionic acid derivative NSAID include, without limitation, Alminoprofen, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen, Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pranoprofen, And Suprofen. Examples of a suitable acetic acid derivative NSAID include, without limitation, Aceclofenac, Acemetacin, Actarit, Alcofenac, Aloxipirin, Amfenac, Aminophenazone, Antraphenine, Azapropazone, Benorilate, Benzydamine, Butibufen, Chlorthenoxacine, Choline Salicylate, Clometacin, Diclofenac, Emorfazone, Epirizole, Etodolac, Feclobuzone, Felbinac, Fenbufen, Fenclofenac, Glafenine, Indometacin, Ketorolac, Lactyl Phenetidin, Metamizole, Metiazinic Acid, Mofebutazone, Mofezolac, Nabumetone, Nifenazone, Niflumic Acid, Oxametacin, Pipebuzone, Propyphenazone, Proquazone, Protozininc Acid, Salicylamide, Sulindac, Tiaramide, Tinoridine, and Zomepirac. Examples of a suitable enolic acid (Oxicam) derivative NSAID include, without limitation, Droxicam, Isoxicam, Lornoxicam, Meloxicam, Piroxicam, and Tenoxicam. Examples of a suitable fenamic acid derivative NSAID include, without limitation, Flufenamic acid, Mefenamic acid, Meclofenamic acid, and Tolfenamic acid. Examples of a suitable selective COX-2 inhibitor include, without limitation, Celecoxib, Etoricoxib, Firocoxib, Lumiracoxib, Meloxicam, Parecoxib, Rofecoxib, and Valdecoxib. 
     Moreover, the compositions may include analgesic agents other than anti-inflammatory agents, such as opiates, local anesthetics such as Lidocain, Mepivacain, Prilocain, Procain, Syntocain, Tetracain, Gingicain, Articain, Bupivacain, Butanilicain, Chloroprocain, or, for example, Polidocanol. 
     Furthermore, the compositions may also include anti-inflammatory agents that could have a secondary effect as analgesics other than the analgesics listed above, which may in part have anti-inflammatory effects, such as hormones, specifically Cortison and corticoids, such as glucocorticoids (e.g., Cortison, Cloprednol, Prednison, Prednisolon, Methylprednisolon, Deflazacort, Fluocortolon, Triamcinolon, Dexamethason, Betamethason) and mineralcorticoids (e.g. Aldosteron, Desoxycorticosteron, Fludrocortison). 
     The composition may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy, for example those methods described in the Examples. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a carrier suitable for administration via an intended route, for example, injection, oral or topical administration routes. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. 
     Exemplary topical formulations of the invention include: 
     (a) a coxib, such as a compound of Formula (III)-(XXII), PAH-100 or mavacoxib; and 
     (b) a solvent, wherein the composition is formulated as a topical dosage form. 
     In embodiments, the solvent includes propylene glycol present at over about 1% w/w of the composition. 
     In embodiments the composition optionally includes an anti-oxidant present at no more than 1000 w/w of the composition. 
     Particular embodiments of formulations suitable for topical use are as follows. 
     
       
         
           
               
            
               
                   
               
               
                 Topical Formulation 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Ideal 
                   
                   
                   
               
               
                   
                 w/w 
                 Range 
                   
                   
               
               
                 Ingredient 
                 % 
                 w-w% 
                 Purpose 
                 Exemplary Alternates 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Mavacoxib 
                 5 
                  0.5-50  
                 API 
                 any other coxib or 
               
               
                   
                   
                   
                   
                 combination thereof 
               
               
                 Propylene 
                 40 
                    1-99.5 
                 Solvent 
                 n-methyl pyrrolidone (NMP), 
               
               
                 Glycol 
                   
                   
                   
                 PEG300, PEG400, water, 2- 
               
               
                 (PG) 
                   
                   
                   
                 pyrrolidone, dimethyl 
               
               
                   
                   
                   
                   
                 sulfoxide (DMSO), Triacetin, 
               
               
                   
                   
                   
                   
                 Triethylcitrate (TEC), glycerin 
               
               
                 Propylene 
                 40 
                  0-75 
                 Penetration Enhancer 
                 Triacetin, Triethylcitrate 
               
               
                 Carbonate 
                   
                   
                   
                 (TEC), benzyl alcohol, n- 
               
               
                 (PC) 
                   
                   
                   
                 methyl pyrrolidone (NMP) 
               
               
                 Ethanol 
                 15 
                  0-25 
                 Co-solvent, additional 
                 Isopropanol (IPA), benzyl 
               
               
                   
                   
                   
                 penetration enhancer, 
                 alcohol, capryllic triglycerides, 
               
               
                   
                   
                   
                 preservative, viscosity 
                 triolein, n-methyl pyrrolidone 
               
               
                   
                   
                   
                 reducer 
                 (NMP) 
               
               
                 Optional 
                 0 
                 0.002-10   
                 anti-oxidants 
                 anti-oxidants (propyl gallate, 
               
               
                   
                   
                   
                   
                 BHT, BHA, Tenox 4 and other 
               
               
                   
                   
                   
                   
                 Tenoxes, Vitamin E and 
               
               
                   
                   
                   
                   
                 analogs, TBHQ, 
               
               
                   
                   
                   
                   
                 methylparaben, propylparaben, 
               
               
                   
                   
                   
                   
                 and all other anti-oxidants) 
               
               
                 Total 
                 100 
               
               
                   
               
            
           
         
       
     
     Particular embodiments of formulations suitable for topical use are as follows. 
     
       
         
           
               
            
               
                   
               
               
                 Topical Formulation 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Ideal 
                   
                   
                   
               
               
                   
                 w/w 
                 Range 
                   
                   
               
               
                 Ingredient 
                 % 
                 w-w% 
                 Purpose 
                 Exemplary Alternates 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 PAH-100 
                 5 
                  0.5-50  
                 API 
                 any other coxib or 
               
               
                 or a 
                   
                   
                   
                 combination thereof 
               
               
                 compound 
                   
                   
                   
                   
               
               
                 of Formula 
                   
                   
                   
                   
               
               
                 (III)-(XXII) 
                   
                   
                   
                   
               
               
                 Propylene 
                 40 
                    1-99.5 
                 Solvent 
                 n-methyl pyrrolidone (NMP), 
               
               
                 Glycol 
                   
                   
                   
                 PEG300, PEG400, water, 2- 
               
               
                 (PG) 
                   
                   
                   
                 pyrrolidone, dimethyl 
               
               
                   
                   
                   
                   
                 sulfoxide (DMSO), Triacetin, 
               
               
                   
                   
                   
                   
                 Triethylcitrate (TEC), glycerin 
               
               
                 Propylene 
                 40 
                  0-75 
                 Penetration Enhancer 
                 Triacetin, Triethylcitrate 
               
               
                 Carbonate 
                   
                   
                   
                 (TEC), benzyl alcohol, n- 
               
               
                 (PC) 
                   
                   
                   
                 methyl pyrrolidone (NMP) 
               
               
                 Ethanol 
                 15 
                  0-25 
                 Co-solvent, additional 
                 Isopropanol (IPA), benzyl 
               
               
                   
                   
                   
                 penetration enhancer, 
                 alcohol, capryllic triglycerides, 
               
               
                   
                   
                   
                 preservative, viscosity 
                 triolein, n-methyl pyrrolidone 
               
               
                   
                   
                   
                 reducer 
                 (NMP) 
               
               
                 Optional 
                 0 
                 0.002-10   
                 anti-oxidants 
                 anti-oxidants (propyl gallate, 
               
               
                   
                   
                   
                   
                 BHT, BHA, Tenox 4 and other 
               
               
                   
                   
                   
                   
                 Tenoxes, Vitamin E and 
               
               
                   
                   
                   
                   
                 analogs, TBHQ, 
               
               
                   
                   
                   
                   
                 methylparaben, propylparaben, 
               
               
                   
                   
                   
                   
                 and all other anti-oxidants) 
               
               
                 Total 
                 100 
               
               
                   
               
            
           
         
       
     
     In one embodiment, an exemplary topical formulation is as follows: 
     
       
         
           
               
            
               
                   
               
               
                 Topical Formulation 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 ID: 
               
               
                   
                 Master Formula 
                 w/w % 
                 PAH-16-04-004 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Mavacoxib 
                 7.5 
                   
               
               
                   
                 Propylene Glycol (PG) 
                 45 
                   
               
               
                   
                 Propylene Carbonate (PC) 
                 27.5 
                   
               
               
                   
                 n-methyl pyrrolidone (NMP) 
                 20 
                   
               
               
                   
                 Total 
                 100 
               
               
                   
                   
               
            
           
         
       
     
     In one embodiment, an exemplary topical formulation is as follows: 
     
       
         
           
               
            
               
                   
               
               
                 Topical Formulation 
               
            
           
           
               
               
               
            
               
                   
                   
                 w/w  
               
               
                   
                 Master Formula 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 PAH-100 or a compound of  
                 7.5 
               
               
                   
                 Formula (M)-(XXII) 
                   
               
               
                   
                 Propylene Glycol (PG) 
                 45 
               
               
                   
                 Propylene Carbonate (PC) 
                 27.5 
               
               
                   
                 n-methyl pyrrolidone (NMP) 
                 20 
               
               
                   
                 Total 
                 100 
               
               
                   
                   
               
            
           
         
       
     
     In one embodiment, an exemplary topical formulation is as follows: 
     
       
         
           
               
            
               
                   
               
               
                 Topical Formulation 
               
            
           
           
               
               
               
            
               
                   
                   
                 w/w 
               
               
                   
                 Master Formula 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 PAH-100 or a compound of  
                 5 
               
               
                   
                 Formula (M)-(XXII) 
                   
               
               
                   
                 Propylene Glycol (PG) 
                 40 
               
               
                   
                 Propylene Carbonate (PC) 
                 40 
               
               
                   
                 Ethanol 
                 15 
               
               
                   
                 Total 
                 100 
               
               
                   
                   
               
            
           
         
       
     
     In one embodiment, an exemplary topical formulation is as follows: 
     
       
         
           
               
            
               
                   
               
               
                 Topical Formulation 
               
            
           
           
               
               
               
            
               
                   
                   
                 w/w 
               
               
                   
                 Master Formula 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Mavacoxib 
                 5 
               
               
                   
                 Propylene Glycol (PG) 
                 40 
               
               
                   
                 Propylene Carbonate (PC) 
                 40 
               
               
                   
                 Ethanol 
                 15 
               
               
                   
                 Total 
                 100 
               
               
                   
                   
               
            
           
         
       
     
     In one embodiment, a topical composition includes: i) a coxib; ii) propylene glycol; iii) propylene carbonate; iv) ethanol; and v) optionally an anti-oxidant. 
     In one embodiment, a topical composition includes: i) a coxib at a concentration of about 0.5 to 50% w/w; propylene glycol at a concentration of about 1 to 99% w/w; iii) propylene carbonate at a concentration of about 0.001 to 75% w/w; and iv) ethanol at a concentration of about 0.001 to 25% w/w. 
     In one embodiment, a topical composition includes: i) coxib at a concentration of about 5 to 15% w/w; ii) propylene glycol at a concentration of about 35 to 45% w/w; iii) propylene carbonate at a concentration of about 35 to 45% w/w; and iv) ethanol at a concentration of about 5 to 20% w/w. 
     Exemplary injectable formulations of the invention include: 
     (a) a coxib, such as a compound of Formula (III)-(XXII), PAH-100 or mavacoxib; and 
     (b) a solvent, wherein the composition is formulated for subcutaneous administration. 
     In embodiments the injectable composition includes: 
     (c) a solvent optionally including at least 0.1% and up to about 85% of one or more excipients (e.g., polyethylene glycol, “PEG” and/or propylene glycol); 
     (d) optionally up to 25% w/w of at least one optional excipient (e.g., ethanol), preservative, penetration enhancer and/or viscosity reducer; and 
     (e) optionally up to 10% w/w of at least one anti-oxidant. 
     Particular embodiments of formulations suitable for subcutaneous administration are as follows. 
     
       
         
           
               
            
               
                   
               
               
                 Injectable Formulation 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Ideal 
                 Range 
                   
                   
               
               
                 Ingredient 
                 w/w % 
                 w/w % 
                 Purpose 
                 Exemplary Alternatives 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Mavacoxib 
                 5 
                  0.5-50 
                 API 
                 any other coxib or combination thereof 
               
               
                 Propylene  
                 50 
                    1-60 
                 Solvent/ 
                 n-methyl pyrrolidone (NMP), PEG300, 
               
               
                 Glycol 
                   
                   
                 Co-solvent 
                 PEG400, water, 2-pyrrolidone, 
               
               
                   
                   
                   
                   
                 dimethyl sulfoxide (DMSO), Triacetin, 
               
               
                   
                   
                   
                   
                 Triethylcitrate (TEC), glycerin 
               
               
                 Polyethylene 
                 40 
                  0.5-85 
                 Solvent/ 
                 n-methyl pyrrolidone (NMP), 
               
               
                 glycol 300 
                   
                   
                 Co-solvent 
                 Propylene glycol, PEG400, water,  
               
               
                 (PEG300) 
                   
                   
                   
                 2-pyrrolidone, dimethyl sulfoxide 
               
               
                   
                   
                   
                   
                 (DMSO), Triacetin, Triethylcitrate 
               
               
                   
                   
                   
                   
                 (TEC), medium chain triglycerides 
               
               
                 Ethanol 
                 5 
                    0-25 
                 Co-solvent,  
                 Isopropanol (IPA), benzyl alcohol, 
               
               
                   
                   
                   
                 additional  
                 capryllic triglycerides, triolein 
               
               
                   
                   
                   
                 penetration 
                   
               
               
                   
                   
                   
                 enhancer, 
                   
               
               
                   
                   
                   
                 preservative, 
                   
               
               
                   
                   
                   
                 viscosity 
                   
               
               
                   
                   
                   
                 reducer 
                   
               
               
                 Other 
                 0 
                 0.002-10 
                 anti-oxidants  
                 anti-oxidants (propyl gallate, BHT, 
               
               
                   
                   
                   
                   
                 BHA, Tenox 4 and other Tenoxes, 
               
               
                   
                   
                   
                   
                 Vitamin E and analogs, TBHQ, 
               
               
                   
                   
                   
                   
                 methylparaben, propylparaben, and all 
               
               
                   
                   
                   
                   
                 other anti-oxidants) 
               
               
                 Total 
                 100 
               
               
                   
               
            
           
         
       
     
     Particular embodiments of formulations suitable for subcutaneous administration are as follows. 
     
       
         
           
               
            
               
                   
               
               
                 Injectable Formulation 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Ideal 
                 Range 
                   
                   
               
               
                 Ingredient 
                 w/w % 
                 w/w % 
                 Purpose 
                 Exemplary Alternatives 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 PAH-100 or a 
                 12 
                  0.5-50 
                 API 
                 any other coxib or 
               
               
                 compound of 
                   
                   
                   
                 combination thereof 
               
               
                 Formula (III)- 
                   
                   
                   
                   
               
               
                 (XXII) 
                   
                   
                   
                   
               
               
                 Propylene  
                 50 
                    1-60 
                 Solvent/Co-solvent 
                 n-methyl pyrrolidone (NMP), 
               
               
                 Glycol 
                   
                   
                   
                 PEG300, PEG400, water,  
               
               
                   
                   
                   
                   
                 2-pyrrolidone, dimethyl 
               
               
                   
                   
                   
                   
                 sulfoxide (DMSO), Triacetin, 
               
               
                   
                   
                   
                   
                 Triethylcitrate (TEC), glycerin 
               
               
                 Polyethylene 
                 33 
                  0.5-85 
                 Solvent/Co-solvent 
                 n-methyl pyrrolidone (NMP), 
               
               
                 glycol 300 
                   
                   
                   
                 Propylene glycol, PEG400, 
               
               
                 (PEG300) 
                   
                   
                   
                 water, 2-pyrrolidone, dimethyl 
               
               
                   
                   
                   
                   
                 sulfoxide (DMSO), Triacetin, 
               
               
                   
                   
                   
                   
                 Triethylcitrate (TEC), medium 
               
               
                   
                   
                   
                   
                 chain triglycerides 
               
               
                 Ethanol 
                 5 
                    0-25 
                 Co-solvent, additional 
                 Isopropanol (IPA), benzyl 
               
               
                   
                   
                   
                 penetration enhancer, 
                 alcohol, capryllic triglycerides, 
               
               
                   
                   
                   
                 preservative, viscosity 
                 triolein 
               
               
                   
                   
                   
                 reducer 
                   
               
               
                 Other 
                 0 
                 0.002-10 
                 anti-oxidants 
                 anti-oxidants (propyl gallate, 
               
               
                   
                   
                   
                   
                 BHT, BHA, Tenox 4 and other 
               
               
                   
                   
                   
                   
                 Tenoxes, Vitamin E and 
               
               
                   
                   
                   
                   
                 analogs, TBHQ, 
               
               
                   
                   
                   
                   
                 methylparaben, propylparaben, 
               
               
                   
                   
                   
                   
                 and all other anti-oxidants) 
               
               
                 Total 
                 100 
               
               
                   
               
            
           
         
       
     
     In one embodiment, a topical composition includes: i) a coxib; ii) propylene glycol; iii) polyethylene glycol; iv) ethanol; and optionally v) an anti-oxidant. 
     In one embodiment, a topical composition includes: i) a coxib at a concentration of about 0.5 to 50% w/w; ii) propylene glycol at a concentration of about 1 to 60% w/w; iii) polyethylene glycol at a concentration of about 0.5 to 85% w/w; and iv) ethanol at a concentration of about 0.001 to 25% w/w. 
     In one embodiment, a topical composition includes: i) a coxib at a concentration of about 5 to 15% w/w; ii) propylene glycol at a concentration of about 45 to 55% w/w; iii) polyethylene glycol at a concentration of about 30 to 35% w/w; and iv) ethanol at a concentration of about 1 to 10% w/w. 
     Exemplary oral formulations of the invention include: 
     (a) a coxib; and 
     (b) a pharmaceutically acceptable carrier, wherein the composition is formulated as a solid or semi-solid dosage form. 
     In embodiments, the oral formulations optionally further include flavoring(s), binder(s), disintegrate(s), lubricant(s) and/or glidant(s). 
     Particular embodiments of formulations suitable for oral administration are as follows. 
     
       
         
           
               
            
               
                   
               
               
                 Oral Formulation 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Ideal 
                 Range 
                   
                   
               
               
                 Ingredient 
                 w/w % 
                 w/w % 
                 Purpose 
                 Exemplary Alternatives 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Mavacoxib 
                 14.4 
                 0.5-90 
                 API 
                 any other coxib or combination 
               
               
                   
                   
                   
                   
                 thereof 
               
               
                 Lactose 
                 50.6 
                   0-99.5 
                 flow agent, filler 
                 siliconized MCC (sMCC), starch 
               
               
                 Monohydrate 
                   
                   
                 diluent 
                 1500 pre-gelatenized starch, 
               
               
                 (FlowLac 100) 
                   
                   
                   
                 dicalciumphosphate (Dical), 
               
               
                   
                   
                   
                   
                 calcium sulfate, Starlac and other 
               
               
                   
                   
                   
                   
                 specialized excipients 
               
               
                 Microcrystalline 
                 16 
                   0-99.5 
                 binder, 
                 Other binder (e.g., starch or 
               
               
                 Cellulose  
                   
                   
                 disintegrant 
                 hydroxypropylmethylcellulose 
               
               
                 (Avicel PH102) 
                   
                   
                   
                 (HPMC)) 
               
               
                 Liver Powder 
                 15 
                   0-40 
                 Flavor 
                 Other flavors (e.g., Provestas, 
               
               
                   
                   
                   
                   
                 chicken, lamb, fish, duck, cheese, 
               
               
                   
                   
                   
                   
                 yeast, and other flavors) 
               
               
                 Croscarmellose 
                 2.5 
                   0-20 
                 disintegrant 
                 Other disintegrants (e.g., sodium 
               
               
                 Sodium 
                   
                   
                   
                 starch glycolate, cros-povidone, 
               
               
                   
                   
                   
                   
                 starch fully, partially and non 
               
               
                   
                   
                   
                   
                 gelatenized, MCC) 
               
               
                 Stearic Acid 
                 0.5 
                   0-50 
                 lubricant 
                 magnesium stearate, sodium glycol 
               
               
                   
                   
                   
                   
                 fumerate, carbowax, PEG3350, 
               
               
                   
                   
                   
                   
                 PEG8000 
               
               
                 Colloidal Silicone 
                 0.5 
                   0-10 
                 glidant 
                 other silicones 
               
               
                 Dioxide 
                   
                   
                   
                   
               
               
                 Magnesium 
                 0.5 
                   0-50 
                 lubricant 
                 magnesium stearate, sodium glycol 
               
               
                 Stearate 
                   
                   
                   
                 fumerate, carbowax, PEG3350, 
               
               
                   
                   
                   
                   
                 PEG8000 
               
               
                 Other 
                 0 
                   0-99.5 
                 excipients for 
                 HPMC or other extended release 
               
               
                   
                   
                   
                 sustained release 
                 excipients 
               
               
                 Total 
                 100 
               
               
                   
               
            
           
         
       
     
     Particular embodiments of formulations suitable for oral administration are as follows. 
     
       
         
           
               
            
               
                   
               
               
                 Oral Formulation 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Ideal 
                 Range 
                   
                   
               
               
                 Ingredient 
                 w/w % 
                 w/w % 
                 Purpose 
                 Exemplary Alternatives 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 PAH-100 or a 
                 8 
                 0.5-90 
                 API 
                 any other coxib or combination 
               
               
                 compound of 
                   
                   
                   
                 thereof 
               
               
                 Formula (III)- 
                   
                   
                   
                   
               
               
                 (XXII) 
                   
                   
                   
                   
               
               
                 Lactose 
                 57 
                   0-99.5 
                 flow agent, filler, 
                 siliconized MCC (sMCC), starch 
               
               
                 Monohydrate 
                   
                   
                 diluent 
                 1500 pre-gelatenized starch, 
               
               
                 (FlowLac ™ 100) 
                   
                   
                   
                 dicalciumphosphate (Dical), calcium 
               
               
                   
                   
                   
                   
                 sulfate, Starlac and other specialized 
               
               
                   
                   
                   
                   
                 excipients 
               
               
                 Microcrystalline 
                 16 
                   0-99.5 
                 binder, 
                 Other binder (e.g., starch or 
               
               
                 Cellulose 
                   
                   
                 disintegrant 
                 hydroxypropylmethylcellulose 
               
               
                 (Avicel ™ PH102) 
                   
                   
                   
                 (HPMC)) 
               
               
                 Liver Powder 
                 15 
                   0-40 
                 Flavor 
                 Other flavors (e.g., Provestas, 
               
               
                   
                   
                   
                   
                 chicken, lamb, fish, duck, cheese, 
               
               
                   
                   
                   
                   
                 yeast, and other flavors) 
               
               
                 Croscarmellose 
                 2.5 
                   0-20 
                 disintegrant 
                 Other disintegrants (e.g., sodium 
               
               
                 Sodium 
                   
                   
                   
                 starch glycolate, cros-povidone, 
               
               
                   
                   
                   
                   
                 starch fully, partially and non 
               
               
                   
                   
                   
                   
                 gelatenized, MCC) 
               
               
                 Stearic Acid 
                 0.5 
                   0-50 
                 lubricant 
                 magnesium stearate, sodium glycol 
               
               
                   
                   
                   
                   
                 fumerate, carbowax, PEG3350, 
               
               
                   
                   
                   
                   
                 PEG8000 
               
               
                 Colloidal Silicone 
                 0.5 
                   0-10 
                 glidant 
                 other silicones 
               
               
                 Dioxide 
                   
                   
                   
                   
               
               
                 Magnesium 
                 0.5 
                   0-50 
                 lubricant 
                 magnesium stearate, sodium glycol 
               
               
                 Stearate 
                   
                   
                   
                 fumerate, carbowax, PEG3350, 
               
               
                   
                   
                   
                   
                 PEG8000 
               
               
                 Other 
                 0 
                   0-99.5 
                 excipients for 
                 HPMC or other extended release 
               
               
                   
                   
                   
                 sustained release 
                 excipients 
               
               
                 Total 
                 100 
               
               
                   
               
            
           
         
       
     
     In one embodiment, an oral composition includes: i) a coxib; ii) lactose monohydrate; iii) microcrystalline cellulose; iv) flavoring; and optionally v) one or more of croscarmellose sodium, stearic acid, colloidal silicon dioxide and magnesium stearate. 
     In one embodiment, an oral composition includes: i) a coxib at a concentration of about 0.5 to 90% w/w; ii) lactose monohydrate at a concentration of about 1 to 99% w/w; iii) microcrystalline cellulose at a concentration of about 1 to 99% w/w; and iv) flavoring at a concentration of about 0.001 to 40% w/w. 
     In one embodiment, an oral composition includes: i) a coxib at a concentration of about 5 to 15% w/w; ii) lactose monohydrate at a concentration of about 50 to 60% w/w; iii) microcrystalline cellulose at a concentration of about 10 to 20% w/w; and iv) flavoring at a concentration of about 5 to 20% w/w. 
     In the methods described herein, an appropriate dosage level will generally be about 0.01 to about 50 mg/kg, such as, for example, 0.25 to about 25 mg/kg per day, such as 0.25 to about 20 mg/kg per day. Within this range the dosage may be 0.25 to 10, 0.5 to 6, 0.25 to 20 mg/kg, 1 to 15 mg/kg (including all intermediate dosages, such as 5.1, 5.2, 5.3 etc. mg/kg) and preferably about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 mg/kg, all in a single dosage form. 
     Dosing will vary by active drug, species and condition. For example, a suitable dosage level for PAH-100 is believed to be about 0.1 to 20.0 mg/kg, 0.2 to 15 mg/kg, 1 to 15 mg/kg, 3 to 10 mg/kg, 1 to 5 mg/kg and all increments thereinbetween, preferably at least 1 mg/kg or higher, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg/kg. 
     For example, a suitable dosage level for buprenorphine in dogs is believed to be about 0.1 to 5.0 mg/kg, 0.2 to 4.5 mg/kg, 0.3 to 4.4 mg/kg, 0.4 to 4.3 mg/kg, 0.5 to 4.2 mg/kg and all increments thereinbetween, preferably at least 0.2 mg/kg or higher, such as 0.3 mg/kg. 
     For the coxib compositions in particular, the compounds need only be administered by single dose, one time for an entire course of treatment to clinically resolve pain for a duration of at least about 48, 72, 96, 120, 144, or 168 hours. In this respect, “clinically resolve pain” is measured by reference to the clinically significant and measurable presence of the active in the animal&#39;s bloodstream for the requisite period of time; e.g., at least about 48, 72, 96, 120, 144, or 168 hours. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition. As such, subsequent doses may be administered as part of a therapeutic regime with administration once every 1, 2, 3, 4, 5, 6, 7 or 8 weeks. Further, different types of dosage forms may be used in combination, for example, weekly injection dosages along with weekly oral dosages. 
     The formulations of the invention are useful in mammals, especially companion animals, and most especially cats and dogs. 
     The following examples are provided to further illustrate the embodiments of the present invention but are not intended to limit the scope of the invention. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used. 
     Example I 
     Exemplary Oral Formulations 
     The following coxib containing formulation was prepared for oral administration. 
     
       
         
           
               
            
               
                   
               
               
                 Oral Formulation 
               
            
           
           
               
               
               
               
            
               
                   
                 Master Formulation 
                 w/w % 
                 Purpose 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 PAH-100 
                 14.4 
                 API 
               
               
                   
                 Lactose Monohydrate  
                 50.6 
                 flow agent, filler, diluent 
               
               
                   
                 (FlowLac ™ 100) 
                   
                   
               
               
                   
                 Microcrystalline Cellulose  
                 16 
                 binder, disintegrant 
               
               
                   
                 (Avicel ™ PH102) 
                   
                   
               
               
                   
                 Liver Powder 
                 15 
                 Flavor 
               
               
                   
                 Croscarmellose Sodium 
                 2.5 
                 disintegrant 
               
               
                   
                 Stearic Acid 
                 0.5 
                 lubricant 
               
               
                   
                 Colloidal Silicone Dioxide 
                 0.5 
                 glidant 
               
               
                   
                 Magnesium Stearate 
                 0.5 
                 lubricant 
               
               
                   
                 Total 
                 100 
               
               
                   
                   
               
            
           
         
       
     
     Example II 
     Pharmacokinetics of a Composition of the Invention 
     3 dogs were dosed orally with the composition of Example I at a dosing concentration of 1 mg/kg, 2 mg/kg and 3 mg/kg. Blood concentrations of coxib were present at clinically significant levels for more than 168 hours following administration of the composition, as shown in  FIG. 1 . 
     Example III 
     Exemplary Subcutaneous Injectable Formulations 
     The following coxib containing formulation was prepared for subcutaneous injection. 
     
       
         
           
               
            
               
                   
               
               
                 Injectable Formulation 
               
            
           
           
               
               
               
            
               
                 Master Formula 
                 w/w % 
                 Purpose 
               
               
                   
               
            
           
           
               
               
               
            
               
                 PAH-100 
                 5 
                 API 
               
               
                 Propylene Glycol 
                 50 
                 Solvent/Co-solvent 
               
               
                 Polyethylene glycol 300  
                 40 
                 Solvent/Co-solvent 
               
               
                 (PEG300) 
                   
                   
               
               
                 Ethanol 
                 5 
                 Co-solvent, additional 
               
               
                   
                   
                 penetration enhancer, 
               
               
                   
                   
                 preservative, viscosity  
               
               
                   
                   
                 reducer 
               
               
                 Total 
                 100 
               
               
                   
               
            
           
         
       
     
     Example IV 
     Pharmacokinetics of a Composition of the Invention 
     1 dog was dosed via subcutaneous injection with the composition of Example III at a dosing concentration of 3 mg/kg. Blood concentrations of coxib were present at clinically significant levels for more than 168 hours following administration of the composition, as shown in  FIG. 1 . 
     Example V 
     Exemplary Topical Formulations 
     The following coxib containing formulation was prepared for topical administration. 
     
       
         
           
               
            
               
                   
               
               
                 Topical Formulation 
               
            
           
           
               
               
               
               
            
               
                   
                 Master Formula 
                 w/w % 
                 Purpose 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 PAH-100 
                 5 
                 API 
               
               
                   
                 Propylene Glycol (PG) 
                 40 
                 Solvent 
               
               
                   
                 Propylene Carbonate (PC) 
                 40 
                 Penetration Enhancer 
               
               
                   
                 Ethanol 
                 15 
                 Co-solvent, additional  
               
               
                   
                   
                   
                 penetration enhancer, 
               
               
                   
                   
                   
                 preservative, viscosity  
               
               
                   
                   
                   
                 reducer 
               
               
                   
                 Total 
                 100 
               
               
                   
                   
               
            
           
         
       
     
     Example VI 
     Pharmacokinetics of a Composition of the Invention 
     1 cat was dosed topically with the composition of Example V at a dosing concentration of 3 mg/kg. Blood concentrations of coxib were present at clinically significant levels for more than 168 hours following administration of the composition, as shown in  FIG. 1 . 
     Example VII 
     Exemplary Topical Formulation 
     The following coxib containing formulation was prepared for topical administration. 
     
       
         
           
               
            
               
                   
               
               
                 Topical Formulation 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 ID: 
               
               
                   
                 Master Formula 
                 w/w % 
                 PAH-16-04-004 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 PAH-100 
                 7.5 
                   
               
               
                   
                 Propylene Glycol (PG) 
                 45 
                   
               
               
                   
                 Propylene Carbonate (PC) 
                 27.5 
                   
               
               
                   
                 n-methyl pyrrolidone 
                 20 
                   
               
               
                   
                 (NMP) 
                   
                   
               
               
                   
                 Total 
                 100 
               
               
                   
                   
               
            
           
         
       
     
     Example VIII 
     Exemplary Oral Formulations 
     The following coxib containing formulation was prepared for oral administration. 
     
       
         
           
               
            
               
                   
               
               
                 Oral Formulation 
               
            
           
           
               
               
               
               
            
               
                   
                 Master Formulation 
                 w/w % 
                 Purpose 
               
               
                   
                   
               
               
                   
                 PAH-100 racemic mixture  
                 8.00% (R + S) 
                   
               
               
                   
                 (D90-14.7 μm)* 
                 (results in 4.00% 
                 API 
               
               
                   
                   
                 S Label Claim) 
                   
               
               
                   
                 Lactose Monohydrate, NF  
                 57 
                 flow agent,  
               
               
                   
                 (Flowlac ™ 100 or #316  
                   
                 filler, diluent 
               
               
                   
                 Fast Flo ™)** 
                   
                   
               
               
                   
                 Microcrystalline Cellulose  
                 16 
                 binder,  
               
               
                   
                 (Avicel ™ PH102) 
                   
                 disintegrant 
               
               
                   
                 Liver Powder 
                 15 
                 Flavor 
               
               
                   
                 Croscarmellose Sodium 
                 2.5 
                 disintegrant 
               
               
                   
                 Stearic Acid 
                 0.5 
                 lubricant 
               
               
                   
                 Colloidal Silicone Dioxide 
                 0.5 
                 glidant 
               
               
                   
                 Magnesium Stearate 
                 0.5 
                 lubricant 
               
               
                   
                 Total 
                 100 
               
               
                   
                   
               
               
                   
                 *API quantity is adjusted for purity and water content. 
               
               
                   
                 **Excipient quantity is adjusted as needed. 
               
               
                   
                 Tablet weights of 250, 375, 1000 and 1500 mg yield tablet strengths of 10, 15, 40 and 60 mg respectively. 
               
               
                   
                 Each tablet had a bisect. 
               
            
           
         
       
     
     Compounding Procedures 
     1. Weigh out all ingredients. 
     2. Screen (20 mesh) all ingredients in the following order: ½ Lactose Monohydrate, ½ Microcrystalline Cellulose, remaining excipients, PAH-100 API, ending with ½ Microcrystalline Cellulose and ½ Lactose Monohydrate. 
     Note: For scale up, consider holding back the Stearic Acid and Magnesium Stearate and dividing the blend time where ½ of the pre-blend is removed Stearic Acid and Magnesium Stearate are sieved into the blender and the ½ pre-blend is added back into the blender. 
     Run V-blender for 300 seconds (approximately 300 revolutions). 
     Tableting Procedure 
     1. Set up tablet press for 250, 375, 1000, or 1500 mg tablets. All tooling will result in a scored tablet. 
     2. Check tablet weights and hardness during startup. 
     3. Check tablet weights periodically throughout batch and, if needed, adjust tablet weight and hardness. 
     4. Package the bulk tablets and apply a label to the container(s). 
     Example IX 
     Exemplary Subcutaneous Injectable Formulations 
     The following coxib containing formulation was prepared for subcutaneous injection. 
     
       
         
           
               
            
               
                   
               
               
                 Injectable Formulation 
               
            
           
           
               
               
               
            
               
                 Master Formula 
                 w/w % 
                 Purpose 
               
               
                   
               
               
                 PAH-100* (delivered as  
                 12.00% (R + S) 
                 API 
               
               
                 50/50 racemic mixture) 
                 (results in 6.00% 
                   
               
               
                   
                 S Label Claim) 
                   
               
               
                 Propylene Glycol 
                 50 
                 Solvent/Co-solvent 
               
               
                 Polyethylene glycol 300  
                 33 
                 Solvent/Co-solvent 
               
               
                 (PEG300)** 
                   
                   
               
               
                 Ethanol 
                 5 
                 Co-solvent, additional 
               
               
                   
                   
                 penetration enhancer, 
               
               
                   
                   
                 preservative, viscosity 
               
               
                   
                   
                 reducer 
               
               
                 Total 
                 100 
               
               
                   
               
               
                 *API quantity is adjusted for purity and water content. 
               
               
                 **Excipient quantity is adjusted based upon API correction factor. 
               
            
           
         
       
     
     Compounding Procedures 
     1. Obtain tare weight of formulation vessel. 
     2. Weigh out and add Propylene Glycol, PEG 300, and Ethanol to formulation vessel. 
     3. Begin mixing and wait for visual homogeneity. 
     4. Add PAH-100 to formulation vessel. 
     5. Mix until visual dissolution at room temperature. 
     Note: For a 300 g product batch, using micronized PAH-100 (d90=14.55 m), dissolution was achieved after approx. 1-1.5 hours (batch 20180515M-5). With non-micronized material (d90=88.17 m), dissolution was achieved after approx. 2-2′A hours (batch 20180412M-82). 
     6. Check batch weight to account for evaporated Ethanol. If needed, add Ethanol to achieve target Ethanol quantity. 
     7. Turn off mixer. 
     8. Sterile filter product and aseptically fill into vials. 
     Example X 
     Exemplary Topical Formulations 
     The following coxib containing formulation was prepared for topical administration. 
     
       
         
           
               
            
               
                   
               
               
                 Topical Formulation 
               
            
           
           
               
               
               
               
            
               
                   
                 Master Formula 
                 w/w % 
                 Purpose 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 PAH-100* (delivered as 
                 5 
                 API 
               
               
                   
                 50/50 racemic mixture) 
                   
                   
               
               
                   
                 Propylene Glycol (PG) 
                 40 
                 Solvent 
               
               
                   
                 Propylene Carbonate (PC) 
                 40 
                 Penetration Enhancer 
               
               
                   
                 Ethanol** 
                 15 
                 Co-solvent, additional  
               
               
                   
                   
                   
                 penetration enhancer, 
               
               
                   
                   
                   
                 preservative, viscosity  
               
               
                   
                   
                   
                 reducer 
               
               
                   
                 Total 
                 100 
               
               
                   
                   
               
               
                   
                 *API quantity is adjusted purity and moisture. 
               
               
                   
                 **Excipient quantity is adjusted as needed. 
               
            
           
         
       
     
     Compounding Procedures 
     1. Weight out and add Propylene Glycol, Propylene Carbonate, and Ethanol to formulation vessel. 
     2. Begin mixing and wait for visual homogeneity. 
     3. Add PAH-100 to formulation vessel. 
     4. Mix until visual dissolution at room temperature. 
     5. Turn off mixer. 
     6. Filter through a Whatman 1 paper filter (or similar, for lab scale). 
     Example XI 
     Safety and Pharmacokinetics of a Composition of the Invention 
     6% (S) PAH-100 Injection for Dogs 
     Safety and pharmacokinetic study PAH18-21 evaluated a single subcutaneous injection of a 6% PAH-100 formulation (formulation of Example IX) in eight dogs at a dosing concentration of 5 mg/kg. Injection site reactions consisted of barely perceptible to well defined erythema and edema and scabbing. Clinical observations included soft feces 5-11 days post dosing. One dog developed a salivary mucocele at the blood collection site. This reaction is not related to blood collection or treatment with a 6% PAH-100 injectable formulation. 
       FIG. 2 : Mean 6% PAH-100 Plasma Concentration-Time Profiles of the (R) and (S) Isomers Following a Single Subcutaneous Injection of 5 mg/kg in Dogs.  FIG. 2  illustrates the chiral analysis of the (R) and (S) isomer in the plasma of dogs dosed at 5 mg/kg with a 6% PAH-100 injectable formulation prepared as described in Example IX. 
     Example XII 
     Safety and Pharmacokinetics of a Composition of the Invention 
     5% PAH-100 Injectable for Dogs 
     Two safety/pharmacokinetic studies, (PAH17-015 and PAH18-011) were conducted at 3 mg/kg with a single injection of a 5% PAH-100 formulation (formulation of Example IX) in dogs. In both studies, dogs were dosed subcutaneously between the shoulder blades and injection site reactions were evaluated. Dermal irritation at the site of injection consisted of discoloration and scabbing, warm to the touch, and slight erythema. Clinical observations included vocalization, salivation, excessive scratching at the injection site and soft feces. 
     Study PAH17-024 evaluated a once a week subcutaneous dose of a 5% PAH-100 formulation (formulation of Example IX) at dosing concentrations of 3 mg/kg and 15 mg/kg for 3-weeks. Clinical observations and dermal irritation at the site of injection were identical to dogs administered a single 3 mg/kg dose. Additional safety assessments included in this study was based on electrocardiographic examinations, clinical and anatomic pathology. Results confirmed there was no effect of the subcutaneous injection of PAH-100 on qualitative or quantitative ECG parameters, clinical pathology values, and histologic findings. Red discoloration in the subcutis at the injection site of 1 dog dosed at 3 mg/kg dose. All other macroscopic changes were considered incidental and not related to the test article. 
       FIG. 3 : Mean 5% PAH-100 Plasma Concentration-Time Profiles Following a Single Subcutaneous Injection of 3 mg/kg in Dogs.  FIG. 3  illustrates the PK curves of the first 3 mg/kg injection from all three studies. 
       FIG. 4 : Mean Plasma Concentration-Time Profiles Following Weekly Subcutaneous Injection for 3-Weeks.  FIG. 4  details the plasma concentrations in dogs dosed at 3 mg/kg and 15 mg/kg weekly for 3-weeks, Study PAH17-024. 
     Example XIII 
     Safety and Pharmacokinetics of a Composition of the Invention 
     5% PAH-100 Injectable and Tablet Treatment in Dogs 
     Study PAH17-016 assessed the safety and pharmacokinetics of a dosing regimen where dogs were received a single subcutaneous injection of a 5% PAH-100 formulation (formulation of Example IX) at dosing concentrations of 2 mg/kg or 10 mg/kg, followed by a weekly oral administration with PAH-100 tablets (formulation of Example VIII) starting 7 days post-injection. Dogs were orally dosed once a week for 6 weeks at dosing concentrations of 1 mg/kg or 5 mg/kg. Injection site reactions, clinical pathology values, and histologic findings were evaluated. Dermal irritation and clinical observations included excessive scratching, mild hair loss, and scabbing at injection site, vocalization during injection, salivation, and soft feces. A nodule developed at the injection site of one dog. There were no test article effects on clinical pathology endpoints. There was no test article related changes macroscopically or microscopically in tissues collected at necropsy. 
       FIG. 5 : Mean Plasma Concentration-Time Profiles Following a Single Subcutaneous Injection Followed by Oral Tablet Administration at 1× and 5× dose.  FIG. 5  illustrates the plasma concentrations in dogs subcutaneously treated weekly for 3-weeks at 3 mg/kg and 15 mg/kg. 
     Example XIV 
     Safety and Pharmacokinetics of a Composition of the Invention 
     PAH-100 Oral Tablet Efficacy (PAH16-013) 
     Nine purpose bred hound dogs with naturally occurring coxofemoral joint disease received each of three treatments, a single oral dose of PAH-100 (3 mg/kg; formulation of Example VIII), 2) no treatment, or 3) carprofen (4.4 mg/kg, PO, q24 hr, 7 doses total). Efficacy was determined by rear limb using a quantified kinetic gait analysis. Blood samples were collected to determine PAH-100 plasma concentration levels. No abnormal clinical observations or adverse events occurred in any of the dogs. Confirming a single dose of PAH-100 at 3 mg/kg is well tolerated. Efficacy results indicate improved limb use in dogs with coxofemoral joint osteoarthritis over a period of 7 days after oral administration of PAH 100 compared to no treatment and daily carprofen administration based on a majority of kinetic outcomes. 
       FIG. 6 : Mean Plasma Concentration-Time Profiles Following Oral Administration with PAH-100 Tablet at 3 mg/kg.  FIG. 6  details the mean PAH-100 plasma concentrations in dogs treated orally at 3 mg/kg. 
     Example XV 
     Field Safety and Efficacy for Postoperative Pain 
     This study evaluated the field safety and effectiveness of a single subcutaneous injection of PAH-100 (formulation of Example IX) for control of postoperative pain associated with either ovariohysterectomy (OVH) or cranial cruciate ligament (CCL) repair in dogs. The investigational veterinary product (IVP; formulation of Example IX) dose rate was 3 mg/kg, but Protocol Amendment 1 raised the dose to 5 mg/kg after 24 dogs were enrolled. Forty-nine (49) dogs were enrolled at 2 study sites. Thirteen (13) dogs were treated with the IVP at a one-time dose rate of 5 mg/kg, 12 dogs were treated with the IVP at a one-time dose rate of 3 mg/kg, and 24 dogs were treated with the CVP (saline). All 25 dogs treated with IVP were included in the safety evaluation, while 12 dogs treated at the 5 mg/kg dose rate and 24 dogs treated with CVP were included in the primary efficacy evaluation. Dogs receiving the 3 mg/kg IVP dose are considered supplemental cases. 
     Dogs enrolled in the study were undergoing either CCL extracapsular repair or OVH surgery. On Day 0, a physical examination was conducted, a baseline pain assessment score was assigned, and blood and serum samples were collected for clinical pathology testing. The IVP or CVP was given 1 hour prior to intubation and then surgery was performed. Dogs were assigned pain scores at specified times through 8 hours post-extubation, unless they required rescue analgesia for pain scores of 6 or greater. 
     On Day 1, the injection site was evaluated for all dogs, including ones that had received rescue analgesia. Pain assessments continued through 30 hours post-extubation unless rescue analgesia was required. 
     On Day 2, the injection site was evaluated for all dogs, including ones that had received rescue analgesia. Pain assessments continued through 54 hours post-extubation unless rescue analgesia was required. 
     On Day 3, a physical examination and injection site evaluation was conducted, and blood and serum was collected for clinical pathology testing. For dogs that had not received rescue analgesia, a final pain assessment was conducted at 72 hours post-extubation. 
     Based on success being defined as pain scores &lt;6 through the 48-hour assessment, the primary IVP efficacy in the 6 OVH cases and 6 CCL cases was 33.3% and 83.3%, respectively. The CVP efficacy in the 13 OVH cases and 11 CCL cases was 38.5% and 45.5%, respectively. 
     There were no serious adverse events and only one case of injection discomfort was judged to be related to IVP administration, while one case of diarrhea was judged to be possibly related to IVP administration. Thus, the low frequency of adverse events attributable to IVP administration demonstrated safe use of this formulation. 
     Although the objects of the disclosure have been described with reference to the above example, it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure. Accordingly, the disclosure is limited only by the following claims.