EP4041245A1 - Therapeutic formulations and uses thereof - Google Patents
Therapeutic formulations and uses thereofInfo
- Publication number
- EP4041245A1 EP4041245A1 EP20883598.3A EP20883598A EP4041245A1 EP 4041245 A1 EP4041245 A1 EP 4041245A1 EP 20883598 A EP20883598 A EP 20883598A EP 4041245 A1 EP4041245 A1 EP 4041245A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- cox
- inhibitor
- concentration
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- 229960002871 tenoxicam Drugs 0.000 description 1
- LZNWYQJJBLGYLT-UHFFFAOYSA-N tenoxicam Chemical compound OC=1C=2SC=CC=2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 LZNWYQJJBLGYLT-UHFFFAOYSA-N 0.000 description 1
- HTJXMOGUGMSZOG-UHFFFAOYSA-N tiaramide Chemical compound C1CN(CCO)CCN1C(=O)CN1C(=O)SC2=CC=C(Cl)C=C21 HTJXMOGUGMSZOG-UHFFFAOYSA-N 0.000 description 1
- 229950010302 tiaramide Drugs 0.000 description 1
- PFENFDGYVLAFBR-UHFFFAOYSA-N tinoridine Chemical compound C1CC=2C(C(=O)OCC)=C(N)SC=2CN1CC1=CC=CC=C1 PFENFDGYVLAFBR-UHFFFAOYSA-N 0.000 description 1
- 229950010298 tinoridine Drugs 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the invention relates generally to therapeutic formulations and more specifically to formulations including a selective cyclooxygenase-2 (COX-2) inhibitor (coxib) and optionally buprenorphine.
- COX-2 selective cyclooxygenase-2
- coxib selective cyclooxygenase-2
- Nonsteroidal anti-inflammatory drugs 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 developed in the 2000s supplanted traditional NSAIDs in some settings by virtue of their comparable efficacy with improved gastrointestinal safety.
- COX-2 inhibitors are available for treatment of pain and inflammation in companion animals.
- 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.
- compositions containing a coxib and optionally buprenorphine are provided herein are compositions containing a coxib and optionally buprenorphine.
- 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.
- 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.
- excipients e.g., polyethylene glycol, “PEG” and/or propylene glycol
- 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.
- 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.
- 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
- 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).
- a suitable pharmaceutical carrier e.g., lactose monohydrate and/or microcrystalline cellulose
- the composition is formulated for oral delivery as a liquid.
- the composition is formulated for oral delivery as a liquid suspension, colloid, emulsion, or homogeneous solution.
- the oral composition is non- aqueous and sterile.
- the formulations of the invention 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): , (II), or isomers or pharmaceutically acceptable salts thereof.
- the formulations of the invention 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
- the formulations include a coxib and optionally buprenorphine and/or one or more NSAIDS.
- a pharmaceutical composition for use in treating a disease or disorder in a mammalian subject 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 R5 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 , —C
- a method of treating a disease or disorder in a subject by administering a formulation of the invention to the subject.
- 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.
- 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.
- a formulation of the invention is delivered to a companion animal such as a cat or dog.
- a method of treating a disease or disorder in a subject by administering a compound of the disclosure to the subject.
- a disease or disorder e.g., pain or an inflammatory disorder
- 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 R5 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
- Figure 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.
- Figure 2 is a graph showing plasma concentrations for formulations of the disclosure administered to subjects in embodiments of the invention.
- Figure 3 is a graph showing plasma concentrations for formulations of the disclosure administered to subjects in embodiments of the invention.
- Figure 4 is a graph showing plasma concentrations for formulations of the disclosure administered to subjects in embodiments of the invention.
- Figure 5 is a graph showing plasma concentrations for formulations of the disclosure administered to subjects in embodiments of the invention.
- Figure 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 [0025] The following terms, definitions and abbreviations apply. Abbreviations used herein have their conventional meaning within the chemical and biological arts.
- a “patient” or “subject” refers to either a human or non-human mammalian animal. Non-human animals include any non-human mammalian animals.
- 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.
- the animals are mammals.
- 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).
- terapéuticaally 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.
- 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.
- 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.
- 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.
- a disorder such as pain or inflammation
- a pharmaceutically acceptable vehicle or diluent such as a pharmaceutically acceptable vehicle or diluent.
- coxib refers to a selective cyclooxygenase-2 (COX-2) inhibitor or “COX-2 inhibitor”.
- 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.
- the coxib is mavacoxib, a non-steroidal anti-inflammatory drug (NSAID) of the coxib class (ATCvet Code QM01AH92).
- NSAID non-steroidal anti-inflammatory drug
- 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.
- the coxib is a “chromene coxib” and is referred to herein as PAH- 100.
- PAH-100 is a member of a structural class of COX-2 selective inhibitors.
- PAH-100 refers of a compound of Formula (I): or an isomer or pharmaceutically acceptable salt thereof, or a compound of Formula (II): 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- (trifluorome
- 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 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 R5 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
- the coxib is a compound of Formula (IV): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (V): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (VI): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (VII): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (VIII):
- the coxib is a compound of Formula (IX): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (X): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (XI): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (XII): or an isomer or pharmaceutically acceptable salt thereof.
- 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–, –SO 2 –, or –CH 2 –; 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, —SO 2 R9, —COR6, —OCOR6, —COOR6, —NR6COR6, — CONR7R8, —NR6SO 2 R9, —SO 2 NR7R8, —NR6CONR7R8, —NR6COOR9 or — NR6SO 2 NR7R8; R6
- the coxib is a compound of Formula (XIV): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (XV): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (XVI): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (XVII): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (XVIII): (XVIII) or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (XIX): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (XX): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (XXI): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is a compound of Formula (XXII): or an isomer or pharmaceutically acceptable salt thereof.
- the coxib is selected from the following compounds: [0059] In embodiments, the coxib is: [0060] In embodiments, the coxib is: [0061]
- 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.
- polymorphs, hydrates, and solvates of the compounds are included in the disclosure, with hydrates being particularly preferred.
- 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.
- 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.
- the administration will be by injection, topically or orally.
- 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.
- 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.
- the compositions may include include a coxib and one or more additional NSAIDS.
- 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.
- acetic acid derivative NSAID examples 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
- 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.
- 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.
- 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.
- 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).
- hormones specifically Cortison and corticoids
- glucocorticoids e.g., Cortison, Cloprednol, Prednison, Prednisolon, Methylprednisolon, Deflazacort, Fluocortolon, Triamcinol
- compositions 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.
- 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.
- 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.
- the solvent includes propylene glycol present at over about 1% w/w of the composition.
- the composition optionally includes an anti-oxidant present at no more than 10% w/w of the composition.
- Particular embodiments of formulations suitable for topical use are as follows.
- Particular embodiments of formulations suitable for topical use are as follows.
- an exemplary topical formulation is as follows: [0077] In one embodiment, an exemplary topical formulation is as follows: [0078] In one embodiment, an exemplary topical formulation is as follows: [0079] In one embodiment, an exemplary topical formulation is as follows: [0080] In one embodiment, a topical composition includes: i) a coxib; ii) propylene glycol; iii) propylene carbonate; iv) ethanol; and v) optionally an anti-oxidant.
- 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.
- 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.
- 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.
- excipients e.g., polyethylene glycol, “PEG” and/or propylene glycol
- at least one optional excipient e.g., ethanol
- preservative, penetration enhancer and/or viscosity reducer e.g., ethanol
- e optionally up to 10% w/w of at least one anti-oxidant.
- a topical composition includes: i) a coxib; ii) propylene glycol; iii) polyethylene glycol; iv) ethanol; and optionally v) an anti-oxidant.
- 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.
- 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.
- 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.
- Particular embodiments of formulations suitable for oral administration are as follows.
- 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.
- 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.
- 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.
- 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.
- 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. [0098] Dosing will vary by active drug, species and condition.
- 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.
- 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.
- 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.
- “clinically resolve pain” is measured by reference to the clinically significant and measurable presence of the active in the animal’s bloodstream for the requisite period of time; e.g., at least about 48, 72, 96, 120, 144, or 168 hours.
- 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.
- 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.
- compositions 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 [00103] The following coxib containing formulation was prepared for oral administration.
- 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 Figure 1.
- EXAMPLE III Exemplary Subcutaneous Injectable Formulations [00105] The following coxib containing formulation was prepared for subcutaneous injection.
- EXAMPLE IV Pharmacokinetics of a Composition of the Invention [00106] 1 dog was dosed via subcutaneous injection with the composition of Example III at a dosing concentration of 3 mg/kg.
- EXAMPLE V Exemplary Topical Formulations
- the following coxib containing formulation was prepared for topical administration.
- EXAMPLE VI Pharmacokinetics of a Composition of the Invention [00108] 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 Figure 1.
- EXAMPLE VII Exemplary Topical Formulation [00109] The following coxib containing formulation was prepared for topical administration.
- EXAMPLE VIII Exemplary Oral Formulations
- the following coxib containing formulation was prepared for oral administration.
- Compounding Procedures [00112] 1. Weigh out all ingredients.
- Figure 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.
- Figure 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.
- 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.
- Figure 3 Mean 5% PAH-100 Plasma Concentration-Time Profiles Following a Single Subcutaneous Injection of 3 mg/kg in Dogs.
- Figure 3 illustrates the PK curves of the first 3 mg/kg injection from all three studies.
- Figure 4 Mean Plasma Concentration-Time Profiles Following Weekly Subcutaneous Injection for 3-Weeks.
- Figure 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 [00149]
- 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.
- Figure 5 Mean Plasma Concentration-Time Profiles Following a Single Subcutaneous Injection Followed by Oral Tablet Administration at 1X and 5X dose.
- Figure 5 illustrates the plasma concentrations in dogs subcutaneously treated weekly for 3-weeks at 3 mg/kg and 15 mg/kg.
- PAH-100 Oral Tablet Efficacy (PAH16-013)
- 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.
- EXAMPLE XV Field Safety and Efficacy for Postoperative Pain [00154] 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.
- 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. [00156] 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. [00157] 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. [00158] On Day 3, a physical examination and injection site evaluation was conducted, and blood and serum was collected for clinical pathology testing.
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