EP0988034A1 - Carprofene inhibant selectivement cox-2 et utilise dans le traitement de la douleur et des inflammations chez les chiens - Google Patents

Carprofene inhibant selectivement cox-2 et utilise dans le traitement de la douleur et des inflammations chez les chiens

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Publication number
EP0988034A1
EP0988034A1 EP98915041A EP98915041A EP0988034A1 EP 0988034 A1 EP0988034 A1 EP 0988034A1 EP 98915041 A EP98915041 A EP 98915041A EP 98915041 A EP98915041 A EP 98915041A EP 0988034 A1 EP0988034 A1 EP 0988034A1
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EP
European Patent Office
Prior art keywords
cox
carprofen
inhibitors
activity
inflammatory
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.)
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Application number
EP98915041A
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German (de)
English (en)
Inventor
Kristin Marie Lundy
Anthony Paul Ricketts
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Pfizer Inc
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Pfizer Inc
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Publication date
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Publication of EP0988034A1 publication Critical patent/EP0988034A1/fr
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention concerns the treatment of pain and inflammation in dogs with anti-inflammatory agents which are non-steroidal anti-inflammatory drugs (NSAIDs), and in particular such agents having a reduced incidence of adverse gastro-intestinal side effects, since such side effects are a prevalent and potentially severe problem in dogs.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs have been more limited, e.g., only two such NSAIDs have been approved by the Food and Drug Administration, Committee on Veterinary Medicine (FDA/CVM), for use in dogs in the United States, i.e., ARQUEL®, meclofenamic acid, and RIMADYL®, carprofen. Consequently, there is less experience and knowledge in veterinary medicine about safety and efficacy issues surrounding the use of NSAIDs in dogs.
  • FDA/CVM Food and Drug Administration, Committee on Veterinary Medicine
  • NSAIDs In veterinary medicine, for example, the most common indication for NSAIDs is the treatment of degenerative joint disease (DJD), which in dogs often results from a variety of developmental diseases, e.g., hip dysplasia and osteochondrosis, as well as from traumatic injuries to joints.
  • DJD degenerative joint disease
  • NSAIDs are also useful in dogs for treating post-surgical acute pain, as well as for treating clinical signs associated with osteoarthritis.
  • This demand for canine NSAID therapy combined with the absence of any approved NSAIDs for this purpose, has resulted in substantial off-label use in dogs of NSAIDs approved for humans, sometimes with disastrous consequences.
  • therapeutic index is sometimes generally defined as the ratio of the LD 50 to the ED 50 of a drug, and is intended to be a statement of how selective the drug is in producing its desired effects As used herein, however, the expression “therapeutic index” is more consistent with the definition utilized in the animal health field, which is the ratio of the maximum tolerated dose in the animal to the minimum effective dose in the animal
  • animal refers, of course, to dogs
  • the maximum tolerated dose in a particular canine subject would typically be determined by a number of different assays and techniques For example, gastrointestinal hemorrhage may be determined by assay methods commonly used to detect occult blood in stool specimens, while endoscopy can be used to detect the occurrence of ulceration or perforation Where the animal is euthanized as part of the study, autopsy can provide valuable information as well
  • Arachidonic acid which is cis-A 5 , cis-A 8 , cis-A eicosatetraenoic acid, is the dominant precursor for many prostaglandins and leukotrienes which are mediators of inflammation.
  • arachidonic acid is released as a result of tissue-specific stimuli by hormones or proteases, or by membrane perturbance, and involves the action of a specific phospholipase A 2 .
  • a free arachidonate results which in the second stage of the cascade is acted on by the bifunctional enzyme prostaglandin endoperoxide synthase, also referred to as prostaglandin H synthase (hereafter PGH synthase), the first activity of which is as a cyclo-oxygenase, while the second activity involves a two-electron reduction.
  • PGH synthase prostaglandin H synthase
  • Most NSAIDs act as inhibitors of the cyclo-oxygenase activity of PGH synthase, and thereby block the production of various prostaglandins, which are locally acting hormones which carry out their functions by binding to specific cellular receptors.
  • the prostaglandins are very potent but are also quickly catabolized.
  • prostaglandins are mediators of the inflammatory process; however, some of these prostaglandins also have a gastrointestinal protective function. Blocking production of these beneficial prostaglandins is one of the chief factors contributing to the adverse gastrointestinal reactions which are experienced with the use of NSAID therapy. Accordingly, there has been an ongoing search for pharmaceutical agents which, while acting as cyclo-oxygenase inhibitors, also by some additional mode of action or another, have substantially reduced gastrointestinal adverse reactions and resulting side effects.
  • COX cyclo-oxygenase
  • COX-1 and COX-2 have a 60% homology, similar K m values, and the same arachidonic acid binding sites, but COX-2 accepts a wider range of substrates than does COX-1.
  • Carprofen racemic 6- chloro- ⁇ -methylcarbazole-2-acetic acid
  • Carprofen racemic 6- chloro- ⁇ -methylcarbazole-2-acetic acid
  • Other members of this class are, e.g., benoxaprofen, cicloprofen, fenoprofen, flurbiprofen, furaprofen, indoprofen, ketoprofen, pirprofen, and suprofen.
  • Carprofen for example, has been shown to be a relatively weak inhibitor of cyclo-oxygenase, but has also been shown, in humans and various animal models, to decrease significantly the pain and swelling, and other symptoms of inflammation. These evaluations of carprofen are described in the technical literature, some of which is cited and discussed further below. Carprofen has also been shown to be inactive with respect to lipoxygenase in the rat, and does not, presumably, block production of leukotrienes. While the mode of action of carprofen still appears to be unknown, it has been demonstrated to have some activity against phopholipase A 2 .
  • COX-2 isozyme isozyme. Also recently in the art, with the above-mentioned discovery of the existence of the constitutive COX-1 and inducible COX-2 isozymes, studies have been conducted using various species in order to ascertain the existence of any stereoselective inhibition specific to one or more of said species. These investigations of the individual activity of the R- and
  • the S-enantiomer is, e.g., three-times as potent as the R-enantiomer in inhibiting both the COX-1 and the COX-2 isozymes in a given species, that with respect to either of these same isozymes, the S-enantiomer shows equal potency in inhibiting both the COX-1 and the COX- 2 isozymes, i.e., the S-enantiomer shows no selective inhibition of COX-2 in that species.
  • carprofen has been found to be a surprisingly potent inhibitor of the COX-2 isozyme in the dog; and further that it is a selective COX-2 inhibitor in the dog.
  • the selectivity of carprofen against COX-2 is as much as two fold greater than that of virtually all other NSAIDs, including carboxylic-acid-moiety-containing NSAIDs, and purportedly
  • COX-2 selective sulfonyl-moiety-containing NSAIDs The selection of carprofen as the preeminent selective inhibitor of the COX-2 isozyme in dogs, from among all other NSAIDs, not only runs counter to the current teachings in the art, but is also a wholly unexpected discovery in terms of the surprising results achieved. The fact that all of the representative other NSAIDs evaluated herein have been approved for administration to humans in the
  • the S-enantiomer of carprofen has been found to be a highly selective inhibitor of the COX-2 isozyme vs. the COX-1 isozyme in the dog, and that this is the case to a significantly greater extent than all other NSAIDs or their S-enantiomers, including carboxylic-acid-moiety-containing NSAIDs, and purportedly COX-2 selective sulfonyl-moiety- containing NSAIDs.
  • the S-enantiomer of carprofen has been found to have, by reason of its being a highly selective inhibitor of the COX-2 isozyme, a surprisingly improved level of anti- inflammatory, analgesic and anti-pyretic activity compared to that of all other NSAIDs, including those having a carboxylic-acid-moiety, or their S-enantiomers, as well as a surprisingly reduced level of adverse gastrointestinal and other reactions compared to that of all other NSAIDs, including those having a carboxylic-acid-moiety, or their S-enantiomers.
  • carprofen belongs to the aryl propionic acid class of NSAIDs, and is as well a member of the subclass of such compounds which are substituted carbazole acetic acids. These compounds and their use as anti-inflammatory, analgesic and anti- rheumatic agents are described in U.S. 3,896,145.
  • the anti-inflammatory activity of carprofen in dogs was investigated by McKellar ef al. and reported in "Pharmacokinetics, tolerance and serum thromboxane inhibition of carprofen in the dog", Journal of Small Animal Practice, 31, 443-448, 1990.
  • a principal mode of action of most NSAIDs is known to be inhibition of the enzyme cyclooxygenase in the generation of inflammatory prostaglandins from arachidonic acid.
  • the subject report indicates that the human and murine COX-2 enzymes are expected to be very similar because of the 87% identity and strict sequence conservation in the cyclo-oxygenase active site Flurbiprofen, a slow-binding competitive inhibitor of both
  • COX- and COX-2 binds in the long hydrophobic channel and excludes substrate from the cyclo-oxygenase active site
  • SC-558 is a diaryl heterocyclic inhibitor with a central pyrazole ring and a sulfonamide group attached to one of the aryl rings
  • COX-2 the channel that leads from membrane to the cyclo-oxygenase active site forks at the SC-558 binding site, with one branch forming a cavity that accepts the bromophenyl ring of SC-558, while the other branch forms a pocket which is virtually inaccessible in the COX-1 structure, but which accommodates the entire phenylsulfonamide moiety in COX-2
  • This pocket is more accessible in COX-2 because valine is substituted for isoleucme, which has a larger side chain, at position 523 Access of the phenylsulfonamide group to the new pocket in COX-2 is facilitated by another isoleucme to valine change at position
  • the subject report embodies the first example of a membrane protein being successfully studied as a target in structure-based drug design, and approximates the current state of the art concerning the structure/activity relationships of NSAIDs to the cyclo- oxygenase isozymes and their resulting anti-inflammatory activity vs their adverse gastrointestinal reactions. It is within the context of this state of the art that the present invention will be seen to be a wholly unexpected development which provides, surprisingly, an optimum efficacy/safety profile for the treatment of inflammation in dogs.
  • any one such combination of anti-inflammatory active agents will probably be based on obtaining a favorable balance of the pharmacokinetic properties of the individual agents involved. For example, rapidity of onset of action may be balanced with extended therapeutic half-life, or a tendency toward the formation of large cellular reservoirs in certain tissues may be balanced with higher rates of plasma protein binding. All such combinations are contemplated to be within the scope of the present invention.
  • the present invention provides any anti-inflammatory selective COX-2 inhibitor satisfying the above-described limitations.
  • selective inhibitory compounds is a preferred subgenus of carprofen compounds useful in treating or preventing pain and inflammatory processes and diseases in a member of the species Canis familiaris of the formula:
  • A is hydroxy, (C-, - C 4 )alkoxy, amino, hydroxy-amino, mono-(C 1 -C 2 )alkylamino, di- ⁇ -C 2 )alkylamino;
  • X and Y are independently H or (C*, - C 2 )alkyl; and n is 1 or 2;
  • R 6 is halogen, (C, - C 3 )alkyl, trifluoromethyl, or nitro;
  • inhibitor of Formula (I) exists as (-)(R) and (+)(S) enantiomers
  • (+)(S) enantiomer alone or where both enantiomers are present together, there is provided a racemic or a non-racemic mixture thereof.
  • the present invention further provides in a preferred aspect of the above-described method of treating or preventing pain and inflammatory processes and diseases in a member of the species Cams familiaris in need of such treatment, administration to said member of an amount therapeutically effective for treating pain and inflammation, of an anti- inflammatory selective COX-2 inhibitory compound for which COX-2 in vitro IC S0 potency in said member is at least 30 fold greater, preferably at least 40 fold greater, more preferably at least 50 fold greater, more preferably still at least 60 fold greater, even more preferably still at least 80 fold greater, and most preferably at least 100 fold greater than its in vitro IC 50 potency against COX-1 in said member, wherein said inhibitor is a member selected from the group of anti-inflammatory compounds consisting essentially of salicylic acid derivatives, p-aminophenol derivatives, indole and indene acetic acids, heteroaryl acetic acids, arylpropionic acids, anthranilic acids, enolic acids, and alkanones
  • the present invention still further provides in another preferred aspect of the above- described method of treating or preventing pain and inflammatory processes and diseases in a member of the species Cams familiaris in need of such treatment, administration to said member of an amount therapeutically effective for treating pain and inflammation, of an anti- inflammatory selective COX-2 inhibitory compound which selectively inhibits substantially only inducible COX-2, with substantially no inhibition of corresponding constitutive COX-1
  • said therapeutically effective amount of an anti-infiammatory compound of Formula (I) as defined, and especially of said (+)(S)-enant ⁇ omer of 6-chloro- ⁇ -methyl-9H-carbazole-2-acet ⁇ c acid is administered systemically to said member of Cams familiaris, wherein said systemic administration comprises (1) injection or infusion into suitable body tissues or cavities of a pharmaceutical composition containing said inhibitor in suitable liquid form for delivering said inhibitor by systemic administration which is intraarte ⁇ al, intra- or transdermal, subcutaneous, intramuscular, intraspinal, intrathecal, or intravenous, where said inhibitor is (a) contained in solution as a solute, (b) contained in the discontinuous phase of an emulsion, or the discontinuous phase of an inverse emulsion which inverts upon injection or infusion, said emulsions containing suitable emulsifying agents, or (c) contained in a suspension as a suspended solid in colloidal or microp
  • Suppositories may be regarded as a special type of implant, since they comprise bases which are solid at room temperature but melt at body temperature, slowly releasing the active ingredient with which they are impregnated into the surrounding tissue of the body, where the active ingredient becomes absorbed and transported to effect systemic administration.
  • Dosage forms which permit transdermal and transmucosal administration to achieve systemic delivery are also contemplated, especially including transdermal patch technology.
  • a solid peroral dosage form selected from the group consisting of delayed-release oral tablet, capsule, caplet, lozenge, troche, and multiparticulates, enteric-coated tablets and capsules which prevent release and absorption in the stomach to facilitate delivery distal to the stomach of the dog, sustained- release oral tablets, capsules and microparticuiates which provide systemic delivery of the active ingredient in a controlled manner over at least a 10-hour period, a fast-dissolving tablet, encapsulated solutions, an oral paste, a granular form incorporated in or to be incorporated in the food of the dog being treated, and a chewable form in which said active ingredient is consumed along with the palatable chew, or may alternatively be delivered by leaching from the body of the chew which is not consumed, during mastication by the dog being treated.
  • a solid peroral dosage form selected from the group consisting of delayed-release oral tablet, capsule, caplet, lozenge, troche, and multiparticulates, enteric-coated tablets and capsules which prevent release and
  • microencapsulated formulations of the active ingredient are also included for use with the above-described dosage forms.
  • said method comprising ingestion of a liquid peroral dosage form selected from the group consisting of a solution, suspension, emulsion, inverse emulsion, elixir, extract, tincture, and concentrate, optionally to be added to the drinking water of the dog being treated.
  • a liquid peroral dosage form selected from the group consisting of a solution, suspension, emulsion, inverse emulsion, elixir, extract, tincture, and concentrate, optionally to be added to the drinking water of the dog being treated.
  • the concentrate liquid form is formulated to be added first to a given amount of water, from which an aliquot amount may be withdrawn for administration directly to the dog or addition to the drinking water of the dog.
  • said therapeutically effective amount of an anti-inflammatory compound of Formula (I) as defined is administered locally to a site of inflammation in said member of Canis familiaris.
  • said local administration comprises: (1) injection or infusion into a local site of inflammation of a pharmaceutical composition containing said inhibitor in suitable liquid form for delivering said inhibitor by local administration which is intraarterial, intraarticular, intrachondrial, intracostal, intracystic, intra- or transdermal, intrafasicular, intraligamentous, intramedulary, intramuscular, intraneural, intraosteai, intrapeivic, intrapericardial, intraspinal, intrasternal, intrasynovial, intratarsal, or intrathecal; including components which provide delayed-release, controlled- release, and/or sustained-release of said inhibitor into said local site of inflammation; where said inhibitor is contained: (a) in solution as a solute; (b) in the discontinuous phase of an emulsion, or the discontinuous phase of an inverse emulsion which inverts upon injection or infusion, said emulsions containing suitable emulsifying agents; or (c) in a
  • compositions to be applied to the skin may be used to deliver the inhibitor active ingredient into a local area, such as an inflammed joint, in need of such treatment.
  • Such compositions may be in the form of gels, lotions, balms, ointments, and other formulations designed for topical application.
  • the therapeutically effective amount of anti-inflammatory inhibitor is administered to said member of the species Canis familiaris in an amount, expressed as mg per kg of body weight of said member per day, ranging from about 0.01 mg/kg to about 20.0 mg/kg/day, preferably from about 0.1 mg/kg to about 12.0 mg/kg/day, more preferably from about 0.5 mg/kg to about 10.0 mg/kg/day, and most preferably from about 0.5 mg/kg to about 8.0 mg/kg/day.
  • Administration of 6-chloro- ⁇ -methyl-9H-carbazole-2-acetic acid is typically provided by dosing at a rate of about 4.0 mg/kg/day.
  • a pharmaceutical composition for treating or preventing pain and inflammatory processes and diseases in a member of the species Canis familiaris in need of such treatment comprising a pharmaceutically acceptable carrier together with an amount therapeutically effective for treating pain and inflammation, of an anti-inflammatory selective inhibitor of cyclo- oxygenase-2 (COX-2) wherein the selectivity ratio of COX-2 to COX-1 is at least 3 : 1 based on ex vivo inhibition levels in whole blood measured at a dose giving > 80% COX-2 inhibition, and preferably > 90% COX-2 inhibition.
  • COX-2 cyclo- oxygenase-2
  • said therapeutically effective anti-inflammatory selective COX-2 inhibitor has an in vitro IC 50 potency of at least 30 fold greater, preferably at least 40 fold greater, more preferably at least 50 fold greater, more preferably still at least 60 fold greater, even more preferably at least 80 fold greater, and most preferably at least 100 fold greater than cyclo- oxygenase-1 (COX-1) in vitro IC 50 potency; wherein said inhibitor is a member selected from the group of anti-inflammatory compounds consisting essentially of salicylic acid derivatives; p-aminophenol derivatives; indole. and indene acetic acids; heteroaryl acetic acids; arylpropionic acids; anthranilic acids; enolic acids; and alkanones.
  • the above-described pharmaceutical composition wherein said inhibitor is a member selected from the group consisting of arylpropionic acids; and further still, said inhibitor is a compound of above-defined Formula (I).
  • the above-described pharmaceutical composition wherein the cyclo-oxygenase-2 (COX-2) in vitro IC 50 potency of the inhibitory compound of Formula (I) is at least 100 fold greater than the cyclo-oxygenase-1 (COX-1) in vitro IC 50 potency thereof; and wherein one of X and Y is H and the other is methyl; and wherein when both resulting enantiomers are present, (+)(S) enantiomer is present in amount of at least 75%.
  • compositions in which said inhibitor comprises 6-chloro- ⁇ -methyl-9/-/-carbazole-2-acetic acid; and wherein when both resulting enantiomers are present together, (+)(S) enantiomer is present in an amount of at least 85%, preferably at least 90%, more preferably at least 95%, and most preferably at least 99%.
  • said inhibitor is comprised entirely of (+)(S) enantiomer of 6-chloro- ⁇ -methyl-9H-carbazole-2-acetic acid.
  • compositions wherein the therapeutically effective amount of anti-inflammatory inhibitor present is sufficient, in the context of the dosage regimen and administration parameters employed, to provide a member being treated with an amount of said inhibitor, expressed as mg per kg of body weight of said member per day, ranging from about 0.01 mg/kg to about 20.0 mg/kg/day, preferably from about 0.1 mg/kg to about 12.0 mg/kg/day, more preferably from about 0.5 mg/kg to about 10.0 mg/kg/day, and most preferably from about 0.5 mg/kg to about 8.0 mg/kg/day.
  • Administration of 6-chloro- ⁇ -methyl-9H-carbazole-2-acetic acid is typically provided by dosing at a rate of about 4.0 mg/kg/day.
  • an anti-inflammatory selective COX-2 inhibitor which selectively inhibits substantially only inducible COX-2, with substantially no inhibition of corresponding constitutive COX-1.
  • said inhibitor is comprised entirely of (+)(S)- enantiomer of 6-chloro- ⁇ -methyl-9/-/-carbazole-2-acetic acid.
  • said therapeutically effective amount of said inhibitor is sufficient, in the context of the dosage regimen and administration parameters employed, to provide a member being treated with an amount of said inhibitor, expressed as mg per kg of body weight of said member per day, ranging from about 0.5 mg/kg/day to about 8.0 mg/kg/day.
  • the above-described pharmaceutical composition in a dosage form which can provide the required therapeutically effective amount for treating pain ahd inflammation, of anti-inflammatory selective COX-2 inhibitor in a convenient regimen.
  • compositions are intended to be long-acting, i.e., providing inhibitor activity for longer than just hours or a single day, and instead providing such activity for several days up to a week or more.
  • the implants and depots in particular are examples of such long-acting pharmaceutical compositions, and some of these are intended to provide inhibitor activity for up to a month or more.
  • the required therapeutically effective amount of inhibitor necessary to treat or prevent pain and inflammation ranges from about 0.01 mg/kg to about 20.0 mg/kg/day, preferably from about 0.1 mg/kg to about 12.0 mg/kg/day, more preferably from about 0.5 mg/kg to about 10.0 mg/kg/day, and most preferably from about 0.5 mg/kg to about 8.0 mg/kg/day.
  • Administration of 6-chloro- ⁇ -methyl-9/-/-carbazole-2-acetic acid is typically provided by dosing at a rate of about 4.0 mg/kg/day.
  • compositions wherein said therapeutically effective amount for treating pain and inflammation, of an anti-inflammatory inhibitor, is provided in a dosage form suitable for systemic administration to said member of Canis familiaris, wherein said pharmaceutical composition contains said inhibitor in suitable liquid form for delivering said inhibitor by: (1 ) injection or infusion which is intraarterial, intra- or transdermal, subcutaneous, intramuscular, intraspinal, intrathecal, or intravenous, wherein said inhibitor: (a) is contained in solution as a solute; (b) is contained in the discontinuous phase of an emulsion, or the discontinuous phase of an inverse emulsion which inverts upon injection or infusion, said emulsions containing suitable emulsifying agents; or (c) is contained in a suspension as a suspended solid in colloidal or microparticulate form, said suspension containing suitable suspending agents; (2) injection or infusion into suitable body tissues or cavities as a depot, wherein said composition provides storage of said inhibitor and thereafter delayed-,
  • compositions which provide delayed-, sustained-, and/or controlled-release of said anti- inflammatory selective COX-2 inhibitor
  • dosage forms which produce > 80% inhibition of COX-2 isozyme activity and result in a plasma concentration of said inhibitor of at least 10 ⁇ g/mL for at least 4 hrs; preferably for at least 8 hrs; more preferably for at least 12 hrs; more preferably still for at least 16 hrs; even more preferably still for at least 20 hrs; and most preferably for at least 24 hrs.
  • the above-described dosage forms which produce > 80% inhibition of COX-2 isozyme activity and result in a plasma concentration of said inhibitor of at least 15 ⁇ g/mL for at least 4 hrs, preferably for at least 8 hrs, more preferably for at least 12 hrs, still more preferably for at least 20 hrs, and most preferably for at least 24 hrs.
  • dosage forms which produce > 90% inhibition of COX-2 isozyme activity and result in a plasma concentration of said inhibitor of at least 20 ⁇ g/mL for at least 4 hrs, preferably for at least 8 hrs, more preferably for at least 12 hrs, still more preferably for at least 20 hrs, and most preferably for at least 24 hrs.
  • Particular dosage forms of the above-described pharmaceutical compositions include suppositories as a special type of implant, comprising bases which are solid at room temperature but melt at body temperature, slowly releasing the active ingredient with which they are impregnated into the surrounding tissue of the body, where the active ingredient becomes absorbed and transported to effect systemic administration; solid peroral dosage forms selected from the group consisting of delayed-release oral tablet, capsule, caplet, lozenge, troche, and multiparticulates, enteric-coated tablets and capsules which prevent release and absorption in the stomach to facilitate delivery distal to the stomach of the dog, sustained-release oral tablets, capsules and microparticulates which provide systemic delivery of the active ingredient in a controlled manner up to a 24-hour period, a fast- dissolving tablet, encapsulated solutions, an oral paste, a granular form incorporated in or to be incorporated in the food of the dog being treated, and a chewable form in which said inhibitor active ingredient is consumed along with the palatable chew, or may alternatively be delivered by leaching from
  • liquid dosage forms when formulated in accordance with methods well known in the art, can either be administered directly to the dog being treated, or may be added to the drinking water of the dog being treated.
  • the concentrate liquid form is formulated to be added first to a given amount of water, from which an aliquot amount may be withdrawn for administration directly to the dog or addition to the drinking water of the dog.
  • compositions wherein said therapeutically effective amount for treating pain and inflammation, of said anti- inflammatory inhibitor, is provided in a dosage form suitable for local administration to a site of inflammation in said member of Canis familiaris, wherein said pharmaceutical composition contains said inhibitor in suitable liquid form for delivering said inhibitor by: (1) injection or infusion into a local site of inflammation, which is intraarterial, intraarticular, intrachondrial, intracostal, intracystic, intra- or transdermal, intrafasicular, intraligamentous, intramedulary, intramuscular, intranasal, intraneural, intraocular, i.e., opthalmic administration, intraosteal, intrapelvic, intrapericardial, intraspinal, intrasternal, intrasynovial, intratarsal, or intrathecal; including components which provide delayed-release, controlled-release, and/or sustained- release of said inhibitor into said local site of inflammation; where said inhibitor is contained: (a) in solution as a solute;
  • the active ingredient of the present invention will desirably be administered in combination with one or more antibiotic, antifungal, antiprotozoal, antiviral or similar therapeutic agents.
  • the active ingredient of the present invention may be administered not only in combination with other NSAIDs, but in combination as well with inhibitors of other mediators of inflammation, comprising one or more members selected from the group consisting essentially of the classes of such inhibitors and examples thereof which include, H-* -receptor antagonists; kinin-B-i - and B 2 -receptor antagonists; prostaglandin inhibitors such as PGD-, PGF- PGI 2 -, and PGE-receptor antagonists; thromboxane A 2 (TXA2-) inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC 4 -, LTD /LTE -, and LTB 4 -inhibitors; PAF-receptor antagonists; gold in the form of an aurothio group together with various hydrophilic groups; immunosuppressive agents, e.g., cyclosporine, azathioprine, and methotrexate; anti- inflammatory glucocortic
  • the anti- inflammatory agents of the present invention are administered in combination with therapeutic agents intended for the treatment of disease conditions, syndromes and symptoms found in older dogs, comprising one or more members selected from the group consisting essentially of the therapeutic agents and conditions being treated which include cognitive therapeutics to counteract memory loss and impairment; anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, including hypertension, myocardial ischemia including angina, congestive heart failure, and myocardial infarction, selected from diuretics, vasodilators such as hydralazine, ⁇ -adrenergic receptor antagonists such as propranolol, angiotensin-ll converting enzyme inhibitors (ACE- inhibitors) such as enalapril used to treat geriatric dogs with mitral insufficiency, and enalapril alone and in combination with neutral endopeptidase inhibitors, angiotensin II receptor antagonists such as losartan, renin inhibitors, calcium channel
  • the above combinations of therapeutic agents are used to treat acute conditions in dogs, irfcluding bacterial infections occurring simultaneously with degenerative joint disease, and to treat chronic conditions in dogs
  • the regimen used for this purpose comprises administration of the anti-inflammatory agents of the present invention in combination with other medications used on a regularly scheduled basis for treating chronic conditions including osteoarthritis, formulation of the anti-inflammatory agents of the present invention with one or more other therapeutic agents which are to form the intended combination, into a convenient dosage form containing all of the drugs forming the combination, including wherein said different drugs have varying half-lives, by creating controlled-release forms of said drugs with different release times which achieves relatively uniform dosing, a medicated feed dosage form in which said drugs used in the combination are present together in admixture in said feed composition
  • co-administration in which the combination of drugs is achieved by the simultaneous administration of said drugs to be given in combination, including co- administration by means of different dosage forms and routes of administration, the use of combinations in accordance with different but
  • Cams familiaris in need of such treatment comprising a suitable container which may be in the form of an outer package and an inner container removably housed therein, enclosed in said container a suitable dosage form of an active ingredient comprising a selective inhibitor of COX-2 wherein the selectivity ratio of COX-2 to COX-1 is at least 3 1 based on ex vivo inhibition levels in whole blood measured at a dose giving > 80% COX-2 inhibition, preferably > 90% COX-2 inhibition, as described elsewhere herein, and associated with said container printed instructional and informational material, which may be attached to said container, enclosed in said container, or displayed as an integral part of said container, said instructional and informational material stating in words which convey to a reader thereof that said active ingredient, when administered to a dog to be treated, effectively inhibits
  • said instructional and inTormational material will state in words which convey to a reader thereof that said active ingredient when administered to a dog to be treated will provide effectively complete inhibition of induced COX-2 in said dog, thereby treating or preventing pain and inflammation therein; but also that when said ingredient is thus administered to said dog it will cause substantially no inhibition of constitutive COX-1 in said dog, whereby undesirable gastrointestinal and other adverse effects resulting from substantial inhibition of said COX-1 will be avoided in effectively most dogs.
  • a package of the type described immediately above comprising a suitable container as described; enclosed in said container an oral dosage form of a compound of Formula (I), which may be in the form of a chewable or ingestible oral tablet, a unit dose packet referred to as a sachet, a suspension made from a unit dose packet, a powder for oral suspension, or an oral suspension perse, which does not exhibit an adverse food effect; and associated with said container printed instructional and informational material as described, which is free of any express or implied limitation with respect to whether said oral dosage form can be taken with or without food.
  • a suitable container as described; enclosed in said container an oral dosage form of a compound of Formula (I), which may be in the form of a chewable or ingestible oral tablet, a unit dose packet referred to as a sachet, a suspension made from a unit dose packet, a powder for oral suspension, or an oral suspension perse, which does not exhibit an adverse food effect; and associated with said container printed instructional and informational material as described,
  • the object of the present invention is to find a solution to a serious problem which has confronted the veterinary field for decades with regard to the need for an effective but safe anti-inflammatory treatment for dogs.
  • the seriousness and intractability of this problem arises from the fact that virtually all anti-inflammatory agents, especially the NSAIDs, which have been tested for use in dogs, have had altogether unacceptable and sometimes dangerous adverse reactions in dogs which have greatly curtailed their use.
  • By far the most wide-spread and threatening of these adverse reactions is disturbance and irritation of the gastrointestinal mucosa leading to ulceration, hemorrhage and eventually perforation and peritonitis.
  • These undesirable adverse reactions are mediated by the inhibition of various prostaglandins by the NSAID inhibitors, resulting in a restricted blood supply to the protective gastrointestinal muscosa, which in turn is seriously diminished both in total mass and in protective functioning.
  • Gastric damage by NSAIDs is brought about by at least two distinct mechanisms. Local irritation by orally administered NSAIDs permits back diffusion of acid into the gastric mucosa, inducing tissue damage. Parenteral administration, on the other hand, can also cause damage and bleeding, which has been correlated with inhibition of the biosynthesis of gastric prostaglandins that serve a cytoprotective function in the gastric mucosa. These prostaglandins, especially PGI 2 and PGE 2 , inhibit acid secretion by the stomach, increase irfucosal blood flow, and promote the secretion of cytoprotective mucus in the intestine.
  • NSAIDs include disturbances in platelet function, the prolongation of gestation or spontaneous labor, changes in renal function, and hypersensitivity reactions. All of the above-described undesirable side effects of NSAIDs probably depend upon blockade of the synthesis of endogenous prostaglandins. Accordingly, there is significant interest in the discovery of NSAIDs which do not result in the systemic production of such undesirable side effects. Dogs are not only especially vulnerable to inflammatory processes and diseases, such as degenerative joint disease, but they are also particularly susceptible to complications from the adverse gastrointestinal reactions which ensue.
  • dog(s) denotes any member of the species Canis familiaris , of which there are a large number of different breeds. While laboratory determinations of biological activity may have been carried out using a particular breed, it is contemplated that the inhibitory compounds of the present invention will be found to be useful for treating pain and inflammation in any of these numerous breeds.
  • the gist of the present invention is the surprising discovery that a small genus of anti-inflammatory agents, of which carprofen, 6-chloro- ⁇ -methyl-9H- carbazole-2-acetic acid, is the best example, possesses a high degree of canine cyclo- oxygenase-2 (COX-2) selectivity, and that this selectivity is unique among the large class of carboxyl- and carboxy(C 1 -C 4 )alkyl aryl and/or heteroaryl anti-inflammatory agents to which the carprofen genus of compounds also belongs.
  • COX-2 canine cyclo- oxygenase-2
  • cyclo-oxygenase an essential enzyme which produces various prostaglandin compounds in the body, beginning with arachidonic acid. It has been established that this enzyme exists in two isozyme forms which are separate and act independently, a constitutive cyclo-oxygenase-1 (COX-1) isozyme and a cycio-oxygenase-2 (COX-2) isozyme.
  • the COX-1 isozyme in dogs is responsible for producing prostaglandins which perform important functions in the stomach, intestine, kidney and blood platelets, some of which are protective in nature, especially with respect to the gastrointestinal mucosa.
  • the COX-2 isozyme in dogs is responsible for producing prostaglandins such as PGE 2 which mediate acute and chronic inflammation within neutrophils, macrophages, endothelial cells and fibroblasts, in which the COX-2 gene is expressed.
  • COX-2 can be induced by endotoxin, lipopolysaccharide (LPS), various cytokines, e.g., IL-1 and TNF, growth factors, e.g., EGF and PDGF, and many other agents.
  • the COX-2 isozyme can be detected by immunoblotting in mononuclear cells of the pleural exudate after carrageenan- induced pleurisy in a rat model.
  • COX-2 isozyme i.e., compounds which provide optimal anti-inflammatory therapy through relatively high levels of COX-2 isozyme inhibition at a dose which also produces minimal undesirable side effects through relatively low levels of COX-1 isozyme inhibition.
  • the only compounds which have been shown to exhibit COX-2 selectivity are those having a sulfonyl or sulfonamido group, rather than a carboxyl group, as is characteristic of the vast majority of classical NSAIDs.
  • the present invention provides a method of selectively inhibiting inducible cyclo-oxygenase-2 (COX-2) with respect to inhibition of corresponding constitutive cyclo-oxygenase-1 (COX-1), and thereby treating or preventing pain and inflammatory processes and diseases associated therewith in a member of the species Canis familiaris in need of such treatment, wherein the selectivity ratio of COX-2 to COX-1 is at least 3 : 1 based on in vivo and ex vivo inhibition levels in whole blood measured at the dose or range of doses giving > 90% COX-2 inhibition, comprising administering to said member an amount therapeutically effective for treating pain and inflammation in accordance with the above-recited limitations, of an anti-inflammatory compound.
  • the present invention further provides the above-described method of treating or preventing pain and inflammatory processes and diseases in a member of the species Canis familiaris wherein said anti-inflammatory selective COX-2 inhibitor comprises a compound of the formula:
  • A is hydroxy, (C, - C 4 )alkoxy, amino, hydroxy-amino, mono-(C 1 -C 2 )alkylamino, di ⁇ C,
  • X and Y are independently H or (C-, - C 2 )alkyl; and n is 1 or 2;
  • R ⁇ is halogen, (C, - C 3 )alkyl, trifluoromethyl, or nitro;
  • inhibitor of Formula (I) exists as (-)(R) and (+)(S) enantiomers
  • (+)(S) enantiomer alone or where both enantiomers are present together, there is provided a racemic or a non-racemic mixture thereof.
  • the preferred carprofen genus of compounds characterized by an ⁇ -methyl-acetic acid functionality, has many times greater canine COX-2 selectivity than any of the carboxyl-containing classical NSAIDs, as well as many times greater canine COX-2 selectivity than some of the sulfonyl and sulfonamide-containing NSAIDs accepted in the art as being highly COX-2 selective compounds.
  • This aspect of the present invention is embodied in a method of treating or preventing inflammatory processes and diseases in a dog comprising administering to them an anti-inflammatory therapeutically effective amount of an inhibitor of canine cyclo-oxygenase-2 (COX-2) for which in vitro IC 50 potency in said dog is at least 50 fold greater than canine cyclo-oxygenase-1 (COX-1) in vitro IC S0 potency in said dog; wherein said inhibitor is a member selected from the group of anti-inflammatory compounds consisting essentially of salicylic acid derivatives; p-aminophenol derivatives; indole and indene acetic acids; heteroaryl acetic acids; arylpropionic acids; anthranilic acids; enolic acids; and alkanones; and in particular is a member selected from the group c ⁇ nsisting of carboxyl- and carboxy(C 1 -C 4 )alkyl aryl and/or heteroaryl anti-inflammatory agents.
  • Carprofen and the genus of carprofen derivatives preferably utilized in the methods and compositions of the present invention may be prepared in accordance with methods of synthesis well known to the organic chemist of ordinary skill.
  • compounds of Formula (I) where R 6 is halogen, (C, - C 3 )alkyl, trifluoromethyl, or nitro; and where R 9 is H or methyl may be prepared by reacting (1) a phenylhydrazine in which the phenyl portion has the desired R 6 substitution and the ⁇ -nitrogen of the hydrazine has the desired R 9 substitution; with (2) a cyclohexanone having the desired R 2 substitution.
  • the resulting 1 ,2,3,4-tetrahydrocarbazole is then aromatized to produce the desired carbazole of Formula (I).
  • the aromatization may be carried out using (1 ) an aromatizing agent, e.g., p-chloranil, o- chloranil, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), sulfur, palladium on carbon, or lead oxide; in the presence of (2) a solvent such as xylene, benzene, toluene, quinoline, dimethylsulfoxide (DMSO), and dimethylformamide (DMF); (3) at a temperature in the range from room temperature to reflux of the reaction mixture, preferably the latter.
  • an aromatizing agent e.g., p-chloranil, o- chloranil, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), sulfur, palladium on carbon, or lead oxide
  • DDQ 2,
  • Compounds of Formula (I) which are acids, i.e., where A is hydroxy, and salts of such acids with bases, can be converted to amides of Formula (I) where A is amino, hydroxyamino, mono-(C 1 -C 2 )alkylamino, and di-(C 1 -C 2 )alkylamino; by (1) forming the corresponding acid chloride by treatment with phosphorus pentachloride (PCI 5 ); followed by (2) reaction with the appropriate amine reactant to form the desired amide, carried out in the presence of an equivalent of pyridine or triethylamine to serve as the base for the proton transfer step and thereby remove the H + CI " which is formed.
  • PCI 5 phosphorus pentachloride
  • step (1) The same acid chlorides which are formed in step (1) can be reacted with the appropriate alkanol to provide the esters of Formula (I) where A Is (C*, -C 4 )alkoxy.
  • This reaction is also desirably carried out in the presence of a base such as pyridine which can neutralize the H + CI " being formed so that it does not interfere with any acid sensitive alkanol reactant.
  • the (S)-enantiomer of the preferred carprofen genus of compounds of Formula (I) having a chiral carbon would possess a surprisingly reduced level of adverse gastrointestinal and other reactions in dogs compared to that of virtually all other NSAIDs having a carboxylic acid moiety, and especially compared to their S-enantiomers.
  • the S- enantiomer of carprofen would have, by reason of its being a very highly selective inhibitor of the canine COX-2 isozyme, a surprisingly improved level of anti-inflammatory, analgesic and anti-pyretic activity in dogs compared to that of virtually all other NSAIDs characterized by a carboxylic acid moiety.
  • One especially preferred embodiment of the present invention is to use only the (S)- enantiomer of carprofen, 6-chloro- ⁇ -methyl-9H-carbazole-2-acetic acid, as the active ingredient or treating agent in the methods and compositions of the present invention.
  • other embodiments are contemplated to be within the scope of this preferred genus of the present invention as well.
  • (S)-enantiomers can be used, and in that event the (S)-enantiomer is present in amount of at least 85%, preferably at least 90%, more preferably at least 95%, and most preferably at least 99%. Since the (R)- and (S)-enantiomers are identical in molecular weight, density, etc., it is unnecessary to state any basis for the above-recited percentages. In other words, they could be percentages by weight, volume, chemical equivalency, etc. The reason for including the above-indicated amounts of the (R)-enantiomer may be as simple as the practicalities of not being required to remove absolutely every last trace of the (R)- enantiomer from the racemic mixture. There can also be reasons for doing so which relate to beneficial overall biological properties.
  • the active ingredient being used as a therapeutic agent comprises a mixture of enantiomers different from a 50:50 mixture, or where the therapeutic agent comprises substantially 100% of the (+)(S) or (-)(R) enantiomer alone
  • the person of ordinary skill in this art will be able to calculate the actual amount of dosage required in a very straightforward manner, simply by multiplying the dosage amounts recited by a factor which reflects the ratio of the amount of enantiomer being used to the amount present for the recited dosage based on a 50:50 mixture of the enantiomers.
  • the recited dosage is 4mg/kg/day for the 50:50 racemic mixture
  • the corresponding dosage amount when substantially 100% of (+)(S) enantiomer is used one-half of the recited amount, i.e., 2mg/kg/day.
  • compositions of the present invention containing a member of the preferred genus of carprofen compounds contemplate the use of racemic mixtures containing 50% of (S)-enantiomer, as well as non-racemic mixtures of about 99% or less of the (S)-enantiomer along with less than 50% of the (R)-enantiomer
  • resolution of racemates of the carprofen genus of compounds of Formula (I) having a chiral carbon into the optically active isomers must be carried out. This can be readily accomplished using known procedures and techniques in the art. For example, some racemic mixtures can be precipitated as eutectics after which they can be separated.
  • diastereomers are formed from the racemic mixture with an optically active resolving agent.
  • an optically active base e.g., D- ⁇ -methylbenzylamine
  • the diastereomers thus formed are then separated by selective crystallization and converted to the corresponding optical isomer.
  • the anti-inflammatory therapeutically active and pharmaceutically acceptable salt forms, prodrugs and metabolites of the preferred carprofen genus of compounds used in the present invention are all of the anti-inflammatory therapeutically active and pharmaceutically acceptable salt forms, prodrugs and metabolites of the preferred carprofen genus of compounds used in the present invention.
  • salts thereof may be formed by treatment with pharmaceutically acceptable bases.
  • bases include alkali metal hydroxides including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal aikoxides, e.g., potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine, and ⁇ /-methylglutamine.
  • bases are alkali metal hydroxides including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal aikoxides, e.g., potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine, and ⁇ /-methylglutamine.
  • aluminum salts of the compounds of Formula (I) are also included.
  • Formula (I) there is included within the scope of the present invention the use as active ifigredients of all analgesic and anti-inflammatory therapeutically active and pharmaceutically acceptable prodrugs and metabolites of the above-recited compounds.
  • Such N-moieties are readily cleaved during metabolism of the compound of Formula (I), making these particular derivatives desirable prodrugs.
  • the present invention has been described in the paragraphs immediately above particularly with regard to the preferred genus of carprofen compounds of Formula (I). However, the present invention contemplates a wider scope with regard to providing anti- inflammatory selective COX-2 inhibitors. As already indicated, such selective COX-2 inhibitors comprise those wherein the selectivity ratio of COX-2 to COX-1 is at least 3 : 1 based on in vivo and ex vivo inhibition levels in whole blood measured at the dose or range of doses giving > 80% COX-2 inhibition.
  • PK pharmacokinetic
  • the most important pharmacokinetic parameters are bioavailability, the fraction of said drug which is absorbed into the systemic circulation; volume of distribution, relating to the amount of space in the body which is available to contain said drug; and clearance, relating to the body's ability to eliminate a particular drug, in accordance with the present invention, the selectivity ratio for COX-2 to COX-1 , which must be at least 3 : 1 , is determined on the basis of ex vivo measurement of the percentage (%) inhibition of each of said isozymes in canine whole blood.
  • the procedures for making said ex vivo measurements may be briefly summarized as consisting of first administering the selective inhibitor test compound at a predetermined total dose level, e.g., 2 mg/lb to preselected dogs.
  • the dose is administered in accordance with a predetermined dosing regimen, e.g., once a day (s.i.d.), twice a day (bid.), etc., after which whole blood samples are collected from each test animal.
  • Assays for COX-1 and COX-2 activity are based on stimulation of said blood with either a calcium ionophore for thromboxane B 2 (COX-1 activity) or lipopolysaccharide (LPS) for prostaglandin E 2 (COX-2 activity), respectively.
  • COX-2 selectivity is an essential feature of the anti-inflammatory inhibitors useful in the present invention, and is required to be in a ratio of at least 3 : 1 compared to inhibition of COX-1 activity. It is insufficient for a given compound simply to possess a 3 : 1 selective ratio, since a given compound might possess the required selective ratio at some point over its total dosage range, but still fail to provide adequate inhibition of COX-2 activity overall. Accordingly, it is additionally required that for an anti-inflammatory inhibitor to be within the scope of the present invention it must also provide > 80% COX-2 activity inhibition, and preferably > 90% COX-2 activity inhibition. This is deemed to be the minimum level of inhibition adequate to provide satisfactory pharmacological activity in terms of treating and preventing pain and inflammation.
  • the potential inhibitor has satisfied (1) the at least 3 : 1 selectivity ratio, and (2) the > 80% COX-2 inhibition limitations required for it to be an anti-inflammatory selective COX-2 inhibitor falling within the scope of the present invention. Because the data from both of these graphs has been compared over the same dose (2 mg/lb) and the same time period of 12 hrs, the third limitation has also been satisfied, namely that the first two limitations be satisfied at the same dose or range of doses.
  • a candidate compound falls within the scope of the present invention if a line parallel to the y-axis and intercepting both curves at some dosage concentration results in data points which satisfy both the 3 : 1 ratio and > 80% inhibition limitations.
  • COX-2 inhibitors which are included therein can be viewed or expressed in different, although essentially equivalent terms to those above-used.
  • the present invention may be considered to provide particularly a method of treating or preventing pain and inflammatory processes and diseases in a member of the species Canis familiaris in need of such treatment, which comprises administering to said member a therapeutically effective amount for treating pain and inflammation, of an anti-inflammatory inhibitor of cyclo- oxygenase-2 (COX-2) for which in vitro IC 50 potency in said member is at least 30 fold greater, preferably at least 40 fold greater, more preferably at least 50 fold greater, more preferably still at least 60 fold greater, even more preferably at least 80 fold greater, and most preferably at least 100 fold greater than cyclo-oxygenase-1 (COX-1) in vitro IC 50 potency in said member; wherein said inhibitor is a member selected from the group of anti- inflammatory compounds consisting essentially of salicylic acid derivatives; p-aminophenol derivatives; indole and inden
  • cyclo-oxygenase-2 (COX-2) in vitro IC 50 potency of the inhibitory compound of Formula (I) is at least 100 fold greater than said cyclo- oxygenase-1 (COX-1) in vitro IC 50 potency thereof; wherein one of X and Y is H and the other is methyl; and wherein when both resulting enantiomers are present together, (+)(S) enantiomer is present in amount of at least 75%.
  • said inhibitor comprises 6-chloro- ⁇ -methyl-9/-/-carbazole-2-acetic acid; and wherein when both resulting enantiomers are present together, (+)(S) enantiomer is present in amount of at least 85%, preferably at least 90%, more preferably at least 95%, and most preferably at least 99%.
  • said inhibitor is comprised entirely of (+)(S)-enantiomer of 6-chloro- ⁇ -methyl-9/-/-carbazole-2-acetic acid.
  • the present invention may also be described as providing a method of selectively inhibiting substantially only inducible cyclo-oxygenase-2 (COX-2), with substantially no inhibition of corresponding constitutive cyclo-oxygenase-1 (COX-1), and thereby treating or preventing pain and inflammatory processes and diseases associated therewith in a member of the species Canis familiaris in need of such treatment, comprising administering to said member a therapeutically effective amount for treating pain and inflammation, of an anti- inflammatory compound of Formula (I) above where R 2 , X , Y , n , A , R 6 , and R 9 are as defined; including the (-)(R) and (+)(S) enantiomers; and all anti-inflammatory therapeutically active and pharmaceutically acceptable salt forms, prodrugs and metabolites of the above- recited compounds.
  • COX-2 substantially only inducible cyclo-oxygenase-2
  • COX-1 constitutive cyclo-oxygenase-1
  • the inhibitor of Formula (I) exists as (-)(R) and (+)(S) enantiomers
  • the (+)(S) enantiomer alone, or where both enantiomers are present together there is provided a racemic or a non-racemic mixture thereof.
  • the present invention may be further described as including the above-recited method of selectively inhibiting substantially only inducible cyclo-oxygenase-2 (COX-2), wherein said inhibitor comprises 6-chioro- ⁇ -methyl-9H-carbazole-2-acetic acid; and wherein when both resulting enantiomers are present, (+)(S) enantiomer is present in amount of at least 85%, preferably at least 90%, more preferably at least 95%, and most preferably at least 99%.
  • said inhibitor is comprised entirely of (+)(S)-enantiomer of 6-chloro- ⁇ -methyl-9/- -carbazole-2-acetic acid.
  • the compounds of Formula (I), or their enantiomers or salts are to be used as active ingredients in the methods and compositions of the present invention, they can be incorporated into standard pharmaceutical dosage forms.
  • they are useful when administered in systemic or local, oral or parenteral applications and for this purpose are combined with the usual pharmaceutical excipients diluents and adjuvants, e g , organic and inorganic inert carrier materials such as water gelatin lactose starch, magnesium stearate, talc, vegetable oils, gums polyalkyleneglycols, efc
  • These pharmaceutical preparations can be employed in a solid form e , as tablets, troches, suppositories, capsules, and especially in combination with or for admixture with a palatable food item suitable for dogs, or they can be administered in liquid form, e g , as solutions, suspensions, standard and inverse emulsions, and elixirs
  • Pharmaceutical excipients and adjuvants
  • the (+)(S) enantiomer will be the predominant component, not only because it is significantly more potent than the (-)(R) enantiomer in inhibiting cycio-oxygenase-2 (COX-2), but also because it is highly selective with respect to inhibiting cyclo-oxygenase-2 (COX-2) as compared to cyclo-oxygenase-1 (COX-1)
  • the (+)(S) enantiomer will be the predominant component, not only because it is significantly more potent than the (-)(R) enantiomer in inhibiting cycio-oxygenase-2 (COX-2), but also because it is highly selective with respect to inhibiting cyclo-oxygenase-2 (COX-2) as compared to cyclo-oxygenase-1 (COX-1)
  • COX-2 cycio-oxygenase-2
  • COX-1 cyclo-oxygenase-1
  • an injection is a single dose of the pharmaceutical composition forced, usually by a syringe, into the tissue involved.
  • the most common types of injections are intramuscular, intravenous, and subcutaneous.
  • an infusion is the gradual introduction of the pharmaceutical composition into the tissue involved.
  • the most common type of infusion is intravenous.
  • Other types of injection or infusion comprise intraarterial, intra- or transdermal (including subcutaneous), or intraspinal especially intrathecal.
  • the anti-inflammatory inhibitor may be contained in solution as the solute.
  • an emulsion which is a dispersion of small globules of one liquid, the discontinuous or internal phase, throughout a second liquid, the continuous or external phase, with which it is immiscible.
  • the two liquids are maintained in an emulsified state by the use of emulsifiers which are pharmaceutically acceptable.
  • the anti-inflammatory inhibitor is a water-insoluble oil, it can be administered in an emulsion of which it is the discontinuous phase.
  • an emulsion can be used. While the inhibitor would most commonly be used as the discontinuous or internal phase of what is referred to as an oil-in-water emulsion, it could also be used as the discontinuous or internal phase of an inverse emulsion, which is commonly referred to as a water-in-oil emulsion.
  • the anti- inflammatory inhibitor is soluble in water and could be administered as a simple aqueous solution.
  • inverse emulsions invert upon injection or infusion into an aqueous medium such as the blood, and offer the advantage of providing a more rapid and efficient dispersion of the inhibitor into that aqueous medium than can be obtained using an aqueous solution.
  • Inverse emulsions are prepared by using suitable, pharmaceutically acceptable emulsifying agents well known in the art.
  • the anti-inflammatory inhibitor has limited water solubility, it may also be administered as a suspended solid in colloidal or microparticulate form in a suspension prepared using suitable, pharmaceutically acceptable suspending agents.
  • the suspended solids containing the inhibitor may also be formulated as delayed-, sustained-, and/or controlled-release compositions.
  • Systemic administration of solids is carried out by instillation, inhalation or insufflation of a pharmaceutical composition in suitable solid form containing the inhibitor.
  • Instillation of the inhibitor may entail installing a solid implant composition into suitable body tissues or cavities.
  • the implant may comprise a matrix of bio-compatible and bio-erodible materials in which particles of a solid inhibitor are dispersed, or in which, possibly, globules or isolated cells of a liquid inhibitor are entrapped. Desirably, the matrix will be broken down and completely absorbed by the body.
  • composition of the matrix is also preferably selected to provide controlled-, sustained-, and/or delayed release of the inhibitor over extended periods of time, even as much as several months.
  • a substantial number of the dosage forms described herein may be formulated so as to provide controlled-, sustained-, and/or delayed release of the active ingredient from said dosage form.
  • the above-described dosage forms which produce > 80% inhibition of COX-2 isozyme activity and result in a plasma concentration of said inhibitor of at least 15 ⁇ g/mL for at least 4 hrs, preferably for at least 8 hrs, more preferably for at least 12 hrs, still more preferably for at least 20 hrs, and most preferably for about 24 hrs. More preferably, there is included the above-described dosage forms which produce > 90% inhibition of COX-2 isozyme activity and result in a plasma concentration of said inhibitor of at least 20 ⁇ g/mL for at least 4 hrs, preferably for at least 8 hrs, more preferably for at least 12 hrs, still more preferably for at least 20 hrs, and most preferably for about 24 hrs.
  • a useful controlled release dosage form of carprofen in accordance with the present invention is one which maintains a carprofen plasma level greater than 2 ⁇ g/mL for most of the day after a single oral dose at 2 mg/lb.
  • Preferred oral controlled release dosage forms of carprofen in accordance with the present invention are ones which maintain a plasma carprofen concentration greater than 10 ⁇ g/mL for a period of time greater than that for which an immediate release dosage form of carprofen maintains a comparable plasma level, when said immediate release dosage form and controlled release dosage form are administered at the same dose, e.g. 2, 1.8, 1.6, or 1.4 mg/lb.
  • preferred 2mg/lb oral controlled release dosage forms of this invention maintain a plasma carprofen concentration greater than 10 ⁇ g/mL for greater than 10.5 hrs.
  • Immediate release carprofen dosage forms containing doses of 1.8, 1.6, and 1.4 mg/lb maintain a plasma carprofen concentration above 10 ⁇ g/mL for 9.5 hrs, 8.5 hrs, and 7.5 hrs, respectively.
  • Preferred 1.8 mg/lb oral controlled release carprofen dosage forms maintain a plasma carprofen concentration above 10 ⁇ g/mL for greater than 9.5 hrs.
  • the threshold durations for 1.6 mg/lb and 1.4 mg/lb doses are 8.5 hrs and 7.5 hrs, respectively.
  • the performance characteristics for preferred oral controlled release carprofen dosage forms at doses higher than 2 mg/lb or less than 1.4 mg/lb can be similarly calculated, assuming linear pharmacokinetics.
  • More preferred oral controlled release carprofen dosage forms are those which maintain a plasma carprofen concentration greater than 10 ⁇ g/mL for a period of time greater than or equal to that observed when an immediate release carprofen dosage form is dosed at any higher dose. These controlled release dosage forms thus maintain at least 80% COX-2 inhibition in canine blood for a period of time longer than that achieved by an immediate release dosage form at a higher dose.
  • Most preferred oral controlled release carprofen dosage forms are those which are able to maintain plasma carprofen levels above approximately 10 ⁇ g/mL for a period of time greater than or equal to the time observed for an immediate release 2 mg/lb carprofen dosage form (10.5 hrs), when said oral controlled release carprofen dosage forms are administered at a dose less than 2 mg/lb.
  • the performance of a 2 mg/lb oral immediate release dosage form is taken as the fundamental standard for purposes of this comparison since 2 mg/lb/day is the currently recommended and accepted efficacious oral dose in accordance with the present invention as described herein.
  • implant always denotes a solid pharmaceutical composition containing the anti-inflammatory inhibitor
  • spot usually implies a liquid pharmaceutical composition containing the anti-inflammatory inhibitor, which is deposited in any suitable body tissues or cavities to form a reservoir or pool which slowly migrates to surrounding tissues and organs and eventually becomes systemically distributed.
  • Suppositories may be regarded as a type of implant, since they comprise bases which are solid at room temperature but melt at body temperature, slowly releasing the active ingredient with which they are impregnated Into the surrounding tissue of the body, where the active ingredient becomes absorbed and transported to effect systemic administration.
  • Systemic administration can also be accomplished by inhalation or insufflation of a powder, i.e., particulate composition containing the inhibitor.
  • a powder i.e., particulate composition containing the inhibitor.
  • the inhibitor in powder form may be inhaled into the lungs using conventional devices for aerosolizing particulate formulations.
  • the inhibitor as a particulate formulation may also be administered by insufflation, i.e., blown or otherwise dispersed into suitable body tissues or cavities by simple dusting or using conventional devices for aerosolizing particulate formulations.
  • These particulate compositions may also be formulated to provide delayed-, sustained-, and/or controlled-release of the anti-inflammatory inhibitor in accordance with well understood principles and known materials.
  • transdermal patches prepared in accordance with well known drug delivery technology may be prepared and applied to the skin of a dog to be treated, whereafter the active agent by reason of its formulated solubility characteristics migrates across the epidermis and into the dermal layers of the dog's skin where it is taken up as part of the general circulation of the dog, ultimately providing systemic distribution of the active ingredient over a desired, extended period of time.
  • implants which are placed beneath the epidermal layer of the skin, i.e. between the epidermis and the dermis of the skin of the dog being treated.
  • Such an implant will be formulated in accordance with well known principles and materials commonly used in this delivery technology, and may be prepared in such a way as to provide controlled-, sustained-, and/or delayed-release of the active ingredient into the systemic circulation of the dog.
  • Such subepidermal (subcuticular) implants provide the same facility of installation and delivery efficiency as transdermal patches, but without the limitation of being subject to degradation, damage or accidental removal as a consequence of being exposed on the top layer of the dog's skin.
  • compositions of special types suitable for oral administration to dogs may also be devised.
  • Pharmaceutical compositions suitable for peroral administration i.e., ingestion by mouth or administration through the mouth, may be solid or liquid.
  • Preferred peroral dosage forms for systemic administration are solids, e.g., palatable oral compositions such as fast dissolving palatable wafers, tablets, capsules, caplets, lozenges, troches, efc, and liquids, e.g., solutions, suspensions, emulsions, elixirs, tinctures, etc.
  • compositions of special types suitable for oral administration to dogs may be used, and include, but are not limited to such items as an oral paste to be delivered to the back of the tongue of the dog being treated, a granular form to be delivered through incorporation in the "dog's food, and a chewable form wherein the active ingredient is consumed along with the palatable chew, or a chewable form which may deliver the active ingredient by leaching from the body of the chew which is not consumed, during mastication by the dog being treated.
  • the formulation of such palatable compositions takes into account canine behavior regarding the extent of mastication of the dosage form which will take place, and the resultant level of dosing.
  • dosage forms intended for oral administration are also suitably formulated to provide controlled-, sustained-, and/or delayed release of the active ingredient.
  • these would include delayed-release oral tablets, capsules and multiparticulates, as well as enteric-coated tablets and capsules which prevent release and absorption of the active ingredient in the stomach of the dog and facilitate enteric delivery distal to the stomach, i.e., in the intestines of the dog.
  • Other typical oral dosage forms would include sustained-release oral tablets, capsules, and multiparticulates which provide systemic delivery of the active ingredient in a controlled manner over a prolonged period of time, e.g., a 24-hour period.
  • a controlled-release oral dosage form may be prepared in the form of a fast-dissolving tablet, which would also preferably include highly soluble salt forms of the active ingredient.
  • a suitable oral dosage form for use in the present invention includes encapsulated solutions, a mixed solid and liquid formulation.
  • Microemulsion formulations also within the scope of the present invention, may also be characterized as a mixed solid and liquid dosage form.
  • the anti-inflammatory inhibitor can be administered locally to a site of inflammation in a dog to be treated.
  • Local vs. systemic administration entails a more focused vs. a more generalized manner of delivering the anti-inflammatory-inhibitor-containing pharmaceutical composition to the dog suffering from pain and inflammation.
  • depots and implants as well as delayed-, sustained-, and controlled-release formulations has tended to blur these distinctions.
  • liquid and solid pharmaceutical compositions containing the anti-inflammatory inhibitor can, for the most part, be used for local administration as well, but with an emphasis on choosing components for said compositions which will tend to promote absorption of the inhibitor into the local tissues at the site of administration, but which will also tend to prevent infiltration and migration of the inhibitor into more outlying and distant tissues, resulting in systemic carryover
  • Such administration is focused on suitable tissues and body cavities into which the anti-inflammatory inhibitor may be injected, infused, implanted, deposited, inserted, instilled, or insufflated
  • Such administration may include, but is not limited to, that which is intraarterial, intraarticular, intrachond ⁇ al, infracostal, intracystic, intra- or transdermal, intrafasicular, intraligamentous, intramedulary, intramuscular, intranasal, intraneural, intraocular, / e opthalmic administration, intraosteal, intrapelvic, intrape ⁇ cardial, intraspinal, intrasternal, intrasynovial, intratarsal, intrathecal, or intravenous
  • compositions in liquid form containing the inhibitor offer the advantage of permitting injections of the liquid into or in close proximity to the site of inflammation This is particularly the case where inflamed joints and degenerative joint disease are involved
  • injection of the inhibitor directly into the joint it is possible to achieve a high concentration of inhibitor in a short period of time, thus not only substantially enhancing access of the inhibitor to the site of inflammation, and thus the therapeutic activity of the inhibitor, but also at the same time minimizing the occurrence of untoward adverse reactions that might otherwise occur
  • the result is a high local concentration of the inhibitor with a correspondingly low systemic carryover concentration
  • Injections may also be made of pharmaceutical compositions containing the inhibitor, where the pharmaceutical composition is in delayed-release, controlled-release, or sustained-release form
  • formulations of recognized composition may be a solids, semi-solids, gels or other liquid/solid combinations in which an erodible matrix or series of coatings is used to provide a continuous release of the inhibitor at a predetermined rate or at variable rates if desired
  • extended-release and “long-acting” as well as others are used to describe these formulations All of these employ various combinations of bioerodible polymers, e g , various ceilulosic polymers, and natural materials, e g , corn starch and magnesium stearate, to obtain slow and/or uniform dispensing of the inhibitor contained within the matrix
  • These pharmaceutical compositions may be injected into the site if suitably liquid or suspendable, or may be delivered by other means if more solid in nature
  • the therapeutically effective amount for treating pain and inflammation of inhibitory compounds of Formula (I) is administered to a dog being treated in an amount expressed as milligrams per kilogram of body weight of said dog, per day "mg/kg/day"
  • the expression *per day” as used herein should not be interpreted as necessarily requiring that any particular dosage form be administered on a daily basis to the dog being treated.
  • the expression "per day” is merely an indication of the smallest convenient but arbitrary segment of time which is being used as part of the overall unit for measuring the dose of anti- inflammatory inhibitor being administered.
  • the dose i.e., the therapeutically effective amount for treating pain and inflammation of the inhibitor will usually range from about 0.01 mg/kg/day to about 20.0 mg/kg/day, preferably from about 0.1 mg/kg/day to about 12.0 mg/kg/day, more preferably from about 0.5 mg/kg/day to about 10.0 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 8.0 mg/kg/day.
  • the fractional amounts are not significant and the dosages would appropriately be rounded to a number which corresponds to unit dosage amounts which are conveniently available.
  • the preferred dosage amounts may be achieved more precisely.
  • the dosage form is, e.g., an injectable liquid
  • the dosage form is, e.g., an oral tablet
  • the 10 mg dose could be approximated by halving a 25 mg tablet
  • the 180 mg dose could be approximated by using a 100 mg tablet together with a 75 mg tablet or three 25 mg tablets, since these are typical dosage amounts for oral tablets.
  • the dosage form most frequently employed is the oral tablet and a large number of dogs are treated on a daily basis
  • added convenience will be obtained through the use of a dispenser containing all of the available dosage amounts of said tablets, e.g., 25 mg, 75 mg, and 100 mg tablets.
  • any preferred dosage amount may be approximated using a combination of said tablets and/or halves thereof. It is necessary for the skilled artisan, such as a veterinarian, not only to determine the preferred route of administration and the corresponding dosage form and amount, but said artisan must also determine the dosing regimen, i.e., the frequency of dosing.
  • Typical dosage forms and amounts would include (1) intravenous administration of carprofen at a dose rate of 4.0 mg/kg/day of bodyweight, injected into the right cephalic vein; (2) oral administration of carprofen at a dose rate of 4.0 mg/kg/day of bodyweight as an oral paste syringed on the back of the tongue, given one hour before feeding; and (3) oral administration of carprofen at a dose rate of 4.0 mg/kg/day of bodyweight as 25 mg, 75 mg, and 100 mg tablet preparations, placed on the back of the tongue of the dog being treated, given one hour before feeding.
  • the active ingredients of the present invention may also be combined with other therapeutically active ingredients which would be readily apparent to the skilled artisan in this field, and which will usually be determined by the circumstances under which the therapeutic agent of the present invention is administered.
  • the active ingredient of the present invention will desirably be administered in combination with one or more antibiotic, antifungal, antiprotozoal, antiviral or similar therapeutic agents.
  • the active ingredient of the present invention may be "administered not only in combination with other NSAIDs of the type described in further detail herein, but in combination as well with inhibitors of other mediators of inflammation, in order to obtain a multi-fold inhibitory action against inflammation.
  • Additional classes of such inhibitors and examples thereof include, e.g., H, -receptor antagonists; kinin-B !
  • prostaglandin inhibitors such as PGD-, PGF- PGI 2 -, and PGE-receptor antagonists; thromboxane A 2 (TXA2-) inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC -, LTD 4 /LTE 4 -, and LTB 4 -inhibitors; PAF-receptor antagonists; gold in the form of an aurothio group together with various hydrophilic groups; immunosuppressive agents, e.g., cyclosporine, azathioprine, and methotrexate; anti-inflammatory glucocorticoids; penicillamine; hydroxychloroquine; anti-gout agents, e.g., colchicine, xanthine oxidase inhibitors, e.g., allopurinol, and uricosuric agents, e.g., probenecid, sulfinpyrazone, and
  • the anti-inflammatory agents of the present invention may also be administered in combination with therapeutic agents intended for the treatment of disease conditions, syndromes and symptoms which are also found in abundance in older dogs.
  • therapeutic agents and the conditions which they are used to treat include, e.g., cognitive therapeutics to counteract memory loss and impairment.
  • Another large class of such therapeutic agents includes anti-hypertensives and other cardiovascular drugs intended to offset hypertension, myocardial ischemia including angina, congestive heart failure, and myocardial infarction, e.g., diuretics, vasodilators such as hydralazine, ⁇ - adrenergic receptor antagonists such as propranolol, angiotensin-ll converting enzyme inhibitors (ACE-inhibitors) such as enalapril used to treat geriatric dogs with mitral insufficiency, and enalapril alone and in combination with neutral endopeptidase inhibitors, angiotensin II receptor antagonists such as losartan, renin inhibitors, calcium channel blockers such as nifedipine, sympatholytic agents such as methyldopa, ⁇ 2 -adrenergic agonist such as clonidine, ⁇ -adrenergic receptor antagonists such as prazosin, and HMG- CoA
  • Still other classes of such therapeutic agents include antineoplastic agents, especially antimitotic drugs including the vinca alkaloids such as vinblastine and vincristine, for treating various cancers; therapeutic agents for treating renal failure; anti-obesity drugs for treating excess weight problems in dogs; anti-parasitic drugs for treating both endo- and ecto-parasites which commonly afflict dogs; and anti-pruritic drugs for treating various types of pruritis in dogs.
  • antineoplastic agents especially antimitotic drugs including the vinca alkaloids such as vinblastine and vincristine, for treating various cancers
  • therapeutic agents for treating renal failure
  • anti-obesity drugs for treating excess weight problems in dogs
  • anti-parasitic drugs for treating both endo- and ecto-parasites which commonly afflict dogs
  • anti-pruritic drugs for treating various types of pruritis in dogs.
  • the anti-inflammatory agents of the present invention would be administered in combination with other medications used on a regularly scheduled basis for treating chronic conditions such as osteoarthritis
  • a convenient dosage form such as an oral tablet
  • Varying half-lives for the different drugs could be accommodated by the person skilled in preparing formulations by creating controlled-release forms of said drugs with different release times so that relatively uniform dosing was achieved
  • a medicated feed used as the dosage form could also be prepared in accordance with well known principles in the art of formulation, in which the drugs used in the combination were simply present together in admixture in the feed composition
  • the present invention also contemplates co-administration in which the combination of drugs is achieved by the simultaneous
  • the present invention has been described in terms of being useful in the treatment and prevention of pain and inflammation, since these most often occur together in tissue injury and disease processes and conditions mediated by COX-2.
  • the inflammatory process itself may have a number of precipitating causes, including infectious agents, ischemia, antigen-antibody interactions, and thermal or other physical injury. The response to each of these causes is characteristically different, but they all have a strong commonality.
  • Clinical symptoms include erythema, edema, tenderness and pain.
  • Three distinct phases can be recognized, but each of these is mediated by different mechanisms.
  • the first, acute transient phase involves local vasodilation and increased capillary permeability;
  • the second, delayed, subacute phase involves infiltration of leukocytes and phagocytic cells;
  • the third, chronic proliferative phase involves tissue degeneration and fibrosis.
  • NSAIDs as a therapeutic class of anti-inflammatory agents, appear to act by inhibiting the enzymatic production and release of prostaglandins, which participate in the pathogenesis of inflammation and fever.
  • the NSAIDs do not inhibit the formation of eicosanoids such as the leukotrienes, which also contribute to inflammation, nor do they interfere with the formation of numerous other mediators of inflammation.
  • the carprofen genus of compounds of Formula (I), and especially carprofen itself, and more especially the (S)-enantiomer of carprofen, alone among the NSAIDs having a carboxylic acid moiety have a surprising and unexpectedly high degree of selectivity for the COX-2 isozyme. While this particular isozyme is an important mediator of inflammation, there are many other important mediators of inflammation that either have no interaction with NSAIDs, or no well understood relationship to the action of NSAIDs.
  • mediators include several classes of leukocytes; cell adhesion molecules; soluble mediators such as C5a, PAF and leukotriene B 4 ; cytokines such as IL-1 and TNF; growth factors such as GM-CSF and TGF- ⁇ , ; histamine, bradykinin and 5-HT. While the compounds of Formula (I) are shown herein to be unique inhibitors of COX-2, there is no intention thereby to be bound to any particular mechanism of action by which the compounds of Formula (I) might exert their anti-inflammatory activity.
  • Salicylic acids aspirin Aspirin; p-Aminophenols . .acetaminophen;
  • Arylpropionic acids ibuprofen, naproxen, flurbiprofen, ketoprofen;
  • Enolic acids oxicams e.g., piroxicam, tenoxicam;
  • the carprofens do not belong to the subclass of heteroaryl acetic acids, because the carprofens are propionic acids, not acetic acids.
  • the carprofens cannot be placed in any of the other subclasses without doing some violence to the bases of classification.
  • the only NSAID approved for treatment of humans which is recognized to have human COX-2 selective activity is nabumetone in the above list, which is not an acid at all but a 2-butanone.
  • the carprofen genus of compounds characterized by an ⁇ -methyl-acetic acid functionality, has many times greater COX-2 selectivity in dogs than any of the carboxyl- containing or sulfonyl- or sulfonamide-containing NSAIDs set out in the above table.
  • COX-2 selectivity of carprofen, a compound of the present invention was made between the COX-2 selectivity of carprofen, a compound of the present invention, and the COX-2 selectivity of certain selected compounds from the above table. The results are illustrated in the below- described working examples. 0 As described above, the selectivity for COX-2 is conventionally determined as the ratio of COX-1 inhibition to COX-2 inhibition, or vice versa.
  • Test drug compounds were solubilized and diluted the day before the assay was to
  • HBSS Hank's balanced salts solution
  • platelets were washed with platelet buffer comprising Hank's buffer (Ca free) with 0.2% "bovine serum albumin (BSA) and 20 mM HEPES.
  • the platelet samples were then adjusted to 1.5 x 10 7 / mL, after which 50 ⁇ l of calcium ionophore (A23187) together with a calcium chloride solution were added to 50 ⁇ l of test drug compound dilution in plates to produce final concentrations of 1.7 ⁇ M A23187 and 1.26 mM Ca.
  • 100 ⁇ l of canine washed platelets were added and the samples were incubated at 37° C for 15 min, after which the reaction was stopped by adding 20 ⁇ l of 77 mM EDTA.
  • TXB 2 thromboxane B 2
  • EIA enzyme-immunoassay
  • the cells were harvested from the culture flasks by scraping, and were then washed with minimal Eagle's media (MEM) combined with 1% fetal bovine serum, centrifuged at 1500 rpm for 2 min, and adjusted to a concentration of 3.2 x 10 5 cells/mL.
  • MEM minimal Eagle's media
  • test sample suspensions were incubated for 1 hr and then centrifuged at 1000 rpm for 10 min at 4° C, after which 50 ⁇ l aliquots of each test drug sample were delivered to EIA plates.
  • the EIA was performed for prostaglandin E 2 (PGE 2 ), and the pg/mL concentration of PGE 2 was calculated from the standard line included on each plate. From this data it was possible to calculate the percent inhibition of COX-2 and the IC 50 values for the test drug compounds. Repeated investigations of COX-1 and COX-2 inhibition were conducted over the course of several months. The results were averaged, and a single COX-1 : COX-2 ratio was calculated. The data obtained, together with an indication of the number of tests conducted for each test sample, are set forth in the following table of values. TABLE 2
  • the objective of this study was to evaluate the inhibitory potency of carprofen against COX-1 and COX-2 activity using an ex vivo procedure on canine whole blood.
  • Test tubes were prepared containing 2 ⁇ L of either (A) calcium ionophore A23187 giving a 50 ⁇ M final concentration, which stimulates the production of thromboxane B 2 (TXB 2 ) for COX-1 activity determination; or of (B) lipopolysaccharide (LPS) to give a 10 ⁇ g/mL final concentration, which stimulates the production of prostaglandin E 2 (PGE 2 ) for COX-2 activity determination.
  • Test tubes used as controls contained vehicle and were unstimulated by the addition of any agent.
  • a 500 ⁇ L sample of blood was added to each of the above-described test tubes, after which they were incubated at 37°C for one hr in the case of the calcium ionophore-containing test tubes, and overnight in the case of the LPS-containing test tubes. After incubation, 10 ⁇ L of EDTA was added to give a final concentration of 0.3%, in order to prevent coagulation of the plasma which sometimes occurs after thawing frozen plasma samples. The incubated samples were centrifuged at 4°C and the resulting plasma sample of -200 ⁇ L was collected and stored at -20°C in polypropylene 96-well plates.
  • EIA enzyme immunoassay
  • the data in Table 3 show that at the 2 mg/kg dose there was significant COX-2 inhibition at all timepoints. At 3- and 6-hours post-dose, there is observed to have been a slight decline in COX-2 inhibition compared to the data obtained for the 10 mg/kg dose. The data in Table 3 also show that at the 2 mg/kg dose there was no significant inhibition of C ⁇ X-1 activity at any of the timepoints involved. This result was consistent with the observed excellent toleration of carprofen by the dogs in the study.
  • the data for the 10 mg/kg dose show that there was complete inhibition of COX-2 activity at every timepoint, and very strong inhibition of COX-1 activity beginning at 1 hr and plateauing over the 3- to 6- hour timepoints. Accordingly, the data in Table 3 clearly demonstrate that at a 2 mg/kg dosage concentration carprofen possesses good COX-2 selectivity. As the dose is increased from 2 to 10 mg/kg, increasing inhibition of COX-1 activity becomes evident.
  • Plasma samples were also assayed for total plasma carprofen concentration using HPLC with a 5 micron, 100x4 6mm Chromtech chiral AGP column and a mobile phase composed of 10 90 v/v 2-propanol 0 1M phosphate buffer pH 6 0, and fluorescence detection (285 nm excitation, 345 nm emission)
  • Plasma samples (0 2 mL) were buffered with 0 05 M citric acid pH 5 1 following the addition of (S)-naproxen as the internal standard, then were extracted with 4 1 v/v diethyl ether dichloromethane
  • the ether layer was separated, then back-extracted with 0 005 M Na 2 C0 3 , after which the organic phase was discarded by aspiration
  • the aqueous phase was buffered with 0 05 M citric acid pH 5 1 , then was again extracted with diethyl ether dichloromethane
  • the ether was then transferred to clean tubes, evaporated under a stream of
  • EXAMPLE 4 Canine in vivo determinations of COX-2 activity inhibition by carprofen in a carrageenan- induced inflammation model
  • This objective of this study was to monitor in vivo COX-2 activity in a subcutaneously implanted chamber during an induced inflammation.
  • the COX-2 enzyme can be detected by western analysis as early as 5 hours after carrageenan treatments (T. Kirchner ef a/., J. Pharmacol. Exp. Then (1997) 282, 1094-1101).
  • COX-1 activity may be simultaneously determined by ex vivo methods as described in Example 2.
  • Six beagle dogs had polyethylene "whiffle" golf balls approximately 4.2 cm in outer diameter surgically implanted under the skin just behind the shoulder blades. They were allowed to recover from the surgery for 1 month before being assigned to experimental groups.
  • the EF sample needed to be purified prior to assay, due to the low amount of PGE 2 found in the in vivo sample. This was accomplished by the use of 4 mL PGE 2 affinity columns (Cayman Chemical). The column was first washed with 10 mL of 0.1 M phosphate buffer then 10 mL water. The EF was then diluted 1 :5 with 0.1 M phosphate buffer and added to the column. The column was washed with 10 mL of the phosphate buffer, then 10 mL of water. Finally, the PGE 2 was removed from the column with 2.5 mL 95% ethanol.
  • Example 3 A study was carried out to obtain data from which to determine useful, preferred, more preferred, and most preferred oral carprofen controlled release dosage forms for use in the present invention.
  • the plasma samples collected from dogs in above-recited Example 3 were also assayed for total plasma carprofen concentration using HPLC with a 5 micron, 100x4.6mm
  • Plasma samples (0.2 mL) were buffered with 0.05 M citric acid pH 5.1 following the addition of (S)-naproxen as the internal standard, then were extracted with 4:1 v/v diethyl ether:dichloromethane. The ether layer was separated, then back-extracted with 0.005 M
  • a useful controlled release dosage form of carprofen in accordance with the present invention is one which maintains a carprofen plasma level greater than 2 ⁇ g/mL for most of the day after a single oral dose at 2 mg/lb.
  • Preferred oral controlled release dosage forms of carprofen in accordance with the present invention are ones which maintain a plasma carprofen concentration greater than 10 ⁇ g/mL for a period of time greater than that for which an immediate release dosage form of carprofen maintains a comparable plasma level, when said immediate release dosage form and controlled release dosage form are administered at the same dose, e.g. 2, 1.8, 1.6, or f.4 mg/lb.
  • preferred 2mg/lb oral controlled release dosage forms of this invention maintain a plasma carprofen concentration greater than 10 ⁇ g/mL for greater than 10.5 hrs.
  • Immediate release carprofen dosage forms containing doses of 1.8, 1.6, and 1.4 mg/lb maintain a plasma carprofen concentration above 10 ⁇ g/mL for 9.5 hrs, 8.5 hrs, and 7.5 hrs, respectively.
  • Preferred 1.8 mg/lb oral controlled release carprofen dosage forms maintain a plasma carprofen concentration above 10 ⁇ g/mL for greater than 9.5 hrs.
  • the threshold durations for 1.6 mg/lb and 1.4 mg/lb doses are 8.5 hrs and 7.5 hrs, respectively.
  • the performance characteristics for preferred oral controlled release carprofen dosage forms at doses higher than 2 mg/lb or less than 1.4 mg/lb can be similarly calculated, assuming linear pharmacokinetics.
  • More preferred oral controlled release carprofen dosage forms are those which maintain a plasma carprofen concentration greater than 10 ⁇ g/mL for a period of time greater than or equal to that observed when an immediate release carprofen dosage form is dosed at any higher dose. These controlled release dosage forms thus maintain at least 80% COX-2 inhibition in canine blood for a period of time longer than that achieved by an immediate release dosage form at a higher dose.
  • Most preferred oral controlled release carprofen dosage forms are those which are able to maintain plasma carprofen levels above approximately 10 ⁇ g/mL for a period of time greater than or equal to the time observed for an immediate release 2 mg/lb carprofen dosage form (10.5 hrs), when said oral controlled release carprofen dosage forms are administered at a dose less than 2 mg/lb.
  • ⁇ release dosage form is taken as the fundamental standard for purposes of this comparison since 2 mg/lb/day is the currently recommended and accepted efficacious oral dose in accordance with the present invention as described herein.
  • controlled release oral dosage form carprofen release rates were calculated which result in canine carprofen plasma concentrations greater than 10 ⁇ g/mL. For ease of computation, these calculated rates were “zero order” rates; thus the computed rates were for controlled release devices which release carprofen at a constant (i.e. zero order) rate. It will be appreciated by those skilled in the art that practical dosage forms release at "zero order” for only a portion of their drug release time, whereafter they release at "first order", or release at "mixed order”.
  • Zero-order release rates resulting in simulated plasma carprofen concentrations above 10 ⁇ g/mL were determined by the method of Zhou and Notari. See Zhou, M. and N. Re, "Methodology for using oral dose pharmacokinetic data to select drugs for prolonged release formulations and validation of the method using simulated data", Biopharm Drug Disp, 1995. 16, 319-331. Average data resulting from the oral administration of 2 mg/lb carprofen to canines in an immediate release formulation were fitted to the equation
  • C (k 0 C, I D n , f )[(e ⁇ s " - 1) / S, - ( ⁇ -** - 1) / S 2 ]
  • ko is the zero-order release rate
  • D ref is the reference dose.
  • T D CR I k 0
  • D CR is the controlled release dose
  • Table 6 shown below demonstrates that oral controlled release carprofen dosage forms (2 mg/lb dose) which release 80% of their incorporated carprofen in a time period ranging from 1.6 to 19.2 hrs have the capacity to give carprofen plasma levels greater than
  • Table 7 shown below demonstrates that oral controlled release carprofen dosage forms (1.8 mg/lb dose) which release 80% of their incorporated carprofen in a time period ranging from 1.6 to 19.2 hrs have the capacity to give carprofen plasma levels greater than
  • Table 8 demonstrates that oral controlled release carprofen dosage forms (1.6 mg/lb dose) which release 80% of their incorporated carprofen in a time period ranging from 1.6 to 19.2 hrs have the capacity to give carprofen plasma levels greater than 10 ⁇ g/mL for greater than 8.5 hrs. Accordingly, these are preferred dosage forms at 1.6 mg/lb.
  • Table 9 demonstrates that oral controlled release carprofen dosage forms (1.4 mg/lb dose) which release 80% of their incorporated carprofen in a time period ranging from 1.6 to 19.2 hrs have the capacity to give carprofen plasma levels greater than 10 ⁇ g/mL for greater than 7.5 hrs. Accordinly, these are preferred dosage forms at 1.4 mg/lb.
  • Controlled release carprofen dosage forms of this invention are particularly useful because they are able to maintain carprofen plasma levels greater than 10 ⁇ g/mL for greater than 10.5 hrs, even when they are administered at doses lower than the preferred efficacious use dose of 2 mg/lb.
  • Table 7 demonstrates that oral controlled release carprofen dosage forms (1.8 mg/lb dose) which release 80% of their incorporated carprofen in a time period ranging from 4.8 to 19.2 hrs have the capacity to give carprofen plasma levels greater than 10 ⁇ g/mL for greater than 10.5 hrs. These are more preferred dosage forms at a dose level of 1.8 mg/lb.
  • Table 8 demonstrates that oral controlled release carprofen dosage forms (1.6 mg/lb dose) which release 80% of their incorporated carprofen in a time period ranging from 4.8 to 19.2 hrs have the capacity to give carprofen plasma levels greater than 10 ⁇ g/mL for greater than 9.5 hrs, i.e., for longer than the duration which a 1.8 mg/lb immediate release dosage form is able to achieve. These are, consequently, more preferred dosage forms at a dose level of 1.6 mg/lb.
  • Table 9 demonstrates that oral controlled release carprofen dosage forms (1.4 mg/lb dose) which release 80% of their incorporated carprofen in a time period of 4.8 to 19.2 hrs have the capacity to give carprofen plasma levels greater than 10 ⁇ g/mL for greater than or equal to 8.5 hrs, i.e., for longer than the duration which a 1.6 mg/lb immediate release dosage form is able to achieve. These are, consequently, more preferred dosage forms at a dose level of 1.4 mg/lb.
  • Most preferred oral controlled release carprofen dosage forms are those which are able to maintain plasma carprofen levels above approximately 10 ⁇ g/mL for a period of time greater than or equal to the time observed for an immediate release 2 mg/lb carprofen dosage form (10.5 hrs), when said oral controlled release carprofen dosage forms are administered at a dose of less than 2 mg/lb.
  • the performance of a 2 mg/lb oral immediate release dosage form is taken as a fundamental standard for purposes of comparison since 2 mg/lb/day is the currently recommended efficacious oral dose in accordance with the present Tnvention.
  • Tables 6-9 are used to define the characteristics of the most preferred oral controlled release dosage forms of the present invention.
  • most preferred oral controlled release carprofen dosage forms are those which release 80% of their incorporated carprofen over the range 6.4 to 19.2 hrs.
  • most preferred oral controlled release carprofen dosage forms are those which release 80% of their incorporated carprofen over approximately 12.8 hrs (10-14 hrs).
  • Carprofen implants are useful for delivery of carprofen over extended time periods, e.g., 3 days, 7 days, 30 days, and so forth. This below-detailed example describes useful and preferred carprofen release rates from implants containing carprofen, and also defines doses associated therewith.
  • the systemic clearance was estimated from the pharmacokinetics observed after oral administration of 2 mg/lb carprofen to dogs, using the equation:
  • AUC where F is the bioavailability (assumed to be 1 for an implant), D is the oral dose, and AUC is the average area under the plasma carprofen concentration vs. time curve, extrapolated to infinity.
  • a clearance of CI 5 mL/hr per lb body weight was obtained.
  • a carprofen release rate R 0 of 50 ⁇ g/lb/hr was calculated, which upon multiplication by 24 hr/day gives a daily input rate of 1.2 mg/lb/day.
  • a total dose of 3.6 mg/lb or 8.4 mg/lb or 36 mg/lb would be required for 3, 7, or 30 day therapy, respectively.
  • the dose and release rate required to maintain a plasma carprofen concentration of 2 ⁇ g/mL are linearly adjusted by multiplication by 0.2.
  • a carprofen release rate of 10 ⁇ g/lb/hr is needed, or 0.24 mg/lb/day.
  • a total dose of 0.72 mg/lb or 1.68 mg/lb or 7.2 mg/lb would be required for 3, 7, or 30 day therapy, respectively.
  • the dose and release rate required to maintain a plasma carprofen concentration of 20 ⁇ g/mL (90% COX-2 inhibition) are linearly adjusted by multiplication by 2.
  • a carprofen release rate of 100 ⁇ g/lb/hr is needed, or 2.4 mg/lb/day.
  • a total dose of 7.2 mg/lb or 16.8 mg/lb or 72 mg/lb would be required for 3, 7, or 30 day therapy, respectively.
  • Useful carprofen implants of the present invention release carprofen into the canine body at a rate of 0.24 mg/lb/day or greater.
  • Preferred carprofen implants of this invention release carprofen into the canine body at a rate of 0.24 to 1.2 mg/lb/day. More preferred carprofen implants of this invention release carprofen into the canine body at a rate of 1.2 to 2.4 mg/lb/day.
  • Useful carprofen implants have a total carprofen dose up to 2 gm, limited by the size of an implant which can be reasonably administered to a dog. Of course, more than one implant may be administered at the same time.
  • COX-2 selectivity activity in members of the species Canis familiaris (dogs) compared to activity in members of the species Rattus norvegicus (white rats) and in Homo sapiens (humans)
  • the " COX-1 inhibitory activity was evaluated in accordance with the effect of racemic carprofen on prostaglandin PGE 2 production as measured in the mucosal lining of the rat stomach, which contains significant amounts of the constitutive COX-1 isozyme. Inhibition of this stomach isozyme results in adverse gastrointestinal side effects.
  • the COX-1 ED 5cl was 6.4 mg/kg, while the COX-2 ED S0 was 0.63 mg/kg.
  • COX-2 inhibitory activity was evaluated in accordance with the effect of racemic carprofen on levels of COX-2 in human umbilical vein endothelial cells (HUVEC) stimulated by IL-1 and phorbol myristate acetate (PMA) in accordance with the method of Habib ef al. described in J. Biol. Chem., 268, 23448-23454, 1993.
  • IL-1 interleukin-1
  • PMA phorbol myristate acetate
  • the COX-1 inhibitory activity was evaluated in accordance with the effect of racemic carprofen on levels of COX-1 as measured by a human washed platelets (HWP) TXB 2 biochemical assay, in accordance with the procedures of Grossman, ef al. described in Inflamm. Res., 44, 253-257, 1995. These platelets are most likely to contain significant amounts of the constitutive COX-1 isozyme.
  • HUVEC (COX-2) IC 50 ( ⁇ M) was 1.20
  • the HWP TXB 2 (COX-1) IC 50 ( ⁇ M) was 0.77.

Abstract

L'invention porte sur des procédés de traitement ou de prévention des inflammations chez les chiens ou des maladies associées à l'activité de cyclo-oxygénase-2 (COX-2) inductive, et simultanément sur la réduction ou l'élimination d'effets secondaires indésirables associés à l'inhibition simultanée de l'activité de cyclo-oxygénase-1 (COX-1) constitutive en sélectionnant sélectivement l'activité de COX-2 en tenant compte de l'activité de COX-1, le rapport de sélectivité ou d'inhibition de l'activité de COX-2 : COX-1 étant au moins de 3 : 1 sur la base des taux d'inhibition ex vivo relevés dans le sang entier; l'inhibiteur est un élément sélectionné dans le groupe des composés anti-inflammatoires constitués principalement des dérives d'acide salicylique, des dérivés de p-aminophénol, d'indole et des acides acétiques d'indène, des acides acétiques d'hétéroaryle, des acides arylproprioniques, des acides anthraniliques, des acides énoliques et des alcanones; l'inhibiteur comprend notamment (+)(S)-énantiomère de l'acide 6-chloro-α-méthyl-9H-carbazole-2-acétique.
EP98915041A 1997-05-05 1998-05-01 Carprofene inhibant selectivement cox-2 et utilise dans le traitement de la douleur et des inflammations chez les chiens Withdrawn EP0988034A1 (fr)

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