FIELD OF THE INVENTION

[0001] The present invention provides methods for treating pain in animals, pharmaceutical formulations useful in those methods, and unit dose forms of those formulations. The invention relates to the fields of biology, chemistry, pharmacology, and veterinary medicine.

DESCRIPTION OF RELATED DISCLOSURES

[0002] Post- operative pain is common after both human and veterinary surgeries. At present, there are very few approved products available to veterinarians to treat and manage post-operative pain compared to those available for their human medical counterparts (Giorgi et al., Am J Animal Vet Sci. 2012;7(4):213-17; US FDA Access Data - Pain).

[0003] Flupirtine, 2-amino-3-ethoxy-carbonylamino-6-4-fluoro-benzylamino- pyridine, is a centrally acting non-opioid, non-NSAID, and non-steroidal analgesic that has been approved for use in people (in Europe) since 1984 (Friedel et al., Drugs. 1993;45(4):548-569; Drug Information Online). Flupirtine's mechanism of action is believed to be as a selective potassium channel opener with NMD A receptor antagonist properties and additional anti- seizure, muscle relaxant and neuroprotective activity (Schuster et al., CNS Drug Reviews. 1998;4(2): 149-64; Kornhuber et al., J Neural Transm. 1999;106:857-67; Harish et al., J Anaesth Clin Pharmacol. 2012;28(2): 172-77). Flupirtine has been used in people for various pain management indications including post-operative pain, trauma, dental extractions, painful muscle spasms, cancer, degenerative joint disease, migraine headaches, and dysmenorrhea (Harish, supra).

[0004] In humans, flupirtine is rapidly absorbed from the gastric mucosa, appearing in the plasma within 15 to 30 minutes and reaching a peak plasma concentration of approximately 800 μg/L at 1.6 to 2 hours after an oral 100 mg dose. Following an oral dose of 100 mg in normal healthy human volunteers, flupirtine reached a peak plasma concentration of 773 μg/L at 1.6 hours (Harish, supra). Moreover, at this dose, the T _½ was 6.5 hours. The oral bioavailability of flupirtine is 90%, and steady-state plasma concentrations are attained within 2 days. Flupirtine is more than 80% reversibly bound to human albumin in vitro. It is equally distributed in the extra and intravascular compartments (Devulder, CNS Drugs. 2010;24(10):867- 81; Friedel, supra, Harish, supra). Flupirtine also maintains cellular glutathione levels (Giorgi, supra). Unlike opioids, tolerance to flupirtine does not appear to develop with sustained use, and it is free of psychological effects (Friedel, supra).

[0005] The potential use of flupirtine as a veterinary pain management drug in dogs has been discussed in literature where it was assessed to have promise as a potential antinociceptive agent for animals, based on its known efficacy in people (Giorgi, supra). Although there are few studies published using flupirtine in dogs, it has been demonstrated that its antinociceptive activity is mediated via non-opioid supraspinal mechanisms, and its activity is not antagonized by high doses of naltrexone (Vaupel, Eur J Pharmacol. 1989;162:447-56). In an exploratory pharmacodynamic study, flupirtine appeared to relieve associated discomfort with median effective doses (ED ₅₀ ) of 3.5 mg/kg and 0.7 mg/kg when dosed orally and intravenously, respectively (Nickel, 1987, Postgraduate Medical Journal 87(63): 19- 28; the study was not powered to demonstrate clinical significance).

[0006] Veterinarians perform millions of dog surgeries each year, and there is no established protocol for the use of pain medications following these surgeries. The only drugs approved for treatment of post-operative pain in dogs are NSAIDs and fentanyl. NSAIDs are generally less effective than opioids in controlling pain and have other well documented side effects. Fentanyl is a controlled narcotic drug that can cause significant sedation, and pets must often be kept in the hospital while receiving fentanyl. There remains a need for new drugs to treat pain in animals, particularly post-operative pain, that are superior to NSAIDS and comparable to opioids, without sedation, the potential for opioid addiction, or the risk of possible diversion and abuse by pet owners.

[0007] The present invention meets this need.

SUMMARY OF THE INVENTION

[0008] In a first aspect, the present invention provides pharmaceutical formulations for the treatment of pain and/or seizures in non-human mammals, including but not limited to cats, dogs, and horses. In a first embodiment, the pharmaceutical formulation comprises a therapeutically effective dose of flupirtine or pharmaceutically acceptable flupirtine salt, including but not limited to flupirtine maleate, and, optionally, a flavoring. [0009] In a second aspect, the invention provides unit dose forms of flupirtine maleate (or other suitable salt) formulated for treatment of pain in dogs. The unit dose forms provided include those with 50, 100, and 200 mg of flupirtine maleate (all amounts and references to "flupirtine" are intended to refer to the maleate salt and molar equivalent amounts of any other pharmaceutically acceptable flupirtine salt and flupirtine), which are suitable for administering the therapeutically effective dose in the range of 5 to 20 mg/kg, including doses in the ranges of 5 to 15 mg/kg and 7 to 12 mg/kg, and specific doses of about 5, 7, and 10 mg/kg. In one embodiment, the unit dose form is an extended release form that is dosed twice a day to treat pain. In another embodiment, the unit dose is an extended release form that is dosed once a day to treat pain. In another embodiment, the unit dose form is an immediate release form that is dosed once or twice a day to treat pain. In one embodiment, the flupirtine is formulated as a particle or granule with other excipients and administered in a capsule. In another embodiment, the flupirtine is formulated as a particle or granule with other excipients and compressed into a tablet, which may be scored to facilitate cleavage into halves or fourths.

[0010] In other embodiments, the invention provides unit dose forms of flupirtine maleate (or other suitable salt) in a flavored, chewable or "crunchable" form suitable for administration to a dog, cat, or horse. In various non-limiting embodiments, the flavoring is beef flavoring, chicken flavoring, fish flavoring, apple flavoring, cinnamon flavoring, malt flavoring, and peanut flavoring, as well as any one or more of suitable sweeteners or sugars.

[0011] In other embodiments, the pharmaceutical formulation is a paste or gel, including but not limited to a gel, ointment, or paste that may be applied to the paw or pelt of an animal for oral consumption by the animal through licking, particularly in the case of a dog or a cat. In some embodiments the paste or gel formulation is directly smeared on the gums, lips, and/or teeth of a horse. For these embodiments, the paste, ointment, or gel formulation is administered in a volume configured to deliver 5 to 20 mg/kg of flupirtine maleate to the animal, i.e., the same ranges and amounts described above for the tablet and capsule unit dose forms. Typical concentrations of flupirtine in these oil, gel, and ointment formulations include those containing 50 mg/mL, 100 mg/mL, and 200 mg/mL of flupirtine maleate. [0012] In some embodiments, the paste or gel formulation may be administered directly to the animal by squeezing the formulation into the animal's mouth. In these embodiments, the unit dose form may be administered via an applicator comprising a tube container , a roll-on applicator, or a syringe-type (barrel and plunger type dispenser) container, wherein the pharmaceutical formulation is contained therein. In some instances, the applicator comprises a single dose of the pharmaceutical formulation in a volume configured to deliver 5 to 20 mg/kg of flupirtine maleate to the animal. In some instances, the applicator comprises a multi- dose container configured to administer two or more doses of the pharmaceutical formulation to the animal, wherein each dose comprises a volume configured to deliver 5 to 20 mg/kg of flupirtine maleate to the animal, optionally using formulations having a concentration of flupirtine maleate of 50 to 200 mg/mL.

[0013] Thus, the unit dose forms of the pharmaceutical formulations of the invention may take any of a number of embodiments. In one embodiment, the unit dose form is a tablet, a sachet or packet containing granules of a pharmaceutical formulation of the invention, or a capsule containing a therapeutically effective amount of flupirtine and one or more pharmaceutically acceptable excipients. In one embodiment, the unit dose form is a tablet; in various embodiments, the tablet contains 50, 100, or 200 mg of flupirtine maleate and one or more pharmaceutically acceptable excipients. In various embodiments, the unit dose forms contain 50, 100, and 200 mg of flupirtine maleate (or equivalent salt of flupirtine) and one or more pharmaceutically acceptable excipients. In any of these tablet embodiments, the tablet may be scored to facilitate breaking it into two equal halves or four quarters, and the formulation employed may optionally include a flavoring.

[0014] In one exemplary embodiment, the present invention provides a pharmaceutical formulation in the form of flupirtine maleate granules, a blend of such granules and one or more pharmaceutically acceptable excipients, and unit dose forms thereof in the form of tablets or capsules, as described in Example 1.

[0015] In a third aspect, the present invention provides a method of treating pain in an animal, particularly a non-human mammal, the method comprising administering a therapeutically effective dose of flupirtine to an animal in need of treatment for pain. In one embodiment, the animal is a dog, and the pain to be treated is post-operative pain, i.e., the pain from an operation or surgical procedure, including but not limited to dental surgery. In one embodiment, the animal is a cat, and the pain to be treated is post-operative pain. In one embodiment, the animal is a horse, and the pain to be treated is post-operative pain. The surgery includes but is not limited to orthopedic or soft-tissue surgery. In one embodiment, the therapeutically effective dose is between 2.5 mg/kg and 10 mg/kg. In one embodiment, the therapeutically effective dose is between 5 mg/kg and 20 mg/kg. In one embodiment the therapeutically effective dose is 7 mg/kg. In one embodiment the therapeutically effective dose is 5 mg/kg.

[0016] In one embodiment, the therapeutically effective dose is administered orally twice daily (bid administration) or thrice daily (tid administration) in an immediate release formulation. In another embodiment, the therapeutically effective dose is administered orally once daily (qd administration) or twice daily in an extended release formulation. In one embodiment, the therapeutically effective dose is administered by injection, including in a depot or other slow release formulation. In another embodiment, the methods, compositions, and unit dose forms of the invention are used to treat pain caused by osteoarthritis (OA), a chronic degenerative joint disease of dogs, cats, and horses, and the therapeutically effective dose of flupirtine is administered for prolonged periods (daily consecutive administration for at least one to several weeks or even one to several months or longer). In various embodiments, a pharmaceutical formulation or unit dose form of the invention is co-administered with one or more other agents, including but not limited to a non-steroidal antiinflammatory drug (NSAID), fentanyl or another opioid drug, and/or diacerein to treat pain, including but not limited to post-operative pain, and/or to prevent seizures in a non-human animal such as a cat, dog, or horse. In any of these embodiments, the animal may be in a fed or fasted state when the drug is administered.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Veterinarians perform millions of surgeries each year. These include spays and neuters of cats and dogs. Other common non-human animal surgeries include cancer surgery, declawing, cruciate repairs and bone fracture repairs. There is no established protocol for the use of pain medications following these surgeries, and pain management practices have traditionally been based on the veterinarian's views on the level of pain associated with a specific surgical procedure and the perceived pain tolerance of the animal. [0018] In surgeries associated with the most severe post-operative pain, fentanyl is commonly used. Fentanyl is a controlled narcotic drug, and pets are often kept in the hospital while receiving fentanyl. The majority of fentanyl is dispensed as fentanyl patches, although such use in pets has not been approved. In 2012, Nexcyon received FDA approval for a transdermal fentanyl solution in dogs, but its use in this format has not been widely accepted by veterinarians. Fentanyl is associated with significant sedation and respiratory depression, undesirable effects of an analgesic. Thus, there are unmet needs in pets receiving painful surgeries, especially where effective and extended pain relief cannot be achieved with a non-narcotic medicine. NSAIDs approved to treat the pain and inflammation associated with osteoarthritis in dogs also are used for post-operative pain.

[0019] Some drugs used for post-operative pain in dogs have been approved by the FDA, while others are used off-label. The most commonly used post-operative pain medication in dogs is Rimadyl, which has been approved by the FDA for this use. NSAIDs like Rimadyl have demonstrated serious side effects that result in prescribed ongoing monitoring of dog health during their use. For example, some dogs have a sensitivity that results in kidney toxicity and, in extreme cases, death. Consequently, there is a need for a drug for post-operative use that is effective in dogs and other animals, but also safer on the liver, gastrointestinal system and kidneys. The present invention provides a non-narcotic analgesic and so addresses an important unmet medical need and may lead to a new standard in pain control.

[0020] The methods, pharmaceutical formulations, and unit dose forms of the present invention provide pain relief in cats, dogs, horses and other non-human animals that is superior to NSAIDS and comparable to some opioids, without the potential for opioid addiction or the risk of possible diversion and misuse by pet owners.

[0021] Another type of pain occurring in dogs is that caused by osteoarthritis

(OA). OA is a chronic, un-remitting degeneration of one or more joints and is common in dogs, increasing in prevalence with age. Current treatment for OA involves use of NSAIDS, drugs which have potential toxicity to the gastrointestinal tract and the liver. Further, NSAIDS are only modestly efficacious and there is the need to new therapies to treat the pain of OA. The pharmaceutical formulations and unit dose forms of the invention are useful in treating the pain of OA. [0022] The pharmaceutically acceptable formulations of the invention contain therapeutically effective doses of flupirtine, a centrally acting non-opioid, non- NSAID, and non-steroidal analgesic. While any pharmaceutically acceptable form of flupirtine may be used in the pharmaceutical formulations of the invention, in some embodiments amorphous or polymorph forms of flupirtine, flupirtine maleate and flupirtine D-gluconate are used. Suitable non-limiting flupirtine salts, polymorphs and formulations compatible for use in the methods of the invention, as well as unit dose forms are described in European Patent Nos. 160658 and 199951; US Patent Nos. 3,998,834 and 4,481,205; and US Patent Application No. 2008/0279930, each of which is incorporated herein by reference. Unless otherwise stated, a reference to flupirtine herein is not intended to be limited to a particular salt or other form of flupirtine, although flupirtine maleate is a suitable form of flupirtine for all methods, formulations, and unit dose forms of the invention.

[0023] Flupirtine' s mechanism of action is believed to be via selective opening of the potassium channel in cells that makes neurons less susceptible to activation. This results in reduced neuron activity. Flupirtine also exhibits /V-methyl- D-aspartate, or NMDA, receptor antagonist properties and additional muscle relaxant and neuroprotective activity. In some embodiments, the pharmaceutical formulations and unit dose forms of the invention are used for various pain management indications, including post-operative pain, trauma, dental extractions and procedures, painful muscle spasms, cancer pain, osteoarthritis pain, and pain from degenerative joint disease, as well as for the prevention of seizures. In some embodiments, the pharmaceutical formulations and unit dose forms of the invention are used for various non-pain indications.

[0024] In one embodiment, the pharmaceutical formulation of the invention is administered in a unit dose form for the treatment of OA. Treatment of OA in accordance with the invention can involve weeks to months of consecutive daily dosing such that QD administration is highly desirable. One difficulty of achieving extended release PK profiles using oral pharmaceutical preparations in the dog is the very rapid transit time in this species. The time from swallowing to the ileo-cecal junction is about three hours. This leaves little opportunity for a tablet formulation to disintegrate, dissolve, and be absorbed before reaching the colon where drug transport across the gut wall is usually sub-optimal. [0025] The present invention provides pharmaceutical formulations and unit dose forms of flupirtine that enhance retention of drugs in the upper gastrointestinal tract of the dog. In one embodiment, flupirtine is incorporated in a matrix that swells and forms a gel upon contact with the fluid contents of the stomach. In this embodiment, the pharmaceutical formulation comprises an excipient that is a suitable release retardant polymer, including but not limited to Polyox WSR 205, Polyox WSR N12K, and HPMC K4M at 10 to 50%.

[0026] Alternatively, the present invention provides a formulation prepared by a hot melt technique using a plasticized methacrylic acid copolymer, such as Eudragit(®) L100-55. Other formulations with enhanced solubility and increased gastric residence time provided in accordance with the invention include low density formulations that float on the stomach contents, high density formulations wherein the dosage form resides at the ventral aspect of the stomach near the pylorus, bio- adhesive and muco-adhesive systems, expansion systems, super-porous hydrogels, raft-forming systems, and floating ion exchange resins. Low density or floating formulation systems may be effervescent or non-effervescent, the latter consisting of a gel-forming or swellable cellulose hydrocolloid, polysaccharide, or matrix polymers like polycarbonate, polyacrylate, polymethacrylates, or polystyrene.

[0027] Microballoons or hollow microspheres can be loaded with flupirtine to prepare a pharmaceutical formulation and unit dose forms in accordance with the invention by simple solvent evaporation or solvent diffusion methods. Alginate beads or drug-porous reservoirs may be utilized in accordance with the invention. Effervescent low density systems involve the generation of a gas which causes the dosage form to float on the surface of the liquid gastric contents. Effervescent systems may include intragastric single-layer or multi-layer floating tablets, multiple-unit floating tablets, use of an inflatable chamber, or use of a combination of an effervescent system and an osmotic system.

[0028] Bio-adhesive formulations provided by the invention incorporate carbopol, chitosan, polycarbophil, lectin, and other suitable substances to enhance adhesion of the formulation to the stomach wall and lining of the small intestine in accordance with the invention. Raft systems for gastric retention are provided by the invention to increase absorption of flupirtine. [0029] All of the above methods of pharmaceutical formulation are applicable to dosing of dogs with flupirtine to achieve extended release characteristics and once or twice daily dosing for the treatment of OA or other pain, or to prevent seizures.

[0030] In some embodiments, the pharmaceutical formulation of the invention comprises a therapeutically effective dose of flupirtine and a flavoring. In other embodiments, the pharmaceutical formulation does not include a flavoring. In various non-limiting embodiments, the flavoring is selected from beef flavoring, chicken flavoring, fish flavoring, and peanut flavoring. In some embodiments, a formulation is provided comprising a flavoring palatable to a canine. In other embodiments, a formulation is provided comprising a flavoring palatable to a feline. Suitable flavorings include beef, chicken, pork, fish, and turkey flavorings, or any other flavoring used for canine and feline foods. In one embodiment, the flavoring is a preparation comprising one or more of beef liver, chicken liver, pork liver, and turkey liver. Suitable vendors of flavorings include, without limitation, PF Inc., Pet Food Ingredients (see http://www.petfoodingredients.com/index.html) and Pharmachem Laboratories, Inc. In one embodiment, the flavoring is beef flavor. In other embodiments, a formulation is provided comprising a flavoring palatable to a horse (e.g., cinnamon and apple flavorings). In some embodiments, including variations of any of the foregoing embodiments, a formulation is provided which includes a sweetener, such as sugar or a sugar substitute. A formulation may further be provided which includes a fruit or spice flavoring palatable to a targeted animal, such as a horse or a dog.

[0031] Some embodiments of the present invention further comprise one or more excipients that impart a texture that makes the unit dose form of that formulation more palatable (and so easier to administer correctly) for a specific animal type. For example, in some embodiments, the pharmaceutical formulation has a crunchy or crispy texture that is readily consumed by a targeted animal, such as a dog or cat. In some embodiments, the pharmaceutical formulation has a smooth texture that is readily consumed by a targeted animal, such as a cat or horse. In some embodiments, the pharmaceutical formulation has a chewy or fibrous texture that is readily consumed by a targeted animal, such as a dog or cat. In some embodiments, the pharmaceutical formulation has a grain-like texture that is readily consumed by a target animal, such as a horse. In some embodiments, the pharmaceutical formulation has a combination of textures, the formulation has two or more different texture components to achieve a desired overall textural experience for the targeted animal.

[0032] In one embodiment, the pharmaceutical formulation is an immediate release formulation. In another embodiment, the pharmaceutical formulation is an extended release formulation. In any embodiment, the formulation can be as described in Example 1, below. In any embodiment, the formulation can be prepared in a unit dose form containing 50, 100, or 200 mg of flupirtine maleate or an equivalent amount of another flupirtine salt or flupirtine base. In some embodiments, a unit dose of a formulation of the invention is a capsule or tablet, which tablet may be a chewable or non-chewable tablet, or an oral disintegrating tablet or film. In other embodiments, the unit dose form may be a paste, ointment, or gel that is administered externally once or twice (e.g., every 12 hours to 24 hours) per day to the pelt of the animal for the animal to consume by licking. In various embodiments, administration is continued for 2, 3, 5, 7, or more consecutive days, including for one, 2, 3, 4 or more weeks, including for one, 2, 3, or 6 or more months. In any of these embodiments, the treatment may be for pain caused by an operation or surgery, including but not limited to dental surgery, or by OA.

[0033] For all embodiments, the pharmaceutical formulation comprises an effective dose of flupirtine maleate. As used herein, the term "effective dose" is understood to describe a dose or amount of flupirtine maleate that produces a therapeutic response or desired effect in some significant fraction of the animals in need of treatment to which the dose or amount has been administered. Thus, the various pharmaceutical formulations of the instant invention comprises an effective dose of flupirtine maleate that is from about 5 mg/kg to about 20 mg/kg.

[0034] In another embodiment, the pharmaceutical formulation is an extended release formulation that allows for once or twice a day dosing, which can be administered for the same time periods as the immediate release formulation unit dose forms. An illustrative suitable extended release formulation for use in the methods of the invention may have the following dissolution properties. A suitable extended release tablet can be demonstrated via dissolution testing using USP Apparatus II, with a paddle speed of 100 rpm, and the tablets placed into Japanese sinkers. For a dissolution media that is 1000 mL 0.1N HC1 at 37°C, and for samples are taken for analysis at 2, 7 and 12 hours, suitable dissolution characteristics are that 15-35% of the flupirtine is released at 2 hours, 55-75% at 7 hours, and by 12 hours NLT 80% of the flupirtine is released.

[0035] In various embodiments, the pharmaceutical formulation is an oil, paste or gel, including but not limited to a paste or gel or oil that may be applied to the paw of the animal for oral consumption through licking, such as in the case of a cat or a dog. In some embodiments, the paste or gel formulation is directly smeared on the gums, lips, and/or teeth of the animal, such as in the case of a horse. In some embodiments, the paste or gel has a long acting, delayed release, or depot formulation of flupirtine. In some embodiments, the pharmaceutical formulation comprises a transdermal gel that may be applied to the skin of the animal, such as the ear, belly, or skin exposed by shaving.

[0036] The present invention also provides unit dose forms of the pharmaceutical formulations of the invention. In one embodiment, the unit dose form is a tablet or capsule containing a therapeutically effective amount of flupirtine and one or more pharmaceutically acceptable excipients. In one embodiment, the unit dose form is a tablet that contains 50 mg, 100 mg, or 200 mg of flupirtine maleate. In one embodiment, the tablet is scored to facilitate breaking it into two equal halves. In one embodiment, the tablet is scored to facilitate breaking it into four equal quarters. In various embodiments, the tablet is a chewable tablet containing a flavoring that appeals to the type of animal to be treated. The tablet may be coated to impart a more attractive appearance and or to make the table more palatable to the target animal, i.e., to facilitate swallowing, to enhance palatability (including by sweetening or masking the taste of one or more other components of the tablet).

[0037] In one embodiment, the unit dose form contains a pharmaceutical formulation prepared as described in Example 1 and is provided in strengths of 50 mg, 100 mg, and 200 mg.

[0038] The present invention also provides methods of treating pain, relieving anxiety, and/or preventing seizures in an animal, particularly a non-human mammal, with the pharmaceutical formulations and unit dose forms of the invention. In one embodiment, the animal is cat. In one embodiment, the animal is a dog. In one embodiment, the animal is a horse. In one embodiment, the animal is suffering postoperative pain following surgery, including but not limited to orthopedic or soft-tissue surgery. In one embodiment, the animal is at risk of suffering a seizure. In one embodiment, the therapeutically effective dose is between 2.5 mg/kg and 20 mg/kg. In one embodiment, the therapeutically effective dose is between 5 mg/kg and 10 mg/kg. In one embodiment, the therapeutically effective dose is between 7 mg/kg and 12 mg/kg. In one embodiment, the therapeutically effective dose is 10 mg/kg. In one embodiment the therapeutically effective dose is 7 mg/kg. In one embodiment the therapeutically effective dose is 5 mg/kg. In one embodiment, the therapeutically effective dose is administered bid or tid administration in an immediate release formulation. In another embodiment, the therapeutically effective dose is administered orally once or twice daily (referred to as qd administration, although "qd administration" is sometimes referred to as "sid administration" if the subject to be treated is an animal, as contemplated herein) in an extended release formulation.

[0039] In one embodiment, the present invention provides a granulated, pharmaceutical blend of flupirtine that can be administered as an analgesic. A suitable blend is described in Example 1. In some instances, the granulated blend is administered directly to an animal. In some instances, the granulated blend is admixed with a food or other carrier that is then orally administered to the animal.

[0040] In one embodiment, the present invention provides an injectable pharmaceutical formulation of flupirtine that can be administered as an analgesic. The drug may be administered in accordance with the invention by an i.v. catheter during surgery, or at the end of surgery, or at the start of the surgery to break the pain acceleration cycle. In one embodiment, the invention provides a long acting injectable (LAI) formulation of flupirtine that is given subcutaneously before, during, or after the end of a surgery. In one embodiment, this formulation provides one, to several days of pain relief.

[0041] In various embodiments, treatment in accordance with the invention will reduce pain, such as post-operative pain, in dogs as measured using the CBPI (see Example 1) or the Glasgow scoring system.

[0042] In some embodiments, treatment of pain or prevention of seizure is accomplished in accordance with the invention by administering flupirtine as provided above in combination with one or more medications selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID), including but not limited to Rimadyl; and an opioid, including but not limited to fentanyl. Thus, in various embodiments, a pharmaceutical formulation or unit dose form of the invention is co- administered with one or more other agents, including but not limited to a nonsteroidal anti-inflammatory drug (NSAID), fentanyl, any other opioid agent, and/or diacerein to treat pain.

[0043] In one embodiment, treatment in accordance with the invention provides a neuroprotective effect in autoimmune optic neuritis.

[0044] In one embodiment, treatment in accordance with the invention provides improved cognitive function in animals. Cognitive dysfunction is observed, for example and without limitation, in some geriatric dogs. In dogs, the condition is referred to as "Cognitive Dysfunction Syndrome," which has characteristics similar to human Alzheimer's disease.

[0045] In another aspect, the present invention provides methods, pharmaceutical formulations, and unit dose forms equivalent to those described above but in which the flupirtine is replaced with a therapeutically effective amount of retigabine.

[0046] Example 1. Flupirtine Formulations and Unit Dose Forms

[0047] This example describes illustrative extended and immediate-release flupirtine maleate formulations of the invention.

[0048] Flupirtine granules can be prepared by a wet granulation process using flupirtine maleate and the following excipients in the following proportions: flupirtine maleate - 43.84%, mannitol - 31.39%; crospovidone 14.906%; hypromellose 3.288%; citric acid 6.576%; and water. To illustrate, 570.25 mg of flupirtine granules can be prepared from flupirtine maleate - 250 mg, mannitol - 179 mg; crospovidone 85 mg; hypromellose 18.75 mg; citric acid 37.5 mg; and water.

[0049] Suitable tablet unit dose forms of the invention are prepared by blending flupirtine granules prepared as described above with other excipients in the following proportions. For the 50 mg unit dose form, the blend comprises 114.05 mg (57%) of flupirtine granules; 62.5 mg (31.3%) of HPMC 4000 cps (hydroxypropyl methylcellulose 4000 cps); 17.45 mg (8.7%) of mannitol; 2 mg (1%) of colloidal silicon dioxide, 2 mg (1%) of talc, and 2 mg (1%) of magnesium stearate to provide a 200 mg tablet that delivers 50 mg of flupirtine maleate. For the 200 mg unit dose form, the blend comprises 456.20 mg (81.5%) of flupirtine granules; 90 mg (16.1%) of HPMC 4000 cps (hydroxypropylmethyl cellulose); 4 mg (0.7%) of colloidal silicon dioxide, 4 mg (0.7%) of talc, and 5.8 mg (1%) of magnesium stearate to provide a 560 mg tablet that delivers 200 mg of flupirtine maleate.

[0050] For the 100 g unit dose form, flupirtine granules can be prepared from flupirtine maleate - 100 mg, mannitol - 82 mg; crospovidone 85 mg; hypromellose 36 mg; citric acid 15 mg; and water. The blend comprises 233 mg (97.1%) of flupirtine granules; 2.6 mg (1.1%) of colloidal silicon dioxide, 2 mg (0.8%) of talc, and 2.4 mg (1%) of magnesium stearate to provide a 240 mg tablet that delivers 100 mg of flupirtine maleate.

[0051] This process yields unit dose forms having the an extended release profile in two unit dose forms ("strengths"), 50 and 200 mg flupirtine maleate, having the composition shown in Table 1.

[0052] Table 1. Extended-release flupirtine maleate formulas

[0053] The unit dose forms of the formulations described in Table 1 provide

12-hours of extended release of flupirtine maleate, allowing for twice-daily dosing for the management of post-operative pain in dogs. The tablet weight is 200 mg for the 50 mg flupirtine maleate dose and 560 mg for the 200 mg flupirtine maleate dose. The tablets are capsule shaped with approximate dimensions of 10 mm x 6 mm and 17 mm x 7.5 mm for the 50 mg and 200 mg strength tablets, respectively. [0054] The extended-release tablets can be manufactured using the following process: after all ingredients are pre-sieved to remove agglomerated particles, the flupirtine maleate, mannitol, crospovidone, and HPMC 5 cps are mixed in a high shear granulator before citric acid/water solution is introduced during the wet granulation step. The wet granules are wet-massed for one minute before being discharged and wet-milled through a 0.039" mesh screen. The screened wet granules are then dried in a fluid bed dryer, dry-milled through a 0.039" mesh screen, then introduced into a blender with HPMC 4000 cps, mannitol, and colloidal silicon dioxide. The ingredients are mixed for 18 minutes before talc and magnesium stearate are added and the final blend mixed for an additional 9 minutes. The blend is then compressed into tablets on a high speed rotary press. Tablets made generally in accordance with the above procedure were used in the clinical study described in Example 3.

[0055] The formulation described in Table 1 is a controlled release formulation, the composition of which can be altered to provide shorter or longer drug release profiles, as needed, by substituting lower or higher viscosity HPMC, a combination of different grades of HPMC, or by substituting other polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, carboxy methylcellulose, polyethylene oxide, and other equivalent polymers. The extended-release formulations may contain flavoring, be coated with an aesthetic coating, or be coated with a flavored aesthetic coating. The extended-release formulation may be dosed either in the fed or fasted mode.

[0056] For various indications, an immediate release flavored chewable tablet of the invention may be preferred. This chewable tablet can take the form of a soft chew or a "crunchy" chew. For the crunchy chewable tablet, the tablet can be scored to allow the tablet to be easily broken in half or even quarters to allow more flexibility in providing the optimal dose for various sized dogs or other animals. An example of an immediate release tablet formulation of the invention (final unit dose composition) is shown in Table 2 (this tablet may also be made in a chewable formulation).

[0057] Table 2. Immediate Release Formulation

Mannitol 53.75 143.0

Microcrystalline cellulose 29.00 73.0

Hydroxypropyl methylcellulose 5 cps 3.75 15.0

Citric Acid 7.50 30.0

Colloidal Silicon Dioxide 2.00 6.3

Talc 2.00 6.3

Magnesium Stearate 2.00 6.4

Total tablet weight: 150 480

[0058] The above immediate release formulation can be a wet granulation that is then blended with the additional excipients prior to compression. Flupirtine maleate does not flow well by itself, but one can form flupirtine granules, and use the granules with microcrystalline cellulose, to prepare a suitable immediate release formulation of the invention. Immediate release formulations differ from extended release formulations in that they do not contain excipients that convey extended release properties to the formulation, such as HPMC 4000 cps.

[0059] Example 2. Demonstration of Therapeutic Efficacy for the Treatment of Post-Operative Pain in Dogs

[0060] An immediate release formulation of flupirtine in 100 mg tablet form, optionally scored for easy cleavage into halves or quarters, is administered to dogs to treat post-operative pain. All doses are administered approximately every 12 hours (bid) at a dose in the range of 5 to 12 mg/kg. Post-surgery, dogs are dosed without regard to time of feeding or intake of food. One of the adverse events possibly associated with flupirtine is hypothermia. Symptomatic treatment for hypothermia (warming the dog) can be provided in accordance with the invention. In this demonstration, surgery occurs on Day 0. At 0.5, 1, 2, 4, and 8 hours post-surgery on Day 0 dogs are evaluated for pain using the short form of the Glasgow composite pain scale instrument. Dogs are also assessed for pain using the Glasgow scale on Day 1 (24 hours post-surgery) and Day 2 (48 hours post- surgery). Hospital discharge is on Day 2. Completion of the owner's scoring on the CBPI (see below) occurs on Day 7.

[0061] Dogs are at the veterinary clinic on the day of surgery (Day 0) and until discharge (Day 2). After that the dogs will primarily reside with their owners and may be housed indoors or outdoors. Each dog is categorized as a treatment success or a treatment failure based upon the use of rescue medication. Use of rescue medication will be triggered by a Glasgow score of 6 or more at any time post-operatively. Study dogs can continue the treatment with the rescue treatment because flupirtine can give added analgesic effect in combination with other analgesic treatment. The primary comparison is the proportion of treatment successes between active drug group versus the placebo group. Manifestations of reduced pain observed by the veterinarian include less sensitivity to touch around a surgery site, less vocalization, increased interaction with humans, increased spontaneous movement, less tachypnea, and reduced heart rate.

[0062] The dogs that discontinue the study prematurely due to lack of efficacy

(rescue) or an adverse event can be scored as treatment failures for demonstration of monotherapy efficacy. Dogs that discontinue the study prematurely for other reasons are excluded from the primary efficacy analysis.

[0063] Secondary efficacy variables include a comparison between active drug and placebo for the CBPI score at Day 7. At screening and on Day 7 the owner will be provided and will complete the CBPI. The CBPI is a validated pain measurement tool. The owner should use notes from the owner diary. The CBPI scores ten measures of severity of pain/dysfunction by the owner with numerical scores of 0 to 10, 10 being the most extreme pain/dysfunction. It also measures an overall impression of how the dog is doing on a 0 to 4 scale. To reduce inter-person variability the same owner should complete the CBPI. The scoring owner should not have access to previous CBPI scores. The owner must not be aware of the investigator's Glasgow scores or the investigator's impressions when completing the CBPI.

[0064] Between Day 2 and Day 7 owners will maintain a diary provided by the sponsor to record and describe adverse events (AEs), if any, and adherence to the dosing schedule. Missed doses will be recorded. The diary is designed to score these measures 'by exception' so that no entry indicates complete adherence to the protocol, no AEs, etc. At study Day 7 the investigator will review the diary, query the owner about notations of AEs, and answer any of the owner's questions. This process will allow the investigator to note any problems with the patient's participation or the dosing by the owner.

[0065] The primary efficacy endpoint for monotherapy will be whether the dog requires rescue therapy for pain. If rescue treatment is needed, then the patient is scored as a failure, and if no rescue treatment is required then the patient is scored as a success. The number of success versus failures between the drug and the placebo groups is used to determine statically different outcomes. Additionally, the change in score on the Glasgow scoring system from the Day 1 visit to the scores at the final visit for the treatment groups will be compared using ANOVA. The change from Day 1 in score on the Glasgow score and CBPI at the scheduled visits will be compared using t-tests. The change from Day 1 in the severity of individual signs of pain will be compared using the nonparametric rank sum test.

[0066] The efficacy analysis is conducted for dogs in the per-protocol population. The secondary efficacy variable is the CBPI response rate, with a response defined as a composite of a reduction of at least 15 on the CBPI total score, as well as no worsening of the general impression score on the CBPI, from the Day 1 visit to the day 7 visit. The CBPI response rate as binomial distribution will be modelled using a generalized linear mixed model with treatment as a fixed effect and site and site by treatment as random effects. If CBPI is significant at two-sided a=0.025 in favor of the flupirtine dose group as compared to placebo, the study is deemed positive in demonstrating the primary efficacy objective of flupirtine for the control of pain. Patients who drop out prematurely for reasons of AEs or lack of efficacy will be considered non-responders.

[0067] The results of this study should demonstrate that administration of flupirtine is efficacious for the treatment of pain in this animal population.

[0068] Example 3. Double-Blinded Veterinary Study - Post- operative Pain in Dogs

[0069] In a currently ongoing double-blinded study, flupirtine was formulated in accordance with the extended release formulation shown in Example 1 and administered in accordance with the invention to evaluate efficacy for the control of post-operative pain in dogs. As of a recent report date, 47 of 73 dogs had successful outcomes, with "success" defined as an animal not requiring "rescue" analgesic treatment during the course of the 3-day study. In this study, dogs undergoing cruciate ligament surgery were treated with either flupirtine prepared as described above at 10 mg/kg or matching placebo tablet. After surgery, the level of a dog's post-surgical pain was evaluated at a series of pre-determined times using the Glasgow Composite Pain Score Form. If an animal's total evaluated score was at or above a predetermined level, that animal was "rescued" using analgesics at the investigator's discretion. In addition, the evaluating investigator could use discretion and "rescue" any animal that appeared in clear discomfort. Pain Score evaluations continue at pre-determined times until study end (at 3 days). As this study is randomized to be 1: 1 for flupirtine tablet and placebo, there is of course a high likelihood that flupirtine treated dogs are represented among the successful 47/73 outcomes.

[0070] In pre-clinical pharmacokinetic studies, dogs were dosed at 5, 10, and

20 mg/kg flupirtine maleate. In these studies, single doses of 5 - 10 mg/kg corresponded to serum levels that exceeded efficacious serum levels in humans (-770 ug/mL or more). In the ongoing clinical trial, a dose of 10 mg/kg, twice daily appears efficacious based on the number of subjects needing additional "rescue" medication to alleviate post-operative discomfort and based on the statistical assumptions for this 1: 1 placebo controlled study, although confirmation is pending due to it being an ongoing double-blinded study. This information, taken as a whole, demonstrates that a therapeutically efficacious dose in dogs for post-operative pain will be in the 5-12 mg/kg range, when dosed orally with a pharmaceutical formulation of the invention, with the dose titrated to the degree of discomfort or sensitivity to the drug seen in patient's and the clinician's discretion.

[0071] Example 4. Treatment of OA in Dogs

[0072] Osteoarthrits (OA) is a degenerative joint disease affecting dogs. Up to

20 percent of dogs have some degree of OA by one year of age and the prevalence increases thereafter as dogs age. Current therapy for OA is with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) which have proven efficacious for this use in controlled trials. However NSAIDs have long term potential for toxicity including ulceration and perforation of the gastrointestinal tract and liver disease. Tramadol, an opioid analgesic, is sometimes also used but suffers from regulatory requirements governing its use.

[0073] Flupirtine is a non-steroidal, non-NSAID, non-opioid compound with a unique mechanism of action and a good safety profile. To demonstrate that flupirtine formulated in accordance with the invention is efficacious in treating OA in dogs, a canine model of OA can be employed. Eighteen laboratory Beagle dogs that are part of an aged Beagle dog colony are randomized into one of three treatment groups in a blinded, cross-over, three period study with a William's design. Dogs receive per os 5 mg/kg bid fhipirtine, 10 mg/kg bid flupirtine, or placebo on Days 1 to 5 of each cycle. The Canine Brief Pain Inventory (CBPI), a scoring system consisting of a modified CBPI instrument for degree of pain and dysfunction, and a generalized scoring of activity level are completed for each dog at Day 0 and Day 5. Flupirtine at the doses stated reduce the degree of pain and dysfunction as manifested by lower scores at Day 5 compared to baseline. The degree of improvement is sufficiently notable to be demonstrative of clinical significance.

[0074] The study above can be conducted with any unit dose form of the invention. In one embodiment, the invention provides an immediate release formulation consisting of pure flupirtine maleate salt in a gelatin capsule. In one embodiment, twice daily dosing of an immediate release formulation is used to treat OA (typically in a dose from 5 to 20, including 5 to 10 and 7 to 12 kg/mg (bid)), and the treatment is continued daily for at least a week, often at least a month, and sometimes a year or longer. In another embodiment, an extended release formulation that allows for once daily dosing is employed in a method of the invention.

[0075] Example 5. Efficacy and Pharmacokinetics of Flupirtine Maleate and Azapropazone in a Post-operative Analgesic Model in Cats Undergoing Onychectomy

[0076] This examples describes a blinded, placebo controlled, laboratory study of flupirtine and azapropazone to control the pain associated with onychectomy. 20 female cats are randomized to 4 groups (placebo, 5 mg/kg flupirtine, 15 mg/kg flupirtine, 20mg/kg azapropazone). Cats are administered study drugs 1 hour prior to surgery and twice daily (placebo, flupirtine) or once daily (azapropazone) for three days post-operatively. Pain assessments are conducted, with the primary effectiveness variable is the need for rescue as determined by the assessor. Clinical observations are conducted to monitor for adverse events. Once rescue is required a plasma sample is collected, the cat is treated with an appropriate analgesic, and the cat will be removed from the study. Following a minimum of a one week washout a single dose pk study will be conducted on the cats to correlate effectiveness results with plasma levels. The study is expected to demonstrate that flupirtine is as efficacious as azaproprazone to control pain in this indication and so suitable to control other pain indications in the cat when dosed in a range of 5 to 12 mg/kg.