Use of (s)-3-amino-4-(difluoromethylenyl) cyclopent-1-ENE-1-carboxylic acid in the treatment of pain

Abstract

Methods and compositions for treating pain are provided which include administering an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In embodiments, compositions for treating pain which include (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, are administered to a subject in need thereof.

Description

[0001] USE OF (S)-3-AMINO-4-(DIFLUOROMETHYLENYL) CYCLOPENT- 1-ENE-l- CARBOXYLIC ACID IN THE TREATMENT OF PAIN

[0002] CROSS REFERENCE TO RELATED APPLICATION

[0003] [1] This application claims benefit of and priority to the U.S. Provisional Application No. 63 / 719,193, filed on November 12, 2024, which is incorporated herein by reference in its entirety.

[0004] TECHNICAL FIELD

[0005] [2] Treatment of pain with (S)-3-amino-4-(difhioromethylenyl) cyclopent- 1-ene-l -carboxylic acid or pharmaceutically acceptable salt thereof.

[0006] BACKGROUND

[0007] [3] Pain is one of the most common complaints by patients in medical treatment. Pain can be categorized as acute, subacute and chronic pain. See, e.g., Banerjee S, Argaez C.

[0008] Multidisciplinary Treatment Programs for Patients with Acute or Subacute Pain: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines [Internet], Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019 May 7. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK546002. Acute pain may be defined as pain that restricts daily activities and duration of about one month or less. Subacute pain may be defined as pain that presents for about one to about three months. Chronic pain may be defined as pain that presents for more than about three months. There can be some overlap between the foregoing time frames.

[0009] [4] Acute pain is typically caused by a sudden event and is of limited duration. It can be caused by physical trauma and / or inflammation, e.g., broken bones, sprains, surgical procedures, bums, infections (viral or bacterial), dental procedures, and sudden illness such as appendicitis or flare-ups of conditions such as diverticulitis and inflammatory bowel syndrome, to name a few. Subacute pain results from the same causes as acute pain, but as stated above is longer lasting than acute pain. Chronic pain is long lasting pain and can last for months or years. Chronic pain can be caused, e.g., by neuropathy, arthritis, migraine headaches, cancer, inflammation, autoimmune diseases, compression conditions such as impingement of nerves, impingement of tendons and / or ligaments, and fibromyalgia, to name a few. Acute pain can transition into subacute pain and then chronic pain if the source of the pain is left untreated, e.g., untreated inflammation can become chronic inflammation.

[0010] [5] Pain can be debilitating and may result in depression, anxiety, loss of appetite, immobility and fatigue. Effective pain management is a complex process, especially when the pain is chronic. Treatment of pain typically involves, e.g., medications, physical therapy, transcutaneous electrical nerve stimulation (TENS), acupuncture and / or mind control techniques. Analgesics such as opioids and nonsteroidal anti-inflammatories, while generally effective, have been associated with serious side effects. Opioids are addictive and subject to abuse and can cause respiratory depression, miosis, drowsiness, nausea, vomiting and constipation.

[0011] Nonsteroidal anti-inflammatories can cause stomach ulcers, kidney disease, hearing loss and tinnitus. Acetaminophen can cause liver damage.

[0012] [6] Pain can be divided by the presumed pathophysiology into somatic, visceral, and neuropathic (also called deafferentation) pain. See, e.g., Cole, Pain Management, Hospital Physician, June 2002, pp.23-30 (“Cole”). As stated in Cole, these subgroups focus on the site of nociception or potential tissue-damaging event. Somatic pain is generally peripheral, visceral pain is usually intra-abdominal, and neuropathic pain typically involves afferent neural pathways. The pain that results from somatic processes is well localized, constant, aching, or gnawing in character. Somatic pain can result from a variety of causes, e.g., fracture, incisional injury, thermal injury and traumatic injury. In contrast, visceral pain is poorly localized but is constant and aching in character and is referred to cutaneous sites. Visceral pain can result from a variety of causes, e.g., bowel obstruction, constipation, endometriosis and metastatic organ involvement. Myofascial pain (i.e., pain arising from muscle and connective tissue) accounts for a considerable amount of chronic non-cancer-related pain.

[0013] [7] Neuropathic pain is defined by the International Association for the Study of Pain (IASP) as pain caused by a lesion or disease of the somatosensory system. Somatosensory nerves are present in the skin, muscles, joints and fascia and include thermoreceptors, mechanoreceptors, chemoreceptors, pruriceptors and nociceptors that send signals to the spinal cord and the brain. Neuropathic pain can begin when nerves are damaged and do not function normally, causing abnormal patterns of electrical activity in nerve cells. These irregular signals can be perceived as pain, even if there is no painful stimulus. Neuropathic pain can result from peripheral neuropathy or central neuropathy. Peripheral neuropathy results from damage to the nerves outside of the brain and spinal cord (peripheral nerves) and can affect motor, sensory, and / or autonomic systems. Central neuropathy can result from any type of injury to the central nervous system (CNS) including vascular (ischemic or hemorrhagic), infectious (abscess, encephalitis, myelitis), demyelinating, traumatic (brain or spinal cord), or neoplastic disorders. Symptoms of neuropathic pain can include intense pain, burning pain, numbness of extremity ends, dysesthesias, sensory ataxia, muscle force reduction and allodynia such as cold allodynia and mechanical allodynia.

[0014] [8] Neuropathic pain may be caused by disease, such as diabetes or autoimmune conditions such as multiple sclerosis or lupus; by injury, such as stroke, a herniated disk in the spine, amputation, e.g., phantom limb; by spinal disorders such as stenosis; by infection, such as herpes (herpetic or post-herpetic), shingles or HIV; from chemical exposure to toxic compounds; or as a side effect from drugs associated with, e.g., chemotherapy, alcohol. Pharmacological treatments for neuropathic pain include certain antidepressants such as tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors and anticonvulsants such as carbamazepine, gabapentin and pregabalin. Opioids, while generally effective against pain, are not considered to be first line treatments for neuropathic pain due to their potential for side effects.

[0015] [9] Vigabatrin is a gamma aminobutyric acid aminotransferase (GABA-AT) inhibitor that has been used to treat treatment resistant epilepsy and infantile spasms. Vigabatrin has been associated with some potentially serious side effects. Its use has been limited due to potential retinal toxicity and subsequent visual field defects. (lS,3S)-3-amino+ difluoromethylenyl-1-cyclopentanoic acid (also known as CPP-115) is a GABA-AT inhibitor which is 186 times more efficient in inactivating GABA-AT than vigabatrin. Preclinical data for CPP-115 has been reported to show that significantly lower drug dosages afford comparable pharmacokinetics, improved tolerability, and a more favorable toxicity profile when compared with vigabatrin. See. Prescot et aL, Neuropsychopharmacology (2018) 43, 646-654. See also, US Patent No.

[0016] 9,993,449, incorporated herein by reference. (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-1 -carboxylic acid (also known as OV329) is a GABA-AT inhibitor that has been shown to be 9.8 times more efficient as an inactivator of GABA-AT than CPP-115. Id.

[0017]

[0010] There exists a need for additional treatments for pain that expand the clinical toolset. SUMMARY

[0018] [U] Methods and compositions for treating pain are provided. In embodiments, methods for treating pain include administering an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In embodiments, compositions for treating pain which include (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid, or a pharmaceutically acceptable salt thereof, are administered to a subject in need thereof. In embodiments, the pain is acute pain. In embodiments, the pain is subacute pain. In embodiments, the pain is chronic pain. In embodiments, the pain is somatic pain. In embodiments, the pain is visceral pain. In embodiments, the pain is neuropathic pain. In embodiments, the pain is associated with physical trauma. In embodiments, the pain is associated with inflammation. In embodiments, the pain is associated with a compression condition. In embodiments, the pain is associated with a surgical procedure. In embodiments, the pain is associated with an infection. In embodiments, the pain is associated with arthritis. In embodiments, the pain is associated with migraine headaches. In embodiments, the pain is associated with cancer. In embodiments, the pain is associated with an autoimmune disease. In embodiments, the pain is associated with a spinal disorder. In embodiments, the pain is associated with a sudden illness. In embodiments, the pain is associated with exposure to toxic compounds. In embodiments, the pain is associated with a substance use disorder. In embodiments, the pain is associated with fibromyalgia. In embodiments, an effective amount of (Sj-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid, or a pharmaceutically acceptable salt thereof, is between about 0.01 mg to about 750 mg. In embodiments, an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-1 -carboxylic acid, or a pharmaceutically acceptable salt thereof, is between about 25 mg to about 125 mg. In embodiments, an effective amount of (5)-3-amino-4-(difluoromethylenyl) cyclopent- 1-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered to a subject once or twice daily.

[0019] DETAILED DESCRIPTION

[0020]

[0012] Methods and compositions for treating pain are provided. In accordance with the present disclosure methods and compositions for treating pain are provided that promote pain relief without unwanted side effects associated with certain commonly used analgesics such as addiction, somnolescence and ataxia. Tn embodiments, methods for treating pain include administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (OV329), or a pharmaceutically acceptable salt thereof. In embodiments, pharmaceutical compositions including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, are administered to a subject experiencing pain to treat the pain. In embodiments, administration of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject in pain diminishes the pain. In embodiments, administration of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject in pain eliminates the pain. In embodiments. (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered to a subject prophylactically to prevent pain.

[0021]

[0013] The term "pain" includes all forms and intensities of pain, including but not limited to acute pain, subacute pain, chronic pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, nociceptive pain, pathological pain and perioperative pain including pre-surgical pain, surgical pain and post-surgical pain. For example: in embodiments, the pain is acute pain; in embodiments, the pain is subacute pain; in embodiments, the pain is associated with physical trauma; in embodiments, the pain is associated with a perioperative procedure; in embodiments, the pain is associated with inflammation; in embodiments, the pain is associated with a compression condition; in embodiments, the pain is associated with arthritis (rheumatoid or osteoarthritis); in embodiments the pain is associated with migraine headaches; in embodiments, the pain is associated with cancer; in embodiments, the pain is associated with infection; e.g., bacterial or viral, e.g., herpes (herpetic or post-herpetic), shingles, Epstein-Barr, or HIV; in embodiments, the pain is associated with an autoimmune disease, e.g., multiple sclerosis, lupus, psoriasis, eczema or Graves’ disease; myasthenia gravis, diabetes and celiac disease; in embodiments, the pain is associated with a spinal cord disorder such as stenosis or degenerative disc disease; and in embodiments, the pain is associated with fibromyalgia. In embodiments, neuropathic pain is characterized by one or more symptoms including intense pain, burning pain, numbness of extremity ends, sensory ataxia, muscle force reduction, paresthesia, dysesthesia, hypoesthesia, hyperesthesia, hypoalgesia, hyperalgesia, mechanical allodynia and / or thermal allodynia. Tn embodiments, the neuropathic pain is associated with diabetic neuropathy. In embodiments, the neuropathic pain is associated with drug abuse. In embodiments, the neuropathic pain is associated with alcoholism. In embodiments, pain is associated with a broken bone, a sprain, a surgical procedure, a dental procedure, or sudden illness such as appendicitis or flare-ups of conditions such as diverticulitis and inflammatory bowel syndrome. In embodiments, the pain is associated with a compression condition such as impingement of nerves, impingement of tendons and / or ligaments. In embodiments, the pain is associated with fibromyalgia. In embodiments, the pain is associated with a thermal injury, e.g., bum or frostbite. In embodiments, the pain is psychosomatic. In embodiments, the pain is associated with an amputation, e.g., phantom limb pain. In embodiments, the pain is associated with chemical exposure to toxic compounds.

[0022]

[0014] The structure of (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid may be represented as follows:

[0023]

[0024]

[0015] In embodiments, (S)-3-amino-4-(difluoromethylenyl)cy cl opent- 1-ene-l -carboxylic acid may be provided as an acid addition salt, a zwitter ion hydrate, zwitter ion anhydrate, hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate. Acid addition salts, include but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethane-disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, pantothenic, p-amino-benzoic, glutamic, benzene sulfonic or theophylline acetic acid addition salts, as well as the 8-halotheophyllines, for example 8-bromo-theophylline. In embodiments, inorganic acid addition salts, including but not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric or nitric acid addition salts may be used.

[0025]

[0016] An effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid, or a pharmaceutically acceptable salt thereof, for treatment of pain herein is surprisingly devoid of or exhibits less unwanted side-effects that are normally associated with GABA-AT inhibitors such as vigabatrin, e.g., reduced motor coordination. In addition, an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid, or a pharmaceutically acceptable salt thereof, for treatment of pain is surprisingly more effective than morphine. Moreover, (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene-l -carboxylic acid ,or a pharmaceutically acceptable salt thereof, has a low addictive potential and therefore, low potential for abuse.

[0026]

[0017] Without wishing to be bound by any particular theory, as a main inhibitory neurotransmitter, GABA is widely expressed in interneurons of the spinal cord and in the brain. Inhibitory interneurons have various functions and reduction of inhibitory GABAergic neuro transmission can cause disinhibition of excitatory transmission which contributes to sensory hypersensitivity and spontaneous pain. Since (S)-3-amino-4-(difluoromethylenyl) cyclopent- 1-ene-l -carboxylic acid, or pharmaceutically acceptable salt thereof, is a GABA-AT inhibitor, it results in an increase in physiologic GABA levels, an increase in tonic inhibition and consequent relief from pain. In addition, GABA has anti-inflammatory activity which also assists in alleviation of pain

[0027]

[0018] In embodiments, the terms "effective amount" or “therapeutically effective amount” may be used interchangeably and refer to an amount of a compound, material, composition, medicament, or other material that is effective to achieve reduction, elimination or prophylaxis of pain with a minimum of side effects normally associated with analgesics or other GABA-AT inhibitors. In embodiments, an “effective amount” herein ranges from about 20 mg to about 125 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid, or a pharmaceutically acceptable salt thereof, given once or twice a day. For example, a pharmaceutical composition including an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, may contain from about 1 mg to about 10 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, or about 120 mg to about 125 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof. In embodiments a pharmaceutical composition containing an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof includes 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, or 125 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof. Amounts below about 20 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene- 1-carboxylic acid or a pharmaceutically acceptable salt thereof are less effective at relieving or eliminating pain than amounts in the effective range. Amounts above about 125 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof may exhibit increased side effects than amounts in the effective range.

[0028]

[0019] In embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene- 1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject at about about 1 mg / per day, 2 mg / per day, 3 mg / per day, 4 mg / per day, 5 mg / per day, 6 mg / per day, 7 mg / per day, 8 mg / per day, 9 mg / per day, 10 mg / per day, 11 mg / per day, 12 mg / per day, 13 mg / per day, 14 mg / per day, 15 mg / per day. 16 mg / per day, 17 mg / per day, 18 mg / per day, 19 mg / per day, 20 mg / per day, 21 mg / per day, 22 mg / per day, 23 mg / per day, 24 mg / per day, 25 mg / per day, 30 mg / per day, 35 mg / per day, 40 mg / per day, 45 mg / per day, 50 mg / per day, 60 mg / per day, 65 mg / per day, 70 mg / per day, 75 mg / per day, 80 mg / per day, 85 mg / per day, 90 mg / per day, 95 mg / per day, 100 mg / per day, 105 mg / per day, 110 mg / per day, 115 mg / per day, 120 mg / per day, 125 mg / per day, 130 mg / per day. 135 mg / per day, 140 mg / per day, 145 mg / per day, 150 mg / per day, 155 mg / per day, 160 mg / per day, 165 mg / per day, 170 mg / per day, 175 mg / per day, 180 mg / per day, 185 mg / per day, 190 mg / per day, 195 mg / per day, 200 mg / per day, 205 mg / per day, 210 mg / per day, 215 mg / per day, 220 mg / per day, 225 mg / per day, 230 mg / per day, 235 mg / per day. 240 mg / per day, 245 mg / per day, or 250 mg / per day, in one or more doses. In embodiments, the subject may be started at a low dose and the dosage is escalated over time.

[0029]

[0020] In embodiments, an “effective amount” herein can range from about 0.01 mg to about 750 mg of (S)-3-amino-4-(difLuoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof given from one to four times or more a day. For example, a pharmaceutical composition including an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof may contain from about 0.01 mg to about 0.1 mg, about 0.1 mg to about 1 mg, 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg, about 140 mg to about 145 mg, about 145 mg to about 150, about 150 mg to about 155 mg, about 155 mg to about 160 mg, about 160 mg to about 165 mg, about 165 mg to about 170 mg, about 170 mg to about 175 mg, about 175 mg to about 180 mg, about 180 mg to about 185 mg, about 185 mg to about 190 mg, about 190 mg to about 195 mg, about 195 mg to about 200 mg, about 200 mg to about 205 mg, about 205 mg to about 210 mg, about 210 mg to about 215 mg, about 215 mg to about 220 mg, about 220 mg to about 225 mg, about 225 mg to about 230 mg, about 230 mg to about 235 mg, about 235 mg to about 240 mg, about 240 mg to about 245 mg, about 245 mg to about 250, about 250 mg to about 255 mg, about 255 mg to about 260 mg, about 260 mg to about 265 mg, about 265 mg to about 270 mg, about 270 mg to about 275 mg, about 275 mg to about 280 mg, about 280 mg to about 285 mg, about 285 mg to about 290 mg, about 290 mg to about 295 mg, about 295 mg to about 300 mg, about 300 mg to about 305 mg, about 305 mg to about 310 mg, about 310 mg to about 315 mg, about 315 mg to about 320 mg, about 320 mg to about 325 mg, about 325 mg to about 330 mg, 330 mg to about 335 mg, about 335 mg to about 340 mg, about 340 mg to about 345 mg, about 345 mg to about 350, about 350 mg to about 355 mg, about 355 mg to about 360 mg, about 360 mg to about 365 mg, about 365 mg to about 370 mg, about 370 mg to about 375 mg, about 375 mg to about 380 mg, about 380 mg to about 385 mg, about 385 mg to about 390 mg, about 390 mg to about 395 mg, about 395 mg to about 400 mg, about 400 mg to about 405 mg, about 405 mg to about 410 mg, about 410 mg to about 415 mg, about 415 mg to about 420 mg, about 420 mg to about 425 mg, about 425 mg to about 430 mg, about 430 mg to about 435 mg, about 435 mg to about 440 mg, about 440 mg to about 445 mg, about 445 mg to about 450, about 450 mg to about 455 mg, about 455 mg to about 460 mg, about 460 mg to about 465 mg, about 465 mg to about 470 mg, about 470 mg to about 475 mg, about 475 mg to about 480 mg, about 480 mg to about 485 mg, about 485 mg to about 490 mg, about 490 mg to about 495 mg, or about 495 mg to about 500 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof.

[0030]

[0021] In embodiments, a pharmaceutical composition containing an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof includes 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 211 mg, 212 mg, 213 mg, 214 mg, 215 mg, 216 mg, 217 mg, 218 mg, 219 mg, 220 mg, 221 mg, 222 mg, 223 mg, 224 mg, 225 mg, 226 mg, 227 mg, 228 mg, 229 mg, 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235 mg, 236 mg, 237 mg, 238 mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 251mg, 252 mg, 253 mg, 254 mg, 255 mg, 256 mg, 257 mg, 258 mg, 259 mg, 260 mg, 261 mg, 262 mg, 263 mg, 264 mg, 265 mg, 266 mg, 267 mg, 268 mg, 269 mg, 270 mg, 271 mg, 272 mg, 273 mg, 274 mg, 275 mg, 276 mg, 277 mg, 278 mg, 279 mg, 280 mg, 281 mg, 282 mg, 283 mg, 284 mg, 285 mg, 286 mg, 287 mg, 288 mg, 289 mg, 290 mg, 291 mg, 292mg, 293 mg, 294 mg, 295 mg, 296 mg, 297 mg, 298 mg, 299 mg, 300 mg, 301 mg, 302 mg, 303 mg, 304 mg, 305 mg, 306 mg, 307 mg308 mg, 309 mg, 310 mg, 311 mg, 312 mg, 313 mg, 314 mg, 315 mg, 316 mg, 317 mg, 318 mg, 319 mg, 320 mg, 321 mg, 322 mg, 323 mg, 324 mg, 325 mg, 326 mg, ' 1 mg, 328 mg, 329 mg, 230 mg, 331 mg, 332 mg, 333 mg, 334 mg, 335 mg, 336 mg, 337 mg, 338 mg, 339 mg, 340 mg, 241 mg, 342 mg, 343 mg, 344 mg, 345 mg, 346 mg, 347 mg, 348 mg, 349 mg, 350 mg, 351mg, 352 mg, 353 mg, 354 mg, 355 mg, 356 mg, 357 mg, 358 mg, 359 mg, 360 mg, 361 mg, 362 mg, 363 mg, 364 mg, 365 mg, 366 mg, 367 mg, 368 mg, 369 mg, 370 mg, 371 mg, 372 mg, 373 mg, 374 mg, 375 mg, 376 mg, 377 mg, 378 mg, 379 mg, 380 mg, 381 mg, 382 mg, 383 mg, 384 mg, 385 mg, 386 mg, 387 mg, 388 mg, 389 mg, 390 mg, 391 mg, 392mg, 393 mg, 394 mg, 395 mg, 396 mg, 397 mg, 398 mg, 399 mg, 400 mg, 401 mg, 402 mg, 403 mg, 404 mg, 405 mg, 406 mg, 407 mg, 408 mg, 409 mg, 410 mg, 411 mg, 412 mg, 413 mg, 414 mg, 415 mg, 416 mg, 417 mg, 418 mg, 419 mg, 420 mg, 421 mg, 422 mg, 423 mg, 424 mg, 425 mg, 426 mg, 427 mg, 428 mg, 429 mg, 430 mg, 431 mg, 432 mg, 433 mg, 434 mg, 435 mg, 436 mg, 237 mg, 438 mg, 439 mg, 440 mg, 441 mg, 442 mg, 443 mg, 444 mg, 445 mg, 446 mg, 447 mg, 448 mg, 449 mg, 450 mg, 451 mg, 452 mg, 453 mg, 454 mg, 455 mg, 456 mg, 457 mg, 458 mg, 459 mg, 460 mg, 461 mg, 462 mg, 463 mg, 464 mg, 465 mg, 466 mg, 467 mg, 468 mg, 469 mg, 470 mg, 471 mg, 472 mg, 473 mg, 474 mg, 475 mg, 476 mg, 477 mg, 478 mg, 479 mg, 480 mg, 481 mg, 482 mg, 483 mg, 484 mg, 485 mg, 486 mg, 487 mg, 488 mg, 489 mg, 490 mg, 491 mg, 492mg, 493 mg, 494 mg, 495 mg, 496 mg, 497 mg, 498 mg, 499 mg, or 500 mg, of (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof.

[0031]

[0022] In embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene- 1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject at from about 0.01 mg / per day to about 750 mg / per day. For example, in embodiments, (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject at about 0.01 mg / per day, about 0.1 mg / per day, about 0.5 mg / per day about 1 mg / per day, about 5 mg / per day, about 10 mg / per day, about 15 mg / per day, about 20 mg / per day, about 25 mg / per day, about 30 mg / per day, about 35 mg / per day, about 40 mg / per day, about 45 mg / per day, about 50 mg / per day, about 60 mg / per day, about 65 mg / per day. about 70 mg / per day. about 75 mg / per day. about 80 mg / per day. about 85 mg / per day. about 90 mg / per day, about 95 mg / per day, about 100 mg / per day, about 105 mg / per day, about 110 mg / per day, about 115 mg / per day, about 120 mg / per day, about 125 mg / per day, about 130 mg / per day, about 135 mg / per day. about 140 mg / per day, about 145 mg / per day, about 150 mg / per day, about 155 mg / per day, about 160 mg / per day, about 165 mg / per day, about 170 mg / per day, about 175 mg / per day, about 180 mg / per day, about 185 mg / per day, about 190 mg / per day, about 195 mg / per day, about 200 mg / per day, about 205 mg / per day, about 210 mg / per day, about 215 mg / per day, about 220 mg / per day, about 225 mg / per day, about 230 mg / per day, about 235 mg / per day, about 240 mg / per day, about 245 mg / per day, about 250 mg / per day, about 255 mg / per day, about 260 mg / per day, about 265 mg / per day, about 270 mg / per day, about 275 mg / per day, about 280 mg / per day, about 285 mg / per day, about 290 mg / per day, about 295 mg / per day. about 300 mg / per day, about 305 mg / per day, about 310 mg / per day, about 315 mg / per day, about 320 mg / per day, about 325 mg / per day, about 330 mg / per day, about 335 mg / per day, about 340 mg / per day, about 345 mg / per day, about 350 mg / per day, about 355 mg / per day. about 360 mg / per day, about 365 mg / per day, about 370 mg / per day, about 375 mg / per day, about 380 mg / per day, about 385 mg / per day, about 390 mg / per day, about 395 mg / per day, about 400 mg / per day, about 405 mg / per day, about 410 mg / per day, about 415 mg / per day, about 420 mg / per day, about 425 mg / per day, about 430 mg / per day, about 435 mg / per day, about 440 mg / per day, about 445 mg / per day, about 450 mg / per day, about 455 mg / per day. about 460 mg / per day, about 465 mg / per day, about 470 mg / per day, about 475 mg / per day, about 480 mg / per day, about 485 mg / per day, about 490 mg / per day, about 495 mg / per day, about 500 mg / per day, about 505 mg / per day, about 510 mg / per day, about 515 mg / per day, about 520 mg / per day, about 525 mg / per day, about 530 mg / per day, about 535 mg / per day. about 540 mg / per day, about 545 mg / per day, about 550 mg / per day, about 555 mg / per day, about 560 mg / per day, about 565 mg / per day, about 570 mg / per day, about 575 mg / per day, about 580 mg / per day, about 585 mg / per day, about 590 mg / per day, about 595 mg / per day. about 600 mg / per day, about 605 mg / per day, about 610 mg / per day, about 615 mg / per day, about 620 mg / per day, about 625 mg / per day, about 630 mg / per day, about 635 mg / per day, about 640 mg / per day, about 645 mg / per day, about 650 mg / per day, about 655 mg / per day, about 660 mg / per day, about 665 mg / per day, about 670 mg / per day, about 675 mg / per day, about 680 mg / per day, about 685 mg / per day, about 690 mg / per day, about 695 mg / per day. about 700 mg / per day, about 705 mg / per day, about 710 mg / per day, about 715 mg / per day, about 720 mg / per day, about 725 mg / per day, about 730 mg / per day, about 735 mg / per day, about 740 mg / per day, about 745 mg / per day, or about 750 mg / per day, in one, two, three, four or more doses. In embodiments, the subject may be started at a low dose and the dosage is escalated over time.

[0032]

[0023] In embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject experiencing pain via a pharmaceutical composition. Pharmaceutical compositions herein encompass dosage forms. Dosage forms herein encompass unit doses. In embodiments, as discussed below, various dosage forms including conventional formulations and modified release formulations can be administered one or more times daily. In embodiments, (S)-3-amino-4-(difluoromethylenyl) cyclopent- 1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject once or twice a day, (e.g., morning and / or evening). In embodiments, (S)-3-amino-4-(difluoromethylenyl) cyclopent- 1-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered to a subject three times a day (e.g.. morning, afternoon and at bedtime, or every 8 hours). In embodiments, (S)-3-amino-4-(difhioromethylenyl) cyclopent- 1-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered to a subject four times a day (e.g., morning, afternoon, evening and at bedtime, or every 6 hours). In embodiments, (S)-3-amino-4-(difluoromethylenyl) cyclopent- 1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject via continuous infusion.

[0024] In embodiments, (S)-3-amino-4-(difluoromethylenyl) cyclopent- 1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject at the start of an acute pain episode, whenever that may occur. In embodiments. (S)-3-amino-4-(difluoromethylenyl) cyclopent- 1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject prophylactically, before a pain episode is expected.

[0033]

[0025] Any suitable route of administration may be utilized, e.g., enterally or parenterally, e.g.. oral, rectal, nasal, pulmonary, vaginal, sublingual, transdermal, intravenous, intraarterial, intramuscular, intraperitoneal and subcutaneous routes. Suitable dosage forms include tablets, capsules, oral liquids, powders, aerosols, transdermal modalities such as topical liquids, patches, creams and ointments, parenteral formulations and suppositories. In embodiments, (S)-3-amino-4- (difluoromethylenyl) cyclopent- 1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is used to manufacture a medicament for treatment of pain.

[0034]

[0026] In embodiments, methods of treating pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain for more than 1 hour after administration to the subject. In embodiments, methods of treating pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cy clopent- 1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain for more than 2 hours after administration to the subject. In embodiments, methods of treating pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain for more than 3 hours after administration to the subject. In embodiments, methods of treating pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain for more than 4 hours after administration to the subject. In embodiments, methods of treating pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain for more than 6 hours after administration to the subject. In embodiments, methods of treating pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject. In embodiments, the pharmaceutical compositions provide improvement of next day functioning of the subject in pain. For example, the pharmaceutical compositions may provide improvement in pain for more than about, e.g„ 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.

[0035]

[0027] In embodiments, methods of treating neuropathic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of neuropathic pain for more than 1 hour after administration to the subject. In embodiments, methods of treating neuropathic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of neuropathic pain for more than 2 hours after administration to the subject. In embodiments, methods of treating neuropathic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of neuropathic pain for more than 3 hours after administration to the subject. In embodiments, methods of treating neuropathic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of neuropathic pain for more than 4 hours after administration to the subject. In embodiments, methods of treating neuropathic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l- carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of neuropathic pain for more than 6 hours after administration to the subject. In embodiments, methods of treating neuropathic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of neuropathic pain for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject. In embodiments, the pharmaceutical compositions provide improvement of next day functioning of the subject in neuropathic pain. For example, the pharmaceutical compositions may provide improvement in one or more symptoms of neuropathic pain for more than about, e.g.. 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours. 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.

[0036]

[0028] In embodiments, methods of treating pain associated with inflammation are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain associated with inflammation for more than 1 hour after administration to the subject. In embodiments, methods of treating pain associated with inflammation are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain associated with inflammation for more than 2 hours after administration to the subject. In embodiments, methods of treating pain associated with inflammation are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-1 -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain associated with inflammation for more than 3 hours after administration to the subject. In embodiments, methods of treating pain associated with inflammation pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain associated with inflammation for more than 4 hours after administration to the subject. Tn embodiments, methods of treating pain associated with inflammation are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain associated with inflammation for more than 6 hours after administration to the subject. In embodiments, methods of treating pain associated with inflammation are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in pain associated with inflammation for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject. In embodiments, the pharmaceutical compositions provide improvement of next day functioning of the subject in pain associated with inflammation. For example, the pharmaceutical compositions may provide improvement in pain associated with inflammation for more than about, e.g., 2 hours, 4 hours. 6 hours, 8 hours, 10 hours. 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.

[0037]

[0029] In embodiments, methods of treating acute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the acute pain for more than 1 hour after administration to the subject. In embodiments, methods of treating acute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the acute pain for more than 2 hours after administration to the subject. In embodiments, methods of treating acute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the acute pain for more than 3 hours after administration to the subject. In embodiments, methods of treating acute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the acute pain for more than 4 hours after administration to the subject. In embodiments, methods of treating acute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difhioromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the acute pain for more than 6 hours after administration to the subject. In embodiments, methods of treating acute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the acute pain for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject. In embodiments, the pharmaceutical compositions provide improvement of next day functioning of the subject in acute pain. For example, the pharmaceutical compositions may provide improvement in acute pain for more than about, e.g., 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.

[0038]

[0030] In embodiments, methods of treating subacute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the subacute pain for more than 1 hour after administration to the subject. In embodiments, methods of treating subacute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the subacute pain for more than 2 hours after administration to the subject. In embodiments, methods of treating subacute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the subacute pain for more than 3 hours after administration to the subject. In embodiments, methods of treating subacute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the subacute pain for more than 4 hours after administration to the subject. In embodiments, methods of treating subacute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the subacute pain for more than 6 hours after administration to the subject. In embodiments, methods of treating subacute pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the subacute pain for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject. In embodiments, the pharmaceutical compositions provide improvement of next day functioning of the subject in subacute pain. For example, the pharmaceutical compositions may provide improvement in subacute pain for more than about, e.g.. 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours. 14 hours, 16 hours. 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.

[0039]

[0031] In embodiments, methods of treating chronic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the chronic pain for more than 1 hour after administration to the subject. In embodiments, methods of treating chronic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the chronic pain for more than 2 hours after administration to the subject. In embodiments, methods of treating chronic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the chronic pain for more than 3 hours after administration to the subject. In embodiments, methods of treating chronic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the chronic pain for more than 4 hours after administration to the subject. In embodiments, methods of treating chronic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the chronic pain for more than 6 hours after administration to the subject. In embodiments, methods of treating chronic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the chronic pain for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject. In embodiments, the pharmaceutical compositions provide improvement of next day functioning of the subject in chronic pain. For example, the pharmaceutical compositions may provide improvement in chronic pain for more than about, e.g.. 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours. 14 hours, 16 hours. 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.

[0040]

[0032] In embodiments, methods of treating somatic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the somatic pain for more than 1 hour after administration to the subject. In embodiments, methods of treating somatic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the somatic pain for more than 2 hours after administration to the subject. In embodiments, methods of treating somatic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the somatic pain for more than 3 hours after administration to the subject. In embodiments, methods of treating somatic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the somatic pain for more than 4 hours after administration to the subject. In embodiments, methods of treating somatic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the somatic pain for more than 6 hours after administration to the subject. In embodiments, methods of treating somatic pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the somatic pain for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject. In embodiments, the pharmaceutical compositions provide improvement of next day functioning of the subject in somatic pain. For example, the pharmaceutical compositions may provide improvement in somatic pain for more than about, e.g.. 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours. 14 hours, 16 hours. 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.

[0041]

[0033] In embodiments, methods of treating visceral pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the visceral pain for more than 1 hour after administration to the subject. In embodiments, methods of treating visceral pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the visceral pain for more than 2 hours after administration to the subject. In embodiments, methods of treating visceral pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the visceral pain for more than 3 hours after administration to the subject. In embodiments, methods of treating visceral pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the visceral pain for more than 4 hours after administration to the subject. In embodiments, methods of treating visceral pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the visceral pain for more than 6 hours after administration to the subject. In embodiments, methods of treating visceral pain are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the visceral pain for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject. In embodiments, the pharmaceutical compositions provide improvement of next day functioning of the subject in visceral pain. For example, the pharmaceutical compositions may provide improvement in visceral pain for more than about, e.g.. 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours. 14 hours, 16 hours. 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.

[0042]

[0034] In embodiments, methods of treating pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia for more than 1 hour after administration to the subject. In embodiments, methods of treating pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia for more than 2 hours after administration to the subject. In embodiments, methods of treating pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia for more than 3 hours after administration to the subject. In embodiments, methods of treating pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia for more than 4 hours after administration to the subject. In embodiments, methods of treating pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia for more than 6 hours after administration to the subject. In embodiments, methods of treating pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in the pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject. Tn embodiments, the pharmaceutical compositions provide improvement of next day functioning of the subject in pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia. For example, the pharmaceutical compositions may provide improvement in pain associated with physical trauma, a compression condition, a perioperative procedure, infection, arthritis, migraine headache, cancer, autoimmune disease, or fibromyalgia for more than about, e.g., 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours. 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.

[0043]

[0035] In embodiments, as mentioned previously, pharmaceutical compositions herein may be provided with conventional release or modified release profiles. Pharmaceutical compositions may be prepared using a pharmaceutically acceptable “carrier” composed of materials that are considered safe and effective. The “carrier” includes all components such as excipients present in the pharmaceutical formulation other than the active ingredient or ingredients. The term “carrier” includes, but is not limited to, excipients such as diluents, binders, lubricants, disintegrants, fillers, and coating compositions. Those with skill in the art are familiar with such pharmaceutical carriers and methods of compounding pharmaceutical compositions using such carriers.

[0044]

[0036] The excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, stabilizers, flavorings, colorants, fillers, binders, disintegrants, lubricants, glidants. thickening agents and coating agents. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.

[0045]

[0037] The pharmaceutical compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, films, dragees, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, lotions, transdermal patches, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution or suspension for intravenous, subcutaneous or intramuscular dosing), or as a suppository for rectal dosing. The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0046]

[0038] In embodiments, a pharmaceutical composition herein may contain (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, in any of the amounts set forth herein and a diluent in an amount from 30% to 90% by weight. Examples of diluents include lactose, microcrystalline cellulose, starch, calcium phosphate, calcium carbonate, sucrose, mannitol, maltodextrin and sorbitol. In embodiments, a pharmaceutical composition herein may contain (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-1 -carboxylic acid, or a pharmaceutically acceptable salt thereof, and a lubricant in an amount, e.g„ from 0.25% to 5.0% by weight. Examples of lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, talc, polyethylene glycols and silicon dioxide. Examples of water-soluble lubricants include sodium benzoate, polyethylene glycol, and adipic acid. In embodiments, a pharmaceutical composition herein may contain (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, and a disintegrant in an amount. e.g„ from 1.0% to 10.0% by weight. There are two classes of disintegrants: traditional disin tegrants, such as starch, and super disintegrants, which include croscarmellose sodium, crospovidone, and sodium starch glycolate.

[0047]

[0039] In embodiments, pharmaceutical compositions herein are modified release dosage forms which provide modified release profiles. Modified release profiles may exhibit immediate release, delayed release, or extended release profiles. Conventional (or unmodified) release oral dosage forms such as tablets, capsules, suppositories, syrups, solutions and suspensions typically release medications into the mouth, stomach or intestines as the tablet, capsule shell or suppository dissolves, or, in the case of syrups, solutions and suspensions, when they are swallowed. The pattern of drug release from modified release (MR) dosage forms is deliberately changed from that of a conventional dosage form to achieve a desired therapeutic objective and / or better patient compliance. Types of MR drug products include orally disintegrating dosage forms (ODDFs) which provide immediate release, extended release dosage forms, delayed release dosage forms (e.g., enteric coated), and pulsatile release dosage forms.

[0048]

[0040] An ODDF is a solid dosage form containing a medicinal substance or active ingredient which disintegrates rapidly, usually within a matter of seconds when placed upon the tongue. The disintegration time for ODDFs generally range from one or two seconds to about a minute. ODDFs are designed to disintegrate or dissolve rapidly on contact with saliva. This mode of administration can be beneficial to people who may have problems swallowing tablets whether it be from physical infirmity or psychiatric in nature. Subjects in pain may exhibit such behavior. ODDF’s can provide rapid delivery of medication to the blood stream through mucosa resulting in a rapid onset of action. Examples of ODDFs include orally disintegrating tablets, capsules and rapidly dissolving films and wafers.

[0049]

[0041] Extended release dosage forms (ERDFs) have extended release profiles and are those that allow a reduction in dosing frequency as compared to that presented by a conventional dosage form, e.g., a solution or unmodified release dosage form. ERDFs provide a sustained duration of action of a drug. Suitable formulations which provide extended release profiles are well-known in the art. For example, coated slow release beads or granules (“beads” and “granules” are used interchangeably herein) in which (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is applied to beads, e.g., confectioners nonpareil beads, and then coated with conventional release retarding materials such as waxes, enteric coatings and the like. In embodiments, beads can be formed in which (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-1 -carboxylic acid or a pharmaceutically acceptable salt thereof is mixed with a material to provide a mass from which the drug leaches out. In embodiments, the beads may be engineered to provide different rates of release by varying characteristics of the coating or mass, e.g., thickness, porosity, using different materials, etc. Beads having different rates of release may be combined into a single dosage form to provide variable or continuous release. The beads can be contained in capsules or compressed into tablets.

[0050]

[0042] In embodiments, modified dosage forms herein incorporate delayed release dosage forms having delayed release profiles. Delayed release dosage forms can include delayed release tablets or delayed release capsules. A delayed release tablet is a solid dosage form which releases a drug (or drugs) such as (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene- 1-carboxylic acid or a pharmaceutically acceptable salt thereof at a time other than promptly after administration. A delayed release capsule is a solid dosage form in which the drug is enclosed within either a hard or soft soluble container made from a suitable form of gelatin, and which releases a drug (or drugs) at a time other than promptly after administration. For example, enteric-coated tablets, capsules, particles and beads are well-known examples of delayed release dosage forms. Enteric coated tablets, capsules and particles and beads pass through the stomach and release the drug in the intestine. In embodiments, a delayed release tablet is a solid dosage form containing a conglomerate of medicinal particles that releases a drug (or drugs) at a time other than promptly after administration. In embodiments, the conglomerate of medicinal particles are covered with a coating which delays release of the drag. In embodiments, a delayed release capsule is a solid dosage form containing a conglomerate of medicinal particles that releases a drug (or drugs) at a time other than promptly after administration. In embodiments, the conglomerate of medicinal particles are covered with a coating which delays release of the drug.

[0051]

[0043] Delayed release dosage forms are known to those skilled in the art. For example, coated delayed release beads or granules in which (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is applied to beads, e.g., confectioners nonpareil beads, and then coated with conventional release delaying materials such as waxes, enteric coatings and the like. In embodiments, beads can be formed in which (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is mixed with a material to provide a mass from which the drug leaches out. In embodiments, the beads may be engineered to provide different rates of release by varying characteristics of the coating or mass, e.g., thickness, porosity, using different materials, etc. In embodiments, enteric coated granules of (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-1 -carboxylic acid or a pharmaceutically acceptable salt thereof can be contained in an enterically coated capsule or tablet which releases the granules in the small intestine. In embodiments, the granules have a coating which remains intact until the coated granules reach at least the ileum and thereafter provide a delayed release of the drug in the colon. Suitable enteric coating materials are well known in the art, e.g., Eudragit® coatings such methacrylic acid and methyl methacrylate polymers and others. The granules can be contained in capsules or compressed into tablets.

[0052]

[0044] In embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene- 1-carboxylic acid or a pharmaceutically acceptable salt thereof is incorporated into porous inert carriers that provide delayed release profiles. In embodiments, the porous inert carriers incorporate channels or passages from which the drug diffuses into surrounding fluids. In embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is incorporated into an ion-exchange resin to provide a delayed release profile. Delayed action may result from a predetermined rate of release of the drag from the resin when the drugresin complex contacts gastrointestinal fluids and the ionic constituents dissolved therein. In embodiments, membranes are utilized to control rate of release from drag containing reservoirs. In embodiments, liquid preparations may also be utilized to provide a delayed release profile. For example, a liquid preparation consisting of solid particles dispersed throughout a liquid phase in which the particles are not soluble. The suspension is formulated to allow at least a reduction in dosing frequency as compared to that drug presented as a conventional dosage form (e.g., as a solution or a prompt drug-releasing, conventional solid dosage form). For example, a suspension of ion-exchange resin constituents or microbeads.

[0053]

[0045] In embodiments, pharmaceutical compositions described herein are suitable for parenteral administration, including, e.g., intramuscular (i.m.), intravenous (i.v.). subcutaneous (s.c.), intraperitoneal (i.p.), or intrathecal (i.t.). Parenteral compositions must be sterile for administration by injection, infusion or implantation into the body and may be packaged in either single-dose or multi-dose containers. In embodiments, liquid pharmaceutical compositions for parenteral administration to a subject include an active substance, e.g., (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof in any of the respective amounts described above. In embodiments, the pharmaceutical compositions for parenteral administration are formulated as a total volume of about, e.g., 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In embodiments, the compositions are contained in a bag, a glass vial, a plastic vial, or a bottle.

[0054]

[0046] Pharmaceutical compositions for parenteral administration provided herein may include one or more excipients, e.g., solvents, solubility enhancers, suspending agents, buffering agents, isotonicity agents, stabilizers or antimicrobial preservatives. When used, the excipients of the parenteral compositions will not adversely affect the stability, bioavailability, safety, and / or efficacy of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof used in the composition. Thus, parenteral compositions are provided wherein there is no incompatibility between any of the components of the dosage form.

[0055]

[0047] In embodiments, parenteral compositions (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof include a stabilizing amount of at least one excipient. For example, excipients may be selected from the group consisting of buffering agents, solubilizing agents, tonicity agents, antioxidants, chelating agents, antimicrobial agents, and preservative. One skilled in the art will appreciate that an excipient may have more than one function and be classified in one or more defined group.

[0056]

[0048] In embodiments, parenteral compositions (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof and an excipient wherein the excipient is present at a weight percent (w / v) of less than about, e.g., 10%, 5%, 2.5%, 1%, or 0.5%. In embodiments, the excipient is present at a weight percent between about, e.g., 1.0% to 10%, 10% to 25%, 15% to 35%, 0.5% to 5%, 0.001% to 1%. 0.01% to 1%, 0.1% to 1%, or 0.5% to 1%. In embodiments, the excipient is present at a weight percent between about, e.g., 0.001% to 1%, 0.01% to 1%, 1.0% to 5%, 10% to 15%, or 1% to 15%.

[0057]

[0049] In embodiments, parenteral compositions of an active substance, e.g., (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof are provided, wherein the pH of the composition is between about 4.0 to about 8.0. In embodiments, the pH of the compositions is between, e.g., about 5.0 to about 8.0, about 6.0 to about 8.0, about 6.5 to about 8.0. In embodiments, the pH of the compositions is between, e.g., about 6.5 to about 7.5, about 7.0 to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. In embodiments, the pH of the aqueous solution is, e.g., about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0, about 8.2, about 8.4, or about 8.6.

[0058]

[0050] It should be understood that the dosage amounts of (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof that are provided herein are applicable to all the dosage forms described herein including conventional dosage forms, modified dosage forms, as well as the parenteral formulations described herein. Those skilled in the art will determine appropriate amounts depending on criteria such as dosage form, route of administration, subject tolerance, efficacy, therapeutic goal and therapeutic benefit, among other pharmaceutically acceptable criteria.

[0059]

[0051] Clinical efficacy of treatment can be monitored using any method known in the art. Measurable parameters to monitor efficacy will depend on the condition being treated. For monitoring the status or improvement of pain, both subjective parameters (e.g., patient reporting) and objective parameters (e.g., f-MRI, allodynia, hyperalgesia, physical exam, gait, mobility, walking distance, nerve conduction velocity, electrophysiology, etc.) can be used. Examples of applicable assays for the measurement of pain are described, e.g., in Younger, et al., Pain Outcomes: A Brief Review of Instruments and Techniques, Curr Pain Headache Rep. 2009 Feb; 13(1): 39-43.

[0060]

[0052] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosure herein belongs.

[0061]

[0053] The term "about" or "approximately" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, "about" can mean a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value.

[0062]

[0054] “Improvement” refers to the treatment of pain including all forms and intensities of pain, including but not limited to acute pain, subacute pain, chronic pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, nociceptive pain, pathological pain, and perioperative pain.

[0063]

[0055] “Improvement in next day functioning” or “wherein there is improvement in next day functioning” refers to improvement after waking from an overnight sleep period wherein the beneficial effect of administration of (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof applies to pain and is discernable, either subjectively by a subject or objectively by an observer, for a period of time, e.g., 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, etc. after waking.

[0064]

[0056] " PK" refers to the pharmacokinetic profile. Cmax is defined as the highest plasma drug concentration estimated during an experiment (ng / ml). Tmaxis defined as the time when Cmax is estimated (min). AUCo-«>is the total area under the plasma drug concentration-time curve, from drug administration until the drug is eliminated (ng*hr / ml or pg*hr / ml). The area under the curve is governed by clearance. Clearance is defined as the volume of blood or plasma that is totally cleared of its content of drug per unit time (ml / min).

[0065]

[0057] " Treating", "treatment" or “treat” can refer to the following: reducing, improving, relieving, ameliorating, mitigating, inhibiting, reversing and / or alleviating pain in a subject, or delaying the appearance of pain (prophylaxis) in a subject. In embodiments, “treating”, “treat” or “treatment” may refer to preventing the appearance of clinical symptoms of a disease or condition in a subject that may be afflicted with or predisposed to the disease or condition, but does not yet experience or display clinical or subclinical symptoms of the disease or condition. "Treating", “treat” or "treatment" also refers to inhibiting or relieving pain, e.g., causing regression of pain or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated may be statistically significant, mathematically significant, or at least perceptible to the subject and / or the physician. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatment are two separate embodiments of the disclosure herein.

[0066]

[0058] "Pharmaceutically acceptable" refers to molecular entities and compositions that are "generally regarded as safe", e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a human. In embodiments, this term refers to molecular entities and compositions approved by a regulatory agency of the federal or a state government, as the GRAS list under section 204(s) and 409 of the Federal Food, Drug and Cosmetic Act, that is subject to premarket review and approval by the FDA or similar lists, the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0067]

[0059] ‘ ‘Co-administered with”, “in combination with”, “administered in combination with”, “a combination of’ or “administered along with” may be used interchangeably and mean that two or more agents are administered in the course of therapy. The agents may be administered together at the same time or separately in spaced apart intervals. The agents may be administered in a single dosage form or in separate dosage forms.

[0068]

[0060] “Subject in need thereof’ includes individuals that are experiencing pain or are about to experience pain with reasonable certainty. The methods and compositions including (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, may be provided to any individual including, e.g., wherein the subject is a neonate, infant, a pediatric subject (6 months to 12 years), an adolescent subject (age 12-18 years) or an adult (over 18 years). Subjects include mammals. “Patient” and “subject” may be used interchangeably herein.

[0069]

[0061] The term “pharmaceutically acceptable salt”, as used herein, refers to derivatives of the compounds defined herein, wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include but are not limited to mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include but are not limited to those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic salts. The pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods.

[0070]

[0062] It should be understood that the examples and embodiments provided herein are exemplary examples and embodiments. Those skilled in the art will envision various modifications of the examples and embodiments that are consistent with the scope of the disclosure herein. Such modifications are intended to be encompassed by the claims.

Claims

What is claimed is:

1. A method of treating pain in a subject in need thereof comprising administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene- 1-carboxylic acid, or a pharmaceutically acceptable salt thereof, to the subject in an amount of from about 0.01 mg to about 750 mg.

2. The method of claim 1, wherein the subject is administered from about 0.1 mg to about 125 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid, or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the subject is administered from about 1 mg to about 20 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent- 1-ene- 1-carboxylic acid, ora pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene- 1-carboxylic acid, or a pharmaceutically acceptable salt thereof, administered to the subject in a twenty-four hour period is between 1 mg and 100 mg.

5. The method of claim 1, wherein (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered from one to four times a day.

6. The method of claim 1, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene- 1-carboxylic acid, or a pharmaceutically acceptable salt thereof, administered to the subject in a twenty-four hour period is between 1 mg and 400 mg.

7. The method of claim 1, wherein the (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-1 -carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered en terally.

8. The method of claim 7, wherein the (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-1 -carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered orally, sublingually, buccally, intranasally or rectally.

9. The method of claim 1, wherein the (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-1 -carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered parenterally.

10. The method of claim 9, wherein the (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene- 1-carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered intravenously, intraarterially, intrathecally, intramuscularly, intraperitoneally or subcutaneously.

11. The method of claim 1, wherein the (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-1 -carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered topically.

12. The method of claim 11, wherein the (5)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene- 1-carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered in a topical liquid, a patch, a cream or an ointment.

13. The method of claim 1, wherein the pain is acute pain.

14. The method of claim 1 , wherein the pain is subacute pain.

15. The method of claim 1, wherein the pain is chronic pain.

16. The method of claim 1, wherein the pain is somatic pain.

17. The method of claim 1, wherein the pain is visceral pain.

18. The method of claim 1, wherein the pain is neuropathic pain.

19. The method of claim 1, wherein the pain is associated with a condition selected from the group consisting of inflammation, physical trauma, a compression condition, arthritis, migraine headache, spinal disorder, sudden illness, cancer, infection, autoimmune disease, exposure to toxic compounds, substance abuse disorder and fibromyalgia.

20. The method of claim 19, wherein the physical trauma is selected from the group consisting of stroke, a herniated disk in the spine, amputation, a broken bone, a sprain, a surgical procedure (perioperative), a dental procedure and a thermal injury; the infection is bacterial or viral; the compression condition is impingement of a neve, impingement of a tendon or impingement of a ligament; the sudden illness is a flare-up of appendicitis, diverticulitis or irritable bowel syndrome; the autoimmune disease is selected from the group consisting of multiple sclerosis, lupus, psoriasis, eczema, Graves’ disease; myasthenia gravis, diabetes and celiac disease; the substance abuse disorder is alcoholism and the spinal disorder is stenosis or degenerative disc disease.

21. The method of claim 20, wherein the infection is the viral infection selected from the group consisting of herpes (herpetic or post-herpetic), shingles, Epstein-Barr and HIV.

22. The method of claim 1, wherein the pain is psychosomatic pain.

23. The method of claim 22 wherein the psychosomatic pain is phantom limb pain.

24. The method of claim 1 wherein the pain is myofascial pain.

25. The method of claim 18, wherein the method reduces at least one symptom of the neuropathic pain selected from the group consisting of intense pain, burning pain, numbness of extremity ends, sensory ataxia, muscle force reduction, paresthesia, dysesthesia, hypoesthesia, hyperesthesia, hypoalgesia, hyperalgesia, mechanical allodynia and thermal allodynia.

26. A composition for use in treating pain comprising ( )-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, in an amount of from about 0.01 mg to about 750 mg.

27. The composition according to claim 26, wherein the amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, is about 0.1 mg to about 125 mg.

28. The composition according to claim 26, wherein the amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 20 mg.

29. The composition according to claim 26, wherein the composition is an enteral dosage form.

30. The composition according to claim 29, wherein the enteral dosage form is an oral dosage form, a sublingual dosage form, a buccal dosage form, and intranasal dosage form, or a rectal dosage form.

31. The composition according to claim 26, wherein the composition is a parenteral formulation.

32. The composition according to claim 31, wherein the parenteral formulation is an intravenous formulation, an intraarterial formulation, an intrathecal formulation, an intramuscular formulation, an intraperitoneal formulation, or a subcutaneous formulation.

33. The composition according to claim 26, wherein the composition further comprises a carrier.

34. The composition according to claim 33, wherein the carrier includes one or more of the following: a diluent, a binder, a lubricant, a disintegrant, a filler, a coating composition, an adjuvant, a stabilizer, a flavoring, a colorant, a glidant, a thickening agent, a solvent, a solubility enhancer, a suspending agent, a buffering agent, a isotonicity agent, a antimicrobial preservative, an antioxidant, a chelating agent.

35. Use of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid, or a pharmaceutically acceptable salt thereof, for manufacture a medicament for the treatment of pain.

Images