Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/275—Nitriles; Isonitriles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
  • A61K31/10—Sulfides; Sulfoxides; Sulfones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a methanesulfonylalkylnitrile compound, or its pharmaceutically acceptable salts.
• the present invention also relates to methods of using the compound for treating inflammation or inflammatory-related disorders and pain.
• Inflammation is a process by which microbes or tissue injury induce the release of cytokines and chemokines from various cell types producing increased blood vessel permeability, upregulation of endothelial receptors, and thus increased egress of various cells of the innate and adaptive immune system which enter surrounding tissue and grossly produce the classical picture of inflammation, i.e. redness, swelling, heat and pain.
• Inflammation is a localized reaction of live tissue due to an injury, which may be caused by various endogenous and exogenous factors.
• the exogenous factors include physical, chemical, and biological factors.
• the endogenous factors include inflammatory mediators, antigens, and antibodies. Endogenous factors often develop under the influence of an exogenous damage. An inflammatory reaction is often followed by an altered structure and penetrability of the cellular membrane. Endogenous factors, namely, mediators, antigens, and autogens define the nature and type of an inflammatory reaction, especially its course in the zone of injury. In the case where tissue damage is limited to the creation of mediators, an acute form of inflammation develops.
• immunologic reactions are also involved in the process, through the interaction of antigens, antibodies, and autoantigens, a long-term inflammatory process will develop.
• Various exogenous agents for example, infection, injury, radiation, also provide the course of inflammatory process on a molecular level by damaging cellular membranes which initiate biochemical reactions.
• pain can be divided into three types: nociceptive, neuropathic, and mix-type.
• Nociceptive pain is the term for pain that is detected by specialized sensory nerves called nociceptors. These nerves are located throughout the soft tissues, such as muscles and skin, as well as the internal organs. There are two types of nociceptive pain: somatic pain and visceral pain. Visceral pain comes from the internal organs. Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly localized pain. Examples include sprains and broken bones. Superficial pain is initiated by activation of nociceptors in the skin or other superficial tissue, and is sharp, well-defined and clearly located. Examples of injuries that produce superficial somatic pain include minor wounds and minor (first degree) burns. Nociceptive pain is usually short in duration and end when the damage recovers. Examples of nociceptive pain include postoperative pain, sprains, bone fractures, burns, bumps, bruises, and inflammatory pain.
• Neuropathic pain is pain caused by damage or disease that affects the somatosensory system. Neuropathic pain is originated from spontaneous ectopic neuron discharge in the nervous system either in central or in peripheral. Due to the underlying etiologies are usually irreversible, most of neuropathic pain are chronic pain. Most people describe neuropathic pain as shooting, burning, tingling, lancinating, electric shock qualities, numbness, and persistent allodynia. The nomenclature of neuropathic pain is based on the site of initiating nervous system with the etiology; for examples, central post-stroke pain, diabetes peripheral neuropathy, post-herpetic (or post-shingles) neuralgia, terminal cancer pain, phantom limb pain.
• Mix-type pain is featured by the coexistence of both nociceptive and neuropathic pain.
• muscle pain trigger central or peripheral neuron sensitization leading to chronic low back pain, migraine, and myofacial pain.
• corticosteroids have a broad spectrum of activities and NSAIDS are more specifically anti-prostaglandin and analgesic. All current therapies have relatively high rates of adverse effects and adverse effects are severe and serious.
• compositions and methods for treating inflammation, inflammatory-related disorders, and pain There is a need for a composition and a method for treating inflammation, inflammatory-related disorders, and pain.
• the composition should be economic and easy to manufacture, and the method should be effective and have no significant side effects.
• the present invention is also directed to a method for treating inflammation, inflammatory-related disorders, and pain.
• the method comprises the step of administering a methanesulfonylalkylnitrile compound or a pharmaceutically acceptable salt thereof to a subject in need thereof.
• the pharmaceutical composition comprising the active compound can be applied by any accepted mode of administration including topical, oral, and parenteral (such as intravenous, intramuscular, subcutaneous or rectal). Topical administration and oral administration are preferred.
• Alkyl refers to groups of from 1 to 12 carbon atoms, either straight chained or branched, preferably from 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms.
• Arylalkyl refers to aryl-alkyl- groups preferably having from 1 to 6 carbon atoms in the alkyl moiety and from 6 to 10 carbon atoms in the aryl moiety. Such arylalkyl groups are exemplified by benzyl, phenethyl and the like.
• “Pharmaceutically acceptable salts,” as used herein, are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.
• Pharmaceutically acceptable salt forms include various crystalline polymorphs as well as the amorphous form of the different salts.
• the pharmaceutically acceptable salts can be formed with metal or organic counterions and include, but are not limited to, alkali metal salts such as sodium or potassium; alkaline earth metal salts such as magnesium or calcium; and ammonium or tetraalkyl ammonium salts, i.e., NX 4 + (wherein X is C 1-4 ).
• methanesulfonylalkylnitriles are effective for treating inflammation, inflammatory-related disorders, and pain.
• R 1 and R 2 are selected from the group consisting of H, straight-chain alkyl, branched alkyl, cycloalkyl, and arylalkyl;
• the active compound is incorporated into any acceptable carrier, including creams, gels, lotions or other types of suspensions that can stabilize the active compound and deliver it to the affected area by topical applications.
• the pharmaceutical composition can be in a dosage form such as tablets, capsules, granules, fine granules, powders, syrups, suppositories, injectable solutions, patches, or the like.
• the above pharmaceutical composition can be prepared by conventional methods.
• the pharmaceutically acceptable carriers may also contain ingredients that include, but are not limited to, saline and aqueous electrolyte solutions; ionic and nonionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and dextrose; pH adjusters and buffers such as salts of hydroxide, phosphate, citrate, acetate, borate; and trolamine; antioxidants such as salts, acids and/or bases of bisulfite, sulfite, metabisulfite, thiosulfite, ascorbic acid, acetyl cysteine, cystein, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherols, and ascorbyl palmitate; surfactants such as lecithin, phospholipids, including but not limited to phosphatidylcholine, phosphatidylethanolamine and phosphatidyl inositiol; poloxamers
• Such pharmaceutically acceptable carriers may be preserved against bacterial contamination using well-known preservatives, these include, but are not limited to, benzalkonium chloride, ethylenediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, or may be formulated as a non-preserved formulation for either single or multiple use.
• preservatives include, but are not limited to, benzalkonium chloride, ethylenediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, or may be formulated as a non-preserved formulation for either single or multiple use.
• Topical formulations including the active compound can be in a form of gel, cream, lotion, liquid, emulsion, ointment, spray, solution, and suspension.
• the inactive ingredients in the topical formulations for example include, but not limited to, lauryl lactate (emollient/permeation enhancer), diethylene glycol monoethyl ether (emollient/permeation enhancer), DMSO (solubility enhancer), silicone elastomer (rheology/texture modifier), caprylic/capric triglyceride, (emollient), octisalate, (emollient/UV filter), silicone fluid (emollient/diluent), squalene (emollient), sunflower oil (emollient), and silicone dioxide (thickening agent).
• lauryl lactate emollient/permeation enhancer
• diethylene glycol monoethyl ether emollient/permeation enhancer
• DMSO solub
• lauryl lactate (for example, at about 0.1-10%, or about 0.2-5%, or about 0.5-5%) is included in the topical gel formulation.
• Lauryl lactate is considered safe for topical administration.
• Lauryl lactate is qualified for human use within pharmaceutical and cosmetic products.
• Lauryl lactate when used in a topical formulation enhances the permeability of the compound.
• Preferably lauryl lactate is purified to achieve ⁇ 90%, preferably ⁇ 95% purity; the high purity mitigates the presence of hydrolytic and oxidative agents.
• DMSO at 0.1-20%, or 0.5-10% (w/w) in the formulation provides suitable solubility of the active compound.
• diethylene glycol monoethyl ether is included in the topical gel formulation.
• Inflammation is a process and a state of tissue pathology resulting from activation and continuation of activity of the innate and acquired components of the immune system.
• the arachidonic acid cascade and cytokine production and action in cell to cell interactions are critical components of immune activation and response, which lead to inflammation.
• Arachidonic acid resides in many cell membranes. When arachidonic acids are cleaved from the membranes, it can produce many of the known eicosinoids including prostaglandins and leucotrienes, which are known pro-inflammatory entities.
• the present invention is directed to a method of treating inflammation and/or pain.
• the active compound can be used as is, or it can be administered in the form of a pharmaceutical composition that additionally contains a pharmaceutically acceptable carrier.
• the method comprises the steps of first identifying a subject suffering from inflammation and/or pain, and administering to the subject the active compound, in an amount effective to treat inflammation and/or pain.
• “An effective amount,” as used herein, is the amount effective to treat a disease by ameliorating the pathological condition or reducing the symptoms of the disease.
• the present invention provides a method to alleviate the symptoms of pain regardless of the cause of the pain.
• the general term “pain” treatable by the present method includes nociceptive, neuropathic, and mix-type.
• the present invention reduces pain of varying severity, i.e. mild, moderate and severe pain; acute and chronic pain.
• the present invention is effective in treating joint pain, muscle pain, tendon pain, burn pain, and pain caused by inflammation such as rheumatoid arthritis.
• the present invention is useful in treating inflammation and/or pain associated in a musculoskeletal system or on the skin.
• the highly innervated, musculoskeletal and skin systems have a high capacity for demonstration of pain.
• the musculoskeletal system has a high capacity for tissue swelling, and the skin has a high capacity for redness, swelling, and heat.
• the degree of tissue damage is frequently magnified out of proportion to the resulting inflammatory response. In the skin for example, merely firm stroking will cause release of the cytokines, IL-1 and TNF.
• the present invention provides a method for treating inflammation and/or pain associated with inflammatory skin diseases such as dermatitis, psoriasis, and acne.
• the method comprises the steps of identifying a subject in need thereof, and administering to the subject the active compound, in an amount effective to treat inflammation and/or pain.
• the acute forms are pruritic with erythema, edema, and micro or macrovesiculation in the areas of skin contact by the initiating factor.
• the chronic forms are pruritic with milder erythema, scaling, lichenification, and possibly fissuring particularly on the hands.
• the present invention is useful to treat common acne, comedonic acne, papulopustular acne, papulocomedonic acne, nodulocystic acne, acne conglobata, cheloid acne of the nape of the neck, recurrent miliary acne, necrotic acne, neonatal acne, occupational acne, acne rosacea, senile acne, solar acne or acne medicamentosa.
• Methanesulfonylalkylnitriles which are effective in inhibiting arachidonic acid induced inflammation and in inhibiting the release of pro-inflammatory cytokine, are effective to treat inflammation and/or pain associated with psoriasis, acne, rosacea, and dermatitis, particularly contact dermatitis, and atopic dermatitis.
• the pharmaceutical composition of the present invention can be applied by local administration and systemic administration.
• Local administration includes topical administration.
• Systemic administration includes oral, parenteral (such as intravenous, intramuscular, subcutaneous or rectal), and other systemic routes of administration.
• the active compound first reaches plasma and then distributes into target tissues.
• Topical administration and oral administration are preferred routes of administration for the present invention.
• Dosing of the composition can vary based on the extent of the injury and each patient's individual response.
• plasma concentrations of active compounds delivered can vary; but are generally 1 ⁇ 10 ⁇ 10 -1 ⁇ 10 ⁇ 4 moles/liter, and preferably 1 ⁇ 10 ⁇ 8 -1 ⁇ 10 ⁇ 5 moles/liter.
• the pharmaceutical composition is administrated orally to the subject.
• the dosage for oral administration is generally 1-50, and preferably 1-5 mg/kg/day.
• the present invention is useful in treating a mammal subject, such as humans, horses, and dogs.
• the present invention is particularly useful in treating humans.
• Percent inhibition was calculated according to the formula: Ic ⁇ It/Ic ⁇ 100, where Ic and It refers to increase of ear thickness (mm) in control and treated mice, respectively.
• ANOVA and Dunnett's test were employed to ascertain significant difference between vehicle control and treated groups. Significance is set at P ⁇ 0.05 level. The results measured at 90 minutes after arachidonic acid application are summarized in Table 3.
• PBMCs peripheral blood mononuclear cells
• PBMCs are stimulated to secrete cytokines using the mitogens lipopolysaccharide and concanavalin A (ConA).
• ConA concanavalin A
• Lipopolysaccharide at 50 pg/mL is used to stimulate the release of interleukin IL-1 ⁇ , IL-6 and tumor necrosis factor TNF ⁇ .
• ConA at 20 ⁇ g/mL is used to stimulate the release of IL-4 and ConA at 5 ⁇ g/mL is used to stimulate interferon IFN ⁇ .
• the corticosteroid dexamethasone 100 nM is used as a positive control.
• the supernatants are assayed for the cytokines using the Luminex Bead kit.
• the percents inhibition of IL-1 ⁇ , IL-6, TNF ⁇ , IL-4 and IFN ⁇ by the active compounds and the positive compound are calculated. The results demonstrate that the active compound has an inhibitory effect on cytokines involved in the inflammatory process.
• This study is done to determine the systemic (plasma) exposure of MSAN after administration by the oral and subcutaneous routes to rats.
• C max average maximum plasma concentrations measured (C max ) after oral dosing and after subcutaneous are determined. The results are expected to demonstrate that significant bioavailability of MSAN after both the oral and subcutaneous routes.
• vehicle 1% Tween 80 in water
• the test compound, dexamethasone (positive control in vehicle), and vehicle are orally administered to mice and evaluated for anti-inflammatory activity in the topical arachidonic acid induced ear swelling model in mice.
• mice Male ICR derived mice weighing 22 ⁇ 2 g are used in this experiment. 10-15 mice are used for each group (active compound, positive control, and vehicle). All animals are maintained in a controlled temperature (22-24° C.) and humidity (60%-70%) environment with 12-hour light/dark cycles for at least one week prior to use.
• Arachidonic acid (0.5 mg in 20 ⁇ L acetone) is applied topically onto the anterior and posterior surfaces of the right ear of test animals to induce inflammation.
• MSAN in vehicle (10 mL/kg) and vehicle (10 mL/kg, 50-150 mg/kg) are orally administered by gavage 1 hour before arachidonic acid, whereas dexamethasone is orally administered by gavage 3 hour before arachidonic acid challenge.
• the thickness of the right ear and the left ear is measured and the difference calculated as an indication of the inflammation in the right ear.
• Significant activity is defined as a statistically significant inhibition (p-value determined by t-test was ⁇ 0.05) in arachidonic acid induced ear swelling relative to the vehicle-treated group.
• Rats are used in the experiment.
• Carrageenan (0.1 mL of a 1% suspension) is injected subcutaneously into the left hind paw to induce inflammation.
• MSAN (1-5%) or vehicle gel is applied to the paw topically at volumes of 0.05, 0.1 0.15 or 2.0 mL, 1.5, 2.5, and 3.5 hours following the carrageenan administration.
• Indomethacin is given orally at 5 mg/kg, 1 hour prior to carrageenan administration.
• the degree of inflammation is determined using a plethysmograph to measure paw volume.
• Analgesia is determined by measuring paw withdrawal to a mechanical stimulus using von Frey filaments. Inflammation and analgesia are measured 4 hours after carrageenan administration.
• MSAN is expected to have anti-inflammatory and/or analgesic properties as measured by a significant decrease in paw volume and/or a significant increase in mechanical pressure needed to elicit paw withdrawal, respectively, as compared to the vehicle control.
• the hot plate test is a test of the pain response in animals; it is used in in testing the effectiveness of analgesics by observing the reaction to pain caused by heat. Licking is a rapid response to painful thermal stimuli that is a direct indicator of nociceptive threshold.
• Rats are used in the experiment. MSAN gel (1-5%) or vehicle gel is applied to the rat hind paw topically in a sufficient amount. One hour later the rat is placed on a 55° C. hot plate, and the time to lick the paw is measured. The positive control, morphine, is given orally at 30 mg/kg, 1 hour prior to hot plate testing. MSAN is expected to have analgesic properties as measured by a significant increase in time to licking as compared to the vehicle control (t-test, p ⁇ 0.05).
• CFA Complete Freund's Adjuvant
• the intensity of the light is adjusted with average group baseline latency from 12 to 14 sec (pre-CFA) and a cut-off latency of 20 sec imposed.
• the latency to withdrawal is obtained for each rat and defined as the heat pain threshold. Twenty four hours after CFA injection, rats are pre-selected (with clear presence of thermal hyperalgesia) for experimentation only if the latency to withdrawal is less than 75% of baseline.
• Test substance or vehicle is either administered orally (20-60 mg/kg) or topically (1-5% gel formulation) to the plantar surface of the hind paw, at 60 minutes before the level of thermal hyperalgesia is again measured (post-treatment). Mean ⁇ SEM of thermal paw withdrawal time is calculated. Unpaired Student's t test is applied for comparison the values of post-treatment between test substance treated group and vehicle control group. Positive activity is considered at P ⁇ 0.05.
• Formalin test is a model of continuous pain resulting from formalin-induced tissue injury.
• the formalin model encompasses inflammatory, neurogenic, and central mechanism of nociception.
• the assay described below relates primarily to the late inflammatory algesic phase sensitive to both strong central analgesic as well as weaker analgesic/anti-inflammatory agents (Hunskaar, et al., J. Neuroscience Meth. 14: 69-76, 1985).
• the formalin test represents a suitable model for testing compounds for treating neuropathic pain (Benson, et al. Proceedings of Measuring Behavior, 2008, Eds. Spink, et al, 324-325).
• Test substance is administered to groups of 8-10 CD-1 derived male mice weighing 23 ⁇ 3 g one hour before subplantar injection of formalin (0.02 ml, 2% solution). Test substance is either administered orally (20-60 mg/kg) or topically (1-5% gel formulation) to the plantar surface of the hind paw. Reduction of the induced hind paw licking time recorded during the following 10 to 30 minute period by 50% or more indicates analgesic activity. MSAN is expected to have analgesic properties as measured by a significant increase in time to licking as compared to the vehicle control (t-test, p ⁇ 0.05).
• Peripheral nerve lesions may generate a syndrome comprising, in addition to spontaneous pain, exaggerated responses to light touch (tactile allodynia).
• Chronic constriction injury model is a neuropathic pain model.
• Rats are pre-selected for experimentation only if the pain threshold 7-14 days after nerve ligation (pre-treatment) is reduced by 10 grams of force relative to the response of the individual paw before nerve ligation (pre-ligation), namely, with clear presence of allodynia.
• Test substance or vehicle is either administered orally (20-60 mg/kg) or topically (1-5% gel formulation) to the plantar surface of the left hind paw.
• the mechanical allodynia test is performed 30 min before (pre-treatment) and 1 and 3 hours after a single dose of test substance or vehicle (post treatment). Paw withdraw thresholds of control and tested compounds are measured.
• Placebo contains the same gel without the active compound.
• Patients with painful osteoarthritis of the knee controlled by a stable dose of standard NSAID therapy for at least 2 months, discontinue use of the NSAIDs for a 7 day washout period. Patients are then randomized in a 1:1:1 ratio (1% active gel, 5% active gel, placebo). A total of up to 150 patients are enrolled and treated for 7 days with follow-up at 8, 10, 14 and 21 days.
• the active gel or placebo is applied to the affected knee 3 times a day for 7 days for a total of 21 treatments given every 4-6 hours while awake.
• NSAIDs may be restarted after the Day 10 visit.
• the primary clinical activity parameters are the measurement of pain at the site of application, as quantified by VAS and the Western Ontario and McMaster University (WOMAC) scale.
• VAS Western Ontario and McMaster University
• WOMAC Western Ontario and McMaster University
• the primary clinical activity endpoint is:
• the secondary clinical activity endpoints are:
• the gel formulation containing MSAN at 1-5% (Example 3) is used in this example.
• Placebo contains the same gel without the active compound.
• Male and female patients with mild to severe atopic dermatitis are enrolled after discontinuation of all treatments for atopic dermatitis for a period of 4 weeks before study initiation. Patients are randomized in a 1:1 ratio (active gel, placebo). A total of 300 patients are enrolled and treated.
• the active gel or placebo is applied twice a day to affected areas of the body for 12 weeks.
• the treatment results are evaluated at 2 week intervals until week 12 and then at 4 weeks after discontinuation of the study medication application.
• Safety is evaluated by general history and physical signs, laboratory testing for hematology, serum chemistry, and urinalysis, and by evaluations of local application site tolerability parameters of erythema, scaling, dryness, stinging/burning utilizing a rating scale of “0” (None) to “3” (Severe).
• Safety is evaluated by general history and physical signs, laboratory testing for hematology, serum chemistry, and urinalysis, and by evaluations of local application site tolerability parameters of erythema, scaling, dryness, stinging/burning utilizing a rating scale of “0” (None) to “3” (Severe).
• the active gel or placebo is applied to the affected area twice a day for 12 weeks.
• the treatment results are evaluated at 2 week intervals until week 12 and then at 4 weeks after discontinuation of the study medication.
• Safety is evaluated by general history and physical signs, laboratory testing for hematology, serum chemistry, and urinalysis, and by evaluations of local application site tolerability parameters of erythema, scaling, dryness, stinging/burning utilizing a rating scale of “0” (None) to “3” (Severe).

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  • 2023-03-17 US US18/185,935 patent/US20230372279A1/en active Pending

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