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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • 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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• This invention relates to compositions for treating pain and methods of medical use.
• Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in such terms.
• Acute pain occurs as a result of tissue injury and is mediated by chemical, mechanical, or thermal stimulation of pain receptors known as nociceptors.
• chronic or persistent pain in itself constitutes a disease which serves no protective biological function.
• Chronic pain is unrelenting and can persist for years and frequently cannot be associated with a single injury.
• Chronic pain predominantly constitutes chronic inflammatory pain (e.g.
• Neurode arthritis or "neuropathic pain” which can be defined as pain initiated or caused by a primary lesion or dysfunction within the nervous system
• Neuropathic pain is associated with a variety of disease states and presents in the clinic with a wide range of symptoms (Woolf and Mannion Lancet 353:1959-64, 1999). It does not require specific pain receptor stimulation although such stimulation can add to the intensity of the pain sensation (Baron Clin J Pan 16 (suppl2):S12-S20, 2003).
• Neuropathic pain may result from disorders of the peripheral nervous system (e.g., peripheral neuropathies) or the central nervous system (i.e., brain and spinal cord).
• Peripheral neuropathies are classified by the number or type of nerves affected or the process affecting the nerves.
• the main classifications of peripheral neuropathy are mononeuropathy, mononeuritis multiplex, polyneuropathy, autonomic neuropathy, or neuritis.
• Peripheral neuropathies can be caused by many factors including genetic diseases, metabolic or endocrine disorders (e.g., diabetes), exposure to toxins (e.g., drugs, heavy metals), inflammatory diseases (e.g., systemic lupus erythematosis), vitamin deficiency (e.g., vitamin B12, vitamin A), physical trauma, certain infectious diseases (e.g., HIV, herpes simplex), cancer, radiation, and chemotherapy.
• genetic diseases e.g., metabolic or endocrine disorders (e.g., diabetes), exposure to toxins (e.g., drugs, heavy metals), inflammatory diseases (e.g., systemic lupus erythematosis), vitamin deficiency (e.g., vitamin B12, vitamin A), physical trauma, certain infectious diseases (e.g., HIV, herpes simplex), cancer, radiation, and chemotherapy.
• toxins e.g., drugs, heavy metals
• inflammatory diseases e.g., systemic
• Neuropathic pain can be characterized by the following clinical features (Teng and Mekhail Pain
• Pain may be felt in a region of sensory deficit.
• Non-noxious stimuli may be painful (allodynia).
• Noxious stimuli may produce greater than normal response (hyperalgesia).
• chemotherapeutic agents such as vincristine, taxol or oxaliplatin
• chemotherapeutic agents causes in most cases the development of dose-limiting chronic neurotoxicity.
• the toxic damage is made evident by ensuing neural dysfunctions such as mechanical and cold allodynia, ongoing burning pain, myalgias, tingling, and numbness (Cavaliere R. and Schiff D. 2006, Curr. Neurol. Neurosci. Rep. 6:218-26).
• the resulting pathological condition is also known as chemotherapy-induced peripheral neuropathy (CIPN).
• CIPN represents an important cause of discomfort and suffering in patients undergoing chemotherapy, which strongly limits the practical applicability of the latter.
• the interruption of chemotherapy is not a valid solution since it leads to worsening of the underlying disease while neurotoxicity is not necessarily removed, as it may persist or even worsen after discontinuation of medication.
• the degree of severity of CIPN depends not only on the drug, duration, and dose used but also on the total cumulative dose applied.
• CIPN is generally alleviated by dose reduction, which may compromise the efficacy of the chemotherapy treatment.
• Patients who already have neuropathic symptoms due to diabetes mellitus, hereditary neuropathies, or earlier treatment with neurotoxic chemotherapy are thought to be more vulnerable to the development of CIPN.
• the present invention provides methods and compositions which treat, alleviate, prevent, diminish or otherwise ameliorate the symptoms associated with peripheral neuropathies (e.g., neuropathic pain) in a subject.
• peripheral neuropathies e.g., neuropathic pain
• Reference to "neuropathic pain” includes the neuropathic component of nociceptive pain.
• the present invention contemplates a method for inducing an analgesic response to neuropathic pain in mammals, particularly humans, by using a novel method to topically administer anti-inflammatory agents.
• the invention provides an improvement to current methods for treating and preventing the symptoms of peripheral neuropathies including neuropathic pain. More specifically, the present invention relates to topically administering a therapeutically effective amount of a pharmaceutically safe therapeutic agent directly to the region exhibiting pain in a subject.
• the compositions and methods of the present invention do not induce overt sedation and/or reduce the side effects associated with agents used in the treatment of pain.
• the invention features a method for treating peripheral neuropathy or treating pain or a symptom associated with sunburn.
• This method includes administering to a subject in need thereof an effective amount of a topical composition including: a) a non-steroidal anti-inflammatory drug (NSAID), e.g., ketoprofen, in the amount of 1 to 15 percent (e.g., 1% to 5%, 4% to 9%, 8% to 12%, 11% to 15%) based on the weight of the composition; b) a non-basic polymeric skin penetration enhancer (e.g., a cross-linked polyacrylic acid interpolymer, a cross-linked polyacrylic acid homopolymer, or a mixture thereof) present in an amount sufficient to enhance skin penetration (e.g., 1.5 to 1.75 percent based on the weight of the composition) of the NSAID, the polymeric skin penetration enhancer being selected from a water-dispersable acid polymer, a polysaccharide gum, or a mixture thereof;
• NSAID
• the composition does not include an anesthetic (e.g., amethocaine, cocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, benzocaine, physostigmine, neostigmine, lidocaine, novocaine or procaine).
• anesthetic e.g., amethocaine, cocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, benzocaine, physostigmine, neostigmine, lidocaine, novocaine or procaine.
• the composition does not include benzyl alcohol.
• the composition of the method further includes d) a chelating agent (e.g., the disodium salt of ethylenediamineteraacetic acid) in the amount of 0.01 to 0.1 percent (e.g., 0.01 to 0.03, 0.02 to 0.04, 0.03 to 0.05, 0.04 to 0.06, 0.05 to 0.07, 0.06 to 0.08, 0.07 to 0.09, or 0.08 to 0.10) based on the weight of the composition.
• a chelating agent e.g., the disodium salt of ethylenediamineteraacetic acid
• any of the foregoing compositions of the method further include e) oxybenzone in the amount of 1 to 15 percent (e.g., 1% to 4%, 3% to 5%, 4%, to 6%, 5% to 7%, 6% to 9%, 8% to 10%, 9% to 11%, 10% to 12%, 11 % to 13%, 12% to 14%, 13% to 15%) based on the weight of the composition.
• oxybenzone in the amount of 1 to 15 percent (e.g., 1% to 4%, 3% to 5%, 4%, to 6%, 5% to 7%, 6% to 9%, 8% to 10%, 9% to 11%, 10% to 12%, 11 % to 13%, 12% to 14%, 13% to 15%) based on the weight of the composition.
• the concentration is less than 10% (w/w) (e.g., 1% to 9%, 1 % to 8%, 1% to 7%, 1% to 6%, 1% to 5%, 2% to 9%, 2% to 8%, 2% to 7%, 2% to 6%, 2% to 5%, 3% to 9%, 3% to 8%, 3% to 7%, 3% to 6%, or 3% to 5%).
• 10% w/w
• the concentration is less than 10% (w/w) (e.g., 1% to 9%, 1 % to 8%, 1% to 7%, 1% to 6%, 1% to 5%, 2% to 9%, 2% to 8%, 2% to 7%, 2% to 6%, 2% to 5%).
• any of the foregoing compositions of the method further include f) an emulsifying agent (e.g., PEG-40 hydrogenated castor oil) in the amount of 0.01 to 1 percent (e.g., 0.01% to 0.03%, 0.02% to 0.04%, 0.03% to 0.05%, 0.04% to 0.06%, 0.05% to 0.07%, 0.06% to 0.08%, 0.07% to 0.09%, or 0.08% to 0.10%) based on the weight of the composition.
• an emulsifying agent e.g., PEG-40 hydrogenated castor oil
• any of the foregoing compositions of the method include g) a water- miscible alkylene glycol (e.g., propylene glycol) in the amount of 7 to 12 percent (e.g., 7% to 9%, 8% to 10%, 9% to 11%, 10% to 12%) based on the weight of the composition.
• a water- miscible alkylene glycol e.g., propylene glycol
• any of the foregoing compositions of the method include h) a cosmetic preservative (benzyl alcohol) in the amount of 0.05 to 0.15 percent (e.g., 0.05% to 0.1%, 0.08% to 0.12%, 0.1 to 0.15%) based on the weight of the composition.
• a cosmetic preservative benzyl alcohol
• any of the foregoing compositions of the method include i) an antioxidant or mixture of antioxidants (e.g., Vitamin E, butylated hydroxytoluene, or a mixture thereof) in the amount of 1 to 1.1 percent based on the weight of the composition.
• an antioxidant or mixture of antioxidants e.g., Vitamin E, butylated hydroxytoluene, or a mixture thereof
• any of the foregoing compositions of the method include j) a pH modifier (e.g., triethanolamine) in an amount sufficient to maintain a pH value of the composition in the range of 4.5 to 6 (e.g., 4.5 to 5, 4.75 to 5.25, 5 to 5.5, 5.25 to 5.75, 5.5 to 6).
• a pH modifier e.g., triethanolamine
• the composition of the method includes a topical composition including a) about 10 percent NSAID (e.g., ketoprofen); b) about 1.25 percent of a cross-linked polyacrylic acid interpolymer and about 0.5 percent of a cross-linked polyacrylic acid homopolymer; c) about 19 percent of a mixture of one or more aliphatic alcohols (e.g., a mixture of about 10 percent ethanol and about 9 percent isopropanol) and about 3 percent of an aliphatic ester (e.g., isopropyl myristate); d) about 0.05 percent of a chelating agent (e.
• NSAID e.g., ketoprofen
• c) about 19 percent of a mixture of one or more aliphatic alcohols e.g., a mixture of about 10
• the disodium salt of ethylenediamineteraacetic acid e) about 10 percent oxybenzone; f) about 0.5 percent of an emulsifying agent (e.g., PEG-40 hydrogenated castor oil); g) about 10 percent of a water-miscible alkylene glycol (e.g., propylene glycol); h) about 1 percent of a cosmetic preservative (e.g., benzyl alcohol); i) about 1.05 percent of a mixture of antioxidants (e.g., a mixture of about 0.05 percent Vitamin E and 1 percent butylated hydroxytoluene); j) about 1.5 percent of a pH modifier (e.g., triethanolamine); k) and the rest water.
• an emulsifying agent e.g., PEG-40 hydrogenated castor oil
• g) about 10 percent of a water-miscible alkylene glycol e.g., propylene glycol
• the composition of the method includes a topical composition including a) about 5 percent NSAID (e.g., ketoprofen); b) about 1.25 percent of a cross-linked polyacrylic acid interpolymer and about 0.5 percent of a cross-linked polyacrylic acid homopolymer; c) about 19 percent of a mixture of one or more aliphatic alcohols (e.g., a mixture of about 10 percent ethanol and about 9 percent isopropanol) and about 3 percent of an aliphatic ester (e.g., isopropyl myristate); d) about 0.05 percent of a chelating agent (e.g., the disodium salt of ethylenediamineteraacetic acid); e) about 5 percent oxybenzone; f) about 0.5 percent of an emulsifying agent (e.g., PEG-40 hydrogenated castor oil); g) about 10 percent of a water-miscible alkylene glycol (e.g.,
• the non-steroidal anti-inflammatory drug is selected from the list consisting of aspirin, diflunisal, salsalate, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, para
• any of the foregoing compositions of the method further include gabapentin in the amount of 8 to 10 percent (e.g., 8% to 9%, 8.5% to 9.5%, 9% to 10%) by weight of the composition.
• the topical composition does not include benzyl alcohol.
• the topical composition is administered in combination with a systemically administered neuroprotective agent (e.g., calcium, magnesium, glutathione, glutamine, carbamaepine, oxycarbazepine, vitamin E, erythropoietin, allopregnanolone, valproate, alpha-lipoic acid, acetyl-L-carnitine or a combination thereof).
• a systemically administered neuroprotective agent e.g., calcium, magnesium, glutathione, glutamine, carbamaepine, oxycarbazepine, vitamin E, erythropoietin, allopregnanolone, valproate, alpha-lipoic acid, acetyl-L-carnitine or a combination thereof.
• the peripheral neuropathy is a compound selected from any of the foregoing methods.
• the peripheral neuropathy is chemotherapy induced peripheral neuropathy (CIPN) or diabetic neuropathy.
• CIPN chemotherapy induced peripheral neuropathy
• the symptom associated with sunburn is selected from the group consisting of: blisters, rashes, redness, swelling, tenderness, headaches, fevers, chills, or fatigue.
• the invention features a method for treating peripheral neuropathy or treating pain or a symptom associated with sunburn.
• This method includes administering to a subject in need thereof an effective amount of a topical composition including: a) a non-steroidal anti-inflammatory drug (e.g., a propionic acid derivative, e.g., ketoprofen, ibuprofen, naproxen, and salts thereof; or an acetic acid derivative, e.g., diclofenac, indomethacin, etodolac, and salts thereof) in an amount of about 1 to about 10 percent by weight (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, to 10%); b) lauryl lactate in the amount of about 1 to about 5 percent by weight (e.g., 1%, 2%, 3%, 4%, to 5%); c) lactic acid in an amount of about 0.5 to about 5 percent by weight
• the topical composition further comprises propylene glycol (e.g., in an amount of about 5 to about 30 percent by weight (e.g., 5%, 6%, 8%, 10%, 15%, 20%, 25%, to 30%), or a nonionic surfactant having an HLB value of at least 12 (e.g., alkoxylated alcohol) in an amount of about 0 to about 7 percent by weight (e.g., 0.5%, 1%. 1.5%, 2%, 2.5%, 3%, 3.5%. 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, to 7%).
• propylene glycol e.g., in an amount of about 5 to about 30 percent by weight (e.g., 5%, 6%, 8%, 10%, 15%, 20%, 25%, to 30%)
• a nonionic surfactant having an HLB value of at least 12 e.g., alkoxylated alcohol
• the watenethanol weight ratio of said carrier is in the range of about 0.3:1 to about 2.6:1 (0.3:1 , 0.5:1 , 0.8:1. 1 :1 , 1.3:1 , 1.5:1 , 1.8:1 , 2.0:1 , 2.2:1 , 2.3:1. to 2.6:1).
• the topical composition includes: a) about 5 percent by weight ketoprofen; b) about 3 percent by weight lauryl lactate; c) about 1.5 percent by weight lactic acid; d) about 3 percent by weight glyceryl monolaurate; e) about 3 percent by weight polyethylene glycol having a HLB value of about 15.7; f) about 10 perecent by weight propylene glycol; and g) a waterethanol weight ratio of about 1.7.
• administering refers to a method of giving a dosage of a pharmaceutical composition to a subject.
• the preferred method of administration may depend on a variety of factors, e.g., the components of the pharmaceutical composition and the nature and severity of the disease, disorder, or condition.
• administered in combination means administering to the patient a pair of active agents, the agents may be administered within 28, 21 , 14, 10, 7, 5, 4, 3, 2, or 1 days; within 24, 12, 6, 3, 2, or 1 hours; or substantially simultaneously.
• the term "anesthetic” refers to a compound or composition that result in anesthesia (i.e., reversible loss of sensation). Examples of include amethocaine, cocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, benzocaine, physostigmine, neostigmine, lidocaine, novocaine and procaine.
• compositions or components thereof are suitable for use in contact with dermal tissue without undue toxicity, incompatibility, instability, allergic response, and the like.
• compositions of the invention refers to a sufficient amount of a composition of the invention to exhibit the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the particular therapeutic agent and the like.
• the compositions of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
• dosage unit form refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific
• therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the condition being treated and the severity of the condition; the activity of the specific compounds employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compounds employed; the duration of the treatment; drugs used in combination or coincidental with the specific composition employed; and like factors well known in the medical arts.
• subject any animal (e.g., a primate, e.g., a human). Any animal can be treated using the methods, compositions, and kits of the invention.
• treatment refers to administering a composition of the invention or a combination therapy of the invention for therapeutic purposes.
• To "prevent or inhibit disease” refers to prophylactic treatment of a subject who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease or condition.
• To treat a condition" or use for therapeutic treatment refers to administering treatment to a subject already suffering from a condition to improve or stabilize the subject's condition.
• Beneficial or desired results can include, but are not limited to, alleviation or amelioration of a disease, a disorder, a condition, or one or more symptoms associated with a disease, a disorder, or a condition; diminishment of extent of disease, disorder, or condition; stabilization (i.e., not worsening) of a disease, disorder, or condition; delay or slowing the progress of a disease, disorder, or condition; and amelioration or palliation of a disease, disorder, or condition.
• Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
• prevention is meant that a prophylactic treatment is given to a subject who has or will have a disease, a disorder, a condition, or one or more symptoms associated with a disease, a disorder, or a condition.
• FIG. 1 A is a chart illustrating the effect of ELS-M11 against taxol-mediated nerve pain in mice, as measured by automated measurement of the avoidance in von Frey hair test.
• FIG. 1 B is a chart illustrating the effect of ELS-M11 against taxol-mediated nerve pain in mice, as measured by cold allodynia behavior in an acetone evaporative cooling test.
• the present disclosure relates to compositions and methods for the treatment of peripheral neuropathies.
• the present disclosure provides dermatologically acceptable compositions for topical administration that can alleviate the symptoms of peripheral neuropathies (e.g., chemotherapy induced peripheral neuropathy) or treating pain or a symptom associated with sunburn.
• the invention also provides combinations of these topical compositions and systemically administered neuroprotective agents to minimize the impact of chemotherapy induced peripheral neuropathy to improve the tolerability of chemotherapeutic agents.
• the methods and compositions of the invention can be used to treat peripheral neuropathy either by preventing the occurrence of pain or by treating one or more symptoms associated with peripheral neuropathy.
• the invention can be used to treat any type of peripheral neuropathy, including chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or idiopathic neuropathy.
• Symptoms and diagnosis of neuropathy can be readily determined by any parameters well known in the art, for example, as described in Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Douleur neuropathique 4 questions (DN4), the Neuropathic Pain Questionnaire (NPQ). Peripheral Neuropathy
• Peripheral neuropathy resulting from chemotherapy or other causes may manifest itself in a variety of ways.
• peripheral neuropathy from a single etiology may manifest differently in different patients. The most common is with sensory disturbances, including both the negative symptom of numbness and the positive symptoms of pain and paresthesias. The sensory symptoms most often start in the distal extremities in a 'glove-and-stocking' distribution. Motor symptoms may occur, usually manifesting as distal weakness such as a foot drop.
• autonomic symptoms may occur which can include orthostatic, cardiovascular, erectile or gastrointestinal disturbances. Autonomic neuropathy may be the hardest to diagnose accurately, and often these symptoms may occur in isolation and not in the presence of a generalized autonomic failure. For example, isolated orthostatic hypotension may be the only autonomic manifestation of vincristine neuropathy. However, autonomic dysfunction usually occurs in the setting of wide-spread peripheral neuropathy, which can range from mild to prominent.
• Peripheral neuropathy is classified according to the number of nerves affected, the type of nerve affected, or the process affecting the nerve.
• Mononeuropathy is classified according to the number of nerves affected, the type of nerve affected, or the process affecting the nerve.
• Mononeuropathy is the classification for peripheral neuropathy that affects a single nerve.
• the most common causes for mononeuropathy are a localized trauma or infection, such as compression of the nerve.
• Direct injury to a nerve, interruption of the blood supply of a nerve (i.e., ischemia), or inflammation are other causes of mononeuropathy. (Examples of conditions classified as
• mononeuropathies are carpal tunnel syndrome and other nerve compression syndromes, axillary nerve palsy, and ulnar neuropathy.
• Mononeuritis multiplex are peripheral neuropathies in which individual noncontiguous nerve trunks are simultaneously or sequentially involved. Mononeutits multiplex may involve deep, aching pain in the lower back, hip, or leg. Conditions that cause or are associated with mononeuritis multiplex include, diabetes mellitus, vasculitk.es, immune-mediated diseases such as rheumatoid arthritis, lupus erythematosus, and sarcoidosis, infections such as, leprosy, lyme disease, and human immunodeficiency virus, amyloidosis, cryoglobulinemia, exposure to certain chemical agents such as trichloroethylene and dapsone.
• diabetes mellitus vasculitk.es
• immune-mediated diseases such as rheumatoid arthritis, lupus erythematosus, and sarcoidosis
• infections such as, leprosy, lyme disease, and human immunodeficiency virus, amyloido
• Polyneuropathy is a pattern of nerve damage wherein many nerve cells in various parts of the body are affected. Polyneuropathy generally presents in one of three patterns, a) distal axonopathy, wherein the cell bodies of the neurons remain intact, but the axons are affected, a common pattern in diabetic neuropathy; b) demyelinating, wherein the myelin sheath around axons is damaged, affecting the ability of axons to control electrical impulses; and c) motor neuron disease or sensory neuronopathy wherein the cell bodies of the neurons are directly affected. Diabetes is the most common cause of polyneuropathy. Other causes include lyme disease, vitamin deficiencies, blood disorders, and exposure to toxins. Autonomic neuropathy
• Autonomic neuropathy is a particular form of polyneuropathy wherein the non-voluntary, non- sensory nervous system is affected. Autonomic neuropathy generally presents in combination with another form of neuropathy. Autonomic neuropathy generally affects internal organs such as the bladder, cardiovascular system, the gastrointestinal tract, and genital organs.
• Neuritis results from inflammation of a nerve or the peripheral nervous system in general.
• Symptoms of neuritis include pain, paresthesia, paresis, hypoesthesia, anesthesia, paralysis, wasting, and loss of relexes.
• Neuritis can have many causes, some exemplary causes are physical injury, infection (e.g., herpes simplex, shingles, leprosy, lyme disease), exposure to chemicals or radiation, diphtheria, diabetes, vitamin deficiencies, autoimmune disease (e.g., multiple sclerosis, Guillian-Barre syndrome), and cancer.
• Specific types of neuritis include polyneuritis, brachial neuritis, optic neuritis, vestibular neuritis, cranial neuritis, and arsenic neuritis.
• Chemotherapy Induced Peripheral Neuropathy CIPN
• Chemotherapy induced peripheral neuropathy is a condition that results from damage to peripheral nerves by chemotherapy drugs used in the treatment of various diseases (e.g., cancer).
• the most common symptoms of CIPN are pain, burning, tingling, loss of feeling, loss of dexterity, balance problems, increased sensitivity to pressure and/or temperature, decreased muscle mass and/or muscle weakness, trouble swallowing, constipation, retention of urine, blood pressure changes, and loss or lack of reflexes.
• CIPN generally affects both sides of the body equally (e.g., the stocking-glove distribution) and can begin anytime after treatment starts. The degree of severity of CIPN depends not only on the drug, duration, and dose used but also on the total cumulative dose applied.
• a pure sensory syndrome e.g., with cisplatin, oxaliplatin, carboplatin
• a mixed sensory-motor neurotoxicity with or without involvement of the autonomic nervous system (e.g., vincristine, taxol)
• previous administration or co-treatment with two or more neurotoxic agents further increases the incidence and severity of neurotoxic effects.
• cisplatin alone induced neurotoxic effects in 49% of patients (Bacon M. and et al. 2003, Int. J. Gynecol. Cancer 13:428-34), whereas when co-administered with paclitaxel, sensory neurotoxicity was observed in 91 % of patients.
• vlncristine-driven neuropathy is mainly characterized by motor and sensory insufficiency (mixed type of neuropathy). While the underlying mechanism is not fully understood as yet, it has been described to involve an alteration of anterograde axonal transport, ultimately leading to axonal degeneration.
• Cis-dichlorodiamine platinum (cisplatin) is the drug of choice for treatment of germ cell cancers. It is also used adjunctively for other solid tumors but the total dose that can be administered is limited by serious adverse effects including renal toxicity and peripheral neurotoxicity.
• the incidence of nephropathy, which was dose limiting, has been significantly reduced by chloride diuresis. Problems of peripheral neuropathy appear soon after the drug is introduced.
• the neuropathy is dose limiting and closely related to total cumulative drug dose. Significant peripheral neurotoxicity is apparent in the majority of adult patients who receive >400-500 mg/m 2 of cisplatin. The neuropathy is predominantly sensory with initial complaints of paresthesiae (abnormal sensation as burning, prickling, formication) in the distal extremities, which may progress to severe sensory ataxia. Neuropathological studies have shown loss of large myelinated fibers and evidence of axonal degeneration. The neuropathy may continue to progress for several months after cessation of cisplatin and symptoms may develop 3-8 wk after the last dose of chemotherapy (Thompson et al., (1984) Cancer. 54(7): 1269-75).
• Taxol is an effective chemotherapeutic agent extensively used in the treatment of solid tumors such as malignant melanoma and ovarian carcinoma. Nevertheless, peripheral neuropathy caused by taxol is increasingly becoming a dose-limiting problem in cancer treatment (Rowinsky E. K., Chaudhry V., Comblath D. R, Donehower R. C. Neurotoxicity of taxol (1993). Monogr. Natl. Cancer Inst. 107-115.). Taxol is a plant alkaloid that suppresses microtubule dynamics through binding to tubulin subunits, causing mitotic arrest in dividing cells (Derry W. B, Wilson L, Jordan M. A.
• NCS nerve conduction studies
• EMG electromyography
• Axonal damage (e.g., caused by a chemotherapeutic such as vincristine), manifests as decreased amplitude on NCS.
• Decreased conduction velocity or increased distal latency would suggest a demyelinating polyneuropathy, as seen in the neuropathy associated with multiple myeloma cancer, such a chronic inflammatory demyelinating polyneuropathy, which requires specific therapy or a polyradiculopathy from metastatic disease, which can be differentiated from peripheral neuropahty by NCS/EMG.
• NCS/EMG may help to determine the degree of nerve damage from CIPN, which may be used as a baseline and can then be followed if new symptoms develop.
• compositions of the invention are also useful in treating pain and symptoms associated with sunburn.
• Sunburn results from too much sun or sun-equivalent exposure. Mild and uncomplicated cases of sunburn usually result in minor skin redness and pain. Initially, the skin turns red about 2 to 6 hours after exposure and feels irritated, the peak effects are noted at 12 to 24 hours. More severe cases of sunburn, also called sun poisoning are complicated by severe skin burning and blistering, massive fluid loss (dehydration), electrolyte imbalance, and possible infection. With too much exposure, severe untreated sunburn can cause shock or poor circulation to vital organs.
• the compositions of the invention are useful for treating the symptoms of sunburn. Symptoms of sunburn include, but are not limited to: blisters, rashes, skin loss, pinkness or redness in skin, skin that feels warm or hot to the touch, tenderness headache, fever, chills and fatigue.
• administration of the compositions described herein to a subject with sunburn will speed up the recovery process and healing from the sunburn (e.g., by 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days) as compared to subjects treated by another method known in the art for treatment of sunburns or untreated subjects.
• the healing of sunburns can be assessed by any standard method known in the art, for example, visual minimal erythema dose (MED) readings, skin reaction measurements, constitutive colorimetric readings, or assessment of melanin pigmentation after UV irradiation by laser scanning confocal microscopy.
• MED visual minimal erythema dose
• a class of compounds useful in the invention are the non-Steroidal Anti-Inflammatory Drugs
• NSAIDs which provide analgesic and antipyretic (fever-reducing) effects, and, in higher doses, antiinflammatory effects.
• nonsteroidal distinguishes these drugs from steroids, which, among a broad range of other effects, have a similar eicosanoid-depressing, anti-inflammatory action.
• NSAIDs are unusual in that they are non-narcotic.
• NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present.
• the widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly prevalent.
• the two main adverse drug reactions associated with NSAIDs relate to gastrointestinal effects and renal effects of the agents. NSAIDs can be classified based on their chemical structure or mechanism of action.
• NSAID classification groups include: Salicylates (e.g., aspirin (acetylsalicylic acid), diflunisal, and salsa late), Propionic acid derivatives (e.g., ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, and loxoprofen), Acetic acid derivatives (e.g., indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, and nabumetone), Enolic acid derivatives (e.g., piroxicam, meloxicam, tenoxicam, droxicam, lomoxicam, and isoxicam), Fenamic acid derivatives (e.g., mefenamic acid, meclofenamic acid, flufenamic acid, and tolfena
• NSAIDs within a group tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. Rather, differences among compounds usually relate to dosing regimens, route of administration, and tolerability profile.
• ketoprofen is a non-steroidal propionic acid derivative. It has potent anti-inflammatory and analgesic activity. Conventionally, ketoprofen and other related drugs have been administered orally; however, this can be accompanied by systemic side effects and/or gastrointestinal irritation. In order to reduce these side effects, these drugs have been formulated as transdermal preparations. The skin permeability of these NSAIDs is known to be higher than other NSAIDs.
• anesthetics which are compounds or compositions that result in anesthesia (i.e., reversible loss of sensation). They differ from analgesics (e.g., NSAIDs) in that analgesics relieve pain without eliminating sensation.
• analgesics e.g., NSAIDs
• Anesthetics are classified into two groups: general anesthetics which result in a loss of consciousness and local anesthetics which result in a loss of sensation for a limited region of the body.
• Examples of local anesthetics include amethocaine, cocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, benzocaine, physostigmine, neostigmine, lidocaine, novocaine and procaine.
• Neuroprotective Agents include amethocaine, cocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, benzocaine, physostigmine, neostigmine, lidocaine, novocaine and procaine.
• neuroprotective agents which are compounds and compositions administered to prevent or slow the damage or loss of neurons.
• Clinical Pharmacology & Therapeutics 90(3):377-386 (2011)); these include, without limitation, calcium, magnesium, glutathione, glutamine, carbamaepine, oxxcarbazepine, vitamin E, erythropoietin, allopregnanolone, valproate, alpha-lipoic acid, acetyl-L-carnitine and combinations, such as calcium and magnesium infusions.
• compositions of the invention may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example, as described in "Remington: The Science and Practice of Pharmacy” (20th ed., ed. A. R. Gennaro, 2000, Lippincott Williams & Wilkins).
• concentration of at least one therapeutic agent in the formulation will vary depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration.
• the composition can be prepared in any useful method.
• at least one therapeutic agent is dissolved in ethanol and added to a mixture of polyethylene glycols (PEGs).
• the composition further includes a skin penetrating enhancer of a dimethyl alanine amide of medium chain fatty acids with carbon units varying between C12 and Cie.
• therapeutic agents alone or combinations thereof may be prepared in an ointment, cream, lotion, foam or spray form.
• unit dispensing would be preferred, where the unit dosage of the therapeutic agent and vehicle would be in the range of 100 mg to 1000 g and most preferred between 100 mg and 500 mg.
• the therapeutic agent in this composition by weight would be in the range of 1% to 30 % (w/w).
• the composition comprises between 1 %-3%, 2.5%-6%, 8%-12%, 10%-20%, or 20-30% (w/w) of at least one therapeutic agent.
• the therapeutic agent is present in the composition in an amount of at least 0.5%, at least 2%, at least 2.5%, at least 3%, at least 5%, or at least 10%, (w/w), and may be, for example, ketoprofen.
• the concentration of a therapeutic agent is less than 10% (w/w) (e.g., 1% to 9%, 1% to 8%, 1% to 7%, 1% to 6%, 1% to 5%, 2% to 9%, 2% to 8%, 2% to 7%, 2% to 6%, 2% to 5%, 3% to 9%, 3% to 8%, 3% to 7%, 3% to 6%, or 3% to 5%).
• 10% w/w
• the dosage of a compound or a combination of compounds depends on several factors, including: the administration method, the type of condition to be treated, the severity of the condition, whether administration first occurs at an early or late stage of the condition, and the age, weight, and health of the patient to be treated.
• the recommended dosage for the agents can be less than or equal to the recommended dose as given in the Physician's Desk Reference, 60 th Edition (2006).
• An agent is usually given by the same route of administration that is known to be effective for delivering it as a monotherapy.
• an agent is dosed in amounts and frequencies equivalent to or less than those that result in its effective monotherapeutic use.
• K is not intended that administration of compounds be limited to a single formulation or delivery method for all compounds of a combination.
• the combination can be administered using separate formulations and/or delivery methods for each compound of the combination using, for example, any of the above-described formulations and methods.
• a first agent is delivered topically, and a second agent is delivered orally.
• compositions of the invention can be provided in any useful form.
• the compositions of the invention may be formulated as solutions, emulsions (including micro emulsions), suspensions, sprays, creams, foams, lotions, gels, powders, or other typical solid, semi-solid, or liquid compositions used for application to the skin or other tissues where the compositions may be used.
• the preferred compositions may also be applied as a patch.
• compositions may contain other ingredients typically used in such products, such as colorants, fragrances, thickeners (e.g., xanthan gum, a fatty acid, a fatty acid salt or ester, a fatty alcohol, a modified cellulose, a modified mineral material, Krisgel 100TM, or a synthetic polymer), antimicrobials, solvents, surfactants, detergents, gelling agents, antioxidants, fillers, dyestuffs, viscosity-controlling agents, preservatives, humectants, emollients (e.g., natural or synthetic oils, hydrocarbon oils, waxes, or silicones), hydration agents, chelating agents, demulcents, solubilizing excipients, adjuvants, dispersants, skin penetrating enhancers, plasticizing agents, preservatives, stabilizers, demutsifiers, wetting agents, sunscreens, emulsifiers, moisturizers, astringents, deodorants, and optionally
• compositions can also include other like ingredients to provide additional benefits and improve the feel and/or appearance of the topical formulation.
• Specific classes of additives commonly use in these formulations include: isopropyl myristate, sorbic acid NF powder, polyethylene glycol, phosphatidylcholine (including mixtures of phosphatidylcholine, such as phospholipon G), Krisgel 100TM, distilled water, sodium hydroxide, decyl methyl sulfoxide (as a skin penetrating enhancer), menthol crystals, butylated hydroxytoluene, ethyl diglycol reagent, and 95% percent (190 proof) ethanol.
• compositions of the invention are sprays. Sprays are advantageous for patients having peripheral neuropathy relative to other topical formulations (e.g., gels and creams), as application of gels and creams to the skin of such patients can be painful.
• the compositions of the invention can have low dynamic viscosity (e.g., less than 1000 cP at 25 °C or less than 900 cP at 25 °C).
• the dynamic viscosity of the compositions of the invention can be at least 1 cP at 25 °C (e.g., at least 2 cP, at least 10 cP, at least 20 cP, at least 50 cP, or at least 100 cP).
• Non-limiting, exemplary ranges of the dynamic viscosity of the compositions of the invention are: 1 cP to 1000 cP, 1 cP to 900 cP, 2 cP to 1000 cP, 2 cP to 900 cP, 10 cP to 1000 cP, 10 cP to 900 cP, 20 cP to 1000 cP, 20 cP to 900 cP, 50 cP to 1000 cP, 50 cP to 900 cP, 100 cP to 1000 cP, or 100 cP to 900 cP).
• the compositions of the invention have a high water content (e.g., at least 15% (w/w), at least 20% (w/w), or at least 25% (w/w)).
• exemplary ranges for the water content of the compositions of the invention are: from 15% (w/w) to 60% (w/w), from 15% (w/w) to 50% (w/w), from 20% (w/w) to 60% (w/w), from 20% (w/w) to 50% (w/w), from 25% (w/w) to 60% (w/w), from 25% (w/w) to 50% (w/w), from 30% (w/w) to 60% (w/w), from 30% (w/w) to 50% (w/w), from 35% (w/w) to 60% (w/w), from 35% (w/w) to 50% (w/w), from 40% (w/w) to 60%(w/w), and from 40% (w/w) to 50% (w/w).
• High water content of the preferred compositions of the invention may be advantageous
• compositions of the invention do not leave an appreciable residue (e.g., leave no film).
• the therapeutic agents may be optionally administered as a pharmaceutically acceptable salt, such as a non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry.
• a pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. For example, S.M. Berge, etal. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference.
• the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below.
• a free base function can be reacted with a suitable acid.
• suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
• metal salts such as alkali metal salts, e.g. sodium or potassium salts
• alkaline earth metal salts e.g. calcium or magnesium salts.
• pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodkJe, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
• alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halkJe, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. earners
• compositions can be formulated using any dermatologically acceptable carrier.
• exemplary carriers include a solid carrier, such as alumina, clay, microcrystalline cellulose, silica, or talc; and/or a liquid carrier, such as water, an alcohol, a glycol, or a water-alcohol/glycol blend.
• the therapeutic agents may also be administered in liposomal formulations that allow therapeutic agents to enter the skin. Such liposomal formulations are described in U.S. Pat. Nos.
• Suitable vehicles of the invention may also include mineral oil, petrolatum, polydecene, stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, or vegetable oil.
• the composition can further include a skin penetrating enhancer, such as those described in "Percutaneous Penetration Enhancers", (eds. Smith EW and Maibach HI. CRC Press 1995).
• skin penetrating enhancers include alkyl ( ⁇ , ⁇ -disubstituted amino alkanoate) esters, such as dodecyl 2- (N,N dimethylamino) propionate (DDAIP), which is described in patent U.S. Pat. Nos.
• a water-dispersible acid polymer such as a polyacrylic acid polymer, a carbomer (e.g., CarbopolTM or Carbopol 940PTM, available from B. F.
• a "cross-linked polyacrylic acid homopolymer * suitable for present purposes is a high molecular weight polymer of acrylic acid cross-linked with polyalkenyl ethers of sugars or polyalcohols such as allyl sucrose, allyl pentacrythiritol, etc., such as Carbopol® 980 NF and the like.
• Carbopol® 980 NF is commercially available from Lubrizol Advanced Materials, Inc., Cleveland, Ohio.
• a "cross-linked polyacrylic interpolymer” suitable for present purposes is a high molecular weight copolymer of acrylic acid and Ci-C» alkylmethyacrylates cross-linked with polyalkenyl ethers of sugars or polyalcohols which contain a heterologous polymer, e.g., a block copolymer of polyethylene glycol and a long chain, e.g., Ci- C24 alkyl acid ester, such as Carbopol® Ultrez 10 NF, and the like.
• Carbopol® Ultrez NF is commercially available from Lubrizol Advanced Materials, Inc., Cleveland, Ohio.
• Suitable polymeric skin penetrating enhancers are cellulose derivatives, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose. Additionally, known transdermal penetrating enhancers can also be added, if desired. Illustrative are dimethyl sulfoxide (DMSO) and dimethyl acetamide (DMA), 2-pyrrolidone, N,N-diethyl-m-toluamide (DEET), 1-dodecylazacycloheptane-2-one (AzoneTM, a registered trademark of Nelson Research), ⁇ , ⁇ -dimethylformamide, N-methyl-2-pyrrolidone, calcium thioglycolate and other enhancers such as dioxolanes, cyclic ketones, and their derivatives.
• DMSO dimethyl sulfoxide
• DMA dimethyl acetamide
• 2-pyrrolidone 2-pyrrolidone
• biodegradable absorption enhancers which are alkyl ⁇ , ⁇ -2-
• Examples of skin penetrating enhancers useful in the present invention include isopropyl myristate; isopropyl palmitate; dimethyl sulfoxide; decyl methyl sulfoxide; dimethylalanine amide of a medium chain fatty acid; dodecyl 2-(N,N-dimethylamino) propionate or salts thereof, such as its inorganic (e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acid addition salts) and organic salts (e.g., acetic, benzoic, salicylic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, cyclohexanesulfamic, picric, and lactic acid addition salts), as described in U.S.
• inorganic e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric
• the skin penetrating enhancer in this composition by weight would be in the range of 0.5% to 10 % (w/w). The most preferred range would be between 1.0% and 5% (w/w). In another embodiment, the skin penetrating enhancer comprises between 0.5% -1%, 1%-2%, 2%-3%, 3%-4%, or4%-5%, (w/w) of the composition.
• Emulsifying agents are used to stabilize emulsions and include both a hydrophobic and hydrophilic component in their chemical structure. They can also aid in the dissolution of ingredients in a solvent in which they would not normally dissolve. Emulsifying agents generally concentrate at and are adsorbed onto the oihwater interface to provide a protective barrier around the dispersed droplets.
• Exemplary emulsifying agents include tragacanth, triethanolamine oleate, potassium oleate, sodium oleate, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, glyceryl monostearate, and polymers, such as Spans® (e.g., Span® 20, 40, 60, 65, 80, 85), Tweens® (e.g., Tween® 20, 21 , 40, 60, 61 , 65, 80, 81 , 85), PEG 400 Monoleate, PEG 400 monostearate, PEG 400 monolauarate, and PEG-40 hydrogenated castor oil (a polyethylene glycol derivative of castor oil).
• Spans® e.g., Span® 20, 40, 60, 65, 80, 85
• Tweens® e.g., Tween® 20, 21 , 40, 60, 61 , 65, 80, 81 , 85
• Emulsifying agents can be classified according to chemical structure or mechanism of action. All emulsifying agents must be chemically stable in the system, inert, and chemically non-reactive with other components of the composition, and nontoxic and nonirritant.
• synthetic emulsifying agents include benzalkonium chloride, benzethonium chloride, alkali soaps (e.g., sodium or potassium oleate), amine soaps (e.g., triethanolamine stearate), detergents (e.g., sodium lauryl sulfate, sodium dioctyl sulfosuccinate, sodium docusate), sorbitan esters (Spans®), polyoxyethylene derivatives of sorbitan esters (Tweens®), or glyceryl esters.
• alkali soaps e.g., sodium or potassium oleate
• amine soaps e.g., triethanolamine stearate
• detergents e.g., sodium lau
• hydrocolloid emulsifying agents examples include vegetable derivatives (e.g., acacia, tragacanth, agar, pectin, carrageenan, lecithin), animal derivatives (e.g., gelatin, lanolin, cholesterol), semi-synthetic agents (e.g., methylcellulose, carboxymethylcellulose), and synthetic agents (e.g., Carbopols®).
• vegetable derivatives e.g., acacia, tragacanth, agar, pectin, carrageenan, lecithin
• animal derivatives e.g., gelatin, lanolin, cholesterol
• semi-synthetic agents e.g., methylcellulose, carboxymethylcellulose
• synthetic agents e.g., Carbopols®
• solid particle emulsifying agents include bentonite, veegum, hectorite, magnesium hydroxide, aluminum hydroxide and magnesium trisilicate.
• Suitable water-miscible alkylene glycols are polyhydric alcohols such as glycerol, dipropylene glycol, polyethylene glycol, propylene carbonate, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, and the like.
• Propylene glycol is the preferred water-miscrible alkylene glycol.
• Propylene glycol is a colorless, nearly odorless, clear, viscous liquid. Propylene glycol acts as a solvent and antimicrobial in the present formulation. The freezing point of water is depressed when mixed with propylene glycol due to increased opportunity for hydrogen bonding. The total propylene glycol concentration should not exceed 12% w/w to avoid a negative effect on permeation and physical stability.
• Lipophilic solvents of the present invention may contain a mixture of one or more aliphatic alcohols (e.g., C2 to Ce monohydric alkanol alcohols) and one or more Ce to C30 aliphatic esters.
• aliphatic alcohols e.g., C2 to Ce monohydric alkanol alcohols
• Ce to C30 aliphatic esters e.g., Ce to C30 aliphatic esters.
• a lipophilic solvent may be one or more Ce to C30 aliphatic esters.
• Suitable monohydric alkanol alcohols are C2 and C3 alkanols such as ethanol, propanol, isopropanol, and the like.
• Isopropyl alcohol and ethyl alcohol are colorless, flammable, chemical compounds. They are miscible in water, alcohol, ether and chloroform. Isopropyl alcohol and ethyl alcohol dissolve a wide range of non-polar compounds. They also evaporate quickly and are relatively non-toxic, compared to alternative solvents. In the present composition, isopropyl alcohol and ethyl alcohol act as solvent and permeation enhancers.
• Suitable aliphatic esters are lauryl lactate, propylene glycol laurate, isopropyl myristate, isopropyl palmitate, propylene glycol caprylate, lanolin, and the like.
• Lauryl lactate, propylene glycol laurate, and isopropyl myristate are the preferred aliphatic esters.
• Lauryl lactate and propylene glycol laurate are the particularly preferred aliphatic esters.
• isopropyl myristate can act as a solvent, stabilizer, as well as an emollient.
• the composition of the invention contains 10% (w/w) to 60% (w/w) of the one or more aliphatic alcohols (e.g., 10% (w/w) to 50% (w/w), 10% (w/w) to 40% (w/w), 20% (w/w) to 60%
• the composition of the invention contains 1% (w/w) to 10% (w/w) of the one or more aliphatic esters (e.g., 1% (w/w) to 6% (w/w), 2% (w/w) to 10% (w/w), 2% (w/w) to 6% (w/w),
• the alcohols present in the compositions contribute to skin permeation; however, the total monohydric alcohol concentration is preferably 50% (w/w) or less (e.g., 45% (w/w) or less, 40% (w/w) or less, or 35% (w/w) or less) to maintain optimum skin permeation.
• the composition can further include a cosmetic preservative, such as those described in "Preservatives for Cosmetics, 3 rd Edition", (Steinberg, D. C. Allured Pub. Corp. 2012).
• Suitable cosmetic preservatives are the parabens such as methylparaben, propylparaben, butylparaben, phenol derivatives such as phenoxyethanol, benzyl alcohol, and the like. Benzyl alcohol is the preferred preservative.
• Benzyl alcohol is partially soluble in water and completely miscible in alcohols and diethyl ether. Benzyl alcohol acts as a bacteriostatic preservative in the present compositions.
• Oxybenzone ((2-Hydroxy-4-methoxyphenyl)-phenylmethanone), molecular formula C14H12O3, absorbs UVB and UVA (ultraviolet) radiation. It forms colorless crystals that are readily soluble in most organic solvents and contributes to the photostability of the composition.
• Antioxidants are included in pharmaceutical formulations to enhance the stability of therapeutic agents that may be susceptible to chemical degradation by oxidation. Antioxidants are typically molecules that exhibit higher oxidative potential than the therapeutic agent or inhibit free radical-induced drug decomposition.
• Exemplary antioxidants include ascorbic acid derivatives (e.g., ascorbic acid, erythorbic acid, sodium ascorbate), thiol derivatives (e.g., thioglycerol, cysteine, acetylcysteine, cystine, dithioerytheritol, dithiothreitol, glutathione), buthylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sulfurous acid salts (e.g., sodium sulfate, sodium bisulfite, acetone sodium bisulfite, sodium metabisulfrte, sodium sulfite, sodium formaldehyde sulfoxylate, sodium thiosulfate), nord
• Vitamin E refers to a group of eight fat-soluble compounds that include both tocopherols and tocotrienols. Vitamin E has many biological functions; the antioxidant function being one of the most important and best known. It acts as such in the present compositions.
• Butylated hydroxytoluene (BHT) is a lipophilic organic compound, chemically a derivative of phenol. It acts as an antioxidant and antimicrobial compound in the present composition.
• Chelating agents are scavengers for trace amounts of metal ions. Most commonly chelation involves a metal ion. Compounds which have this ability are known as chelating agents or chelating ligands. Many reactions, including many oxidation and decomposition reactions, are catalyzed by trace amounts of metallic ions present in formulations. Many drugs can be degraded through oxidation and hydrolytic reactions which are catalyzed by metal ions. The presence of metallic ions can therefore significantly accelerate the degradation of these drugs. Chelating agents are useful in preventing degradation for drugs in formulations. EDTA (ethylene diamine tetraacetic acid) and its salts are examples of powerful chelating agents. EDTA is known to stabilize drugs in solution by retarding their oxidation. Exemplary chelating agents include EDTA, a salt of EDTA (e.g., the disodium salt of EDTA), deferoxamine, sodium
• diethyldithiocarbamate diethyldithiocarbamate, penicillamine, pentetate calcium, a sodium salt of pentetic acid,
• dimercaptosuccinic acid triethylenetetramine, nitrilotriacetic acid, irans-diaminocyclohexanetetraacetic acid (DCTA), diethylenetriaminepentaacetic acid, / ⁇ /s(aminoethyl)glycolether-N,N,N',N'-tetraacetic acid, iminodiacetic acid, acetic acid, tartaric acid, fumaric acid, or a salt thereof.
• DCTA irans-diaminocyclohexanetetraacetic acid
• Edetate disodium is also known as the disodium salt of ethylenediaminetetraacetic acid (EDTA).
• EDTA is available in several salt forms, notably disodium EDTA and calcium disodium EDTA.
• EDTA is mainly used to sequester metal ions in aqueous solution. In personal care products, it is added to cosmetics to improve their stability toward air. It acts as a chelating agent that helps bind free radicals and impurities in the present composition. pH Modifiers
• Exemplary pH modifiers include aceitic acid, adipic acid, ammonium carbonate, ammonium hydroxide, ammonium phosphate, boric acid, citric acid, diethanolamine, fumaric acid, hydrochloric acid, malic acid, nitric acid, propionic acid, potassium acetate, potassium bicarbonate, potassium chloride, potassium citrate, potassium metaphosphate, potassium phosphate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium chloride, sodium citrate, sodium glycolate, sodium hydroxide, sodium lactate, sodium phosphate, sodium proprionate, succinic acid, sulfuric acid, tartaric acid, triethanolamine, or
• Triethanolamine is an organic compound that is both a tertiary amine and a triol. Like other amines, triethanolamine is a base and functions as a pH modifier in the present composition.
• Triethanolamine is used primarily as an emulsifier and surfactant. Triethanolamine neutralizes fatty acids, adjusts and buffers the pH, and solubilizes oils and other ingredients that are not fully soluble in water. Administration
• compositions in liquid form can be applied from absorbent pads; used to impregnate bandages and other dressings, or formulated as topical sprays.
• composition in solid form including semi-solid form, can be applied from a tube; or be applied directly onto the skin of the subject.
• composition in liquid form or solid form can be applied by using an applicator to spread the composition onto the skin.
• the composition may also be applied to the skin under occlusive dressing in a dermal delivery system (e.g., a transdermal patch).
• a composition is preferably applied to the skin as an ointment via an applicator containing at least one therapeutic agent on a swab applicator.
• the composition may be applied as a lotion, spray or foam from a tube or tin.
• the compositions can include a clear aqueous ethanolic solution prepared by first combining the therapeutic agent or combinations of one or more therapeutic agents (e.g., a NSAID, such as, ketoprofen, ibuprofen, naproxen and salts thereof, pizoxicam, meloxicam, tenoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, or celecoxib) in an amount in the range of about 1 to about 10 percent by weight, preferably about 5 percent by weight, based on the total weight of the solution, with lauryl lactate, lactic acid, and glyceryl monolaurate and dissolving the obtained admixture by gradual addition, at ambient temperature of alternating aliquots of water and ethanol, followed by the addition of propylene glycol.
• a NSAID such as, ketoprofen, ibuprofen, naproxen and salts thereof
• pizoxicam meloxicam
• tenoxicam mefen
• a non-ionic surfactant can also be used and can be added to the admixture prior to the addition of water or ethanol.
• the composition is applied as a lotion from a droptainer dispenser for larger volumes.
• the composition may be applied using the fingers to rub the composition onto the skin.
• a transdermal patch with the composition or at least one therapeutic agent can also be used and applied.
• compositions and methods of the invention can include formulatk>n(s) of compound(s) that, upon administration to a subject, result in a concentration of the compound(s) that treats peripheral neuropathy.
• the compound(s) may be contained in any appropriate amount in any suitable carrier substance, and are generally present in an amount of 2.5-15% by weight of the total weight of the composition.
• the composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously or intramuscularly), rectal, dermatological, cutaneous, nasal, vaginal, inhalant, skin (patch), ocular, intrathecal, or intracranial administration route.
• the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
• the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
• compositions according to the invention or used in the methods of the invention may be formulated to release the active compound immediately upon administration or at any predetermined time or time period after administration.
• the latter types of compositions are generally known as controlled release formulations, which include (i) formulations that create substantially constant concentrations of the agent(s) of the invention within the body over an extended period of time; (ii) formulations that after a predetermined lag time create substantially constant concentrations of the agent(s) of the invention within the body over an extended period of time; (iii) formulations that sustain the agent(s) action during a predetermined time period by maintaining a relatively constant, effective level of the agent(s) in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the agent(s) (sawtooth kinetic pattern); (iv) formulations that localize action of agent (s), e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ; (v) formulations that achieve convenience of dosing, e.
• Administration of therapeutic agents in controlled release formulations may be useful where the therapeutic agent has (i) a narrow therapeutic index (e.g., the difference between the plasma
• concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; (ii) a narrow slow absorption rate by or through the epithelium and/or dermis; or (iii) a short biological half-life, so that frequent dosing during a day is required in order to sustain a therapeutic level.
• controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings.
• the compound(s) are formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the compound(s) in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, molecular complexes, microspheres, nanoparticles, patches, and liposomes.
• Mixture A In a suitable vessel, EDTA (5g) was dissolved in purified water (5,500g) with stirring. To the solution of EDTA in water, Carbopol 980 NF (50g) was added with vigorous stirring until completely dissolved. Subsequently, Carbopol Ultrez (125g) was added with vigorous stirring until completely dissolved.
• Mixture B In a separate vessel, Cremophor (50g), a-tocophenol acetate oil (5g), ethyl alcohol (1g), propylene glycol (1 ,000g), isopropyl alcohol (900g), isopropyl myristate (300g), and benzyl alcohol (100g) were mixed together with stirring.
• Mixture A In a suitable vessel, EDTA (5g) was dissolved in purified water (5,500g) with stirring. To the solution of EDTA in water, Carbopol 980 NF (50g) was added with vigorous stirring until completely dissolved. Subsequently, Carbopol Ultrez (125g) was added with vigorous stirring until completely dissolved.
• Mixture B In a separate vessel, Cremophor (50g), a-tocophenol acetate oil (5g), ethyl alcohol (1g), propylene glycol (1 ,000g), isopropyl alcohol (900g), and isopropyl myristate (300g) were mixed together with stirring.
• oxybenzone (500g) and BHT (100g) were added at 30- 40°C with stirring until completely dissolved.
• Mixture B was then added to mixture A with vigorous stirring.
• a solution of triethanolamine (100g) in purified water (115g) was added with vigorous stirring.
• a solution of Methanol amine (50g) in purified water (100g) was added until the pH was between 4.5-5.5 or purified water (100g) was added if the pH was already between 4.5-5.5.
• the mixture was homogenized with a high viscosity mixer. This gel base was used to formulate the therapeutic agents into final formulations.
• the topical compositions prepared in this example are clear, sprayable, aqueous ethanolic solutions including a nonsteroidal anti-inflammatory drug (NSAID).
• NSAID nonsteroidal anti-inflammatory drug
• the aqueous spray solutions in this example contain the NSAID in the range of about 1 to about 10 percent by weight, preferably about 5 percent by weight.
• the aqueous spray solution also contains lauryl lactate (C15H30O3) in the range of about 1 to about 5 percent by weight, lactic acid (CaHeOs) in the range of about 0.5 to about 5 percent by weight, glyceryl monolaurate (C15H3O4) in the range of about 2 to about 5 percent by weight.
• the aqueous spray solution optionally includes propylene glycol (CsHeCfe) in the range of about 5 to about 30 percent by weight.
• the remainder of the solution is constituted by water and ethanol in the range of about 0.3:1 to about 2.6:1 watenethanol.
• the aqueous spray solution can also include a nonionic surfactant having a hydrophile-lipophile balance (HLB) value of at least 12.
• the nonionic surfactant can be polyethylene glycol ether of cetyl alcohol represented by the formula (CH3(CH2)i4CH2(OCH2CH2)nOH, where n has an average of 10, and having a HLB value of about 15.7.
• the aqueous spray solution is prepared by first combining the NSAID with lauryl lactate, lactic acid, and glyceryl monolaurate, and dissolving the mixture by gradual addition, at ambient temperature, of alternating aliquots of water and ethanol, followed by the addition of propylene glycol.
• the nonionic surfactant is added, if desired, to the mixture prior to the addition of water and ethanol.
• the following tables provide the components by weight percentage of aqueous spray formulations with various therapeutic agents.
• 1 Swiss ReliefTM spray gel contains 4 wt% dclofenac sodium together with inactive ingredients isopropyl alcohol, soy bean lecithin, ethanol, dsodium phosphate, dodecahydrate, sodium dhodrogen phosphate dehydrate, sodium edetate, propylene glycol, peppermint oil, ascorbyl palmrtate, hydrochloric acid (10% w/w), sodium hydroxide (10% w/w), and purified water.
• mice Mouse model of PIPN - C57BL6j mice were exposed to paclltaxel (4 mg kg bw) by 5 Injections on days 1 , 3, 5, 7 and 9, following an established protocol for induction of clinically-relevant PIPN in mice REF.
• Mice were treated daily with topical-transdermal applications to hind-paws, starting day 1 until 0 euthanasia on day 15.
• One group of mice were treated with ELS-M11 , the control group with vehicle control.
• sensory withdrawal thresholds for mechanical cues, cold-induced no cifensive behavior, and conditional place preference - a pain-dependent choice behavior in freely moving animals - were measured on days 4 and 15. The results are illustrated in FIGs. 1 A and 1 B.
• ELS-M11 is disclosed in WO 2014 052313 and is registered under the trademark TOPOFENTM.

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