WO2013067591A1 - Formulations topiques pour gestion de la douleur - Google Patents

Formulations topiques pour gestion de la douleur Download PDF

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WO2013067591A1
WO2013067591A1 PCT/AU2012/001379 AU2012001379W WO2013067591A1 WO 2013067591 A1 WO2013067591 A1 WO 2013067591A1 AU 2012001379 W AU2012001379 W AU 2012001379W WO 2013067591 A1 WO2013067591 A1 WO 2013067591A1
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pain
neuropathy
drug
opioid
topical
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PCT/AU2012/001379
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English (en)
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Kathy NIELSEN
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Relevare Australia Pty Ltd
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K9/08—Solutions
    • 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
    • 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
    • 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
    • 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

Definitions

  • the present disclosure relates generally to the field of pain management, including methods and formulations for the topical management of pain, such as localized pain ' .
  • the present disclosure further teaches combination therapy to topically ameliorate more intense levels of pain.
  • Pain is a sensory and emotional experience of varying levels of intensity associated with actual or potential tissue or nerve damage. Pain can range in severity (mild, moderate or severe) and duration (acute or chronic). In considering approaches to treat pain, there is a distinction between acute pain and chronic or persistent pain. Acute pain occurs as a result of tissue injury, and is of short duration, generally less than a month but may last a few months. Acute pain is mediated by chemical, mechanical or thermal stimulation of pain receptors known as nociceptors. This type of pain is referred to a nociceptive pain. In contrast to acute nociceptive pain, chronic or persistent pain in itself constitutes a disease, extending long after an injury has healed, and typically results from a chronic illness or appears spontaneously and persists for undefined reasons and frequently cannot be associated with a single injury.
  • chronic pain include chronic lower back pain and pain resulting from bone cancer and advanced arthritis.
  • chronic pain predominantly constitutes neuropathic pain which can be defined as pain initiated or caused by a primary lesion or dysfunction within the nervous system (Mersky & Bogduk (1994) Classifications of Chronic Pain, 2 nd edn. Seattle IASP Press: 394; De Andres & Garcia-Ribas, (2003) Pain Practice 5:1-7).
  • Neuropathic pain is associated with a variety of disease states and patients present in the clinic with a wide range of symptoms (Wool & Mannion (1999) Lancet 555:1959-64). It does not require specific pain receptor stimulation although such stimulation can add to the intensity of the pain sensation (Baron, (2003) Clin J Pan 16 (72):S12-S20).
  • Opioids have been used in pain management, however, the dose response curves for the treatment of neuropathic pain are shifted to the right of those for the treatment of nociceptive pain (Teng and Mekhail (2003), Pain Practice 5:8-12; De Andres and Garcia- Ribas, (2003) supra; Suite et al. (2003) J. Pain Symptom Management 25:1 123-1 131). Due to the diminished effects of opioids in subjects suffering from more intense neuropathic pain, the use of opioids is often frequent and sustained. This over use can be associated with addiction, the development of tolerance and an increase in the number and severity of side effects associated with opioid use.
  • the skin is innervated with around one million afferent nerve fibres with most terminating in the face and extremities.
  • the cutaneous nerves contain axons with cell bodies in the dorsal root ganglia.
  • the main nerve trunks entering the subdermal fatty tissue each divide into smaller bundles and groups of myelinated fibers fan out in a horizontal plane to form a branching network from which fibres ascend, usually accompanying blood vessels, to form a mesh of interlacing nerves in the superficial dermis.
  • the axons are enveloped in Schwann cells and as they run peripherally, an increasing number lack myelin sheaths.
  • Nerve fibres course into the skin through the dermis, and many of them end at the dermal-epidermal border where many of the sensory receptor structures are located. Most end in the dermis; some penetrate the basement membrane, but do not travel far into the epidermis. Thus, for topically applied analgesic drugs to be effective, they must be transported through the stratum corneum to reach the dermis, rich in nerve fibres. Distribution into deep tissue can occur though local blood vessel distribution, where lipophilic drugs may accumulate to serve as depot reservoirs. While transfer of drugs into general circulation does occur to some extent (depending on the nature of the drug and the topical formulation), systemic absorption of drugs topically applied is often slow and incomplete and this first-pass metabolism is largely avoided.
  • topical administration can be particularly advantageous in that relatively high concentrations of the active drug can be obtained at or around the local sites of application.
  • the low concentrations found in plasma after topical administration relative to those found after oral or iv administration means that the risks of systemic effects contributing to adverse reactions is low.
  • topically applied NSAIDs have lower incidence of gastrointestinal (GI) adverse effects than tablet formulations.
  • Administration of physiologically active agents through topical application is useful as it provides a simple dosing regime and also provides a relatively slow and controlled route for release of a physiologically active agent into the systemic circulation.
  • agents applied topically specifically for analgesia include capsaicin, local anesthetics (e.g, lidocaine), rubefacients or counterirritants (e.g, menthol, camphor, others), and herbal products (e.g, arnica, comfrey, and others).
  • Opioid analgesics are also considered useful in topical formulation as inflammatory as from animal and human clinical studies support the involvement of peripheral opioid receptors in analgesia, especially in the presence of inflammation.
  • Lidoderm a patch containing 5% w/w lidocaine, a Na + Channel blocker which acts as a local anaesthetic, is indicated for post-herpetic neuralgia (PHN) and Qutenza, a patch formulation containing 8% w/w capsaicin which is a TRPV1 channel agonist, is also indicated for PHN.
  • PPN post-herpetic neuralgia
  • Qutenza a patch formulation containing 8% w/w capsaicin which is a TRPV1 channel agonist
  • Flupirtine is a centralling acting, non-opioid analgesic that is marketed in Germany for various pain states, including musculoskeletal pain and has been proposed for use in the treatment of various neuropathic pain states and for fibromyalgia. It belongs to the triamino pyridine class and has analgesic as well as muscle relaxant and anticonvulsant activity (Friedel and Fitton (1993) Drugs 45 (4) :54&-569; Devulder (2010) CNS Drugs 24(70 ⁇ :867-881).
  • Flupirtine is available as the maleate salt (2-amino-6-(4-fluoro- benzylamino)-pyridin-3-yl)-carbamic acid ethyl ester) and is only available for oral or rectal administration.
  • Retigabine (Ethyl 2-amino-4-(4-fluorobenzylamino) phenylcarbamate), is a closely related analogue of flupirtine, has recently been approved as Potiga® for the approved for the treatment of partial seizures, the most common type of seizure seen in people with epilepsy. It has also been proposed for the treatment of neuropathic pain. Retigabine is only available as an oral medication. A review of retigabine and its clinical potential is provided in Blackbum-Munro et al. (2005) CNS Drug Reviews 11 (7,): 1-20.
  • K v 7 channels The mechanism by which flupirtine and retigabine, exert their analgesic action is through enhancement of the "M" current which is the current transmitted by a family of potassium channels variously termed G-coupled Inwardly Rectifying potassium (GIRK) channels, KCNQ channels (with the standardisation of nomenclature, these channels are referred to as K v 7 channels).
  • GIRK G-coupled Inwardly Rectifying potassium
  • KCNQ channels with the standardisation of nomenclature, these channels are referred to as K v 7 channels.
  • This enhancement of neural v 7 channel activity causes a hyperpolarizing shift in the voltage gating to reduce neural excitability and inhibit nociceptive stimulation and transmission.
  • K v 7 channel openers offer broad scope of therapeutic potential since they can potentially reduce any form of excitation in nerve cells that possess v 7, not just excitation that results from M-channel inhibition.
  • K v 7 openers Other more serious side effects of this class of K v 7 openers are adverse bladder effects, especially urinary retention which has been highlighted as a side effect of retigabine (Potiga [Registered]) by regulatory agencies and may result in a requirement for increased patient monitoring. It has been postulated that the expression of K v 7.4 in the bladder is responsible for these side effects (Rode et al. (2010) Eur. J. Pharm. 638, 121-127). Flupirtine has also been reported to elicit urinary retention and there are cases of green-tinged urine after flupirtine administration at high doses (Hufschmidt et al. (2009) J. Neurol. 256, 1 169-1 170).
  • liver toxicity related to flupirtine administration (Puis et al. (201 1) Virchows Arch 458:109-716). As liver toxicity is the primary reason for drug withdrawals, it is necessary to reduce or eliminate the frequency of such events. An important observation is that these side effects of flupirtine and retigabine are due to systemic effects resulting from oral or rectal administration.
  • v 7 openers such as retigabine and flupirtine which provide efficacious doses, but with reduced side effects.
  • K v 7 channel openers such as retigabine and flupirtine achieve efficacy though routes of administration that provide significant plasma concentrations, however, it has been recognized in accordance with the present disclosure that these agents can achieve efficacy in certain conditions with low or reduced plasma concentrations.
  • a topical formulation is an alternative method of drug delivery for v 7 channel openers, which can deliver appropriate dosage to a localized site to provide an analgesic effect while minimising and/or slowing eliminating systemic circulation.
  • topically applied Kv7 openers include minimal adverse events, ease of application and suitability for self administration, improved patient compliance, reduced drug-to-drug interactions and the potential to combine with systemically-delivered analgesics such as opioids to treat a broad range of nociceptive and peripheral neuropathic conditions.
  • K v 7 channel openers can be formulated in a topical formulation such that these agents are able to permeate through the stratus corneum and to the site of action to provide an analgesic effect which is useful in treating numerous pain conditions. It has also been found that these agents can be combined in a topical formulation with other analgesics such as opioids to provide a stronger analgesic effect useful for moderate-to-severe pain conditions common in acute, chronic and neuropathic pain.
  • the instant specification teaches, therefore, methods and topical compositions useful in the treatment, alleviation, prevention, diminishment or amelioration of pain in a subject.
  • Taught herein is a method for inducing an analgesic response to pain in a subject comprising topically administering to the subject an amount of a v 7 potassium channel opener or a pharmaceutically acceptable salt, derivative, homolbg, analog or pro-drug thereof suitable for topical use.
  • This aspect is suitable for mild to moderate levels of pain including nociceptive pain arising from conditions such as musculoskeletal pain, headaches, joint pain, osteoarthritic pain, back pain and the like. For more intense pain, i.e.
  • the K v 7 potassium channel opener can be used in combination with an opioid effective to reduce the level of or otherwise ameliorate the sensation of pain.
  • an opioid effective to reduce the level of or otherwise ameliorate the sensation of pain.
  • This aspect is suitable for chronic pain conditions, both neuropathic and nociceptive including peripheral neuropathic pain, post-operative pain and the like such as diabetic peripheral neuropathy (DPN), post-herpetic neuralgia (PHN), severe osteoarthritic pain and chemotherapy-induced pain and tumor pain and other pain types.
  • DPN diabetic peripheral neuropathy
  • PPN post-herpetic neuralgia
  • severe osteoarthritic pain severe osteoarthritic pain
  • chemotherapy-induced pain and tumor pain and other pain types such as chemotherapy-induced pain and tumor pain and other pain types.
  • higher dosages of the Kv7 opener may be used on its own without an opioid to treat moderate to intense pain.
  • the K v 7 potassium channel opener is also suitable for other conditions that are often associated with neuropathic and musculoskeletal pain such as fibromyalgia, or mixed nociceptive/neuropathic pain such as cancer related pain or back pain.
  • the v 7 potassium channel opener and optionally the opioid may be topically administered to the site of the sensation of pain or remote thereto.
  • the topical delivery reduces the risk of adverse side effects exhibited by direct systemic administration such as oral or intravenous delivery.
  • a K v 7 potassium channel opener and an opioid when both a K v 7 potassium channel opener and an opioid are used they may be co-administered to the same site or to proximal but separate sites.
  • the v 7 potassium channel opener may be administered separately as an adjunct opioid treatment where such opioid is administered orally, intravenously or through other routes of administration.
  • the composition containing the v 7 potassium channel opener as the active pharmaceutical ingredient may be in any of a range of forms including a lotion, ointment, paste, cream, gel, compress, spray, foam, dispersion,, solution, mist, impregnated bandage, patch, emulsion, suspension, applicator, dipstick, mouth wash or nasal or other spray.
  • the composition may contain both a v 7 potassium channel opener and an opioid in a single composition or separate compositions may be employed each with one or other of the K v 7 potassium channel opener or the opioid. Both compositions may then be combined on use or administered separately as required.
  • the pain is localized pain.
  • the K v 7 potassium channel opener alone or in combination with an opioid further comprises use of a dermal penetration enhancer.
  • the v 7 potassium channel opener may also be referred to as K v 7 voltage-gated K+ channel opener, a CNQ channel opener, a GIRK opener or an M type K+ channel opener.
  • the Kv7 potassium channel opener may also be referred to as an agonist or gating modifier.
  • the potassium channel subtype may be denoted by any or each of CNQ2, CNQ3, CNQ3, KCNQ4, KCNQ5 etc or equivalently as K v 7.2, K v 7.3, K v 7.4, v 7.5 etc.
  • K v 7 potassium channel openers contemplated herein are flupirtine, retigabine and their pharmacologically acceptable salts, derivatives, homologs, analogs and pro-drugs as well as other gating modulators such as toxin- and non-toxin based molecules which target the voltage-sensitive domain of the v 7 channel.
  • the K v 7 potassium channel opener is more selective towards v 7.2-7.5 subtypes, compared to V7.I subtypes.
  • the K v 7 potassium channel opener is selected from flupirtine, retigabine and a pharmaceutically acceptable salt, derivative, homolog, analog or pro-drug thereof suitable for topical use; bicyclic analogs of retigabine disclosed in Patent Application Nos. mx/a/2009/005652, 198905, US2007024607, 1020097013070, WO/2008/066900; CNQ channel openers described in Patent Application Nos. PA/a/2003/005497, PA/a/2003/003339, WO/2002/080898, WO/2002/0496283 and WO/2001/022953 and Kv7 openers described in Wu et al. (2003) J. Med. Chem.
  • the present disclosure enables a method of inducing an analgesic response in a subject suffering pain by topically administering to the subject a v 7 potassium channel opener such as flupirtine or retigabine or a pharmaceutically acceptable salt, derivative, homolog, analog or pro-drug thereof suitable for topical use, and optionally concurrently, separately or sequentially with an opioid, such as but not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dexocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, di
  • This aspect is particularly but not exclusively useful in the amelioration of moderate to intense pain.
  • the analgesic response is induced by the topical application of a K v 7 potassium channel opener such as flupirtine or retigabine or a pharmaceutically acceptable salt, derivative, homolog, analog or pro-drug thereof suitable for topical use.
  • the present specification is instructional on the use of a K v 7 potassium channel opener alone or in combination with an opioid in the man facture of a topical medicament for inducing an analgesic response in the treatment of pain in a subject.
  • flupirtine or retigabine is used alone in the treatment of mild to moderate pain such as but not limited to nociceptive pain.
  • flupirtine or retigabine is used in combination with an opioid to treat moderate to severe pain such as but not limited to acute nociceptive pain, chronic pain or neuropathic pain.
  • the present disclosure is therefore instructional as to the treatment of pain based on levels of intensity.
  • the pain is mild to moderate and includes nociceptive pain conditions such as musculoskeletal pain, trauma, dysmenorrhea, headaches, back pain, myofascial pain, migraine, etc and nerve pain such as neuralgia and neuritis.
  • the pain is moderate to severe such as chronic pain, peripheral neuropathic pain, cancer pain (chemotherapy induced and tumor induced), post-operative pain and - moderate-to-severe forms of the pain types described above.
  • the pain is associated with mixed neuropathic and musculoskeletal pain such as fibromyalgia, or mixed nociceptive/neuropathic pain such as cancer related pain or back pain.
  • Yet another embodiment taught herein is a topical formulation for inducing analgesia in response to pain in a subject, the formulation comprising a v 7 potassium channel opener together with a pharmaceutical excipients suitable for topical use. Still another embodiment is a topical formulation for inducing analgesia in response to pain in a subject, the formulation comprising a v 7 potassium channel opener and an opioid together with a pharmaceutical excipients suitable for topical use.
  • kits comprising a first composition comprising a K v 7 potassium channel opener and a second composition comprising an opioid, each composition further comprising a pharamaceutical excipients for topical use wherein, depending on the level of pain, the first composition is used alone or in combination with the second composition.
  • the formulation further comprises a penetration enhancer.
  • the K v 7 potassium channel opener is selected from flupirtine, retigabine and a pharmaceutically acceptable salt, derivative, homolog, analog or pro-drug thereof suitable for topical use.
  • the opioid is selected from one or more of the opioids listed above or a pharmaceutically acceptable salt, derivative, homolog, analog or pro-drug thereof.
  • the formulation may, for example, be in the form of a sustained release or slow release formulation, gel, lotion, cream, solution, spray, foam, mist, compress, impregnated bandage, emulsion, suspension, paste, patch, dispersion, applicator, dip stick, mouth wash, nasal spray or other sprays, and the like.
  • the formulation may be topically applied to the site of the pain or remote thereto.
  • Topical includes buccal and sublingual.
  • Such topical formulations may also be used for transdermal delivery of the active agents.
  • the topical formulation may be in a kit form wherein each active agent is maintained and dispensed separately to a surface or admixed prior to dispensation.
  • the kit may comprise a single composition comprising the K v 7 potassium channel opener alone or together with an opioid.
  • the present disclosure further teaches a method of treating a condition which has a pain component, the treatment comprising the administration of v 7 potassium channel opener and optionally an opioid or a pharmaceutically acceptable salt, derivative, homolog, analog or pro-drug thereof suitable for topical use.
  • the v 7 potassium channel opener is flupirtine or retigabine or a pharmaceutically acceptable salt, derivative, homolog, analog or pro-drug thereof suitable for topical use.
  • the opioid is selected from the list above.
  • the instant disclosure is instructional for an agent for inducing an analgesic response in a subject to pain, the agent comprising a K v 7 potassium channel opener and an opioid.
  • the present disclosure teaches an agent for topically inducing an analgesic response in a subject to pain, the agent comprising flupirtine or retigabine or a pharmaceutically acceptable salt, derivative, homolog, analog or pro-drug thereof and an opioid.
  • the present disclosure also enables the use of a v 7 potassium channel opener alone or in combination with an opioid in the manufacture of a topical medicament for the treatment of pain in a subject.
  • the topical compositions enabled herein are administered to a subject in therapeutically effective amounts. Any type of pain may be treated provided there is a localized focus or site of pain to which the composition can be directly or proximal ly applied. Distal application, however, is encompassed by the teachings of the present disclosure.
  • a therapeutically effective amount means the amount required to at least partly attain the desired effect, i.e. to alleviate to at least a clinically acceptable level the symptoms of pain.
  • Reference to a "subject" includes a human.
  • a v 7 potassium channel opener is also referred to as a v 7 voltage-gated K+ channel opener, a CNQ channel opener, a GIRK channel opener and an M type + channel opener.
  • the K v 7 potassium channel opener is also referred to as an agonist or gating modifier.
  • the potassium channel subtype may be denoted by any or each of KCNQ2, CNQ3, KCNQ3, CNQ4, CNQ5 etc or equivalent ⁇ as K v 7.2, v 7.3, K v 7.4, K v 7.5 etc.
  • v 7 potassium channel openers examples include flupirtine and retigabine and their pharmacologically acceptable salts, derivatives, homologs, analogs and pro-drug forms as well as other gating modulators such as toxin- and non-toxin based molecules which target the voltage-sensitive domain of the K v 7 channel.
  • gating modulators such as toxin- and non-toxin based molecules which target the voltage-sensitive domain of the K v 7 channel.
  • An example of a non-toxin- based molecule gating modifier is NH29 which increases K v 7 channel current by targeting the voltage-sensing domain (Peretz et al. 2(010) Proc. Natl. Acad. Sci. USA 107(35): 15637- 15642).
  • a chemical molecule including a modified toxin or non- toxin-based molecule which targets the voltage-sensing domain of the v 7 potassium channel to thereby increase channel current is also contemplated herein as a K v 7 potassium channel opener.
  • flupirtine and retigabine act on KCNQ 2/3 channels and other CNQ isoforms ( v 7.2-7.5) but do not act on KCNQ1 (K v 7.1) channels which are cardiac muscle channels involved in cardiac rhythm.
  • K v 7 potassium channel opener which acts as an analgesic.
  • the opener does not enhance K v 7.1 currents, or is more selective to K v 7.2-7.5 subtypes than to v 7.1.
  • the "compound”, “agent”, “active agent”, “chemical agent”, “pharmacologically active agent”, “medicament”, “active” and “drug” include a v 7 potassium channel opener such as flupirtine or retigabine as well as an opioid such as alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dexocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl, butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, f
  • the terms also encompass pharmaceutically acceptable and pharmacologically active ingredients of those active agents specifically mentioned herein including but not limited to salts, derivatives, homologs, analogs and pro-drugs and the like suitable for topical use.
  • pharmaceutically acceptable and pharmacologically active ingredients of those active agents specifically mentioned herein including but not limited to salts, derivatives, homologs, analogs and pro-drugs and the like suitable for topical use.
  • compound “agent”, “active agent”, “chemical agent” “pharmacologically active agent”, “medicament”, “active” and “drug”
  • a “derivative” includes esters, amides and protonated forms of these agents.
  • Opioids include codeine, morphine, oxycodone, fentanyl and alfentanil.
  • Reference to a "compound”, “agent”, “active agent”, “chemical agent” “pharmacologically active agent”, “medicament”, “active” and “ drug” includes combinations of two or more actives such as a K v 7 potassium channel opener and an opioid.
  • a “combination” also includes multi-part compositions such as a two-part pharmaceutical kit where the agents are provided separately and then admixed together prior to topical dispensation or separately topically dispensed to a subject.
  • an effective amount and “therapeutically effective amount” of an agent as used herein mean a sufficient amount of the agent to provide the desired therapeutic or physiological effect or outcome. This effect is the treatment, alleviation, prevention, diminishment or amelioration of pain or its various symptoms and manifestations. Undesirable effects, e.g. side effects, are sometimes manifested along with the desired therapeutic effect; hence, a practitioner balances the potential benefits against the potential risks in determining what is an appropriate "effective amount”.
  • the exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, mode of administration and the like. Thus, it may not be possible to specify an exact "effective amount”. However, an appropriate "effective amount” in any individual case may be determined by one of ordinary skill in the art using only routine experimentation.
  • any type of pain may be treated by the compositions taught herein.
  • mild to moderate pain including but not limited to nociceptive pain is treated by the topical application of a composition comprising K v 7 potassium channel opener and one or more pharmaceutically acceptable excipients.
  • nociceptive pain such as a musculoskeletal pain, osteoarthritic pain, joint pain, back pain, headaches and the like.
  • More moderate to severe pain is treated with a composition comprising a v 7 potassium channel opener and an opioid and one or more pharmaceutically acceptable excipients (including the separate application of a K v 7 potassium channel opening and an opioid).
  • moderate to severe pain can be treated by increased dosages of the Kv7 opener alone.
  • Examples include chronic pain, peripheral neuropathic pain and post-operative pain and the like. Examples include diabetic neuropathy, post-herpetic neuralgia (PHN), shingles and chemotherapy induced pain. Other type of pain may be treated by the topical application of a composition comprising v 7 potassium channel opener and one or more pharmaceutically acceptable excipients included conditions that cause mixed pain type such as fibromyalgia, cancer pain and back pain.
  • the site of administration may correlate to the source of pain or the formulations may be topically administered to a site remote from the source or sensation of pain.
  • a v 7 potassium channel opener and an opioid are administered, they may be topically administered to the same site or to proximal but distinct sites.
  • the K v 7 potassium channel opener may be administered as an adjunct to opioid therapy, the latter being administered by any route of administration, including oral and systemic.
  • administration includes topical application, pasting, smearing, spraying, applying, contacting and the like.
  • a salt, derivative, homolog, analog or pro-drug being "pharmaceutically acceptable” includes a pharmaceutical form which is not biologically or otherwise undesirable, i.e.
  • the material may be administered to a subject without causing any or a substantial adverse reaction.
  • the formulations herein may also contain a pharmaceutically acceptable excipient which includes a carrier or diluent which is encompassed by the term "pharmaceutical vehicle".
  • Excipients include carriers and other additives such as diluents, detergents, coloring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like suitable for topical use.
  • v 7 potassium channel opener alone may be topically applied.
  • K v 7 potassium channel opener a combination of the K v 7 potassium channel opener and an opioid can be applied.
  • an elevated dose of the Kv7 potassium channel opener may also be used on its own.
  • Treating" a subject may involve prevention of a condition or other adverse physiological event such as neuropathic pain in a susceptible subject as well as treatment of a clinically symptomatic subject by ameliorating the symptoms of the condition while also treating the sensation of neuropathic pain.
  • a "subject" as used herein refers to an animal, including a mammal such as a human who can benefit from the topical pharmaceutical formulations and methods enabled herein. There is no limitation on the type of animal that could benefit from the presently described pharmaceutical formulations and methods. A subject regardless of whether a human or non-human animal may be referred to as an individual, patient, animal, host, target or recipient. The compounds and methods described herein have applications in human medicine, veterinary medicine as well as in general, domestic or wild animal husbandry. [0049] Mammals include humans and other primates such as orangutangs, gorillas and marmosets as well as livestock animals, laboratory test animals, companion animals and captive wild animals.
  • laboratory test animals include mice, rats, rabbits, simian animals, guinea pigs and hamsters. Rabbits, rodent and simian animals provide a convenient test system or animal model. Livestock animals include sheep, cows, pigs, goats, horses and donkeys.
  • the present disclosure teaches a method of inducing an analgesic response to pain in a subject by the topical application of a v 7 potassium channel opener analgesic alone or in combination with an opioid.
  • the term "subject” is intended to encompass both humans and non-human subjects including laboratory test animals.
  • pain is to be understood to mean both nociceptive and neuropathic pain, these pain types being of intensities covering the range from mild to severe pain.
  • categories of pain which may be treated by the methods enabled herein include musculoskeletal pain, osteoarthritic pain, osteoporosis pain, back pain, headaches, migraines, myofascial pain and the like resulting in mild to moderate levels of pain.
  • Other examples include moderate to severe levels of pain such as post-operative pain, chronic pain, peripheral neuropathic pain such as induced by diabetic peripheral neuropathy (DPN), post-herpetic neuralgia (PHN), HIV-neuropathic pain and cancer pain such as chemotherapy-induced cancer pain and tumor-induced cancer pain.
  • DPN diabetic peripheral neuropathy
  • PPN post-herpetic neuralgia
  • HIV-neuropathic pain such as chemotherapy-induced cancer pain and tumor-induced cancer pain.
  • pain are induced or exacerbated by rheumatoid arthritis or other rheumatoid diseases; mixed connective tissue disease; scleroderma; sarcoidosis; tropical myeloneuropathies; herpes simplex infection; cytomegalovirus infection; cranial nerve palsies; drug-induced neuropathy; industrial neuropathy; lymphomatous - mediated disorders, chronic idiopathic sensory neuropathy; acute pain autonomic neuropathy; compressive neuropathy; diabetes; trauma, or conditions; general neuropathic conditions, such as peripheral neuropathy, pain, reflex-sympathetic dystrophy, and painful scar; specific neuralgias at any location of the body; back pain; diabetic neuropathy; alcoholic neuropathy; metabolic neuropathy; inflammatory neuropathy; chemotherapy-induced neuropathy, herpetic neuralgias; traumatic odontalgia; endodontic odontalgia; mastectomy, thoracotomy pain; spinal-cord-injury; abdominal-injur
  • the method enabled herein induces an analgesic response to pain being suffered by a patient.
  • a patient in this context, is also referred to as a subject, individual, animal, host, target or recipient.
  • the terms "analgesia” and “analgesic response” are intended to describe a state of reduced sensibility to pain.
  • the sensibility to pain is reduced by at least 20%, including by at least 30%, including by at least 30%, including by at least 70% and including by at least 85%.
  • the sensibility to the pain is completely, or substantially completely, removed.
  • the present specification is, therefore, instructional on a method for inducing an analgesic response to pain in a subject, the method comprising topically administering to the subject an amount of a K v 7 potassium channel opener for a time and under conditions effective to reduce the level of or otherwise ameliorate the sensation of pain.
  • the pain includes from mild to moderate pain.
  • Another aspect of the present invention provides a method of inducing an analgesic response to neuropathic pain in a subject, the method comprising topically administering to the subject amounts of K v 7 potassium channel opener and an opioid, separately or sequentially with respect to the other, for a time and under conditions effective to reduce the level of or otherwise ameliorate the sensation of pain.
  • the pain includes from moderate to severe pain.
  • an elevated dose of the Kv7 potassium channel opener may also be used on its own.
  • K v 7 potassium channel opener includes flupirtine and retigabine and their pharmaceutically acceptable salts, derivatives, homologs, analogs and pro-drugs suitable for topical use as well as other K v 7 potassium channel opener analgesics.
  • a method of inducing an analgesic response to pain in a subject comprising topically administering to the subject a K v 7 potassium channel opener selected from flupirtine, retigabine and their pharmaceutically acceptable salts, derivatives, homologs, analogs and pro-drugs suitable for topical use for a time and under conditions effective to reduce the level of or otherwise ameliorate the sensation of pain.
  • a K v 7 potassium channel opener selected from flupirtine, retigabine and their pharmaceutically acceptable salts, derivatives, homologs, analogs and pro-drugs suitable for topical use for a time and under conditions effective to reduce the level of or otherwise ameliorate the sensation of pain.
  • a method of inducing analgesia in a subject suffering pain by topically administering to the subject a v 7 potassium channel opener selected from flupirtine, retigabine and their pharmaceutically acceptable salts, derivatives, homologs, analogs and pro-drugs and an opioid for a time and under conditions effective to reduce the level of or otherwise ameliorate the sensation of pain.
  • a v 7 potassium channel opener selected from flupirtine, retigabine and their pharmaceutically acceptable salts, derivatives, homologs, analogs and pro-drugs and an opioid for a time and under conditions effective to reduce the level of or otherwise ameliorate the sensation of pain.
  • the K v 7 potassium channel openers and opioids are referred to as the "active agents".
  • An effective amount of the v 7 potassium channel opener and optionally an additive or synergistic effective amount of an opioid is proposed, when topically administered concurrently, separately or sequentially with respect to each other includes an analgesic response to pain.
  • the active agents may be administered either as a combined form, i.e. a single topical composition containing the active agents, or as discrete dosages at the same site or at proximal sites.
  • the active agents are proposed to be administered within a time frame allowing the desired analgesic effect or additive or synergistic analgesic effect to be achieved.
  • the timing of administration should allow each of the active agents or their active metabolites to simultaneously be present on the patient within their respective therapeutic concentration ranges.
  • the time between the delivery of a v 7 potassium channel opener and an opioid is between seconds, minutes, hours, days or weeks.
  • the time between re-delivery of a K v 7 potassium channel opener is also between seconds, minutes, hours, days or weeks.
  • opioid compounds include any compound that is physiologically acceptable in mammalian systems and is a full or at least partial agonist of an opioid receptor. Specific examples of opioid compounds are listed herein.
  • K v 7 potassium channel opener alone or in combination with an opioid may further involve the administration of another analgesic agent.
  • analgesic agent is intended to encompass known and as yet unknown compounds (including pharmaceutically acceptable salts, derivatives, homologs, analogs or pro-drugs thereof) that are effective for treatment of pain a subject, including opioids and compounds such as aspirin, indomethacin, naproxen, fenoprofen, sulindac, diclofenac, indoprofen, nitroglycerin, propanolol, valproate, timolol, atenolol, alprenolol, cimetidinze, clonidine, imipramine, levodopa, chloropromazine, reserpine, methyl-dopa, dihydroxyphenylalanine, provaloxyloxyethyl ester of alpha-methyldopa hydrochloride, theophylline, calcium gluconate, ferrous lactate, vincamine, diazepam, phenoxy
  • GABAergic drugs include compounds that enhance the action of gamma aminobutyric acid (GABA) in the central nervous system; these include drugs that act directly on receptors such as baclofen, muscimol, alcohols, neurosteroids and benzodiazepines, drugs such as vigabatrin that cause inhibition of extra neuronal enzymatic breakdown of GABA, drugs such as topiramate that modulate GABA-coupled ion channels and drugs such as tiagabine that inhibit the reuptake of synaptic GABA by neurons and glial cells.
  • the analgesic agents may be administered systemically or orally in combination with the topical administration of the K v 7 potassium channel opener alone or in combination with an opioid or may be administered topically.
  • K v 7 potassium channel opener selected from flupirtine, retigabine and their pharmaceutically acceptable salts, derivatives, homologs, analogs and pro-drugs and an opioid selected from alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dexocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl, butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, eth
  • the terms also encompass pharmaceutically acceptable and pharmacologically active ingredients of those active agents specifically mentioned herein including but not limited to salts, derivatives, homologs, analogs and pro-drugs and the like suitable for topical use.
  • pharmaceutically acceptable salt, derivative, homolog, analog or prodrug is intended to convey any pharmaceutically acceptable tautomer, salt, pro-drug, hydrate, solvate, metabolite or other compound which, upon administration to the subject, is capable of providing (directly or indirectly) the compound concerned or a physiologically (e.g. analgesically) active compound, metabolite or residue thereof.
  • a suitable derivative is an ester formed from reaction of an OH or SH group with a suitable carboxylic acid, for example and H0 2 C-(CH 2 )n-C0 2 H (where n is 1-10 such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and C0 2 H-CH 2 phenyl.
  • the active compounds may be in crystalline form, either as the free compounds or as solvates (e.g! hydrates). Methods of solvation are generally known within the art.
  • salts of the active agents taught herein are generally pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts can also be used, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulfphonic, toluenesulphonic, benzenes
  • pro-drug is used herein in its broadest sense to include those compounds which can be converted in vivo to the compound of interest (e.g. by enzymatic or hydrolytic cleavage). Examples thereof include esters, such as acetates of hydroxy or thio groups, as well as phosphates and sulphonates. Processes for acylating hydroxy or thio groups are known in the art, e.g. by reacting an alcohol (hydroxy group), or thio group, with a carboxylic acid. Other examples of suitable pro-drugs are described in Bundgaard (1985), Design of Pro-drugs, Elsevier the disclosure of which is included herein in its entirety by way of reference.
  • metabolite includes any compound into which the active agents can be converted in vivo once administered to the subject. Examples of such metabolites are glucuronides, sulfates and hydroxylates. [0071 J It will be understood that active agents as described herein may exist in tautomeric forms.
  • tautomer is used herein in its broadest sense to include compounds capable of existing in a state of equilibrium between two isomeric forms. Such compounds may differ in the bond connecting two atoms or groups and the position of these atoms or groups in the compound. A specific example is keto-enol tautomerism.
  • the compounds for use in development of topical formulations may be electrically neutral or may take the form of polycations, having associated anions for electrical neutrality.
  • Suitable associated anions include sulfate, tartrate, citrate, chloride, nitrate, nitrite, phosphate, perchlorate, halosulfonate or trihalomethylsulfonate.
  • the active agents are topically administered for therapy.
  • topical includes buccal and sublingual.
  • the delivery system may, for example, be in the form of a sustained release or slow release formulation, lotion, gel, cream, patch, ointment, solution, spray, foam, mist, compress, impregnated bandage, emulsion, dispersion, applicator, dip stick, mouthwash, nasal spray and the like.
  • an "effective amount" includes an additive or synergistic effective amount which takes into account amounts of each of the K v 7 potassium channel opener and the opioid.
  • an "effective amount” refers to an amount of active agent that provides the desired analgesic activity when topically administered according to a suitable dosing regime. This includes an additive or synergistic effective amount which takes into account amounts of each of the K v 7 potassium channel opener and the opioid (and optionally a further analgesic). Dosing may occur at intervals of several seconds, minutes, hours, days, weeks or months. Suitable dosage amounts and regimes can be determined by the attending physician or veterinarian.
  • flupirtine or retigabine or pharmaceutically acceptable salts, derivatives, homologs, analogs or pro-drugs thereof may be topically applied to a subject at a rate of between about 1 to about 300 mg/mm 2 surface area every from about 1 hour to up to about 50 hours, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 hours, such as 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 1 1, 1 1.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200 or 300 mg/mm 2 surface area.
  • Useful times are from about 6 hours to about 24 hours, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24. Useful times are between from about 12 to about 24 hours. Such as 12, 13, 1 ' 4, 15, 16, 17,18, 19, 20, 21, 22, 23 or 24 hours.
  • Dosing of the analgesic agent, such as an opioid can be determined by the attending physician in accordance with dosing rates in practice.
  • fentanyl can be administered in an amount of from about 10 ⁇ to 100 ⁇ g/mm surface area whereas morphine may be administered in an amount of 1 to 10 mg/mm 2 , also on an hourly basis.
  • the administration amounts may be varied if administration is conducted more or less frequently. In many instances topical administration will be conducted on the basis of when the patient requires pain relief.
  • flupirtine or retigabine or other v 7 potassium channel opener or a pharmaceutically acceptable salt, derivative, homolog, analog or pro-drug thereof and optionally an opioid are used to manage pain and induce an analgesic response prior to, during or following treatment of a disease, condition or pathology. Examples of pathologies are those listed above.
  • the topical formulations described herein can further comprise additional ingredients that can increase the analgesic effectiveness of the v 7 potassium channel opener and optionally an opioid.
  • additional ingredients that can increase the analgesic effectiveness of the v 7 potassium channel opener and optionally an opioid.
  • Such ingredients facilitate the effect of a combination of compounds or of individual compounds by increasing absorption and/or penetration and/or lateral spread, provide for a more comprehensive pain management regimen, decrease the side effect profile of the base composition, and the like.
  • magnesium ions e.g., from magnesium oxide or other magnesium preparations
  • antagonize ionic calcium in the nervous system enhancing the ameliorating effect on neuropathic pain.
  • compositions described herein can further comprise non-physiologically active ingredients or components usually admixed in such topical preparations.
  • compositions may also include additional ingredients such as other carriers, moisturizers, oils, fats, waxes, surfactants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, dyestuffs, lower alkanols, humectants, emollients, dispersants, sunscreens such as radiation blocking compounds or particularly UV -blockers, antibacterials, antifungals, disinfectants, vitamins, antibiotics, or other antiacne agents, as well as other suitable materials that do not have a significant adverse effect on the activity of the topical composition.
  • additional ingredients such as other carriers, moisturizers, oils, fats, waxes, surfactants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, dyestuffs, lower alkanols, humectants, emollients, dispersants, sunscreens such as radiation blocking compounds or particularly
  • Additional inactive ingredients for inclusion in the carrier include sodium acid phosphate moisturizer, witch hazel extract carrier, glycerin humectant, apricot kernel oil emollient, corn oil dispersant, and the like. Those of skill in the art will readily recognize additional inactive ingredients, which can be admixed in the compositions described herein.
  • compositions described herein optionally contain other ingredients.
  • triethanolamine can be added as a crosslinking agent.
  • a preservative such as betahydoxytoluene can also be added.
  • Other irritation reducing agents can also be included.
  • an irritation reducing agent includes, but is not limited to, glycerol.
  • semi-solid testosterone formulations are prepared with propylene glycol and/or butylene glycol as the glycol component, ethyl alcohol and/or isopropyl alcohol as the alcohol component.
  • Preservatives, a cross-linking agent, and additional irritation reducing agents may be included in the formulations.
  • topical compositions and methods taught herein are effective to induce local analgesia and to treat pain.
  • topical compositions and methods enabled herein can be used to treat or prevent pain related to or induced by any of the conditions listed herein
  • the methods and formulations described herein can provide a treatment of applying the compositions described herein to an affected area of a subject with neuropathic pain.
  • the methods described herein can include treating peripheral neuropathic pain, comprising the step of topical administration of a pharmaceutical composition of K v 7 opener in a topical vehicle to the affected area of a subject in need of such treatment.
  • the methods and compositions described herein can be effective for neuropathies, such as peripheral neuropathies, associated with diseases such as those listed herein.
  • a typical topical formulation comprises a conventional aqueous or non-aqueous vehicle, for example, a cream, gel, ointment, lotion or paste or in the form of a medicated plaster, patch or membrane.
  • “application situs” relates to a site suitable for topical application with or without the means of a device, patch, or dressing, e.g. the spinal column, behind the ear, on the arm, back, chest, abdomen, leg, top of foot, etc.
  • the cream can be applied to the site of pain or the spine dermatome(s) of the pain site, e.g., L2-S2 for any leg, knee, or foot neuropathy.
  • Topical delivery also includes numerous different systems for the topical delivery of active agents known in the art. Topical delivery systems include but are not limited to passive devices such as drug-in-adhesive transdermal patches and "active" transdermal technologies such as iontophoresis, electroporation, sonophoresis, magnetophoresis, microneedle devices and those devices that use thermal energy to make the skin more permeable including for lateral spread of the ingredients.
  • passive devices such as drug-in-adhesive transdermal patches and "active" transdermal technologies such as iontophoresis, electroporation, sonophoresis, magnetophoresis, microneedle devices and those devices that use thermal energy to make the skin more permeable including for lateral spread of the ingredients.
  • Transdermal drug delivery devices are available from the 3M Drug Delivery Systems Division (St. Paul, Minn., USA), Noven Pharmaceuticals, Inc. (Miami, Fla., USA), ImaRx (Tucson, Ariz., USA), Elan Corporation (Dublin, Ireland), Novosis AG (Miesbach, Germany), Ultrasonic Technologies (St. Albans, Vt., USA), Antares Pharma (Exton, Pa., USA), Altea Therapeutics (Tucker, Ga., USA), Iomed, Inc. (Salt Lake City, Utah, USA), MacroChem Corp (Lexington, Mass., USA), Sontra Medical Corporation (Franklin, Mass., USA), Vyteris, Inc.
  • the topical compositions described herein can be made by cold compounding. This is significant since one or more of the compounds admixed in the topical compositions described herein may be sensitive to heat or other types of energy. Thus the activity of the composition may be detrimentally affected as a result of the formulation of the compositions in other manners.
  • the ingredients of this topical composition can be merely mixed together, without heating and using a sufficient amount of the carrier to provide a substantially homogeneous cream, ointment or gel.
  • the one or more ingredients are dissolved, dispersed or suspended prior to cold compounding in order to ensure substantially homogeneous distribution of the active ingredients in the composition.
  • the components are separated into those which are water-soluble and those which are oil-soluble.
  • the water-soluble components can be mixed together in one vessel to form a solution and the oil-soluble components can be mixed together in a separate vessel and heated (e.g., 70°C to 80°C) to form a solution.
  • the two solutions can then be mixed and the mixture allowed to cool.
  • This method requires nothing more than two beakers and a heating apparatus. Homogenation is achieved using a high-shear rate blender or other suitable apparatus.
  • Still another aspect enabled herein is a treatment protocol for a disease condition in a subject, the protocol comprising the steps of topically administering to the subject, an effective amount of a v 7 potassium channel opener or a pharmaceutically acceptable salt, derivative, homolog, analog or pro-drug thereof alone or in combination with an opioid effective to reduce the level of or otherwise ameliorate the sensation of neuropathic pain.
  • the disease condition may include any of those listed herein.
  • Administration of the disease condition may be sequential or simultaneous or independent of the active agent or agents.
  • a topical composition comprising a K v 7 potassium channel opener or a pharmaceutically acceptable salt, derivative, homolog, analog or pro-drug thereof, together with one or more pharmaceutically acceptable carriers and optionally other medicaments such as another analgesia.
  • the pharmaceutically acceptable additives may be in the form of carriers, diluents, adjuvants and/or excipients and they include all conventional solvents, dispersion agents, fillers, solid carriers, coating agents, antifungal or antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and slow or controlled release matrices.
  • Dermal penetration agents are typically added to assist in the transport of the active pharmaceutical ingredient across the stratum corneum into the dermis and local tissue, and depending upon the nature of the dermal penetration agent, into the bloodstream.
  • Examples of dermal penetration agents include dimethylsulfoxide (DMSO), tocopheryl analogs such as tocopheryl phosphate, terpenes such as menthol, eucalyptol and d-limonene, octyl-salicylate, padimate O, surfactants (anionic, cationic zwitterionic and/or nonionic), fatty acids, fatty esters, fatty amines, Azone-like compounds, azacyclo compounds, sodium salts of fatty acids, propylene glycol, isopropyl alcohol, salicylic acid, lauryl alcohol, commercial products such as Lipoderm (Registered) or transcutol P and others known in the art.
  • DMSO dimethylsulfoxide
  • tocopheryl analogs such
  • the active agents may be presented in the form of a kit of components adapted for allowing concurrent, separate or sequential administration of the active agents.
  • Each carrier, diluent, adjuvant and/or excipient must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the composition and physiologically tolerated by the subject.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, diluents, adjuvants and/or excipients or finely divided solid carriers or both, and then if necessary shaping the product.
  • the topical formulations herein may also be administered in a sustained (i.e. controlled) or slow release form on the skin or in a body cavity such as the oral cavity, ear, cavity, rectal and anal cavity, vaginal cavity, nasal cavity, scalp, urinogenitary cavity and gastrointestinal cavity.
  • a sustained release preparation is one in which the active ingredient is slowly released to a surface of the body of the subject once administered and maintains the desired drug concentration over a minimum period pf time.
  • the preparation of sustained release formulations is well understood by persons skilled in the art. Dosage forms may include transdermal forms.
  • the active ingredients may be suspended as slow release particles or within liposomes, for example.
  • compositions taught herein may be packaged for sale with other active agents or alternatively, other active agents may be formulated with flupirtine or retigabine or its pharmaceutical salts, derivatives, homologs, analogs or prodrugs thereof and optionally an opioid.
  • active agents for use herein may also be presented in veterinary compositions. These may be prepared by any suitable means known in the art. Examples of such compositions include those adapted for topical application, e.g. creams, ointments, gels, lotions, drenches (including aqueous and non-aqueous solutions or suppressions), powders and pastes for application to be taught.
  • compositions comprising Kv7 openers, retigabine and flupirtine
  • Topical compositions are prepared which comprise retigabine or flupirtine.
  • Compositions are prepared according to standard protocols, known in the art.
  • Target concentrations of active ingredient are set at 1-5% w/w to provide a topical formulation of sufficiently high concentration of active pharmaceutical ingredient to be effective in alleviating pain.
  • Compositions are tested for solubility in aqueous and non-aqueous solutions, varying conditions like pH, solvent composition, addition of anti -oxidants, penetration enhancers, buffers, preservatives in developing a drug product as a cream, gel or suspension. Resulting samples are tested for stability over 0-3 months to help identify the most suitable compositions for continued development.
  • formulations that provide sufficient concentration and stability of active substance are: a. A non-aqueous solvent system for retigabine base,
  • An analytical method is prepared by Chemical Analysis Pty Ltd (Melbourne, Victoria, Australia) to allow the assessment of the chemical stability of retigabine from both the base and dihydrochloride salt in the formulation vehicles.
  • An HPLC method equipped with UV detection (254nm) is used. The HPLC conditions are triethylamine buffer:methanol 30:70 for the mobile phase using a flow rate of 0.7ml/min.
  • AZorbax (Registered) Extend CI 8 250 x 4.6 column is used. Samples are prepared in diluted hydrochloric acid and then further diluted in methanol to a concentration resulting in approximately 1 mg/ml of retigabine. Solutions are assayed against an in-house retigabine standard prepared at approximately 1 mg/ml.
  • Solutions are prepared by dissolving retigabine in a mixture of all the other components at ambient temperature.
  • the antioxidant butylated hydroxytoluene is included as retigabine is susceptible to oxidation, although the amount and choice of anti-oxidant requires optimization.
  • Ethanol 44.0 41.0 [0101] Aqueous Solvent Vehicle ⁇ Acidified aqueous solvent solutions are capable of dissolving retigabine at high concentrations. Therefore, samples of an aqueous solvent system are developed.
  • the active formulations are prepared are shown in Table 2. Solutions of the aqueous solvent systems are prepared by dissolving the retigabine and propyl gallate in the solvents excluding the water and lactic acid. To this solution, the water is added and finally the lactic acid added. The antioxidant is included since retigabine is susceptible to oxidation. However, due to potential solubility issues when butylated hydroxytolene is used in these types of systems, propyl gallate is chosen for this preparation. Precipitation is observed in aqueous solvent conditions which may be attributed to insolubility of retigabine, therefore, the aqueous solvent system is less amenable to producing a stable topical formulation than non-aqueous solvent systems.
  • Aqueous Suspension Vehicle The suspension formulations prepared are given in Table 3. Both retigabine and retigabine dihydrochloride are evaluated in this prototype vehicle. The suspension system is also used to gauge the effect of pH on chemical stability and potentially drug skin penetration of the retigabine and retigabine dihydrochloride.
  • the suspension vehicle is prepared by grinding a concentrated dispersion of the retigabine or retigabine dihydrochloride in a poloxamer 407/ / water mixture. This concentrated dispersion is processed with an Ultraturax T25 dispersion mixer fitted with the 15mm diameter head. Particle size reduction is achieved by 15 minutes centrifugation at 1 1,000 rpm. The processed retigabine or retigabine dihydrochloride concentrated dispersion is microscopically examined.
  • the remaining ingredients are added to the retigabine or retigabine dihydrochloride concentrated dispersion, blending to form the respective creams.
  • Variation in the suspension formulations can be made by varying ball mill, bead mill, colloid mill and precipitation methods as well as ingredients.
  • the factors that affect choice are final required particle size and physical properties of the dispersed phase. For example, a smaller particle size may be required to increase skin penetration, in which case, pre- milling is required.
  • One of the most straight-forward manufacturing methods is to have the drug pre-milled to the required particle size before dispersion. Using this method, the manufacture of the wet phase is achieved by blending.
  • Samples of the retigabine vehicles prepared according to the methods above are were packed into glass vials with polypropylene caps and stored under controlled conditions. The storage conditions used are either 5°C or 40°C. Samples of each prototype are analyzed before a trial is started and then again at the 2 weeks and 1 month time points. A summary of the physical characterisation and analytical results is given in Table 4 for the solvent formulations and Table 5 for the aqueous suspension formulations.
  • Aqueous suspension systems Suspension systems have been developed using both the retigabine base and the dihydrochloride salt as sources of the drug. For each drug source, two prototypes are developed, one at pH 5 and one at pH 7.
  • compositions comprising Flupirtine and Oxycodone
  • Topical compositions comprising flupirtine and oxycodone are formulated using standard protocols known in the artherein will have good chemical stability.
  • the known oral analgesic flupirtine maleate was evaluated in the following formulation vehicles to develop a commercial topical formulation for use in pain indications.
  • the vehicles described here although not currently suitable for commercialization, can be readily converted to appropriate topical vehicles.
  • Non-Aqueous Vehicle Solutions are prepared by dissolving flupirtine maleate (1%) in a mixture of all the other components (butylated hydroxtoluene (1 %), dimethyl isosorbide (15%), Diethylene Glycol Monoethyl Ether (25%) and alcohol (48%)) at ambient temperature.
  • the antioxidant was included as it is known that flupirtine maleate is susceptible to oxidation. The choice and concentration of antioxidant present is not optimized.
  • Aqueous Ethanolic Vehicle It was found that an acidified aqueous ethanol solution was capable of dissolving more flupirtine maleate than either ethanol or water alone. Samples of 2% flupirtine maleate with ethanol, water and lactic acid and optionally butylated hydroxytoluene are prepared. Solutions are prepared by dispersing the flupirtine maleate and BHT (if used) in the ethanol. To this mixture the water is added and finally the lactic acid added. This mixture is stirred at ambient temperature until a clear solution is obtained. The antioxidant is included as it is known that flupirtine maleate is susceptible to oxidation.
  • Aqueous Suspension Vehicle Two systems are evaluation for the suspension system to gauge the effect of pH on chemical stability of the flupirtine maleate.
  • the suspension vehicle is prepared by grinding a concentrated dispersion of the flupirtine maleate in a poloxamer 407/water mixture. This concentrated dispersion is processed with an Ultraturax T25 dispersion mixer fitted with the 15mm diameter head. The concentrated dispersion is processed for 15 minutes at 1 1,000 rpm. The processed flupirtine maleate concentrated dispersion is examined microscopically. The crystals of flupirtine maleate appeared well dispersed with an average size of approximately 50 ⁇ with some agglomerates up to 70 ⁇ . The flupirtine maleate concentrated dispersion is then blended into the remaining ingredients.
  • flupirtine maleate Five formulations of flupirtine maleate are successfully prepared, including one non-aqueous solvent system (1% flupirtine), two aqueous ethanol solvent systems (2% flupirtine) and two suspensions (5% flupirtine). The results showed that flupirtine is unstable and poorly soluble in the non-aqueous solvent system. One of the two aqueous ethanol systems showed up to a 13% loss of flupirtine maleate after one month at 40°C, which was be improved by the addition of an anti-oxidants. Acidification prior to dissolution of the flupirtine maleate improved the formulation characteristics. The aqueous suspensions showed the best results with high chemical stability of the pH 5 vehicle. It is recommended to prepare flupirtine suspension formulations with reduced particle size of the flupirtine maleate (i.e. to less than ⁇ ) to further improve the physical and chemical characteristics. EXAMPLE 3
  • a number of in vitro models are available to measure the permeation of topical formulations through the skin.
  • a most commonly used system for in vitro skin penetration studies is the static Franz cell diffusion cell system.
  • test formulations are applied to excised skin mounted on a cell diffusion system.
  • the best source of skin is dermatomed human skin from patients who underwent elective surgery, although cadaver skin samples or excised rat skin or pig skin (Okyar et al. (2008)y4c/a Pharmaceutica Sciencia 50:247-256) are also commonly used.
  • Receptor fluid samples are collected at regular .intervals over the exposure period for each cell. Residual formulation is removed at the end of the exposure period by washing, wiping or tape- stripping. Diffusion cell washes, skin surface material removal samples, epidermis, dermis and receptor-fluid samples are then analysed for drug content.
  • a system employing Franz diffusion cells (FDC-400, Crown Glass Company, Somerville, N.J.) was used for the permeation studies.
  • the receptor-phase volume was 133.5 ml and the receptor temperature maintained at 35 ⁇ 0.5°C within a water jacket. bath.
  • An amount of 20% ethanol/phosphate buffered saline at pH 7.4 was used as receptor medium.
  • Human skin was sourced from elective surgery (full thickness female abdominal skin, single donor). The skin sample was mounted between the donor and receptor compartments of the cell and clamped with the dermal side in contact with the receptor medium.
  • Topical composition (@ 20 ⁇ / ⁇ 2 ) was applied to the stratum corneum (donor) side.
  • the average dermal concentration across the 5 samples is 128ng/mg based on assumptions of epidermal thickness of 0.2mm, dermal thickness 1 mm and Franz cell 1 cm 2 . Assuming a benchmark skin concentration of 100 ng/mg to provide analgesia, the amounts delivered are sufficient to provide an analgesic effect.
  • results show that samples of retigabine and retigabine dihydrochloride salt do penetrate the skin and can therefore reach the target K v 7 channels located in peripheral nerves in the dermal layer.
  • results for the retigabine suspension formulations are encouraging and support further development to optimize conditions for a commercial product. Improvements in formulation characteristics and dermal penetration may be made by milling of the active pharmaceutical prior to formulation to reduce particle size, optimally to below 50 as low as 10 microns. Further improvements may be made by the optimisation of excipients and penetration enhancers in the formulation, the latter which are well known to markedly improve the penetration of the active ingredient.
  • ketoprofen and formulation with transdermal base lipoderm markedly improved its cutaneous absorption (http://www.pccarx.com/about- pcca/pcca-news/item/47-pcca-lipoderm-and-ketoprofen-transdermaI-study/).
  • tape stripping is used to assess cutaneous drug or excipient levels in the skin after topical dermatological treatment, either in the removed tape-strips, or directly in the tape-stripped skin (Herkenne et al. (2007) Pharmaceutical Research 25(]):&7- ⁇ 03; Escobar-Chavez (2008) J. Pharm. 11 (7 :104-130).
  • Topical formulations may be tested in humans directly or using animal models such as the animal models used to test acute anti-inflammatory activity, anti-hyperalgesic activity and anti-nociceptive activity (Sanna et al. (2009) Current Drug Delivery 6:93- 100).
  • animal models such as the animal models used to test acute anti-inflammatory activity, anti-hyperalgesic activity and anti-nociceptive activity (Sanna et al. (2009) Current Drug Delivery 6:93- 100).
  • a review of commonly used pain animal models is given in Mogil (2009) Nature Rev. Neurosc. 70:283-294 (and references therein).
  • a model for inflammatory pain and neuropathic pain can be found in Goodchild et al. (2008) Pain Medicine 9:928-938, except administration by the interperetoneal route is replaced by topical application, at the site of pain.
  • the following describes the application of two animal models of pain: (i) inflammatory pain as measured by the carrageenan paw inflammation model; and (ii) peripheral neuropathic pain
  • Inflammation of the right hind paw is induced by an intraplantar injection of carrageenan (100 mL of a 2% carrageenan solution in saline). Time is allowed for the induction of inflammation (2 hours). Paw withdrawal latencies (time measured in seconds taken to withdraw the inflamed paw) are measured using noxious heat from an infrared beam focused onto the plantar surface of the right hind paw in freely moving animals using apparatus from Ugo Basile. Paw withdrawal latencies are measured every 10 minutes before the induction of inflammation_with carrageenan injections until three stable readings are obtained.
  • paw withdrawal thresholds are measured 60, 1 10, and 120 minutes after the carrageenan injection to confirm the development of hyperalgesia, a decrease in paw withdrawal latency typically from control pre-carrageenan level of 12 seconds down to 6 seconds.
  • the test drug or drug combination is injected and paw pressure values measured at 10-minute intervals for the following 40 minutes.
  • Replicate values of paw withdrawal latencies for each time of measurement and drug treatment are combined to calculate means. These are plotted as time-response curves to assess the time of onset and the period of stability of the response to drug treatment (time of stable response).
  • the time of stable response involves three readings after the drug injections: for example at 140, 150, and 160 minutes. For each rat, these readings are averaged (postdrug) as are the pretreatment readings. All the pretreatment values from rats in each treatment group are combined as are the corresponding postdrug values to calculate means and SEM.
  • STZ- induced diabetic rats are prepared b injection ip with STZ (150 mg/kg total dose) dissolved in 0.9% sodium chloride solution. The 150 mg dose is given in two 80 mg/kg injections on consecutive days. The induction of diabetes is confirmed 1 week after injection of STZ by measurement of tail vein blood glucose levels with AccuCheck Active test strips and a reflectance colorimeter (AccuCheck Glucometer, Roche, Castle Hill,NSW, Australia). Only animals with final blood glucose levels >15 mM are deemed to be diabetic. The rats are retested for hyperglycaemia once per week to confirm continued high blood glucose readings.
  • Hyperalgesia is assessed using the paw pressure test. Tests take place 5 weeks after the first injection of STZ. Animals that have paw pressure nociceptive thresholds below 30 g (60% of the value in normal weight-matched rats) are deemed to have developed hyperalgesia/neuropathic pain and thus are used in further experiments.
  • Nociceptive Test After the successful documentation of the development of hyperalgesia in diabetic animals by the paw pressure test, more extensive nociceptive testing paradigms are carried out in diabetic neuropathic animals and in weight-matched controls; the control rats are 1-2 weeks younger.
  • Paw pressure (PP) is measured by the method using a Ugo Basile algesimeter (Apelex; probe 1 mm, weight: 10 g); increasing pressure is applied to the left hind paw until vocalization or sharp paw withdrawal is elicited.
  • Paw withdrawal thresholds are measured for a group of weight-matched controls and also in drug treatment groups of rats, 20 and 10 minutes before, immediately before (time 0), and also at 20, 30, and 40 minutes after topical application of drug product or vehicle.
  • a trial design is an open label dose escalation study carried out on patients with pain associated with cancer. All patients referred to the palliative care unit with cancer- related pain are considered eligible for entry if they had been receiving opioids for at least 48 hours. The trial lasts eight days. On day 0 the patients are assessed with respect to pain and side effect experiences as well as drug usage. On day 1 there is 24 hours observation and baseline measurements before commencement on flupirtine at a dose of 0.5 to 100mg/mm2 surface area four times daily (qid) topically applied. If the pain is not controlled and there is no evidence of dose limiting side effects as judged by the patient or clinician, the dose is escalated by 100 to 300 mg/mm2, topically applied. Once the patient is pain-free, there is no further dose escalation.
  • Each patient is asked to categorize their pain and assess it in four ways [average pain; least pain; pain right now; and worst pain in the previous 24 hours] and to score it on a numerical 10 point scale ranging from 1 ("no pain") to 10 ("pain as bad as you can imagine”). They are also be asked to score percentage pain relief (0-100%) and how the pain is affecting their everyday activity on numerical activity scales ranging from 1 ("pain does not interfere") to 10 (“pain completely interferes”). The patients are asked to complete this questionnaire on a daily basis. Patients are also asked specifically , about indigestion, change in appetite, drowsiness, nausea, unsteadiness of gait and any other symptoms that develop at each study visit. These "side effects” are scored on a 1 to 4 scale corresponding to "not at all” to "very much”.
  • the trial design is placebo-controlled dose-response study carried out on patients with pain associated with PHN to test an effective clinical dose of topical flupirtine or topical retigabine against placebo, applied 2 times daily for three weeks.
  • the patient population is subjects with PHN who have been suffering significant pain for at least three months.
  • Subjects who enter the trial must have a score of at least 4 on the 1 1 -point numerical pain score.
  • the trial lasts eight days. On day 0 the patients are assessed with respect to pain and side effect experiences as well as drug usage.
  • the primary endpoint is the baseline average daily pain score compared to the average daily pain score at day 21, measured on the 1 1 -point numerical pain scale. Secondary endpoints included pain relief, a responder analysis and changes in the McGill Pain Questionairre, sleep quality and patient global satisfaction. Patients are also asked specifically about indigestion, change in appetite, drowsiness, nausea, unsteadiness of gait and any other symptoms that develop at each study visit.
  • topical flupirtine or retigabine for the treatment of the signs and symptoms of osteoarthritis of the knee is evaluated in double-blind controlled trials involving patients treated with topical flupirtine or retigabine compared to topical placebo and/or topical vehicle solution, applied directly to the study knee 4x daily for 3 weeks according to the methods of Niethard et al. (2005) J. Rheumatol 32(12 :2384-92.

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Abstract

La présente invention se rapporte d'une manière générale au domaine de la gestion de la douleur, comprenant des procédés et des formulations permettant la gestion topique de la douleur, telle qu'une douleur localisée. La présente invention concerne en outre une polythérapie permettant d'améliorer par voie topique des niveaux de douleur plus intenses.
PCT/AU2012/001379 2011-11-10 2012-11-09 Formulations topiques pour gestion de la douleur WO2013067591A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
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US20140371322A1 (en) * 2013-06-13 2014-12-18 Professional Compounding Centers Of America Phenoxybenzamine Transdermal Composition
US10744174B1 (en) 2016-03-16 2020-08-18 Robert Alonso Composition(s) and method(s) for topically treating pain
WO2021113757A1 (fr) * 2019-12-06 2021-06-10 Xenon Pharmaceuticals Inc. Utilisation d'un agent d'ouverture du canal potassique kv7 pour le traitement de la douleur
US20210213009A1 (en) * 2019-12-13 2021-07-15 Xenon Pharmaceuticals Inc. Methods of treating pain

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WO2001010381A2 (fr) * 1999-08-04 2001-02-15 Icagen, Inc. Procedes therapeutiques ou prophylactiques de la douleur et de l'anxiete
WO2007104717A1 (fr) * 2006-03-15 2007-09-20 Neurosearch A/S Quinazolinones et leur application en tant qu'agents activant le canal potassique
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WO2009000038A1 (fr) * 2007-06-28 2008-12-31 Cnsbio Pty Ltd Procédés et compositions de combinaison pour le traitement d'une douleur neuropathique
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WO2010085848A1 (fr) * 2009-01-30 2010-08-05 Relevare Aust. Pty Ltd Agents de lutte contre l'abus de médicaments, procédés et compositions
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WO2007104717A1 (fr) * 2006-03-15 2007-09-20 Neurosearch A/S Quinazolinones et leur application en tant qu'agents activant le canal potassique
WO2008110872A2 (fr) * 2006-06-23 2008-09-18 Foamix Ltd. Compositions moussantes et kits comprenant un ou plusieurs parmi un agent de canal, un agent cholinergique, un donneur d'oxyde nitrique et des agents apparentés, et leurs utilisations
WO2009000038A1 (fr) * 2007-06-28 2008-12-31 Cnsbio Pty Ltd Procédés et compositions de combinaison pour le traitement d'une douleur neuropathique
EP2206699A1 (fr) * 2008-12-24 2010-07-14 AWD.pharma GmbH & Co.KG Forme cristalline de flupirtine (ester éthyl d'acide carbamique 2-amino-6-(4-fluoro-benzylamino)-pyridin-3-yl)
WO2010085848A1 (fr) * 2009-01-30 2010-08-05 Relevare Aust. Pty Ltd Agents de lutte contre l'abus de médicaments, procédés et compositions
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140371322A1 (en) * 2013-06-13 2014-12-18 Professional Compounding Centers Of America Phenoxybenzamine Transdermal Composition
US10744174B1 (en) 2016-03-16 2020-08-18 Robert Alonso Composition(s) and method(s) for topically treating pain
WO2021113757A1 (fr) * 2019-12-06 2021-06-10 Xenon Pharmaceuticals Inc. Utilisation d'un agent d'ouverture du canal potassique kv7 pour le traitement de la douleur
CN114786658A (zh) * 2019-12-06 2022-07-22 泽农医药公司 Kv7钾离子通道开放剂治疗疼痛的用途
US20210213009A1 (en) * 2019-12-13 2021-07-15 Xenon Pharmaceuticals Inc. Methods of treating pain

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