WO2008080194A1 - Compositions analgésiques et leurs utilisations - Google Patents

Compositions analgésiques et leurs utilisations Download PDF

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Publication number
WO2008080194A1
WO2008080194A1 PCT/AU2008/000003 AU2008000003W WO2008080194A1 WO 2008080194 A1 WO2008080194 A1 WO 2008080194A1 AU 2008000003 W AU2008000003 W AU 2008000003W WO 2008080194 A1 WO2008080194 A1 WO 2008080194A1
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donor
subject
nmol
pain
condition
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PCT/AU2008/000003
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English (en)
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Maree Therese Smith
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The University Of Queensland
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Priority claimed from AU2006907305A external-priority patent/AU2006907305A0/en
Application filed by The University Of Queensland filed Critical The University Of Queensland
Publication of WO2008080194A1 publication Critical patent/WO2008080194A1/fr
Priority to US12/494,183 priority Critical patent/US8822509B2/en
Priority to US14/466,795 priority patent/US20150051404A1/en
Priority to US15/669,834 priority patent/US9994534B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • 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
    • 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
    • A61K31/04—Nitro compounds
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • This invention relates generally to compositions and methods for inducing, promoting or otherwise facilitating pain relief. More particularly, the present invention relates to the use of sub-normovasodilatory doses of nitric oxide donors in the therapeutic management of vertebrate animals including humans, for the prevention or alleviation of pain, especially neuropathic pain. According to some embodiments of the present invention, nitric oxide donors are administered by any suitable route so as to provide concentrations of NO that are about 1 A to 10 "15 of those known to induce vasodilation in normal circulations.
  • Painful diabetic neuropathy is a common and debilitating peripheral nerve complication of diabetes mellitus.
  • symptoms e.g. pain, abnormal sensations
  • Patients may present with one or more symptoms including burning sensations, lancinating and deep aching pains, depending upon the extent of nerve injury ⁇ Boulton, Diabetes Metab Res Rev 19: S16-21 2003).
  • Numbness, tingling, and a sensation of tightness in the extremity are also commonly associated with PDN (Boulton, Diabetes Metab Res Rev 19: S 16-21 2003).
  • unpleasant abnormal sensations disaethesia
  • enhanced sensitivity to stimulation hypereraesthesia
  • a heightened response to painful stimuli hyperalgesia
  • a distorted sense of touch producing allodynia innocuous stimuli such as light brushstrokes of the skin produce pain
  • the vascular dysfunction theory proposes that changes in the blood supply to the nerves (the neurovasculature or vasa nervorum) occur secondary to haemodynamic abnormalities (such as accelerated platelet aggregation and increased blood viscosity) (Fusman et al. Acta Diabetol 38(3): 129-34 2001).
  • haemodynamic abnormalities such as accelerated platelet aggregation and increased blood viscosity
  • pathological changes in the small blood vessels of the neurovasculature may occur (such as reduction of the production of nitric oxide from the endothelial cells of blood vessels and acceleration of the reactivity on vasoconstrictive substances) (McAuley et al. Clin Sci (Lond) 99(3): 175-9 2000).
  • nitric oxide is the most potent and hence is a likely candidate for reduced synthesis and consequent diabetes-induced constrictions in vascular tone. As well as relaxing vascular smooth muscle, it also inhibits the processes of platelet aggregation, mitogenesis and proliferation of cultured vascular smooth muscle, and leucocyte adherence (Wroblewski et al. Prev Cardiol
  • Nitric oxide is produced by the vascular endothelium by a group of enzymes called nitric oxide synthases. There are three isoforms of nitric oxide synthase (NOS) named according to their activity or the tissue type in which they were first described. These enzymes all convert the endogenous substrate, L-arginine, into L- citrulline, producing NO in the process.
  • NOS nitric oxide synthase
  • nitric oxide donors such as L-arginine can broadly prevent, attenuate and/or reverse the development of reduced analgesic sensitivity to an opioid receptor agonist such as morphine in neuropathic conditions, including peripheral neuropathic conditions such as PDN (see International Publication No. WO 2003/078437).
  • This finding that nitric oxide donors can restore the analgesic sensitivity of opioid analgesics such as morphine in subjects with neuropathic conditions was significant because it allowed the use of these analgesics for treating or preventing pain in conditions, for which they were previously considered ineffective.
  • nitric oxide (NO) donors which directly or indirectly generate NO at concentrations that are smaller than those known to induce vasodilation in normal circulations (also referred to herein as sub-normovasodilatory (SNV) concentrations), are effective in producing analgesia in subjects with a neuropathic condition without the need for co-administering opioid analgesics.
  • SNV concentrations can broadly range from about 1 A to about 10 "15 of those known to induce vasodilation in normal circulations.
  • one aspect of the present invention provides methods for the treatment or prophylaxis of a neuropathic condition in a subject.
  • the neuropathic condition is treated or prevented by administering to the subject at least one NO donor at a level that enhances NO and that does not alter normal systemic vascular tone in the subject.
  • the NO donor is suitably administered without co-administration of an opioid analgesic.
  • the methods of treating or preventing the neuropathic condition consist essentially of administering the NO donor(s).
  • the level of NO is a sub-normovasodilatory (SNV) concentration that ranges from about Vi to about 10 "15 of a reference concentration required to induce vasodilation in an anatomical site of a reference subject lacking a vascular condition, which suitably but not exclusively associates with the neuropathic condition to be treated or prevented.
  • SNV sub-normovasodilatory
  • Illustrative anatomical sites include kidney, skin, skeletal muscle, arm, leg, tail and gastro-intestinal tract.
  • the NO donor is suitably administered in the form of a composition comprising a pharmaceutically acceptable carrier and/or diluent.
  • the composition may be administered by injection, by topical application, or by the buccal, sublingual, rectal or oral routes, including sustained-release modes of administration, over a period of time and in amounts which are effective for delivering a SNV concentration of NO as broadly described above.
  • the NO donor is provided in a sustained release formulation ⁇ e.g., transdermal patch), which delivers a SNV concentration of NO as broadly described above.
  • the NO donor is a slow-release NO donor that delivers an SNV concentration of NO as broadly described above.
  • the present invention contemplates the use of a composition that consists essentially of at least one NO donor for producing analgesia in a subject, especially in a subject having a neuropathic condition, which is suitably a peripheral neuropathic condition such as PDN or a related condition, wherein the composition comprises at least one NO donor at a level that enhances NO and that does not alter normal systemic vascular tone in the subject.
  • the composition excludes an opioid analgesic or is used to produce analgesia in the absence of coadministering an opioid analgesic.
  • Figure 1 is a graphical representation showing that tactile (mechanical) allodynia is folly developed by -9-10 wks post-STZ administration.
  • Figure 2 is a graphical representation showing that single s.c. bolus doses (8-800 fmol/kg) of the NO donor, PRGl 00, produces dose-dependent relief of tactile allodynia, the defining symptom of painful diabetic neuropathy (PDN), in STZ- diabetic rats at 10 wks post-STZ administration
  • PDN painful diabetic neuropathy
  • Figure 3 is a graphical representation showing that single s.c. bolus doses (8-800 pmol/kg) of the NO donor, PRGlOO, produces dose-dependent relief of tactile allodynia, the defining symptom of painful diabetic neuropathy (PDN), in STZ- diabetic rats at 14 and 24 wks post-STZ administration.
  • PDN painful diabetic neuropathy
  • Figure 4 is a graphical representation showing that neither single s.c. bolus doses of vehicle (DMSO:water, 90:10) nor the NO donor PRGlOO at 80 fmol/kg- 8 ⁇ mol/kg, significantly altered mean ( ⁇ SEM) systolic blood pressure of adult male normotensive non-diabetic Wistar rats for up to 1 h post-dosing.
  • DMSO DMSO:water, 90:10
  • ⁇ SEM mean
  • single s.c. bolus doses of PRGlOO at 80 ⁇ mol/kg to similar animals significantly reduced systolic blood pressure at 30 min post-dosing relative to pre-dosing baseline measurements of systolic blood pressure.
  • the term "about” refers to a quantity, level, concentration, value, dimension, size, or amount that varies by as much as 30%, 20%, or 10% or even as much as 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% to a reference quantity, level, concentration, value, dimension, size, or amount.
  • allodynia refers to pain that results from a non-noxious stimulus i.e., a stimulus that does not normally provoke pain.
  • examples of allodynia include, but are not limited to, cold allodynia, tactile allodynia (pain due to light pressure or touch), and the like.
  • analgesia is used herein to describe states of reduced pain perception, including absence from pain sensations as well as states of reduced or absent sensitivity to noxious stimuli. Such states of reduced or absent pain perception are induced by the administration of a pain-controlling agent or agents and occur without loss of consciousness, as is commonly understood in the art.
  • analgesia encompasses the term "antinociception", which is used in the art as a quantitative measure of analgesia or reduced pain sensitivity in animal models.
  • causalgia refers to the burning pain, allodynia and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes.
  • complex regional pain syndromes is meant the pain that includes, but is not limited to, reflex sympathetic dystrophy, causalgia, sympathetically maintained pain, and the like.
  • phrases “consisting essentially of,” “consists essentially of and the like refer to the components which are essential in order to obtain the advantages of the present invention and any other components present would not significantly change the properties related to the inventive concept. Put another way, these phrases refer to the inclusion of any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrases “consisting essentially of,” “consists essentially of and the like indicate that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.
  • an effective amount in the context of treating or preventing a condition (e.g. a neuropathic condition) is meant the administration of that amount of active to an individual in need of such treatment or prophylaxis, either in a single dose or as part of a series, that is effective for the prevention of incurring a symptom, holding in check such symptoms, and/or treating existing symptoms, of that condition.
  • the effective amount will vary depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.
  • hyperalgesia is meant an increased response to a stimulus that is normally painful.
  • neuropathic pain any pain syndrome initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system.
  • neuropathic pain include, but are not limited to, thermal or mechanical hyperalgesia, thermal or mechanical allodynia, painful diabetic neuropathy, postherpetic neuralgia, pantom limb pain, sciatica, chemotherapy-induced neuropathy, HIV- AIDS-associated neuropathy, nerve entrapment pain, and the like.
  • nitric oxide donor any substance that is converted into, degraded or metabolised into, or provides a source of in vivo nitric oxide or NO and includes any and all forms of NO which exist under physiological conditions.
  • NO donor includes and encompasses any compound which mimics the effects of NO, generates or releases NO through biotransformation, any compound which generates NO spontaneously, any compound which spontaneously releases NO, or any compound which in any other manner generates NO or a NO-like moiety when administered to a subject.
  • Nociceptive pain refers to the normal, acute pain sensation evoked by activation of nociceptors located in non-damaged skin, viscera and other organs in the absence of sensitization.
  • Pain as used herein is given its broadest sense and includes an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage and includes the more or less localised sensation of discomfort, distress, or agony, resulting from the stimulation of specialised nerve endings.
  • ⁇ pain there are many types of pain, including, but not limited to, lightning pains, phantom pains, shooting pains, acute pain, inflammatory pain, neuropathic pain, complex regional pain, neuralgia, neuropathy, and the like (Dorland's Illustrated Medical Dictionary, 28 th Edition, W. B. Saunders Company, Philadelphia, Pa.).
  • the goal of treatment of pain is to reduce the severity of pain perceived by a treatment subject.
  • pharmaceutically acceptable carrier is meant a solid or liquid filler, diluent or encapsulating substance that may be safely used in topical, local or systemic administration.
  • pharmaceutically compatible salt refers to a salt which is toxicologically safe for human and animal administration.
  • This salt may be selected from a group including hydrochlorides, hydrobromides, hydroiodides, sulphates, bisulphates, nitrates, citrates, tartrates, bitartrates, phosphates, malates, maleates, napsylates, fumarates, succinates, acetates, terephthalates, pamoates and pectinates.
  • prodrug is used in its broadest sense and encompasses those compounds that are converted in vivo to a NO donor according to the invention. Such compounds would readily occur to those of skill in the art, and include, for example, compounds where a free hydroxy group is converted into an ester derivative. Prodrug forms of compounds may be utilised, for example, to improve bioavailability, mask unpleasant characteristics such as bitter taste, alter solubility for intravenous use, or to provide site-specific delivery of the compound.
  • slow-release nitric oxide donor or “slow-release NO donor” is meant any substance that is converted or degraded or metabolised into, or provides a source of in vivo nitric oxide or NO over an extended period of time, thereby delivering a low concentration of nitric oxide into the blood stream.
  • the slow-release nitric oxide donor is administered in an amount such that nitric oxide is delivered at a rate of 0.000001 nmol/kg/hour to 2.0 nmol/kg/hour.
  • vertebrate subject refers to any subject, particularly a vertebrate subject, and even more particularly a mammalian subject, for whom therapy or prophylaxis is desired.
  • Suitable vertebrate animals include, but are not restricted to, primates, avians, livestock animals (e.g., sheep, cows, horses, donkeys, pigs), laboratory test animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats, dogs) and captive wild animals (e.g., foxes, deer, dingoes).
  • a preferred subject is a human in need of treatment or prophylaxis for a peripheral neuropathic condition, especially PDN.
  • a peripheral neuropathic condition especially PDN.
  • SNC concentration refers to a level of NO donor, which enhances NO and that does not alter normal systemic vascular tone in the subject.
  • sustained-release formulation of nitric oxide donor refers to a formulation of an NO donor that is adapted to release nitric oxide at a rate of 0.000001 nmol/kg/hour to 2.0 nmol/kg/hour or a range selected from 0.00001 nmol/kg/hour to 2.0 nmol/kg/hour, 0.0002 nmol/kg/hour to 1.0 nmol/kg/hour, 0.0005 nmol/kg/hour to 1.0 nmol/kg/hour, 0.0001 nmol/kg/hour to 0.5 nmol/kg/hour, 0.0002 nmol/kg/hour to 0.2 nmol/kg/hour, 0.0005 nmol/kg/hour to 0.1 nmol/kg/hour or 0.001 nmol/kg/hour to 0.05 nmol/kg/hour, 0.005 nmol/kg/hour to 0.01 nmol/kg/hour.
  • the sustained release formulation may be any formulation capable of releasing NO at this rate.
  • Illustrative sustained release formulations are transdermal patches adapted to deliver 0.1 nmol to 500 nmol per 24 hours, especially 10 nmol to 100 nmol per 24 hours, more especially 20 nmol to 60 nmol per 24 hours, most especially about 50 nmol over 6, 9, 12, 18, 24 or 30 hours.
  • does not alter normal systemic vascular tone is meant not affecting mean arterial pressure so as to produce inappropriate systemic vasodilation with effects such as hypotension, headache, flushing in a normal subject or in a subject lacking a vascular condition (e.g., a neuropathic condition such as PDN).
  • a vascular condition e.g., a neuropathic condition such as PDN
  • the present invention provides methods for producing analgesia in a subject having a neuropathic condition. These methods generally comprise administering to the subject at least one NO donor at a level that enhances NO and that does not alter normal systemic vascular tone in the subject. Suitably, this level equates to one that does not induce vasodilation, or not appreciably, in "healthy” or non-NO deficient circulations.
  • the level of NO is a sub-normovasodilatory (SNV) concentration that ranges from about Vz to about 10 "ls of those currently used in clinical applications.
  • SNV sub-normovasodilatory
  • the method of the present invention has particular utility in the prevention and/or alleviation of the painful symptoms associated with neuropathic conditions.
  • neuropathic conditions There are many possible causes of neuropathic conditions and it will be understood that the present invention contemplates the treatment and/or prevention of pain associated with any neuropathic condition regardless of the cause.
  • the neuropathic conditions are a result of diseases of the nerves (primary neuropathy) and neuropathy that is caused by systemic disease (secondary neuropathy), such, as but not limited to diabetic neuropathy, Herpes Zoster (shingles)-related neuropathy, phantom limb pain, uraemia-associated neuropathy, amyloidosis neuropathy, HIV sensory neuropathies, hereditary motor and sensory neuropathies (HMSN), hereditary sensory neuropathies (HSNs), hereditary sensory and autonomic neuropathies, hereditary neuropathies with ulcero-mutilation, nitrofurantoin neuropathy, tomaculous neuropathy, neuropathy caused by nutritional deficiency and neuropathy caused by kidney failure.
  • secondary neuropathy such, as but not limited to diabetic neuropathy, Herpes Zoster (shingles)-related neuropathy, phantom limb pain, uraemia-associated neuropathy, amyloidosis neuropathy, HIV sensory neuropathies, hereditary motor and sensory neuropathies (HMSN), heredit
  • neuropathic condition is a peripheral neuropathic condition such as PDN or related condition.
  • the neuropathic condition may be acute or chronic and, in this connection, it will be understood by persons of skill in the art that the time course of a neuropathy will vary, based on its underlying cause. With trauma, the onset of symptoms may be acute, or sudden, with the most severe symptoms being present at the onset or developing subsequently. Inflammatory and some metabolic neuropathies have a subacute course extending over days to weeks. A chronic course over weeks to months usually indicates a toxic or metabolic neuropathy. A chronic, slowly progressive neuropathy over many years occurs with most hereditary neuropathies or with a condition termed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Neuropathic conditions with symptoms that relapse and remit include the Guillian-Barre syndrome.
  • CIDP chronic inflammatory demyelinating polyradiculoneuropathy
  • the NO donor includes and encompasses any substance that is converted into, or degraded or metabolised into, or provides a source of, in vivo NO, inclusive of NO in its various redox forms.
  • NO nitric oxide
  • the presence of nitric oxide (NO) in biological systems is usually inferred based on its physiological effect.
  • NO nitric oxide
  • several different redox forms of NO such as the NO free radical (NO.), the nitrosonium cation (NO+), the nitroxyl anion (NO-) or other oxides of nitrogen (NOx) are known to exist under physiological conditions and there is no clear evidence to suggest that one form is favored over another (Butler et al. 1995, Trends Pharmacol. Sci. 16:18-22; Stamler et al.
  • NO is also know to react with thiols to form S-nitrosothiols (RS-NO) and may represent a long-term storage form for NO.
  • This category includes compounds having differing structural features.
  • NO donors include, but are not limited to: metabolic precursors of NO such as L-arginine and L-citrulline; so-called "organonitrates" such as nitroglycerin (GTN), glyceryl trinitrate, isosorbide 5-mononitrate (ISMN), isosorbide dinitrate (ISDN), pentaerythritol tetranitrate (PETN), erythrityl tetranitrate (ETN), amino acid derivatives such as N- hydroxy-L-arginine (NOHA), N 6 -( 1 -iminoethyl)lysine) (L-NIL) 5 L-N 5 -( 1 - iminoethyl)orni
  • GTN nitroglycer
  • the organic nitrates GTN, ISMN, ISDN, ETN, and PETN, as well as nicorandil are commercially available in pharmaceutical dosage forms.
  • NONOate and DEA-NONOate are commercially available from Biotium, Inc. 183 Shoreline Court, Richmond, Calif., USA.
  • the NO donor is suitably selected from [3-(lH-Imidazol-4-yl)propyl]guanidines-containing furoxan moieties, as for example, described in Bertinaria et al. (2003, Bioorganic & Medicinal Chemistry 11: 1197-1205), NO-donor phenols as described, for example, in Boschi et al. (2006, J Med. Chem.
  • the NO donor is PRGlOO, as disclosed in Example 1.
  • an NO donor is administered at a level that enhances NO and that does not alter normal systemic vascular tone in the subject.
  • the level of NO is a sub-normovasodilatory (SNV) concentration that ranges from about 1 A to about 10 "15 of a reference concentration required to induce vasodilation in an anatomical site of a reference subject lacking a vascular condition, which is suitably the neuropathic condition.
  • Vasodilation may be measured using any suitable technique for defining SNV concentrations. Illustrative methods for measuring vasodilation include, but are not limited to, measuring systolic blood pressure (e.g., in a limb or tail), by measuring blood flow in ears or using the vasodilation assay described in Pharmacol Res. 39(3): 217-20 (1999).
  • systolic blood pressure is measured in normotensive experimental animals (e.g., rats) that are lightly sedated via intraperitoneal injection of Zoletil (tiletamine 15 mg/kg, zolazepam 15 mg/kg), using an inflatable tail-cuff.
  • normotensive experimental animals e.g., rats
  • Zoletil tiletamine 15 mg/kg, zolazepam 15 mg/kg
  • Representative SNV concentration ranges include from about V 2 to about 1/20, V 2 to about 1/50, 1 A to about 10 "1 , 10 '1 to about 10 "15 , 10 “2 to about 10 “15 , 10 '3 to about 10 '15 , 10 “4 to about 10 "15 , lO '5 to about 10 "15 , 10 "6 to about 10 "15 , 10 '2 to about 10-' 3 , 10 '2 to about 10 '12 , 10 "2 to about 10 "11 , 10 '2 to about 10 “10 , 10 “2 to about 10 “9 , 10 “2 to about 10 “8 , 10 “2 to about 10 “7 , or 10 “2 to about 10 “6 of the reference concentration.
  • the amount of NO donor that is administered as a bolus is in the range of 0.000001 nmol/kg to 2 nmol/kg, 0.00001 nmol/kg to 2 nmol/kg, 0.0001 nmol/kg to 2 nmol/kg, 0.001 nmol/kg to 2 nmol/kg, 0.001 nmol/kg to 1 nmol/kg, 0.001 nmol/kg to 0.6 nmol/kg, 0.004 nmol/kg to 0.4 nmol/kg, preferably in a range selected from 0.005 nmol/kg to 0.3 nmol/kg, 0.006 nmol/kg to 0.2 nmol/kg, 0.007 nmol/kg to 0.1 nmol/kg, 0.008 nmol/kg to 0.09 nmol/kg, 0.009 nmol/kg to 0.08 nmol/kg, 0.01 nmol/kg to 0.07 nmol
  • the NO donor is adapted to release nitric oxide at a rate of 0.00001 nmol/kg/hour to 2.0 nmol/kg/hour, 0.0001 nmol/kg/hour to 2.0 nmol/kg/hour, 0.0002 nmol/kg/hour to 2.0 nmol/kg/hour or in a range selected from 0.001 nmol/kg/hour to 1.0 nmol/kg/hour, 0.005 nmol/kg/hour to 1.0 nmol/kg/hour, 0.001 nmol/kg/hour to 0.5 nmol/kg/hour, 0.002 nmol/kg/hour to 0.2 nmol/kg/hour, 0.005 nmol/kg/hour to 0.1 nmol/kg/hour, or 0.01 nmol/kg/hour to 0.05 nmol/kg/hour.
  • the NO donor is a transdermal patch adapted to release 0.5 nmol to 500 nmol, especially 10 nmol to 100 nmol, more especially 20 nmol to 60 nmol and even more especially about 50 nmol over 6, 9, 12, 18, 24 or 30 hours.
  • the level of NO donor administered is effective for treating or preventing a neuropathic condition, including a peripheral neuropathic condition such as PDN or a related condition, and especially for the treatment or prevention of pain in neuropathic conditions, including the prevention of incurring pain, holding pain in check, and/or treating existing pain.
  • a neuropathic condition including a peripheral neuropathic condition such as PDN or a related condition
  • the treatment or prevention of pain in neuropathic conditions including the prevention of incurring pain, holding pain in check, and/or treating existing pain.
  • Whether pain has been treated is determined by measuring one or more diagnostic parameters which is indicative of pain (e.g., subjective pain scores, tail-flick tests and tactile allodynia) compared to a suitable control.
  • a "suitable control" is an animal not treated with the nitric oxide donor, or treated with the pharmaceutical composition without nitric oxide donor.
  • a "suitable control" may be the individual before treatment, or may be a human (e.g., an age-matched or similar control) treated with a placebo.
  • the treatment of pain includes and encompasses without limitation: (i) preventing pain experienced by a subject which may be predisposed to the condition but has not yet been diagnosed with the condition and, accordingly, the treatment constitutes prophylactic treatment for the pathologic condition; (ii) inhibiting pain initiation or a painful condition, i.e., arresting its development; (iii) relieving pain, i.e., causing regression of pain initiation or a painful condition; or (iv) relieving symptoms resulting from a disease or condition believed to cause pain, e.g., relieving the sensation of pain without addressing the underlying disease or condition.
  • compositions for producing analgesia and especially for treating, preventing and/or alleviating the painful symptoms of a neuropathic condition generally comprise at least one NO donor at a level that enhances NO and that does not alter normal systemic vascular tone in the subject, as broadly described above.
  • the effect of the compositions of the present invention may be examined by using one or more of the published models of pain/nociception or of neuropathy, especially peripheral neuropathy, and more especially PDN, known in the art. This may be demonstrated, for example using an animal model which assesses the onset and development of tactile allodynia, the defining symptom of PDN, as for example described herein.
  • the analgesic activity of the compounds of this invention can be evaluated by any method known in the art. Examples of such methods are the Tail-flick test (D 'Amour et al. 1941, J Pharmacol. Exp. and Ther. 72: 74-79); the Rat Tail Immersion Model, the Carrageenan-induced Paw Hyperalgesia Model, the Formalin Behavioral Response Model (Dubuisson et al. 1977, Pain 4: 161-174), the Von Frey Filament Test (Kim et al. 1992, Pain 50: 355-363), the Chronic Constriction Injury, the Radiant Heat Model, and the Cold Allodynia Model (Gogas et al. 1997, Analgesia 3: 111-118), the paw pressure test of mechanical hyperalgesia (Randall and Selitto, 1997, Arch Int
  • the NO donors may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, maleic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms.
  • the dose of NO donor administered to a patient should be sufficient to achieve a beneficial response in the patient over time such as a reduction in, or relief from, pain, especially neuropathic pain.
  • the quantity of the compound(s) to be administered may depend on the subject to be treated inclusive of the age, sex, weight and general health condition thereof. This quantity, however, will be one that enhances NO and that does not alter normal systemic vascular tone in the subject. In this regard, precise amounts of the NO donor(s) for administration will depend on the judgement of the practitioner.
  • the physician may evaluate severity of the pain symptoms associated with nociceptive or inflammatory pain conditions or numbness, weakness, pain, loss of reflexes and tactile allodynia associated with neuropathic conditions, especially peripheral neuropathic conditions such as PDN.
  • those of skill in the art may readily determine suitable dosages of the nitric oxide donors of the invention without undue experimentation.
  • the NO donor-containing compositions will generally contain about 0.001% to 90%, about 0.1% to 50%, or about 1% to about 25%, by weight of NO donor, the remainder being suitable pharmaceutical carriers and/or diluents etc.
  • the dosage of the nitric oxide donor can depend on a variety of factors, such as the individual nitric oxide donor, mode of administration, the species of the affected subject, age and/or individual condition.
  • the NO donor(s) may be formulated and administered systemically, topically or locally. Techniques for formulation and administration may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., latest edition.
  • Suitable routes may, for example, include buccal, sublingual, oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • the therapeutic agents of the invention may be formulated in aqueous solutions, suitably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • compositions of this invention may be formulated for administration in the form of liquids, containing acceptable diluents (such as saline and sterile water), or may be in the form of lotions, creams or gels containing acceptable diluents or carriers to impart the desired texture, consistency, viscosity and appearance.
  • acceptable diluents such as saline and sterile water
  • Acceptable diluents and carriers are familiar to those skilled in the art and include, but are not restricted to, ethoxylated and nonethoxylated surfactants, fatty alcohols, fatty acids, hydrocarbon oils (such as palm oil, coconut oil, and mineral oil), cocoa butter waxes, silicon oils, pH balancers, cellulose derivatives, emulsifying agents such as non- ionic organic and inorganic bases, preserving agents, wax esters, steroid alcohols, triglyceride esters, phospholipids such as lecithin and cephalin, polyhydric alcohol esters, fatty alcohol esters, hydrophilic lanolin derivatives, and hydrophilic beeswax derivatives.
  • ethoxylated and nonethoxylated surfactants include, but are not restricted to, ethoxylated and nonethoxylated surfactants, fatty alcohols, fatty acids, hydrocarbon oils (such as palm oil, coconut oil, and mineral oil), cocoa butter waxes,
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterise different combinations of active compound doses.
  • the formulations of the invention can be provided in the form of a tablet, patch, troche, or in free form, such as a gel, ointment, cream, or gum.
  • Dosage forms of the NO donors may also include injecting or implanting controlled releasing devices designed specifically for this purpose or other forms of implants modified to act additionally in this fashion.
  • Controlled release of an active compound of the invention may be achieved by coating the same, for example, with hydrophobic polymers including acrylic resins, waxes, higher aliphatic alcohols, polylactic and polyglycolic acids and certain cellulose derivatives such as hydroxypropylmethyl cellulose.
  • controlled release may be achieved by using other polymer matrices, liposomes and/or microspheres.

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Abstract

La présente invention concerne des compositions et des procédés permettant d'induire, de favoriser ou de faciliter le soulagement de la douleur. L'invention concerne plus particulièrement l'utilisation de doses vasodilatatrices sub-normales de donneurs d'oxyde nitrique pour la gestion thérapeutique d'animaux vertébrés, y compris les humains, dans un but de prévention ou de soulagement de la douleur, en particulier la douleur neuropathique. Selon certains modes de réalisation de la présente invention, les donneurs d'oxyde nitrique sont administrés par n'importe quelle voie appropriée de manière à assurer des concentrations en NO qui sont égales à environ ½ à 10-15 de celles dont l'on sait qu'elles induisent la vasodilatation dans une circulation normale.
PCT/AU2008/000003 2006-12-29 2008-01-02 Compositions analgésiques et leurs utilisations WO2008080194A1 (fr)

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US12/494,183 US8822509B2 (en) 2006-12-29 2009-06-29 Pain-relieving compositions and uses therefor
US14/466,795 US20150051404A1 (en) 2006-12-29 2014-08-22 Pain-relieving compositions and uses therefor
US15/669,834 US9994534B2 (en) 2006-12-29 2017-08-04 Pain-relieving compositions and uses therefor

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WO2010108110A3 (fr) * 2009-03-20 2011-01-13 Edwards Lifesciences Corporation Surveillance du découplage périphérique
EP2307013A1 (fr) * 2008-07-02 2011-04-13 The University Of Queensland Compositions de donneurs d oxyde nitrique contenant du furoxane soulageant la douleur et leurs utilisations

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WO2006066362A1 (fr) * 2004-12-24 2006-06-29 The University Of Queensland Procedes de traitement de la douleur
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WO2003078437A1 (fr) * 2002-03-20 2003-09-25 The University Of Queensland Procedes et compositions contenant des donneurs d'oxyde nitrique et des analgesiques opioides
WO2006066362A1 (fr) * 2004-12-24 2006-06-29 The University Of Queensland Procedes de traitement de la douleur
EP1690558A1 (fr) * 2005-02-11 2006-08-16 NOLabs AB Dispositif de traitment de troubles d'origine diabetique
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Publication number Priority date Publication date Assignee Title
EP2307013A1 (fr) * 2008-07-02 2011-04-13 The University Of Queensland Compositions de donneurs d oxyde nitrique contenant du furoxane soulageant la douleur et leurs utilisations
EP2307013A4 (fr) * 2008-07-02 2012-06-13 Univ Queensland Compositions de donneurs d oxyde nitrique contenant du furoxane soulageant la douleur et leurs utilisations
AU2009266408B2 (en) * 2008-07-02 2014-08-28 The University Of Queensland Pain-relieving compositions of furoxan NO donors and uses thereof
WO2010108110A3 (fr) * 2009-03-20 2011-01-13 Edwards Lifesciences Corporation Surveillance du découplage périphérique
CN102413760A (zh) * 2009-03-20 2012-04-11 爱德华兹生命科学公司 监控外周退耦

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