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WO2004032844A2 - Compositions et methodes de traitement de la douleur - Google Patents

Compositions et methodes de traitement de la douleur Download PDF

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Publication number
WO2004032844A2
WO2004032844A2 PCT/US2003/031481 US0331481W WO2004032844A2 WO 2004032844 A2 WO2004032844 A2 WO 2004032844A2 US 0331481 W US0331481 W US 0331481W WO 2004032844 A2 WO2004032844 A2 WO 2004032844A2
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Prior art keywords
pain
prostaglandin
norepinephrine
precursor
antagonist
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Ceased
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PCT/US2003/031481
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WO2004032844A3 (fr
Inventor
Stephen J. Peroutka
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Synergia Pharma Inc
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Synergia Pharma Inc
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Priority to AU2003275433A priority Critical patent/AU2003275433A1/en
Publication of WO2004032844A2 publication Critical patent/WO2004032844A2/fr
Publication of WO2004032844A3 publication Critical patent/WO2004032844A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone

Definitions

  • opioids are used in the treatment of pain, including, e.g., sympatholytics, membrane stabilizing agents, opioids, anti-depressants, antagonists to excitatory amino acid neurotransmitters, non-steroidal anti-inflammatory drugs ("NSAIDS"), etc.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • opioids are widely used to treat pain, accounting for over 5% of all prescription drug sales in the United States in the year 2001.
  • opioids have many debilitating side effects that limit their usefulness at all doses. For instance, they can cause nausea, vomiting, and respiratory depression.
  • chronic use of even conventional opioids can lead to tolerance, dependence, abuse, and addiction.
  • a number of number of different neurotransmitters, hormones, and other biological molecules are known to mediate these pain pathways, including, e.g., potassium, serotonin, bradykinin, histamine, prostaglandins, leukotrienes, and substance P. See, e.g., Principles of Neural Science, Kandel et al., 1991, Pages 385-399. Although many of these molecules have been targeted for pain management, due to the complexity of the nervous system and pain perception, not all have been effective.
  • Pain can be defined as the perception of an aversive or unpleasant sensation that originates from a specific region of the body. It arises from the activation of specialized sensory receptors, known as nociceptors, that provide information about tissue damage and other excitatory stimuli. Pain is always subjective, and can be assessed on various scales, including verbal numerical scales (where "0" is no pain, and "10” is the worst pain a subject can imagine), word scales (e.g., none, mild, moderate, severe, and excruciating), and visual analog scales.
  • the quality of it can also be evaluated, e.g., whether it is aching, throbbing, shooting, stabbing, gnawing, sharp, tender, burning, exhausting, tiring, penetrating, nagging, numb, uncomfortable, and unbearable.
  • the present invention relates to methods of treating pain in a subject in need thereof, comprising administering effective amounts of a norepinephrine ("NE") precursor and a prostaglandin ("PG") antagonist.
  • NE norepinephrine
  • PG prostaglandin
  • treating is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving, etc., a painful condition. Any amount of improvement in the perception of pain is considered useful, and the clinical efficacy of such treatment can be assessed using any of the pain scales utilized by a healthcare practitioner, including those mentioned above.
  • the amounts of the NE precursor and PG antagonist administered to a subject can be effective to increase the ratio between secreted post-ganglionic norepinephrine and secreted post-ganglionic prostaglandin at levels to treat pain. While not wishing to be bound by any theory, it has been found herein that an imbalance in the relative levels of norepinephrine and prostaglandin is a primary factor in causing and/or sustaining pain. Although it had been previously known that prostaglandins are pain modulators, the combined role of norepinephrine in contributing to the pain syndrome had not been recognized.
  • Post-ganglionic sympathetic neurons regulate a number of effector organs, including smooth muscle (e.g., comprising blood vessels), glands, and cardiac muscle. In addition to the manufacture and secretion of norepinephrine, these neurons also produce prostaglandins, especially PGE2 and PGI2. Stimulation of the sympathetic neurons leads to an increased secretion of PGE2 and PGI2 (Davis et al, 1971, Webb et al, 1978, Trevisani et al, 1982, Serneri et al, 1983, Gonzales et al, 1989, Sherbourne et al, 1992).
  • a key insight into the pathogenesis of pain is the fact that the ability of the SNS to synthesize prostaglandins is essentially unlimited since they are derived from highly abundant fatty acids. This fact is in striking contradistinction to NE in the SNS, whose synthesis is limited by a rate-limiting enzyme (dopamine beta-hydroxylase) and whose storage is limited by synaptic vesicle capacity. Thus, while NE levels decrease with repeated SNS stimulation, prostaglandin synthesis remains stable or becomes elevated. Pain treatment can be accomplished in accordance with the present invention by restoring the ratio between NE and PG to a level that is effective to decrease or prevent pain.
  • a norepinephrine precursor comprises any compound that is converted into the neurotransmitter norepinephrine.
  • dopa decarboxylase that can be converted to norepinephrine
  • norepinephrine such as threo-3- (3,4-dihydroxyphenyl)serine
  • dopamine beta-hydroxylase that can be converted to norepinephrine, such as dopamine
  • a prostaglandin antagonist is any compound that blocks the biological activity of a prostaglandin, including by inhibiting its synthesis or prostaglandin receptor blockade.
  • an antagonist can be a receptor antagonist, i.e., it binds to a prostaglandin receptor without eliciting the biological response normally stimulated by the receptor agonist.
  • Receptor antagonism can be competitive, where the antagonist competes directly with the agonist at the receptor's ligand binding site, or it can be non-competitive.
  • An antagonist can block prostaglandin activity by inhibiting its production.
  • Prostaglandin synthesis begins with the cell membranes with the production of arachidonate from various phospholipids.
  • the key enzyme involved in arachidonate synthesis is phospholipase A2.
  • Lipocortins or annexins are proteins that inhibit the activity of phospholipase A2, thereby limiting prostaglandin production.
  • Anti-inflammatory corticosteroids induce the synthesis of lipocortins, inhibiting the activation of phospholipase A2 and the subsequence production of prostaglandins.
  • the cyclooxygenase also referred to as prostaglandin H synthase
  • the cyclooxygenase also referred to as prostaglandin H synthase
  • COXl and COX2 Non- steroidal anti-inflammatory drugs
  • NSAIDs such as aspirin, indomethacin, diclofenac, and ibuprofen
  • Prostaglandin H2 is the precursor of a variety of physiologically relevant prostaglandins. The specific prostaglandin molecules derived from it are completely dependent upon the local tissue expression of certain enzymes. Inhibitors of any of the enzymes and/or cofactors involved in the prostaglandin synthetic pathway can be used in accordance with the present invention as prostaglandin antagonists.
  • Useful PG synthesis inhibitors include, but are not limited to non-selective COX inhibitors or COX-2 selective inhibitors, e.g., salicylic acids (e.g., aspirin, salicylate, and diflunisal), acetic acids (e.g., diclofenac, indomethacin, sulindac, and tolmetin), propionic acids (e.g., fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, naproxen, and pirprofen), anthranilic acids (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, and tolfenamic acid), pyrazolones (e.g., phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, and dipyrone), oxicams (e.g., piroxicam), etc.
  • PGE2 and PGI2 are enzyme inhibitors, preventing, reducing, blocking, decreasing, etc., the synthesis of post- ganglionic sympathetic prostaglandins. As a result, less biological PG activity is experienced. Prostaglandin activity is mediated by specific receptors. At present, 9 distinct receptor subtypes have already been identified. For PGE2, multiple receptor receptor subtypes have been identified, EPl, EP2, EP3, and EP4. PGE2 activity is mediated by the IP receptor subtype. Both PGE2 and PGI2 stimulate sensory fibers and function as key pain signaling molecules (Taiwo and Levine, 1990, Janig et al, 1996).
  • prostaglandins In the nervous system, stimulation of the EP2, EP4, and IP receptors by these prostaglandins result in an increase in cAMP levels in sensory neurons, thereby sensitizing the cell to all other stimuli.
  • PKA protein kinase A
  • Depolarization of sensory neurons requires sodium channel activation and leads directly to release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) (Hingten et al, 1995, Kopp et al, 2002).
  • the prostaglandin antagonists of the present invention can be used to decrease, reduce, lessen, diminish, etc., the cAMP levels in post-synaptic neurons.
  • Receptor antagonists that can be used in accordance with the present invention, include, but are not limited to, those disclosed in U.S. Pat. No. 6,211,197, EP4RA (e.g., EP4 antagonist; To ita et al., Bone, 30(1): 159-63, 2002), selective EP4 antagonist AH23848B, AH22921X, EP4-selective antagonist AE3-208, DP/EPl/EP2-rece ⁇ tor antagonist AH6809, etc.
  • EP4RA e.g., EP4 antagonist; To ita et al., Bone, 30(1): 159-63, 2002
  • the combination of the NE precursor and PG antagonist can be administered at any times and in any effective form.
  • the compounds can be administered simultaneously, e.g., as a single composition or dosage unit (e.g., a pill or liquid containing both compositions), or they can be administered as separate compositions, but at the same time (e.g., where a subject swallows a composition containing the NE precursor, and a second composition containing the PG antagonist).
  • the active agents can also be administered sequentially at different times. For instance, the combination can be administered at once, as soon as the onset of pain is experienced, followed by separate administration of the NE precursor and PG antagonist at appropriate intervals. Any effective amounts of the agents can be used.
  • the precursor and antagonist can be synergistic, i.e., where the joint action of the agents is such that the combined effect is greater than the algebraic sum of their individual effects.
  • DOPS is typically administered from about 100 mg to about 600 mg per single dose, but when administered in combination with a PG antagonist much less can be administered, e.g., from about 50 mg to about 300 mg per single dose.
  • the PG synthesis can be administered in dosages that are less than those when administered alone, e.g., 0.5, 0.25. 0.1 of the dosages normally administered. Administering lower dosages can be especially advantageous in eliminating side-effects and non-specificity associated with higher dosages.
  • PG inhibitors such as aspirin and ibuprofen can cause gastrointestinal disturbances, such as dyspepsia, peptic ulcer, GI bleeding, etc. Low doses can avoid such adverse reactions. Moreover, the combination can provide quicker and longer lasting relief from the pain. Amounts can be administered in a multiple doses over the course of the day, e.g., in order to treat a subject.
  • the specific dose level and frequency of dosage may vary, and can depend upon a variety of factors, including the activity of the specific active agents, their metabolic stability and length of action, rate of excretion, mode and time of administration, and the age, body weight, general health, gender, diet, and severity, intensity, and frequency of the onset of the headache, of the particular condition of the subject undergoing therapy.
  • the amounts of the NE precursor and PG antagonist can be effective to increase the ratio between secreted post-ganglionic norepinephrine and secreted post-ganglionic prostaglandin at levels to decrease pain.
  • Post-ganglionic synapses manufacture and secrete norepinephrine and prostaglandin (e.g., PGE2 and PGI2) into the synaptic cleft.
  • PGE2 and PGI2 secrete norepinephrine and prostaglandin
  • Increasing the levels of secreted NE maintaining, and/or decreasing the levels of secreted PG results in an increase of the NE/PG ratio and can be utilized to treat pain in a susceptible subject. Any quantity of increase can be used, e.g., 10%, 20%, 50%, 100%, 200%, etc., as long as such increase is effective in treating the target pain.
  • the present invention also relates to pharmaceutical compositions comprising, consisting essentially of, consisting of, a norepinephrine precursor and a prostaglandin antagonist, and a pharmaceutically-acceptable carrier.
  • a composition can contain a precursor which is L-threo-DOPS (or a pharmaceutically-acceptable salt thereof, or a derivative thereof) and an antagonist which a prostaglandin synthesis inhibitor.
  • the amounts of the NE precursor and PG antagonist can be present in any useful amounts, e.g., amounts that effective in the unit dosage form to treat pain.
  • any type of pain can be treated in accordance with the present invention, including, e.g., acute pain, chronic pain, neurogenic pain, nerve injury pain, muscular pain, fibromyalgia, myofascial pain syndrome, osteoarthritis, rheumatoid arthritis, arthritic pain, inflammatory pain, headache, tension headaches, migraine (insert REF), neuropathic pain, and post-operative pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, menstrual pain, joint pain, pain during labor and delivery, pain resulting from bums, including sunburn, post partum pain, angina pain, and genitourinary tract-related pain including cystitis, etc.
  • Headache pain that can be treated in accordance with the present invention include, e.g., migraine without aura, migraine with aura, tension-type headache, premenstrual headache, etc.
  • Migraine without aura can be associated with, e.g., hemicranial or bilateral pain, pulsating head pain, steady nonpulsatile head pain, nausea, vomiting, photophobia, phonophobia, and osmophobia.
  • Migraine with aura has similar symptoms, but subjects also experience aura.
  • Subjects with tension-type headaches can experience, e.g., bilateral, occipital, or frontal head pain, aching, tight, and-squeezing head pain, and nausea.
  • Olesen, Cephalalgia, Volume 8, Supplement 7, 1988 see, e.g., Olesen, Cephalalgia, Volume 8, Supplement 7, 1988.
  • Threo-3-(3,4-dihydroxyphenyl)serine is a synthetic amino acid precursor of NE (Freeman R., Clin. Neuropharm., 14, 296-304, 1991). DOPS is directly converted to NE via the actions of dopa decarboxylase (DDC) (also known as L-aromatic amino acid decarboxylase or AAAD). It has four stereoisomers, L-threo-DOPS, D-threo-DOPS, L-erythro-DOPS, and D-erythro-DOPS. Of the four, L-threo-DOPS is preferred, but a racemate can also be used.
  • DDC dopa decarboxylase
  • AAAD L-aromatic amino acid decarboxylase
  • DOPS Peak plasma levels of DOPS occurs 3 hour after oral ingestion whereas peak NE levels occur 5 hours after ingestion. Increased plasma levels of both molecules remain at least 12 hours after oral administration of DOPS (S Suzuki T, Higa S, Sakoda S, Ueji M, Hayashi A, Takaba Y, Nakajima A.; Eur J Clin Pharmacol 1982;23(5):463-8). Specific uptake of DOPS has also been demonstrated in microvessel preparations (Hardebo JE, Falck B, Owman C.Acta Physiol Scand 1979 Oct; 107(2): 161-7). Although threo-3 -(3 ,4-dihydroxyphenyl)serine is known as a norepinephrine precursor, the present invention includes any ameliorative effect, regardless of its mechanism of action or how it is achieved.
  • DOPS has been used to treat motor or speech disturbances (e.g., U.S. Pat. No. 5,656,669), Parkinson's disease, cerebral ischemia (e.g., EP 887 078), urinary incontinence (e.g., U.S. Pat. No. 5,266,596), orthostatic hypotension (Freeman, 1991), and pain (e.g., U.S.
  • Takagi e.g., Eur. Neuropsychopharm., 6: 43-47, 1996) discloses alleged analgesic effects of L-DOPS (100 mg), including in a patient experiencing a cluster headache.
  • Threo-3 -(3 ,4-dihydroxyphenyl) serine can be prepared according to any suitable method. These processes include those described in, e.g., U.S. Pat. Nos. 4,480,109,
  • compositions of threo-3 -(3, 4-dihydroxyphenyl)serine can also be used, including addition salts, e.g., inorganic acids, such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids, such as fumaric acid, citric acid, tartaric acid, and succinic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid
  • organic acids such as fumaric acid, citric acid, tartaric acid, and succinic acid.
  • Any pharmacologically active derivative of threo-3-(3,4-dihydroxyphenyl)serine can be used.
  • These include, e.g., N-methyl-3-(3,4-dihydroxyphenyl)serine alkyl esters, such as N-methyl-D,L-threo-3-(3,4-dihydroxyphenyl)serine and N-methyl-L-threo-3-(3,4 dihydroxyphenyl)serine, lower alkyl esters, methyl esters, ethyl esters, n-propyl esters, isopropyl esters, etc., as described in U.S. Pat. No. 5,288,898.
  • Active agents in accordance with the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally (e.g., as drops or a spray), local, non-oral, such as aerosal, spray, inhalation, subcutaneous, intravenous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. It can be administered alone, or in combination with any ingredient(s), active or inactive.
  • any effective route including, e.g., oral, parenteral, enteral, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally (e.g., as drops or a spray), local, non-oral, such as aerosal, spray, inhalation, subcutaneous, intravenous, intramuscular, buccal, sublingual, rec
  • Nasal compositions can be formulated and dispensed conventionally. See, e.g., Bommer, Pages 854-862 in Encyclopedia of Pharmaceutical Technology, Swarbrick and
  • nasal delivery systems include, but are not limited to, nasal drops, pipettes, squeeze bottles, pressurized systems, aerosols, mechanical dispensing systems, mechanical pump (e.g., with a metering chamber), etc.
  • the viscosity, thixotropy, surface tension, density, etc., of the composition can be selected to achieve the desired dosage of the composition with the selected nasal delivery system.
  • a L-DOPS composition administered to the nasal cavity See, also. WO9425017.
  • Nasal delivery is not restricted to liquid drug formulations or suspensions.
  • Powder dispensing systems can also be used to dispense nasal formulations of the present invention.
  • the combination of a NE precursor and PG antagonists can be co-administered together in a single nasal formulation, or the agents can be administered separately, e.g., where only one of the ingredients (e.g., L-DOPS or a PG synthesis inhibitor) is administered nasally, and the other by another route.
  • Active agents can be combined with any pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers any pharmaceutical carrier, such as the standard carriers described, e.g., Remington 's Pharmaceutical Science, Eighteenth Edition, Mack Publishing company, 1990.
  • suitable carriers are well known in the art and can include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solutions, phosphate buffered saline containing Polysorb 80, water, emulsions such as oil/water emulsion and various type of wetting agents.
  • Other carriers may also include sterile solutions, tablets, coated tablets pharmaceutical and capsules.
  • Such carriers typically contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols.
  • excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols.
  • Such carriers can also include flavor and color additives or other ingredients.
  • Compositions comprising such carriers are formulated by well known conventional methods.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose and the like.
  • additives include, e.g., antioxidants and preservatives, coloring, flavoring and diluting agents, emulsifying and suspending agents, such as acacia, agar, alginic acid, sodium alginate, bentonite, carbomer, carrageenan, carboxymethylcellulose, cellulose, cholesterol, gelatin, hydroxyethyl cellulose, hydroxppropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, octoxynol 9, oleyl alcohol, povidone, propylene glycol monostearate, sodium lauryl sulfate, sorbitan esters, stearyl alcohol, tragacanth, xanthan gum, and derivatives thereof, solvents, and miscellaneous ingredients such as microcrystalline cellulose, citric acid, dextrin, dextrose, liquid glucose, lactic acid, lactose, magnesium chloride, potassium metaphosphate, starch, and the like.
  • the active agent or the novel composition of this invention may be in a form suitable for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups and elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and typically such compositions contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives in order to provide pharmaceutically elegant and palatable preparations.
  • excipients may be for example, diluents such as lactose, calcium carbonate, sodium carbonate, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • diluents such as lactose, calcium carbonate, sodium carbonate, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, corn starch or alginic acid
  • binding agents for example starch, gelatin or acacia
  • lubricating agents for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated. Coating can be included to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pats. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or miscible solvents such as propylene glycol, PEGs and ethanol
  • an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth and acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoo
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl or n-propyl p- hydroxybenzoate
  • colouring agents for example ethyl or n-propyl p- hydroxybenzoate
  • flavouring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
  • the individual agents or the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxy-ethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain demulcents, preservatives, flavorants and coloring agents.
  • compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • Injectable compositions are typically in the form of sterile solutions or suspensions, which include the active ingredient in a parenterally-acceptable diluent.
  • sterile water dextrose 5% in water (D5W)
  • Ringer's solution and isotonic saline, as well as mixcures thereof.
  • Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used.
  • Sterile, injectable oil is occasionally employed as a solvent or suspending medium in intramuscular preparations.
  • a representative example is peanut oil.
  • fatty acids such as oleic acid, preservatives, buffers and local anesthetics find use in the preparation of intramuscular injectables.
  • the active ingredient may also be administered rectally or intravaginally as suppositories.
  • suppositories can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary room temperature but molten at normal or elevated body temperature. Examples of such materials include cocoa butter and polyethylene glycols.

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Abstract

L'invention concerne des méthodes de traitement de la douleur chez un sujet nécessitant ce traitement. Ces méthodes consistent à administrer des doses efficaces de précurseur de noradrénaline ("NE") et un antagoniste de prostaglandine ("PG"). Un précurseur NE peut être une thréo-3-(3,4 dihydroxyphényl)sérine, un dérivé de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci. Un antagoniste PG peut être un inhibiteur de cyclooxygénase (par exemple, COX-1 ou COX-2).
PCT/US2003/031481 2002-10-07 2003-10-06 Compositions et methodes de traitement de la douleur Ceased WO2004032844A2 (fr)

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AU2003275433A AU2003275433A1 (en) 2002-10-07 2003-10-06 Compositions and methods for treating pain

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US41626802P 2002-10-07 2002-10-07
US60/416,268 2002-10-07

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WO2004032844A2 true WO2004032844A2 (fr) 2004-04-22
WO2004032844A3 WO2004032844A3 (fr) 2004-10-21

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WO2008112562A1 (fr) * 2007-03-09 2008-09-18 Chelsea Therapeutics, Inc. Droxidopa et composition pharmaceutique de celle-ci pour le traitement de la fibromyalgie
EP1809104A4 (fr) * 2004-09-23 2009-04-29 Alexander Michalow Methodes permettant de reguler les systemes de neurotransmetteurs en induisant des contre-adaptations
US8158149B2 (en) 2004-05-12 2012-04-17 Chelsea Therapeutics, Inc. Threo-DOPS controlled release formulation
US8383681B2 (en) 2007-05-07 2013-02-26 Chelsea Therapeutics, Inc. Droxidopa and pharmaceutical composition thereof for the treatment of mood disorders, sleep disorders or attention deficit disorders
US8460705B2 (en) 2003-05-12 2013-06-11 Chelsea Therapeutics, Inc. Threo-DOPS controlled release formulation
US9364453B2 (en) 2011-05-17 2016-06-14 Lundbeck Na Ltd. Method of treating postural reflex abnormality caused by parkinson's disease

Family Cites Families (1)

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JP3559572B2 (ja) * 1993-01-29 2004-09-02 住友製薬株式会社 急性痛および慢性痛用鎮痛剤

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8460705B2 (en) 2003-05-12 2013-06-11 Chelsea Therapeutics, Inc. Threo-DOPS controlled release formulation
US8968778B2 (en) 2003-05-12 2015-03-03 Lundbeck Na Ltd. Threo-DOPS controlled release formulation
US8158149B2 (en) 2004-05-12 2012-04-17 Chelsea Therapeutics, Inc. Threo-DOPS controlled release formulation
EP1809104A4 (fr) * 2004-09-23 2009-04-29 Alexander Michalow Methodes permettant de reguler les systemes de neurotransmetteurs en induisant des contre-adaptations
WO2008112562A1 (fr) * 2007-03-09 2008-09-18 Chelsea Therapeutics, Inc. Droxidopa et composition pharmaceutique de celle-ci pour le traitement de la fibromyalgie
US8008285B2 (en) 2007-03-09 2011-08-30 Chelsea Therapeutics, Inc. Droxidopa and pharmaceutical composition thereof for the treatment of fibromyalgia
EP2468271A1 (fr) * 2007-03-09 2012-06-27 Chelsea Therapeutics, Inc. Droxidopa et composition pharmacéutique de celle-ci pour le traitement de la fibromyalgie
AU2008226541B2 (en) * 2007-03-09 2013-05-09 Chelsea Therapeutics, Inc. Droxidopa and pharmaceutical composition thereof for the treatment of fibromyalgia
US8383681B2 (en) 2007-05-07 2013-02-26 Chelsea Therapeutics, Inc. Droxidopa and pharmaceutical composition thereof for the treatment of mood disorders, sleep disorders or attention deficit disorders
US9364453B2 (en) 2011-05-17 2016-06-14 Lundbeck Na Ltd. Method of treating postural reflex abnormality caused by parkinson's disease

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