WO2005092337A1 - 6 ?-oxymorphol et technique d'utilisation - Google Patents

6 ?-oxymorphol et technique d'utilisation Download PDF

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Publication number
WO2005092337A1
WO2005092337A1 PCT/US2005/009574 US2005009574W WO2005092337A1 WO 2005092337 A1 WO2005092337 A1 WO 2005092337A1 US 2005009574 W US2005009574 W US 2005009574W WO 2005092337 A1 WO2005092337 A1 WO 2005092337A1
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oxymoφhol
dosage range
isomer
weight
administered
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PCT/US2005/009574
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English (en)
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Richard Carliss
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Endo Pharmaceuticals Inc.
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Publication of WO2005092337A1 publication Critical patent/WO2005092337A1/fr

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    • 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

Definitions

  • the present invention relates to analgesics, and specifically to opioid analgesics.
  • Oxymo ⁇ hol the metabolite of oxymo ⁇ hone, is a drug belonging to the general class of opioid analgesic compounds.
  • the prime action of opioid analgesic drugs is to stimulate the opioid receptor, thereby producing analgesia.
  • Oxymo ⁇ hone (14-hydroxydihydromo ⁇ hinone) is indicated for the treatment of moderate-to- severe pain.
  • Oxymo ⁇ hone is a semisynthetic opioid agonist derived from thebaine, with a significantly higher analgesic potency than that of mo ⁇ hine. Its structure is related to mo ⁇ hine, differing in a ketone group substitution at the C-6 position of mo ⁇ hine and saturation of the 7-8 double-bond.
  • oxymo ⁇ hone has a hydroxyl group on the saturated hexane ring. The ketone group substitution makes the molecule more lipid soluble, conferring greater potency and more rapid onset of action than the hydroxylated, structurally- related compound mo ⁇ hine.
  • Oxymo ⁇ hol (“6-hydroxyoxymo ⁇ hone” or "6-OH oxymo ⁇ hone”) is oxymo ⁇ hone which has been hydroxylated at the 6- position. This hydroxylation occurs in vivo in humans after administration of oxymo ⁇ hone, and the oxymo ⁇ hone metabolite, oxymo ⁇ hol, is formed. Oxymo ⁇ hol as a metabolite of oxymo ⁇ hone is well known (see for example, Cone et al., 1983 Metabolism and Disposition vol. 11, pp 446-450). It has recently been found that oxymo ⁇ hol is an active metabolite and not only binds the opioid receptor but also causes analgesia.
  • US patent publication US2003130297 discloses this administration of oxymo ⁇ hol to achieve analgesia.
  • Oxymo ⁇ hol is believed to achieve analgesia according to the same mechanism as mo ⁇ hine or other opioids. That is, oxymo ⁇ hol stimulates an opioid receptor to achieve analgesia.
  • the 6-hydroxylation substitution of oxymo ⁇ hone is made through selective reduction of the ketone group of the oxymo ⁇ hone molecule in vivo, which results in two enantiomers, 6 ⁇ - oxymo ⁇ hol and 6 3-oxymo ⁇ hol. Because in vivo production is not stereo-specific, oxymo ⁇ hol is formed in vivo as a mixture of optical isomers, or enantiomers.
  • the degree of reduction of urinary oxymo ⁇ hone of ⁇ -oxymo ⁇ hol or 6/3-oxymo ⁇ hol is variable across species, but 6a: remains below detectable limits or consistently low in all species relative to 6 ⁇ (Cone et al., 1983 Metabolism and Disposition vol 1 1 , pp 446-450).
  • Enantiomers are structurally identical compounds which differ only in that one isomer is a mirror image of the other and the mirror images cannot be superimposed. This phenomenon is known as chirality. Many biological molecules exist as enantiomers and exhibit chirality. Although structurally identical, enantiomers can have profoundly different effects in biological systems: one enantiomer may have a specific biological activity while the other enantiomer has no biological activity at all, or may have an entirely different form of biological activity.
  • the present invention relates to optically pure 6 ⁇ -oxymo ⁇ hol, as well as a method of treating pain, in a patient in need of pain relief, by administering to the patient an amount of optically pure 6 ⁇ -oxymo ⁇ hol or a pharmaceutically acceptable salt thereof sufficient to cause analgesia, while minimizing side effects associated with 6/3-oxymo ⁇ hol, the primary enantiomer of oxymo ⁇ hol.
  • the method is particularly useful in treating pain while reducing the amount of opioid given to a patient. In these applications, it is important to have a composition which is a potent analgesic and which minimizes the adverse side effects of opioids by reducing the dosage amount by eliminating the 6/3 enantiomer.
  • FIGURES Figure 1 is a graph of the results of a tail-flick assay in rats showing relative potency of several opioids.
  • Figure 2 is a graph of the results of a hot plate assay in rats showing relative potency of several opioids.
  • Figure 3 is a graph of the number of abdominal constrictions in a mouse phenylquinone writhing model test.
  • the present invention relies on the analgesic activity of the 6a- enantiomer of oxymo ⁇ hol to provide analgesia, while simultaneously reducing the amount of opioid administered to oxymo ⁇ hol users.
  • the optically pure 6 ⁇ - isomer of oxymo ⁇ hol which is substantially free of the 6 ⁇ - enantiomer, is administered alone, or in combination with one or more other active pharmaceutical ingredients (APIs) in adjunctive treatment, to an individual in whom pain relief is desired.
  • optically pure 6o> isomer of oxymo ⁇ hol refers to the levorotatory optically pure isomer of 6,14 dihydroxy, dihydromo ⁇ hinone (Formula I) and to any pharmacologically acceptable salt or ester thereof.
  • 6 alpha oxymorphol 6 beta oxymorphol Formula I Formula II
  • the 6 ⁇ and 6 ⁇ forms of oxymo ⁇ hol were tested to determine relative binding to opioid receptors. Both enantiomers exhibited characteristic opioid binding. The binding of the two enantiomers to opioid receptors was similar. This indicates that the potency of the two enantiomers should be similar. However, it has been discovered that 6o.-oxymo ⁇ hol is su ⁇ risingly more potent than 6
  • ⁇ enantiomer is either not detectable or found in vanishing small concentrations (Cone et al, 1983 Metabolism and Disposition vol 11, pp 446-450), it would not be expected to contribute to the analgesic efficacy of either oxymo ⁇ hone or the 6a, 6/3 mixture of oxymo ⁇ hol, produced as a metabolite in humans.
  • the 6 ⁇ - isomer of the present invention oxymo ⁇ hol is administered to an individual in need of analgesia.
  • 6 ⁇ -oxymo ⁇ hol is administered to an individual before pain is experienced (as with surgical pain), or after the onset of pain.
  • Such pain may be may be of any origin and any type, including nociceptive, somatic, or neuropathic. Such pain may be acute, as from an accident, or it may be chronic, as from cancer or a permanent injury.
  • optically pure 6 ⁇ -oxymo ⁇ hol is administered prophylactically, that is, before the pain begins, as with surgery, to prevent its occurrence or to reduce the extent to which it occurs.
  • the 6 ⁇ -oxymo ⁇ hol the present invention can be administered by any acceptable route of administration of an opioid.
  • routes include, but are not limited to injection (whether intrathecal, intramuscular, intravenous, subcutaneous or other), oral, topical, parenteral, nasal, transdermal, rectal, sublingual or via an implanted reservoir containing the drug.
  • the form in which the drug will be administered e.g., tablet, capsule, solution, emulsion
  • the dosage form used will also depend on the intended duration of analgesia, and may include immediate-release or extended release dosage forms.
  • the quantity of the drug to be administered will be determined on an individual basis, and will be based, at least in part, on consideration of the patient's size, whether the patient is opioid na ⁇ ve, the severity of the symptoms to be treated, the duration of action desired, and the result sought. In general, quantities of optically pure ⁇ -oxymo ⁇ hol sufficient to reduce or eliminate a patient's pain will be administered.
  • the actual dosage (quantity administered at a time) and the number of administrations per day will depend on the mode of administration, for example, by injection or oral administration. As with any opioid, the smallest effective dose to relieve pain should be administered.
  • Doses as small as .01 mg/kg or as high as about 10 mg/kg of the optically pure 6a- isomer of oxymo ⁇ hol given every four hours will generally be adequate to produce the desired analgesic effect.
  • oral administration e.g., tablet or syrup
  • a dose of about 1 mg to about 160 mg two to four times daily is administered to produce the desired effect.
  • parenteral administration similar quantities are given on the same schedule (i.e. about 1 mg to about 160 mg two to four times daily).
  • the compound of the present invention can also be administered in any other route normally used for administration of opioids, including (but not limited to) buccal, transdermal, intranasal, or sublingual administration.
  • extended release formulations intended for twice, or once-daily administration may contain two to four times the dose of an immediate release formulation referred to above.
  • Devices such as implantable pumps, or transdermal patches, may contain many times the 6 ⁇ -oxymo ⁇ hol than that of oral or parenteral dosage forms for use over extended periods of from one day to one month, or longer.
  • the optically pure 6 ⁇ - isomer of oxymo ⁇ hol can be administered together with one or more other drug(s).
  • an antiasthmatic drug such as theophylline or terbutaline, or an antihistamine can be given with or in close temporal proximity to administration of optically pure, ⁇ ooxymo ⁇ hol.
  • a combination can be administered which includes 6 ⁇ -oxymo ⁇ hol and an NSAID such as aspirin, ibuprofen, ketoprofen or naproxen, a COX-2 inhibitor including celecoxib or rofecoxib, or another analgesic such as acetaminophen.
  • the two (or more) active pharmaceutical ingredients can be administered in one composition or as two separate entities. For example, they can be administered in a single capsule, tablet, powder, or liquid, etc. or as individual compounds.
  • the components included in a particular composition, in addition to optically pure 6a- oxymo ⁇ hol and one or more other APIs, are determined primarily by the manner in which the composition is to be administered.
  • a composition to be administered in inhalant form can include, in addition to the APIs, a liquid carrier and/or propellant.
  • a composition to be administered in tablet form can include a filler (e.g., lactose), a binder (e.g., carboxymethyl cellulose, gum arabic, gelatin), an adjuvant, a flavoring agent, a coloring agent, a lubricant, and a coating material (e.g., wax or a plasticizer).
  • a composition to be administered in liquid form can include the combination of drugs and, optionally, an emulsifying agent, a flavoring agent and/or a coloring agent. These are intended to be only non-limiting examples of excipients which may be used in conjunction with the pharmaceutical ingredient of the present invention.
  • the optically pure 6 ⁇ - isomer of oxymo ⁇ hol, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more other APIs is administered to an individual periodically as necessary to reduce pain.
  • the present composition and method provide an effective treatment for pain while minimizing the undesirable side effects associated with oxymo ⁇ hol use. These side effects include central nervous system depression, nausea, constipation, and vomiting.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • Suitable acids for pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, ascorbic, benzenesulfonic (besylate), benzoic, boric, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, glutaric, glycerophosphoric, hydrobromic, hydrochloric, hydroiodic, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, salicylic, succinic, sulfuric, tartaric acid, terephthalic, p-toluenesulfonic, and the like.
  • suitable pharmaceutically acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Suitable pharmaceutically acceptable salts also include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2- hydroxyethylamine, bis-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N- benzyl-.beta.-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
  • metal salts such as for example aluminium, alkali metal salts such as lithium
  • optically pure or substantially free of the 6/3- enantiomer means that in a composition, at least 75% by weight of the oxymo ⁇ hol in the composition is the 6a- isomer (Formula I) of oxymo ⁇ hol and 25% by weight or less is the 6/3- isomer (Formula II).
  • the oxymo ⁇ hol in the composition at least 90% by weight is the 6 ⁇ - isomer of oxymo ⁇ hol and 5% by weight or less in the 6/3- isomer. More preferably, at least 95% by weight is the 6a- isomer of oxymo ⁇ hol and 5% by weight or less is the 6/3- isomer.
  • compositions which comprise a safe and effective amount of 6a- oxymo ⁇ hol, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier.
  • safe and effective amount means an amount of the subject compound sufficient to induce analgesia, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • a safe and effective amount of the subject compound will vary with the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
  • compositions of the subject invention preferably comprise from about 0.0001% to about 99% by weight of the subject compound, more preferably from about 0.01% to about 90%; also preferably from about 0.1% to about 50%, also preferably from about 1% to about 25%, and also preferably from about 5% to about 10%.
  • compositions of the subject invention contain a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal.
  • compatible means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
  • Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or animal being treated.
  • substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as Tween; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; water; isotonic s
  • a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is generally determined by the way the compound is to be administered.
  • the preferred pharmaceutically- acceptable carrier is sterile, physiological saline, with blood-compatible suspending agent, the pH of which has been adjusted to about 7.4.
  • Other modes of administration will be familiar to those skilled in the art, as will the preferred pharmaceutically-acceptable carrier for each.
  • the preferred modes of administering the subject compound are oral and parenteral.
  • the preferred unit dosage forms are therefore tablets, capsules, lozenges, chewable tablets, orally disintegratable tablets, sublingual tablets, buccal tablets, solutions, emulsions, suspensions, and the like.
  • Such unit dosage forms comprise a safe and effective amount of the subject compound, which for immediate release dosage forms is preferably from about 0.01 mg to about 200 mg, more preferably from about 0.1 mg to about 100 mg, more preferably still from about 0.5 mg to about 25 mg, also preferably from about 1 mg to about 25 mg, also preferably from about 5 mg to about 10 mg.
  • Controlled (or extended) release dosage forms would have commensurately more of the subject compound, depending on the dosing schedule. For a twice daily dosing, the amount of the subject compound would be double to triple the ranges above, whereas for once daily dosing, four to six times the amounts set forth above would typically be used.
  • the pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for oral administration are well-known in the art.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
  • Coloring agents such as the FD&C dyes, can be added for appearance.
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above.
  • the selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the pu ⁇ oses of the subject invention, and can be readily made by a person skilled in the art.
  • Oral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Such liquid oral compositions preferably comprise from about 0.001% to about 5% of the subject compound, more preferably from about 0.01% to about 0.5%.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Oral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions useful for attaining systemic delivery of the subject compound include sublingual and buccal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • dosage forms may also include foaming or gas-generating agents, such as sodium carbonate and ascorbic acid.
  • compositions of the subject invention include solids, such as tablets and capsules, and liquids, such as solutions, suspensions, and emulsions (preferably in soft gelatin capsules), comprising a safe and effective amount of a subject compound intended for administration via the gastrointestinal tract by oral administration.
  • Such compositions intended for four-hour administration preferably comprise from about 0.01 mg to about 100 mg per dose, more preferably from about 0.1 mg to about 50 mg per dose.
  • Such compositions can be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released over time to extend the desired action.
  • Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, acrylic coatings, polyvinylpyrrolidone, waxes and shellac. Such dosage also typically include several times as much of the subject compound as noted above. Compositions of the subject invention may optionally include other active pharmaceutical ingredients.
  • Non-limiting examples of APIs which may be inco ⁇ orated in these compositions include: antihistamines, including; hydroxyzine preferably at a dosage range of from about 25 to about 400 mg; doxylamine, preferably at a dosage range of from about 3 to about 75 mg; pyrilamine, preferably at a dosage range of from about 6.25 to about 200 mg; chlo ⁇ heniramine, preferably at a dosage range of from about 1 to about 24 mg; phenindamine, preferably at a dosage range of from about 6.25 to about 150 mg; dexchlo ⁇ heniramine, preferably at a dosage range of from about 0.5 to about 12 mg; dexbrompheniramine, preferably at a dosage range of from about 0.5 to about 12 mg; clemastine, preferably at a dosage range of from about 1 to about 9 mg; diphenhydramine, preferably at a dosage range of from about 6.25 to about 300 mg; azelastine, preferably at a dosage range of from
  • Non-clinical pharmacology studies were conducted in vivo in mice, and using in vitro opioid receptor binding assays, in order to more fully describe the action of ⁇ -oxymo ⁇ hol and 6/3- oxymo ⁇ hol in the production of analgesia.
  • a standard screening assay was used to profile the receptor binding selectivity for each enantiomers against different receptor subtypes, ⁇ , K and ⁇ . These assays were performed to determine the opioid receptor subtypes for which these compounds exhibit activity.
  • Oxymo ⁇ hone and 6-hydroxyoxymo ⁇ hone and mo ⁇ hine also exhibit binding activity at each of these three opioid receptor subtypes.
  • Each of 6c.-oxymo ⁇ hol and 6/3-oxymo ⁇ hol were also tested against a battery of different non-opioid receptor subtypes classified as either transmitter-related, ion channels, or brain gut peptide receptors. No activity was detected at ⁇ 1 ⁇ M, indicating a high degree of opioid receptor binding specificity for both enantiomers. Both enantiomers exhibited equivalent exclusive binding selectivity and affinity for each of the opioid receptor subtypes; that is, no other receptors in a NovaScreen profile of different classes of receptors exhibited affinity for either enantiomer of 6-hydroxyoxymo ⁇ hone.
  • Table 1 shows the binding affinity (Ki and IC 5 0) for each of the opioid receptor subtypes (selectivity) exhibited by either the ⁇ cu-oxymo ⁇ hol or 6/3-oxymo ⁇ hol enantiomer.
  • Table 1 6 ⁇ -oxymo ⁇ hol 6 3-oxymo ⁇ hol Ki/ICjn (nM) Ki/ICsn (nM) ⁇ : 4.2/1 1 ⁇ : 3.1/8.3 K: 790/1777 K: 430/997 ⁇ : >1700/ ⁇ : 1700/
  • the receptor binding profiles were similar for both the 6 ⁇ and 6/3 enantiomers, indicating that in vivo analgesic activity should be similar.
  • Figures 1 and 2 show the results of these tests.
  • the 6 ⁇ enantiomer When given at equivalent doses, the 6 ⁇ enantiomer exhibited significantly greater analgesic activity across all analgesic assays in the mouse.
  • the 6 ⁇ enantiomer of 6- hydroxyoxymo ⁇ hone was more potent than the 6/3 enantiomer in the tail flick and the hot plate model as well as in the phenylquinone writhing test.
  • the ⁇ -oxymo ⁇ hol or 6/3- oxymo ⁇ hol or oxymo ⁇ hone or mo ⁇ hine were given at doses between 0.1 and 10 mg/kg s.c. (subcutaneous) or orally as indicated in the figures.
  • Figure 3 shows the number of abdominal constrictions in a mouse phenylquinone writhing (PQW) model. The number of constrictions is diminished by mo ⁇ hine (5mg/kg) or by 6 ⁇ - oxymo ⁇ hol (2-5mg/kg) or by 6/3-oxymo ⁇ hol (5-10mg/kg). Drugs were given orally. This data shows that for the same dose (5 mg/kg) of enantiomer, the 6c.

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Abstract

La présente invention concerne une composition comprenant un composé 6?-oxymorphol optiquement pur. Cette invention concerne aussi une technique de traitement de la douleur chez un patient nécessitant un soulagement, par administration à une personne d'une quantité de 6?-oxymorphol optiquement pur ou d'un sel de ce composé répondant aux normes pharmaceutiques, suffisante pour calmer la douleur. Cette technique convient particulièrement pour le traitement de la douleur et permet de réduire la quantité d'opioïde donnée à un patient.
PCT/US2005/009574 2004-03-22 2005-03-21 6 ?-oxymorphol et technique d'utilisation WO2005092337A1 (fr)

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WO2008144320A2 (fr) * 2007-05-17 2008-11-27 Endo Pharmaceuticals, Inc. Opioïde et procédés de fabrication et d'utilisation de celui-ci
US8475823B2 (en) 2008-04-18 2013-07-02 Medtronic, Inc. Baclofen formulation in a polyorthoester carrier
US8956642B2 (en) 2008-04-18 2015-02-17 Medtronic, Inc. Bupivacaine formulation in a polyorthoester carrier

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ATE548400T1 (de) * 2009-12-12 2012-03-15 Bayer Materialscience Ag Klebstoffverbundsystem zum abdecken, verschliessen oder verkleben von zellgewebe
EP2536509B1 (fr) 2010-02-15 2018-04-11 Coatings Foreign IP Co. LLC Dispositif de pulvérisation de deux composants et son utilisation
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US8973522B2 (en) 2011-03-14 2015-03-10 Axalta Coating Systems Ip Co., Llc Dual feeding spray device and use thereof
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WO2005092934A1 (fr) 2005-10-06
AU2005227303A1 (en) 2005-10-06
CN1934141A (zh) 2007-03-21
EP1732956A1 (fr) 2006-12-20
BRPI0508215A (pt) 2007-07-17
CA2557439A1 (fr) 2005-10-06
WO2005092934A8 (fr) 2007-01-11
JP2007530734A (ja) 2007-11-01

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