WO2008051760A2 - Polytherapie utilisee dans le traitement de la douleur - Google Patents

Polytherapie utilisee dans le traitement de la douleur Download PDF

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WO2008051760A2
WO2008051760A2 PCT/US2007/081598 US2007081598W WO2008051760A2 WO 2008051760 A2 WO2008051760 A2 WO 2008051760A2 US 2007081598 W US2007081598 W US 2007081598W WO 2008051760 A2 WO2008051760 A2 WO 2008051760A2
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pain
pharmaceutically acceptable
acceptable salt
group
ampa
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PCT/US2007/081598
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WO2008051760A3 (fr
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James Conrad Eisenach
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King Pharmaceuticals Research And Development, Inc.
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Priority claimed from US11/872,800 external-priority patent/US20080108603A1/en
Priority claimed from US11/872,859 external-priority patent/US20080108622A1/en
Priority claimed from US11/872,878 external-priority patent/US20080113969A1/en
Application filed by King Pharmaceuticals Research And Development, Inc. filed Critical King Pharmaceuticals Research And Development, Inc.
Priority to CA002666925A priority Critical patent/CA2666925A1/fr
Publication of WO2008051760A2 publication Critical patent/WO2008051760A2/fr
Publication of WO2008051760A3 publication Critical patent/WO2008051760A3/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention provides synergistic combinations for the treatment of conditions associated with pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine.
  • the present invention relates to the use of an allosteric adenosine A 1 receptor enhancer in conjunction with opioid analgesics or 2-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate antagonists for alleviating pain, e.g., postoperative pain.
  • opioid analgesics or 2-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate antagonists for alleviating pain, e.g., postoperative pain.
  • Adenosine is an endogenous nucleoside present in all cell types of the body. It is endogenously formed and released into the extracellular space under physiological and pathophysiological conditions characterized by an increased oxygen demand/supply ratio. This means that the formation of adenosine is accelerated in conditions with increased high energy phosphate degradation.
  • the biological actions of adenosine are mediated through specific adenosine receptors located on the cell surface of various cell types, including nerves. The hyper-reactive nerves increase adenosine release due to an increase in metabolic activity.
  • Adenosine A 1 receptors are widely distributed in most species and mediate diverse biological effects. The following examples are intended to show the diversity of the presence Of A 1 receptors rather than a comprehensive listing of all such receptors.
  • a 1 receptors are particularly ubiquitous within the central nervous system (CNS), with high levels being expressed in the cerebral cortex, hippocampus, cerebellum, thalamus, brain stem, and spinal cord.
  • CNS central nervous system
  • Immuno-histochemical analysis using polyclonal antisera generated against rat and human adenosine A 1 receptors has identified different labeling densities of individual cells and their processes in selected regions of the brain.
  • Adenosine A 1 receptor mRNA is widely distributed in peripheral tissues such as the vas deferens, testis, white adipose tissue, stomach, spleen, pituitary, adrenal, heart, aorta, liver, eye and bladder. Only very low levels Of A 1 receptors are thought to be present in lung, kidney, and small intestine.
  • Adenosine has been proposed as treatment for pain states derived from nociception including acute pain, tissue injury pain and nerve injury pain.
  • Adenosine modulates the pain response by stimulating adenosine A 1 receptors present in the dorsal root of the spinal cord and higher brain centers (spraspinal mechanisms).
  • Adenosine A 1 agonists have been shown to be effective treatment for pain in animal pain models. However, A 1 agonists also cause cardiovascular side effects and CNS side effects such as heart block, hypotension and sedation.
  • the present invention relates to a class of compounds known as allosteric adenosine A 1 receptor modulators or allosteric adenosine A 1 receptor enhancers.
  • T-62 also known as T-62, has been previously demonstrated to reduce inflammatory and neuropathic pain and shown to be orally effective and avoid of the adverse side effects associated with administration of adenosine (Li et al., J. Pharmacol. Exp. Ther. 2003, 305, 950-955; Li et al., Pain 2002, 97, 117-125; Pan et al. Anesthesiology 2001, 95, 416- 420; U.S. Patents No. 6,248,774 and No. 6,489,356).
  • T-62 interacts synergistically with opioids and AMPA/kainate antagonists in alleviating pain, in particular postoperative pain.
  • the present invention relates to a combination, such as a combined preparation or a pharmaceutical composition, respectively, for achieving a synergistic therapeutic effect comprising alleviating pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, in a warm-blooded animal, including man, in need thereof, which combination comprises synergistic amounts of an allosteric adenosine A 1 receptor enhancer, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of:
  • the present invention relates to a method for achieving a synergistic therapeutic effect comprising alleviating pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, in a warm-blooded animal, including man, in need thereof, which method comprises administering to said warm-blooded animal synergistic amounts of an allosteric adenosine A 1 receptor enhancer, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of:
  • FIG. 6 shows an isobologram of the combination of T-62 with morphine which demonstrates a synergistic interaction between T-62 and morphine;
  • FIG. 7 shows an isobologram of the combination of T-62 with NBQX which demonstrates a synergistic interaction between T-62 and NBQX;
  • FIG. 8 shows a graphical presentation of the anti-hypersensitivity effects of three allosteric adenosine A 1 receptor enhancers in neuropathic pain model in male Spraque- Dawley rats, i.e., T-62 and compounds of formulae (Ib) and (Ic).
  • the present invention provides synergistic combinations for the treatment of conditions associated with pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine.
  • the present invention relates to the use of an allosteric adenosine A 1 receptor enhancer in conjunction with opioid analgesics or AMPA/kainate antagonists for alleviating pain, e.g., postoperative pain.
  • allosteric adenosine A 1 receptor modulator or "allosteric adenosine A 1 receptor enhancer” as used herein refers to a class of compounds that appear to enhance adenosine A 1 receptor function by stabilizing the high affinity state of the receptor-G-protein complex. This property may be measured as an increase in radioligand binding to the adenosine A 1 receptor.
  • An enhancer that increases agonist binding can do so by either accelerating the association of an agonist to the receptor, or by retarding the dissociation of the "receptor-ligand” complex and, therefore, must bind to a site different from the agonist recognition site. This putative site is termed as the allosteric site, and presumably, compounds that bind to this site and enhance the agonist effect are termed as "allosteric enhancers".
  • AMPA/kainate antagonist refers to both competitive and non-competitive AMPA receptor antagonists which may additionally exhibit antagonist activity towards the other glutamate receptors, e.g., the kainate receptors.
  • terapéuticaally effective amount refers to an amount of a drug or a therapeutic agent that will elicit the desired biological or medical response of a tissue, system or an animal (including man) that is being sought by a researcher or clinician, e.g., provides significant analgesic activity.
  • treatment shall be understood as the management and care of a patient for the purpose of combating the disease, condition or disorder.
  • warm-blooded animal, mammal or patient are used interchangeably herein and include, but are not limited to, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits, mice and laboratory animals.
  • the preferred mammals are humans.
  • pharmaceutically acceptable salt refers to a non-toxic salt commonly used in the pharmaceutical industry which may be prepared according to methods well- known in the art.
  • the term "combination" of an allosteric adenosine A 1 receptor enhancer, in particular T-62, and another therapeutic agent referred to herein above, or in each case, a pharmaceutically acceptable salt thereof means that the components can be administered together as a pharmaceutical composition or as part of the same, unitary dosage form.
  • a combination also includes administering an allosteric adenosine A 1 receptor enhancer, in particular T-62, or a pharmaceutically acceptable salt thereof, and another therapeutic agent referred to herein above, or a pharmaceutically acceptable salt thereof, each separately but as part of the same therapeutic regimen.
  • the components, if administered separately, need not necessarily be administered at essentially the same time, although they can if so desired.
  • a combination also refers, for example, administering an allosteric adenosine A 1 receptor enhancer, in particular T-62, or a pharmaceutically acceptable salt thereof, and another therapeutic agent, or a pharmaceutically acceptable salt thereof, as separate dosages or dosage forms, but at the same time.
  • a combination also includes separate administration at different times, in any order and by any route of administration.
  • the allosteric adenosine A 1 receptor enhancers to which the present invention applies are any of those enhancing the function of adenosine A 1 receptors in vivo and, therefore, having pharmaceutical utility, e.g., as therapeutic agents for reducing pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, in particular postoperative pain.
  • Suitable allosteric adenosine A 1 receptor enhancers include, but are not limited to, 2-amino-3-acylthiophene derivatives, e.g., those disclosed in U.S. Patents No. No. 6,323,214 and No. 6,727,258, the entire contents of which are incorporated herein by reference.
  • the allosteric adenosine A 1 receptor enhancer of the present invention is selected from the group consisting of the compound T-62 of the formula
  • the allosteric adenosine A 1 receptor enhancer of the present invention is the compound T-62 of formula (Ia).
  • the allosteric adenosine A 1 receptor enhancers of the present invention may be prepared using methods well known in the art, e.g., the compounds of formulae (Ia), (Ib) and (Ic) may be prepared using methods disclosed in U.S. Patents No. 6,323,214 and No. 6,727,258, or as described by Corral et al. in Afinidad 1978, 35(354), 129-33.
  • opioids have been described in the art, e.g., those generally used as pain relievers, narcotics and/or anesthetics and include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, apocodeine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, cyclorphen, cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, e
  • Preferred opioids for the combination and use according to the present invention include hydrocodone, hydromorphone, morphine, oxycodone and oxymorphone, in particular morphine, or in each case, a pharmaceutically acceptable salt thereof.
  • AMPA/kainate antagonists include, but are not limited to, antagonists such as NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline), CNQX (6-cyano-7- nitro-quinoxaline-2,3-dione, DNQX (6,7-dinitroquinoxaline-2,3-dione), PNQX (1 ,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido[3,4-f]quinoxaline-2,3-dione), and compounds disclosed in U.S. Patent No. 6,117,873, e.g., becampanel of the formula those disclosed in U.S. Patent No.
  • the allosteric adenosine A 1 receptor enhancers of the present invention, and the combination partners thereof, may be present as their pharmaceutically acceptable salts. If these compounds have, e.g., at least one basic center such as an amino group, they can form acid addition salts thereof. Similarly, the compounds having at least one acid group (for example -COOH) can form salts with bases.
  • the corresponding active ingredients, or a pharmaceutically acceptable salts may also be used in the form of a solvate, such as a hydrate, or including other solvents used, e.g., those employed in their crystallization.
  • a combination according to the present invention comprises an aliosteric adenosine A 1 receptor enhancer, e.g., T-62, or a pharmaceutically acceptable salt thereof, and an opioid, e.g., hydrocodone, hydromorphone, morphine, oxycodone or oxymorphone, in particular morphine, or in each case, a pharmaceutically acceptable salt thereof.
  • an opioid e.g., hydrocodone, hydromorphone, morphine, oxycodone or oxymorphone, in particular morphine, or in each case, a pharmaceutically acceptable salt thereof.
  • an allosteric adenosine A 1 receptor enhancer e.g., T-62, or a pharmaceutically acceptable salt thereof
  • an AMPA/kainate antagonist e.g., NBQX
  • the structure of the active agents identified by generic or tradenames may be taken from the actual edition of the standard compendium "The Merck Index", or the Physician's Desk Reference, or from databases, e.g., Patents International (e.g., IMS World Publications) or Current Drugs. Accordingly, any person skilled in the art is fully enabled to identify the active agents of the present invention. Likewise, a person skilled in the art is fully enabled to manufacture and test the pharmaceutical indications and properties in standard test models known in the art, both in vitro and in vivo.
  • drug efficacy may be assessed using pain models such as carrageenan model (Guilbaud and Kayser, Pain 1987, 28, 99-107) for acute inflammatory pain; FCA model (Freund's Complete Adjuvant; Hay et al., Neuroscience 1997, 78(3), 843-850) for chronic inflammatory pain; CCI model (Chronic Constriction Injury; Bennett and Xie, Pain 1988, 33, 87-107) and the Chung model (Kim and Chung, Pain 1992, 50, 355-363) for neuropathic pain; or postincisional hypersensitivity model (Obata et al., Anesthesiology 2004, 100, 1258-1262) for postoperative pain.
  • CCI model Choronic Constriction Injury
  • Bennett and Xie Pain 1988, 33, 87-107
  • Chung model Kim and Chung, Pain 1992, 50, 355-363
  • postincisional hypersensitivity model Obata et al., Anesthesiology 2004, 100, 1258-12
  • the allosteric adenosine A 1 receptor enhancers T-62, and compounds of formulae (Ib) and (Ic), all exert dose-dependent anti- allodynic effects in the Chung model of chronic neuropathic pain, the compound of formula (Ic) being the most potent enhancer of the three agents.
  • the compound T-62 (i.t.) produces a modest effect in the postincisional hypersensitivity model of postoperative pain.
  • T-62 is combined with morphine or NBQX, FIG. 6 and FIG. 7, respectively, the observed ED 40 vaiues for said combinations are 5% and 11% of ihe theoretical additive dose, respectively, demonstrating in each case a synergistic interaction between the drugs.
  • the present invention provides a combination, such as a combined preparation or a pharmaceutical composition, respectively, for achieving a synergistic therapeutic effect comprising alleviating pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, in a warm-blooded animal, including man, in need thereof, which combination comprises synergistic amounts of an allosteric adenosine A 1 receptor enhancer, e.g., T- 62, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of:
  • the present invention provides a method for achieving a synergistic therapeutic effect comprising alleviating pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, in a warm-blooded animal, including man, in need thereof, which method comprises administering to said warm-blooded animal synergistic amounts of an allosteric adenosine A 1 receptor enhancer, e.g., T-62, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of:
  • the present invention relates to the use of an allosteric adenosine A 1 receptor enhancer, e.g., T-62, or a pharmaceutically acceptable salt thereof, in combination with (1) an opioid; or (2) an AMPA/kainate antagonist; or in each case, a pharmaceutically acceptable salt thereof; for achieving a synergistic therapeutic effect comprising alleviating pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, in particular postoperative pain.
  • an allosteric adenosine A 1 receptor enhancer e.g., T-62
  • a pharmaceutically acceptable salt thereof in combination with (1) an opioid; or (2) an AMPA/kainate antagonist; or in each case, a pharmaceutically acceptable salt thereof; for achieving a synergistic therapeutic effect comprising alleviating pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, in particular postoperative pain.
  • the present invention relates to the use of an allosteric adenosine A 1 receptor enhancer, e.g., T-62, or a pharmaceutically acceptable salt thereof, in combination with (1) an opioid; or (2) an AMPA/kainate antagonist; or in each case, a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for achieving a synergistic therapeutic effect comprising alleviating pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, in particular postoperative pain.
  • a synergistic therapeutic effect comprising alleviating pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, in particular postoperative pain.
  • the present invention provides pharmaceutical compositions comprising an allosteric adenosine A 1 receptor enhancer, preferably T-62, or a pharmaceutically acceptable salt thereof, in an amount effective to potentiate the analgesic effect of a second therapeutic agent selected from the group consisting of:
  • an opioid preferably hydrocodone, hydromorphone, morphine, oxycodone or oxymorphone, in particular morphine, or in each case, a pharmaceutically acceptable salt thereof;
  • an AMPA/kainate antagonist preferably NBQX, becampanel, talampanel, tezampanel, perampanel or NS-1209, or in each case, a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier; for alleviation of pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine.
  • the present invention provides pharmaceutical compositions comprising: (1) an opioid, preferably hydrocodone, hydromorphone, morphine, oxycodone or oxymorphone, in particular morphine, or a pharmaceutically acceptable salt thereof; or (2) an AMPA/kainate antagonist, e.g., NBQX, becampanel, talampanel, tezampanel, perampanel or NS-1209, or a pharmaceutically acceptable salt thereof; in amount such that, following administration of a combination of the present invention, a synergistic therapeutic effect is achieved; and a pharmaceutically acceptable carrier.
  • an opioid preferably hydrocodone, hydromorphone, morphine, oxycodone or oxymorphone, in particular morphine, or a pharmaceutically acceptable salt thereof
  • an AMPA/kainate antagonist e.g., NBQX, becampanel, talampanel, tezampanel, perampanel or NS-1209, or a pharmaceutically acceptable salt thereof
  • the present invention provides a pharmaceutical composition for achieving therapeutic effect comprising alleviating pain, including acute pain, e.g., postoperative pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, in a warm-blooded animal, including man, in need thereof, which composition comprises synergistic amounts of an allosteric adenosine A 1 receptor enhancer, preferably T-62, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of:
  • an opioid preferably hydrocodone, hydromorphone, morphine, oxycodone or oxymorphone, in particular morphine, or in each case, a pharmaceutically acceptable salt thereof;
  • an AMPA/kainate antagonist preferably NBQX, becampanel, talampanel, tezampanel, perampanel or NS-1209, or in each case, a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • an allosteric adenosine A 1 receptor enhancer in particular, T-62, or a pharmaceutically acceptable salt thereof, in combination with (1) an opioid, e.g., hydrocodone, hydromorphone, morphine, oxycodone or oxymorphone, preferably morphine, or in each case a pharmaceutically acceptable salt thereof; or (2) an AMPA/kainate antagonist, e.g., NBQX, becampanel, talampanel, tezampanel, perampanel or NS-1209, or in each case, a pharmaceutically acceptable salt thereof; may be co-administered as a pharmaceutical composition.
  • the components may be administered together in any conventional dosage form, usually also together with a pharmaceutically acceptable carrier or
  • the allosteric adenosine A 1 receptor enhancers of the present invention may be formulated into pharmaceutical compositions suitable for administration via a variety of routes, such as oral or rectal, transdermal, intrathecal and parenteral administration to mammals, including man.
  • the pharmaceutical composition comprising an allosteric adenosine A 1 receptor enhancer, in particular, T-62, or a pharmaceutically acceptable salt thereof, or a combination partner thereof, can take the form of solutions, suspensions, tablets, pills, capsules, powders, microemulsions, unit dose packets and the like.
  • tablets and gelatin capsules comprising the active ingredient together with: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine and/or vegetable oil; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbants, colorants, flavors and sweeteners.
  • Injectable compositions are preferably aqueous isotonic solutions or suspensions, and supposito
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-90%, preferably about 1-80%, of the active ingredient(s), conveniently from 30-95% for tablets and capsules, and 3-50% for liquid preparations.
  • the dosage of the active ingredients can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
  • Preferred dosages for the active ingredients of the pharmaceutical combinations according to the present invention are therapeutically effective dosages, especially those which are commercially available.
  • doses employed for adult human treatment will typically be in the range of 0.02-5000 mg/day, preferably 1-1500 mg/day, e.g., for a patient of approximately 75 kg in weight.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the dosage or dosages which will result in optimal synergistic effects is achieved by coordinating the pharmacokinetic properties, such as volume of distribution and T max , of the therapeutic agents of this invention so that the therapeutic windows of each agent overlap to the maximum extent possible.
  • Such dosages are readily determined by one skilled in the art.
  • the doses of T-62 to be administered to warm-blooded animals, including man, of approximately 75 kg body weight, especially the doses effective for enhancing the adenosine A 1 receptor function, e.g., to alleviate pain, are from about 1 mg to about 1 g, preferably from about 10 mg to about 500 mg.
  • Two per day are an option, one for daytime use and one for nighttime use. Since there is the potential of an allosteric adenosine A 1 receptor enhancer to cause sedation at a high dose, the higher doses are recommended for nighttime use.
  • a dose of from about 100 to about 500 mg dose of T-62 is recommended for daytime use while a dose from about 600 to about 1000 mg is recommended as a nighttime dose.
  • Suitable doses and dosage forms of opioids that may be employed in the combinations of the present invention include, but are not limited to, those that are commercially available, and those described in U.S. Patent Application Publication No. 2004/0161382.
  • Suitable doses and dosage forms of AMPA/kainate antagonists are known in the art and include, e.g., those disclosed in published preclinical and/or clinical study reports, e.g., tezampanel may be administered to a human patient in a total daily dosage of about 40 to about 100 mg (single dose, sc), and talampanel may be administered to a human patient in a total daily dosage of about 75 to about 300 mg (tid, po).
  • kits may comprise, e.g., two separate pharmaceutical compositions: (1) a composition comprising an allosteric adenosine A 1 receptor enhancer, in particular T-62, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent; and (2) a composition comprising another therapeutic agent selected from the group consisting of an opioid and an AMPA/kainate antagonist, or in each case, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • the amounts of (1) and (2) are such that a synergistic therapeutic effect is achieved.
  • the kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet, wherein each compartment contains a plurality of dosage forms (e.g., tablets) comprising, e.g., (1) or (2).
  • the kit may contain separate compartments each of which contains a whole dosage which in turn comprises separate dosage forms.
  • An example of this type of kit is a blister pack wherein each individual blister contains two (or more) tablets, one (or more) tablet(s) comprising a pharmaceutical composition (1), and the second (or more) tablet(s) comprising a pharmaceutical composition (2).
  • the kit comprises directions for the administration of the separate components.
  • kits form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • a kit therefore comprises:
  • composition comprising an allosteric adenosine A 1 receptor enhancer, in particular T-62, or a pharmaceutically acceptable salt thereof, in an amount effective to potentiate the analgesic effect of another therapeutic agent in the kit, and a pharmaceutically acceptable carrier or diluent, in a first dosage form;
  • composition comprising another therapeutic agent selected from the group consisting of an opioid and an AMPA/kainate antagonist, or in each case, a pharmaceutically acceptable salt thereof, in an amount such that, following administration, a synergistic therapeutic effect is achieved, and a pharmaceutically acceptable carrier or diluent, in a second dosage form; and
  • An allosteric adenosine Ai receptor enhancer e.g., T-62, or a pharmaceutical salt thereof, or the combination partners thereof, can be administered by various routes of administration.
  • Each agent can be tested over a wide-range of dosages to determine the optimal drug level for each therapeutic agent alone, or in the specific combination thereof, to elicit the maximal response.
  • treatment groups consisting of at least 6 animals per group. Each study is best performed in away wherein the effects of the combination treatment group are determined at the same time as the individual components are evaluated.
  • drug effects may be observed with acute administration, it may be preferable to observe certain responses in a chronic setting.
  • a long-term study, when appropriate, is of sufficient duration to allow for the full development of compensatory responses to occur and, therefore, the observed effect will most likely depict the actual responses of the test system representing sustained or persistent effect.
  • an allosteric adenosine A 1 receptor enhancer e.g., T-62, or a pharmaceutically acceptable salt thereof
  • an opioid e.g., T-62
  • an AMPA/kainate antagonist e.g., AMPA/kainate antagonist
  • Greater efficacy can also be documented as a prolonged duration of action. The duration of action can be monitored as either the time to return to baseline prior to the next dose or as the area under the curve (AUC).
  • Single drug injection For single drug administration, a volume containing 5 ⁇ l_ drug is used, followed by 10 ⁇ L of saline. The anti-hypersensitivity effects for single drugs at three doses with logarithmic spacing are studied over a 210 min observation period with testing at 30 min interval. Dose response curves are first constructed, and ED 40 values for single drugs are then determined at the time of peak effect.
  • T-62 may be obtained from King Pharmaceuticals (Cary, NC). T-62 is dissolved in saline with 20% DMSO. Morphine may be purchased from Astra Pharmaceutical Products, Inc. (Westborough, MA). NBQX and the remaining chemicals may be purchased from Sigma Chemical Co. (St. Louis, MO). Saline is used as vehicle for morphine and NBQX.
  • T-62 (i.t.) reduced mechanical hypersensitivity in a time dependent manner over the 3 hour period of observation. Injection of 20% DMSO in saline had no effect on withdrawal thresholds. The time of peak effect ranged from 60 to 90 min after injection (FIG. 1).
  • T-62 may be obtained from King Pharmaceuticals (Gary, NC) in dry powder form. T-62 is screened through a #40 screen and then added to a mixture of propylene glycol monocaprylate (Capryol 90 ), caprylocaproyl macrogol-8 glycerides (Labrasol ), super refined soybean oil (USP) and polysorbate 80 (Crillet 4 HP®) at 5O 0 C ( ⁇ 5°C) while mixing with a propeller mixer to dissolve T-62. The mixture/solution is sparged with nitrogen throughout the process. The resulting solution has a density of 1.006 g/mL at 25°C, and may then be encapsulated into soft elastic gelatin capsules (Capsugel, Inc.) to afford a dose of 30 mg/mL (Table 1).
  • T-62 (dry powder) is milled using a Quadro Comil 197 with screen (2A018R01530) and impeller (2A16011730212) at 2400 rpm. The milled T-62 is then added to a mixture of super refined soybean oil (USP), propylene glycol monocaprylate (Capryol 90 ), caprylocaproyl macrogol-8 glycerides (Labrasol ), and polysorbate 80 (Crillet 4 HP ) at 50-55 0 C. The mixture is stirred until T-62 dissolved. The mixture/solution is sparged with nitrogen throughout the process. The resulting solution may then be encapsulated into hard gelatin capsules (Capsugel) to afford a dose of 70 mg/mL (Table 2).
  • Capryol 90 41.67 caprylocaproyl macrogol-8 glycerides (Labrasol ) 16.70 super refined soybean oil (USP) 25.00 polysorbate 80 (Crillet 4 HP®) 8.30
  • T-62 (dry powder) is milled using a Quadra Comil 197 with screen (2A018R01530) and impeller (2A16011730212) at 2400 rpm. The milled T-62 is then micronized using a Glen Mills Jet Mill with nitrogen as the propellant. T-62 is passed through the Jet Mill twice to reduce the particle size to a mean diameter of 12.2 ⁇ m. The micronized T-62 is added to a mixture of super refined soybean oil (USP) with propylene glycol monocaprylate (Capryol 90 ), caprylocaproyl macrogol-8 glycerides (Labrasol ), and
  • the mixture/solution is sparged with nitrogen throughout the process.
  • the resulting solution may then be encapsulated into hard gelatin capsules (size 00 Capsules, obtained from Capsugel ) to afford a dose of 70 mg/mL (Table 3).
  • T-62 8.33 propylene glycol monocaprylate (Capryol 90 ) 41.67 caprylocaproyl macrogol-8 glycerides (Labrasol ) 16.70 super refined soybean oil (USP) 25.00 polysorbate 80 (Crillet 4 HP®) 8.30 TOTAL 100
  • T-62 dry powder
  • the milled T-62 is then added to a mixture of propylene glycol monocaprylate (Capryo! 90 ), caprylocaproyl macrogol-8 glycerides
  • T-62 (dry powder) is milled using a Quadro Comil 197 with screen (2A018R01530) and impeller (2A16011730212) at 2400 rpm.
  • the milled T-62 is then added to a mixture of super refined soybean oil (USP) with propylene glycol monocaprylate (Capryol 90 ), caprylocaproyl macrogol-8 glycerides (Labrasol ), polysorbate 80 (Crillet 4 HP ) and ethanol at 45 ⁇ 5°C using a propeller type mixer to dissolve T-62.
  • the mixture/solution is sparged with nitrogen throughout the process.
  • Super refined soybean oil is then added with continued mixing.
  • the solution is allowed to return to room temperature, and then pumped though a 5 ⁇ m Meissner filter capsule.
  • the resulting solution may then be encapsulated into soft elastic gelatin capsules (size 00 Capsules, obtained from

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Abstract

L'invention concerne des combinaisons synergiques destinées au traitement d'affections associées à une douleur, notamment une douleur aiguë, par exemple la douleur postopératoire, la douleur chronique, la douleur inflammatoire, la douleur neuropathique et la douleur associée à la migraine. L'invention concerne en particulier l'utilisation d'un activateur de récepteur allostérique d'adénosine A1 combiné à des analgésiques opioïdes ou de l'acide 2-amino-3-hydroxy-5-méthyl-4-isoxazole-propionique (AMPA)/des antagonistes de kaïnate, pour soulager la douleur, notamment la douleur postopératoire.
PCT/US2007/081598 2006-10-19 2007-10-17 Polytherapie utilisee dans le traitement de la douleur WO2008051760A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA002666925A CA2666925A1 (fr) 2006-10-19 2007-10-17 Polytherapie utilisee dans le traitement de la douleur

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US85281506P 2006-10-19 2006-10-19
US60/852,815 2006-10-19
US11/872,800 US20080108603A1 (en) 2006-10-19 2007-10-16 Combination therapy for the treatment of pain
US11/872,859 US20080108622A1 (en) 2006-10-19 2007-10-16 Combination therapy for the treatment of pain
US11/872,878 US20080113969A1 (en) 2006-10-19 2007-10-16 Combination therapy for the treatment of pain
US11/872,800 2007-10-16
US11/872,859 2007-10-16
US11/872,878 2007-10-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9370203B2 (en) 2008-03-07 2016-06-21 Bayer Intellectual Property Gmbh Use of alternan as texturizing agent in foodstuffs and cosmetics

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6489356B2 (en) * 2000-09-05 2002-12-03 Edward Leung Method for treating pain in humans
US20040097562A1 (en) * 1996-11-05 2004-05-20 Jes Olesen Method for treating tension-type headache
US20060009478A1 (en) * 2003-10-15 2006-01-12 Nadav Friedmann Methods for the treatment of back pain

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040097562A1 (en) * 1996-11-05 2004-05-20 Jes Olesen Method for treating tension-type headache
US6489356B2 (en) * 2000-09-05 2002-12-03 Edward Leung Method for treating pain in humans
US20060009478A1 (en) * 2003-10-15 2006-01-12 Nadav Friedmann Methods for the treatment of back pain

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9370203B2 (en) 2008-03-07 2016-06-21 Bayer Intellectual Property Gmbh Use of alternan as texturizing agent in foodstuffs and cosmetics
US10463606B2 (en) 2008-03-07 2019-11-05 Bayer Intellectual Property Gmbh Use of alternan as texturizing agent in foodstuffs and cosmetics

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CA2666925A1 (fr) 2008-05-02

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