Pharmaceutical compositions for sleep apnea

Abstract

Pharmaceutical compositions are provided for the pharmacological treatment of breathing disorders and, more specifically, to compositions containing agents having serotonin receptor modulating activity for the alleviation of sleep apnea (central and obstructive) and other sleep-related breathing disorders wherein the active ingredients are released such as to extend effective blood plasma concentrations across the period of sleep.

1 .- 37 . (canceled) 
     
     
         38 . An orally administrable pharmaceutical composition that modifies the release of a serotonin receptor antagonist wherein the release of antagonist from the pharmaceutical composition results in a therapeutically effective level of antagonist in the blood plasma of a subject over a continuous period in excess of 4 hours. 
     
     
         39 . A pharmaceutical composition as claimed in  claim 38 , wherein the continuous period extends to between 6 and 14 hours from administration of the composition. 
     
     
         40 . A pharmaceutical composition as claimed in  claim 38 , wherein the continuous period extends to between 7 and 12 hours from administration of the composition. 
     
     
         41 . A pharmaceutical composition as claimed in  claim 38 , wherein the continuous period extends to between 8 and 10 hours from administration of the composition. 
     
     
         42 . A pharmaceutical composition as claimed in  claim 38 , which provides a therapeutically effective level of the antagonist for a continuous period initiated at from 0 to 2 hours from administration of the composition and extending to between 6 and 14 hours from administration of the composition. 
     
     
         43 . A pharmaceutical composition as claimed in  claim 38 , which provides a therapeutically effective level of the antagonist over a continuous period initiated at from 15 minutes to 1.5 hours from administration of the composition and extending to between 7 and 12 hours from administration of the composition. 
     
     
         44 . A pharmaceutical composition as claimed in  claim 38 , which provides a therapeutically effective level over a continuous period initiated at from 15 minutes to 1.5 hours from administration and extending to 8 to 10 hours from and administration of the composition. 
     
     
         45 . A pharmaceutical composition as claimed in  claim 38 , wherein the antagonist has a plasma half life of less than 6 hours. 
     
     
         46 . A pharmaceutical composition as claimed in  claim 38 , wherein the antagonist has a plasma half life of 3 to 5 hours. 
     
     
         47 . A pharmaceutical composition as claimed in  claim 38 , wherein the antagonist is ondansetron. 
     
     
         48 . A pharmaceutical composition as claimed in  claim 38 , wherein the antagonist is released in two or more pulses. 
     
     
         49 . A pharmaceutical composition as claimed in  claim 48 , wherein the first pulse of antagonist is released within 30 minutes of oral administration and the second pulse is released between 1 hour and 4 hours of administration. 
     
     
         50 . A pharmaceutical composition as claimed in  claim 48 , wherein the antagonist is ondansetron and the first pulse of ondansetron is released within 30 minutes of administration and the second pulse of ondansetron is released between 1 and 3 hours of administration. 
     
     
         51 . A pharmaceutical composition as claimed in  claim 38 , further comprising a dose of one or more of a selective serotonin reuptake inhibitor (“SSRI”), a serotonin and norepinephrine reuptake inhibitor (“SNRI”), and a serotonin receptor agonist. 
     
     
         52 . A pharmaceutical composition as claimed in  claim 38 , further comprising an SSRI selected from the group consisting of fluoxetine, paroxetine, milnacipran, sertraline, citalopram, escitalopram, and fluvoxamine. 
     
     
         53 . A pharmaceutical composition according to  claim 52 , wherein the SSRI is fluoxetine. 
     
     
         54 . A pharmaceutical composition as claimed in  claim 48 , further comprising an SNRI. 
     
     
         55 . A pharmaceutical composition according to  claim 54 , wherein the SNRI is chosen from venlafaxine, duloxetine, and milnacipran. 
     
     
         56 . A pharmaceutical composition according to  claim 54 , wherein the serotonin receptor antagonist is ondansetron and the SNRI is milnacipran. 
     
     
         57 . A pharmaceutical composition according to  claim 48 , wherein the antagonist is ondansetron and is immediately released. 
     
     
         58 . A pharmaceutical composition according to  claim 48  wherein the antagonist is ondansetron and is extendedly released. 
     
     
         59 . A pharmaceutical composition according to  claim 48 , wherein the antagonist is ondansetron and the ondansetron blood plasma levels have a C max  of below approximately 1200 ng/ml. 
     
     
         60 . A pharmaceutical composition according to  claim 59 , wherein the C max  is below approximately 800 ng/ml. 
     
     
         61 . A pharmaceutical composition according to  claim 59 , wherein the C max  is below approximately 400 ng/ml. 
     
     
         62 . A pharmaceutical composition according to  claim 48 , further comprising at least one other active compound chosen from analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxiolytics, sedatives, hypnotics, antipsychotics, bronchodilators, anti asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastrointestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, and anti-narcoleptics. 
     
     
         63 . A pharmaceutical composition according to  claim 48  further comprising at least one other active compound chosen from aceclofenac, acetaminophen, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amlodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram, clomipramine, clonazepam, clonidine, clonitazene, clorazepate, clotiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cyproheptadine, demexiptiline, desipramine, desomorphine, dexamethasone, dexanabinol, dextroamphetamine sulfate, dextromoramide, dextropropoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimetacrine, divalproex, tizatriptan, dolasetron, donepezil, dothiepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, fenamates, fenoprofen, fentanyl, fludiazepam, fluoxetine, fluphenazine, fiurazepam, flurbiprofen, flutazolam, fluvoxamine, frovatriptan, gabapentin, galantamine, gepirone,  Ginkgo biloba , granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen, iprindole, ipsapirone, ketanserin, ketoprofen, ketorolac, lesopitron, levodopa, lipase, lofepramine, lorazepam, loxapine, maprotiline, mazindol, mefenamic acid, melatonin, melitracen, memantine, meperidine, meprobamate, mesalamine, metapramine, metaxalone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, methylsalicylate, methysergid(e), metoclopramide, mianserin, mifepristone, minaprine, mirtazapine, moclobemide, modafinil, molindone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, naratriptan, nefazodone, neuronatin, nomifensine, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxaflozane, oxaprozin, oxazepam, oxitriptan, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin, phendimetrazine, phenmetrazine, phenylbutazone, phenyloin, phosphatidylserine, pimozide, pirlindole, piroxicam, pizotifen, pizotyline, pramipexole, prednisolone, prednisone, pregabalin, propranolol, propizepine, propoxyphene, protriptyline, quazepam, quinupramine, reboxetine, reserpine, risperidone, ritanserin, rivastigmine, rizatriptan, rofecoxib, ropinirole, rotigotine, salsalate, sertraline, sibutramine, sildenafil, sulfasalazine, sulindac, sumatriptan, tacrine, temazepam, tetrabenazine, thiazides, thioridazine, thiothixene, tiapride, tiasipirone tiospirone, tizanidine, tofenacin, tolmetin, toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan, Zolpidem, zopiclone and isomers, salts, and combinations thereof. 
     
     
         64 . A pharmaceutical composition according to  claim 48 , wherein the antagonist is ondansetron which is in the form of a therapeutically equivalent dose of an individual ondansetron enantiomer or pharmaceutically acceptable salts thereof. 
     
     
         65 . A pharmaceutical composition according to  claim 48 , wherein the antagonist is ondansetron which is in the form of a therapeutically equivalent dose of a mixture of ondansetron enantiomers or pharmaceutically acceptable salts thereof. 
     
     
         66 . A pharmaceutical composition according to  claim 64 , wherein the ondansetron is in the form of a therapeutically equivalent dose of the active metabolite of ondansetron or pharmaceutically acceptable salts thereof. 
     
     
         67 . A pharmaceutical composition according to  claim 48 , further comprising an enteric coating. 
     
     
         68 . A pharmaceutical composition according to  claim 48 , wherein the antagonist is ondansetron and wherein the administrable ondansetron unit dose is from 1 to 100 mg. 
     
     
         69 . A pharmaceutical composition according to  claim 48 , wherein the antagonist is ondansetron and wherein the administrable ondansetron unit dose is from 4 to 40 mg. 
     
     
         70 . A pharmaceutical composition according to  claim 38 , wherein the antagonist is ondansetron present in an amount ranging from 4 to 40 mg and wherein the composition further comprises 2 to 20 mg fluoxetine. 
     
     
         71 . A kit comprising a composition as claimed in  claim 38 , wherein the antagonist is provided in different dosage units to allow for dosage escalation. 
     
     
         72 . The kit as claimed in  claim 71 , wherein the antagonist is ondansetron. 
     
     
         73 . The kit as claimed in  claim 71 , further comprising instruction on taking the formulation once daily before bedtime. 
     
     
         74 . A method of ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof a composition according to  claim 38 . 
     
     
         75 . The method of  claim 74 , wherein the sleep-related breathing disorder is chosen from obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring. 
     
     
         76 . A pharmaceutical composition according to  claim 51 , wherein the antagonist is ondansetron and is immediately released. 
     
     
         77 . A pharmaceutical composition according to  claim 51 , wherein the antagonist is ondansetron and is extendedly released. 
     
     
         78 . A pharmaceutical composition according to  claim 51 , wherein the antagonist is ondansetron and the ondansetron blood plasma levels have a C max  of below approximately 1200 ng/ml. 
     
     
         79 . A pharmaceutical composition according to  claim 51 , further comprising at least one other active compound chosen from analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxiolytics, sedatives, hypnotics, antipsychotics, bronchodilators, anti asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastrointestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, and anti-narcoleptics. 
     
     
         80 . A pharmaceutical composition according to  claim 51 , wherein the antagonist is ondansetron which is in the form of a therapeutically equivalent dose of an individual ondansetron enantiomer or pharmaceutically acceptable salts thereof. 
     
     
         81 . A pharmaceutical composition according to  claim 51 , wherein the antagonist is ondansetron which is in the form of a therapeutically equivalent dose of a mixture of ondansetron enantiomers or pharmaceutically acceptable salts thereof 
     
     
         82 . A pharmaceutical composition according to  claim 51 , wherein the ondansetron is in the form of a therapeutically equivalent dose of the active metabolite of ondansetron or pharmaceutically acceptable salts thereof. 
     
     
         83 . A pharmaceutical composition according to  claim 51 , further comprising an enteric coating. 
     
     
         84 . A pharmaceutical composition according to  claim 51 , wherein the antagonist is ondansetron and wherein the administrable ondansetron unit dose is from 1 to 100 mg. 
     
     
         85 . A pharmaceutical composition according to  claim 84 , wherein the antagonist is ondansetron and wherein the administrable ondansetron unit dose is from 4 to 40 mg. 
     
     
         86 . A method of ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof a composition according to  claim 51 . 
     
     
         87 . The method of  claim 86 , wherein the sleep-related breathing disorder is chosen from obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring.