US 20030053956A1
`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2003/0053956 A1
`Hofmann
`(43) Pub. Date:
`Mar. 20, 2003
`
`(54) ALKYLARYL POLYETHER ALCOHOL
`POLYMERS FOR TREATMENT AND
`PROPHYLAXIS OF SNORING, SLEEP
`APNEA, SUDDEN INFANT DEATH
`SYNDROME AND FOR IMPROVEMENT OF
`NASAL BREATHING
`
`Publication Classification
`
`Int. Cl.7 ..................................................... .. A61L 9/04
`(51)
`(52) U.S.Cl.
`.............................................................. .. 424/45
`
`(76)
`
`Inventor: Thomas Hofmann, Seattle, WA (US)
`
`(57)
`
`ABSTRACT
`
`Correspondence Address:
`HANA VERNY
`PETERS, VERNY, JONES & SCHMITT, LLP
`SUITE 6
`385 SHERMAN AVENUE
`PALO ALTO, CA 94306 (US)
`
`(21) Appl. No.:
`
`10/056,524
`
`(22) Filed:
`
`Jan. 23, 2002
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/264,166, filed on Jan.
`24, 2001.
`
`Amethod and composition for treatment and prophylaxis of
`snoring, sleep apnea or sudden infant death syndrome and
`for improvement of nasal breathing in mammals by nasal
`and/or pharyngeal administration of tyloxapol or a related
`alkylaryl polyether alcohol polymer. A spray, liquid or solid
`composition comprising from about 0.01 to about 20%
`(W/v), equivalent to about 100 yg/ml to about 200 mg/ml, of
`tyloxapol or another alkylaryl polyether alcohol polymer
`alone or in admixture with pharmaceutically acceptable
`excipients and additives. The composition is administered as
`a spray, liquid, liquid drops, lozenges or powder suitable for
`nasal and/or pharyngeal application.
`
`|PR2015-01099
`|PR2015-01097
`
`|PR2015-01100
`|PR2015-01105
`
`Lupin EX1097
`Page 1
`
`

`
`Patent Application Publication Mar. 20, 2003 Sheet 1 of 3
`
`US 2003/0053956 A1
`
`Fléi
`
`Snoring Loudness (Visual Analog Scale)
`
`10 -
`
`p = 0.004
`
`
`
`
`
`VisualAnalogScale(VAS)
`
`
`
`
`
`
`
`Control
`
`Control
`
`TNS 1%
`
`TNS 1%
`
`Study Day
`
`
`Figure 1: Snoring is rated by the subject’s bed partner on a scale of 0-10, and treatment nights (3 + 4,
`TNS 1%) are compared to control nights (1 + 2, no treatment).
`
`Page 2
`
`Page 2
`
`

`
`Patent Application Publication Mar. 20, 2003 Sheet 2 of 3
`
`US 2003/0053956 A1
`
`Apnea Hypopnea Index (AHI)
`
`,
`,,
`F I (2 Z
`
`E 4°
`E so
`20
`
`;____.___
`N
`
`* \
`
`'
`
`Camrol: 23.8 :13
`ms: 15: 9.3
`P= 0.13
`
` E
`
`AHI Control
`
`AHI TNS 1%
`
`Figure 2: AHI is defined as the number of Apneas and Hypopneas per hour, and is also referred to as
`“RDI” (Respiratory Distress Index)
`
`Sleep Efficiency (SE)
`
`1316.3
`
`SE[''/nofthenight]
`
`SE Control
`
`SE TNS 1%
`
`Control: 77.0 1: 12.6
`TNS: 83.1 t 7.6
`P = 0.1
`
`Figure 3: Sleep Efficiency is defined as the time asleep (measured by EEG) as a percentage of the
`time in bed.
`
`Page 3
`
`Page 3
`
`

`
`Patent Application Publication Mar. 20, 2003 Sheet 3 of 3
`
`US 2003/0053956 A1
`
`Arousal Index (Arl)
`
`F I G. 171
`
`Arousals/hour
`
`Arl Control
`
`Arl TNS 1%
`
`Control: 34.2 1 11.5
`‘l'NS:27.0 t 8.2
`P = 0.09
`
`Figure 4: Arousal Index describes the number of (respiratory and EEG-based) arousals per hour.
`
`Page 4
`
`Page 4
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`

`
`US 2003/0053956 A1
`
`Mar. 20, 2003
`
`ALKYLARYL POLYETHER ALCOHOL
`POLYMERS FOR TREATMENT AND
`PROPHYLAXIS OF SNORING, SLEEP APNEA,
`SUDDEN INFANT DEATH SYNDROME AND FOR
`IMPROVEMENT OF NASAL BREATHING
`
`[0001] This application is based on and claims priority of
`the provisional application Ser. No. 60/264,166 filed on Jan.
`24, 2001.
`
`BACKGROUND OF THE INVENTION
`
`[0002]
`
`1. Field of the Invention
`
`[0003] The current invention concerns a method and com-
`position for treatment and prophylaxis of snoring, sleep
`apnea or sudden infant death syndrome and for improvement
`of nasal breathing in mammals by nasal and/or pharyngeal
`administration of tyloxapol or a related alkylaryl polyether
`alcohol polymer. In particular, the present invention pro-
`vides a spray, liquid or solid composition comprising from
`about 0.01 to about 20% (w/v), equivalent to about 100
`yg/ml to about 200 mg/ml, of tyloxapol or another selected
`alkylaryl polyether alcohol polymer alone, in combination,
`or in admixture with pharmaceutically acceptable excipients
`and additives. The composition is administered as a spray,
`liquid, liquid drops, lozenges or powder suitable for nasal
`and/or pharyngeal application.
`
`[0004]
`
`2. Background of the Invention
`
`[0005] Snoring and related sleep apnea are amongst the
`most troublesome sleeping impairments. Snoring is not only
`a nuisance for other people, but it has been shown, similarly
`to sleep apnea, to correlate with increased daytime sleepi-
`ness and decreased alertness and work performance.
`
`[0006] As a consequence of snoring and sleep apnea,
`normal sleep rhythm is disturbed and oxygen saturation is
`decreased ensuing in following tiredness and decrease in
`alertness and performance. Sleep apnea is characterized by
`repetitive episodes of upper airway obstruction that occurs
`during sleep and is usually associated with blood oxygen
`desaturation, snoring and daytime sleepiness.
`
`[0007] Sleep apnea is defined as cessation of air flow for
`more than ten seconds, occurring at least ten times per hour
`at night (Clinics in Chest Medicine, 19:1 (1998) and Diag-
`nostic and Coding Manual, The International Classification
`System of Sleep Disorders, Rochester, Minn. (1990)).
`
`[0008] Sleep apnea often leads to increased blood pres-
`sure, EKG changes, arrhythmia, neurologic changes, and
`even to increased risk for stroke (Clinics in Chest Medicine
`19:1 (1998).
`
`[0009] A milder form of sleep disordered breathing affects
`many millions of people in the United States. Additionally,
`several million people suffer from an even more severe form
`of sleep disordered breathing (National Commission on
`Sleep Disorders Research, Bethesda, Md. (1995).
`
`[0010] Pathophysiologically, snoring and sleep apnea are
`characterized by a recurrent closure of the pharyngeal air-
`way during sleep. Upper airway patency is influenced by
`muscle
`activity,
`anatomical
`features, vasomotor
`tone,
`mucosal adhesive forces and inflammation (Clinics in Chest
`Medicine, 19:1 (1998)).
`
`[0011] Snoring is an inspiratory sound which arises during
`a person’s sleep. It is believed to be generally caused by the
`narrowing of the nasopharyngeal airway which is caused by
`a turbulent airflow during relaxed breathing which vibrates
`the soft parts of the oropharyngeal passage, such as the soft
`palate, the posterior faucial pillars of the tonsils and the
`uvula. While snoring is unpleasant for other people,
`it is
`typically not dangerous to the snorer and may cause fatigue.
`On the other hand, sleep apnea causes disruption in the sleep
`pattern and can result in daytime tiredness, loss of alertness
`and productivity. It would thus be advantageous to provide
`a treatment for both snoring and sleep apnea.
`
`[0012] The current treatments of sleep apnea and snoring
`are dominated by both pharmacological and non-pharmaco-
`logical treatments, however, none of these have been found
`entirely satisfactory.
`
`treatment
`nonpharmacological
`of
`[0013] Examples
`include positive pressure therapy, such as nocturnal venti-
`lation, continuous positive airway pressure, oral appara-
`tuses, such as tongue retainers and jaw protractors, and
`surgical management, such as uvulopalatopharyngoplastic
`surgery comprising removal of accessory pharyngeal tissue.
`A comprehensive overview of these techniques is given in
`Clinics in Chest Medicine, 19(1):55-68 (1998); Clinics in
`Chest Medicine, 19(1):69-76 (1998); and Clinics in Chest
`Medicine, 19(1):77-86 (1998), among others.
`
`treatment
`[0014] Numerous other non-pharmaceutical
`modalities have been proposed and used, however, these
`treatments, similar to those described above, are not entirely
`satisfactory and effective. Amongst
`these modalities are
`techniques used to manipulate a sleep position by, for
`example sewing a marble or tennis ball into a pyjama to
`avoid supine sleeping, visual or electric manipulation trig-
`gered by microphones or mild electrical shock devices, or
`mechanical devices used to manipulate the head position.
`
`[0015] Other treatments utilize such conservative mea-
`sures as weight loss, reduction of alcohol consumption and
`avoidance of medications which influence muscular tone.
`
`[0016] Pharmacological treatment modalities include the
`systemic application of the therapeutic agents, such as
`tricyclic
`antidepressants, medroxyprogesterone
`acetate,
`tryptophane and other agents. All these agents have been
`used only with limited success,
`in part because they can
`cause undesirable secondary reactions.
`
`[0017] Some attempts were made to treat and prevent
`snoring and sleep apnea with various topically administered
`agents. In this regard,
`to date, the following nasal spray
`applications have been suggested as possible treatments for
`snoring.
`
`[0018] Phosphocholinamine as a topical spray (Am. J.
`Otolaryngol:, 8: 236 (1987)),
`topical administration of
`methylsulfonylmethane to the nasal epithelium (U.S. Pat.
`No. 5,569,679), and a mixture of surface active agents
`including Polysorbate 80, commercially available under the
`trade name Sonarex®, were suggested and/or are available
`as a topical spray for snoring.
`
`[0019] The idea of nasal sprays to treat snoring dates back
`to 1955, when surface active substances, but not tyloxapol or
`alkylaryl polyether alcohol polymers, were first proposed for
`this purpose in U.S. Pat. Nos. 2,989,437 and 4,668,513 and
`
`Page 5
`
`Page 5
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`

`
`US 2003/0053956 A1
`
`Mar. 20, 2003
`
`in German patent 3,046,125. The patent application WO
`98/46245 proposes use of phospholipid lung surfactants for
`treatment of sleep apnea.
`
`[0020] Other proposed treatment for snoring include the
`use of mucopolysaccharides (U.S. Pat. No. 5,516,765), use
`of surfactant, preservatives and microbiocides (DE 3,917,
`109), pilocarpine (U.S. Pat. No. 5,502,067), a mixture of
`herbal enzymes (U.S. Pat. No. 5,618,543) and use of ubide-
`carone, a lipid existing in mitochondria (JP 1,165,522). U.S.
`Pat. No. 5,569,679 proposes using a solution of 1-20%
`methylsulfonylmethane along with an analgesic compound.
`
`[0021] The inventors of U.S. Pat. No. 5,618,543 propose
`a mixture of natural enzymes and herbs as a remedy for
`snoring and allergies, given preferably as tablets. The U.S.
`Pat. No. 2,989,437 describes a combination of an anti-
`inflammatory and an anti-bacterial substance as a nasal
`decongestant which could decrease snoring. The U.S. Pat.
`No. 4,668,513 proposes, as a treatment for snoring, a com-
`position comprising a surface active substance, a preserva-
`tive, and a bactericidal or fungicidal substance in the form
`of a nasal spray.
`
`[0022] None of the above treatments have been found to
`be effective for treatment of snoring and thus far none have
`been routinely utilized in practice.
`
`[0023] Thus the need for effective, practical and non-
`invasive treatment of snoring persist.
`
`[0024] Alkylaryl polyether alcohol polymers and particu-
`larly tyloxapol are compounds which are known for their
`mucolytic activity and have been previously used for inha-
`lation treatment of lung inflammation. These compounds are
`generally classified as dispersants.
`
`[0025] The U.S. Pat. No. 5,849,263 describes a pharma-
`ceutical composition containing from 0.125% to 5% of
`tyloxapol useful for inhalation purposes, and suggests strat-
`egies to reduce hypertonicity to avoid bronchospasm upon
`inhalation into the lung. Other related proposals for the use
`of tyloxapol are as a treatment for lung inflammation asso-
`ciated with cystic fibrosis (Australian Patent AU 717 537),
`pulmonary inflammation (WO 97/38 699), and as an anti-
`oxidant (U.S. Pat. No. 5,512,270).
`
`[0026] Specifically, the above described prior inventions
`relate to aerosol treatments of respiratory inflammation and
`cystic fibrosis. The inventors describe in a detailed fashion
`the oxidant-mediated injury in the lung,
`the effect of
`hydroxyl group(s), other free radicals, cytokines and inflam-
`matory parameters. These factors,
`in combination with
`hyperviscous mucous production, play a role in cystic fibro-
`SIS.
`
`[0027] While some of these patents disclose the use of
`tyloxapol aerosol in the pulmonary diseases, and briefly
`mention its possible use for relief of nasal rhinitis, rhinosi-
`nusitis or other inflammation, they do not describe, disclose
`or suggest a possible use of tyloxapol for treatment of
`snoring, sleep apnea or improvement of nasal breathing.
`
`[0028] The compounds which are subject of this invention
`have never before been used or their use suggested for
`treatment of snoring and/or sleep apnea and/or sudden infant
`death syndrome and/or improvement of nasal breathing.
`
`ant tyloxapol to the posterior pharyngeal region prior to
`sleep in order to reduce sleep apnea. The described active
`compounds are natural or synthetic lung surfactants rather
`than dispersants and antioxidants. The application does not
`teach the use of a nasal spray and the use of tyloxapol for
`treatment of snoring.
`
`[0030] The current invention is based on a discovery that
`tyloxapol and related alkylaryl polyether alcohol polymers
`can decrease, prevent or treat snoring, sleep apnea, sudden
`infant death syndrome and sleep disturbances connected
`therewith in humans as well as improve nasal breathing
`following physical exertion,
`impaired breathing or post-
`surgical breathing trauma in mammals.
`
`[0031] None of the above described disclosures teaches
`the current invention of administering tyloxapol or related
`alkylaryl nasally and/or pharyngeally to treat snoring and
`sleep apnea, to prevent sudden infant death syndrome and to
`improve nasal breathing.
`
`[0032] Use of tyloxapol or related alkylaryl polyether
`alcohol polymers has never been proposed as a treatment for
`snoring and/or sleep apnea, or as a method to improve nasal
`breathing. Alkylaryl polyether alcohol polymers such as
`tyloxapol are known to be active as mucolytics, antioxi-
`dants, free radical scavengers, and as dispersant agents. This
`group of compounds is distinct from the other compounds
`previously used or proposed for use in treatment of snoring
`and sleep apnea and other diseases and conditions described
`herein.
`
`[0033] The current invention specifically describes the use
`of topical nasal and pharyngeal compositions comprising
`one or several alkylaryls for treatment of snoring, sleep
`apnea, sudden infant death syndrome and improvement of
`nasal breathing.
`
`[0034] All patents, patent applications and publications
`described herein are hereby incorporated by reference.
`
`SUMMARY
`
`[0035] One aspect of the current invention is a method for
`treatment or prevention of snoring, sleep apnea, sudden
`infant death syndrome and sleep disorders and for improve-
`ment of sleep pattern, alertness and nasal breathing by
`administering to a subject in need thereof a composition
`comprising from about 0.01 to about 20% of alkylaryl
`polyether alcohol polymer or a combination thereof with or
`without admixture with a pharmaceutically acceptable
`excipient or additive.
`
`[0036] Another aspect of the current invention is a method
`for prevention and treatment of snoring in humans by
`administering to a subject in need thereof a composition
`comprising from about 0.2 to about 20% of alkylaryl poly-
`ether alcohol polymer or a combination thereof.
`
`[0037] Still another aspect of the current invention is a
`method for prevention and treatment of snoring in humans
`by administering to a subject in need thereof a composition
`comprising from about 1 to about 10% of tyloxapol alone or
`in admixture with a pharmaceutically acceptable excipient
`and/or additive administered nasally and/or pharyngeally
`prior to or during sleep.
`
`[0029] WO98/46245 proposes administration of phospho-
`lipid lung surfactants containing minute amounts of dispers-
`
`[0038] Still another aspect of the current invention is a
`method for prevention and treatment of snoring in humans
`
`Page 6
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`Page 6
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`

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`US 2003/0053956 A1
`
`Mar. 20, 2003
`
`by administering to a subject in need thereof from about
`0.045 to about 3 ml of a nasal/pharyngeal spray comprising
`from about 1 to about 100 mg/ml of tyloxapol alone or in
`admixture with a pharmaceutically acceptable excipient
`and/or additive administered nasally and pharyngeally prior
`to sleep up to a total daily dose of 3 grams.
`
`[0039] Yet another aspect of the current invention is a
`method for treatment and prevention of sleep apnea in
`humans by administering to a subject in need thereof a
`composition comprising from about 0.5 to about 20% of one
`or a combination of several alkylaryl polyether alcohol
`polymers.
`
`[0040] Still another aspect of the current invention is a
`method for prevention and treatment of sleep apnea in
`humans by administering to a subject in need thereof a
`composition comprising from about 0.5 to about 20% of
`tyloxapol alone or in admixture with a pharmaceutically
`acceptable excipient and/or additive administered nasally
`and/or pharyngeally prior to or during sleep.
`
`[0041] Still yet another aspect of the current invention is
`a method for prevention and treatment of sleep apnea in
`humans by administering to a subject in need thereof from
`about 0.045 to about 3 ml of a composition comprising from
`about 10 to about 150 mg/ml of tyloxapol alone or in
`admixture with a pharmaceutically acceptable excipient
`and/or additive administered nasally and/or pharyngeally
`prior to or during sleep up to a total daily dose of 3 grams.
`
`[0042] Another aspect of the current invention is a method
`for prevention of sudden infant death in infants comprising
`administering a composition comprising alkylaryl in con-
`centration from about 0.01 to about 5% of selected alkylaryl
`administered to a nostril of an infant before sleep one or
`several times a day.
`
`[0043] Still yet another aspect of the current invention is
`a method for prevention and treatment of sudden infant
`death syndrome in infants by administering to an infant from
`about 0.015 (1 drop) to about 0.5 ml of a composition
`comprising from about 0.1 to about 50 mg/ml of tyloxapol
`alone or in admixture with a pharmaceutically acceptable
`excipient and/or additive administered to an infant nasally
`prior to or during sleep one or several times a day up to a
`daily dose of 1 gram.
`
`[0044] Still yet another aspect of the current invention is
`a method for improvement of sleep pattern, treatment of
`sleep disorders and for improvement of day alertness by
`administering to a subject in need thereof a nasal spray or
`another composition comprising from about 0.2 to about
`20% of tyloxapol alone or in combination with pharmaceu-
`tically acceptable excipients and/or additives.
`
`[0045] Still yet another aspect of the current invention is
`a method for improvement of nasal breathing during and
`following the physical performance such as competitive
`sports, diving, flying, high altitude climbing, horse racing,
`etc.,
`in mammals, including humans, or improving nasal
`breathing in mammals having anatomically or functionally
`impaired nasal passageways by administering to a subject in
`need thereof a nasal spray composition comprising from
`about 0.2 to about 20% (2-200 mg/ml) of tyloxapol alone or
`in combination with pharmaceutically acceptable excipients
`and/or additives prior to or following the physical perfor-
`
`mance up to a daily dose of 3 grams for humans and more
`than 10 grams for large animals.
`
`[0046] Still yet another aspect of the current invention is
`a composition comprising one or a combination of several
`alkylaryl polyether alcohol polymers having a structure of
`general formula
`
`O(RO)yH
`
`O(RO)yH
`
`(1)
`
`R1
`
`R1
`
`[0047] wherein R is ethylene, R1 is tertiary octyl, X
`is greater than 1, and Y is an integer from 8 to 18, or
`a pharmaceutically acceptable salt thereof.
`
`[0048] Yet another aspect of the current invention is a
`composition comprising tyloxapol having a general formula
`
`OH
`
`OH
`
`OH
`
`(11)
`
`/(CH2CH2O)m /(CH2CH2O)m /(CH2CH2O)m
`
`O:
`
`O
`
`O
`
`O
`
`I
`
`O
`
`O
`
`I
`
`1:
`
`CH3
`
`X:(|::Y X:(FY X:(|::Y
`Z
`Z
`Z
`
`[0049] wherein X is hydrogen or methyl, Y is hydro-
`gen or methyl, Z is hydrogen or straight or branched
`hydrocarbon chain of 1-8 carbons, m is an integer
`from 6-8 and n is an integer equal to or smaller than
`5, or a pharmaceutically acceptable salt thereof.
`
`[0050] Still another aspect of the current invention is a
`spray, liquid or solid nasal or pharyngeal composition com-
`prising from about 0.01 to about 20%, that is from about 0.1
`to about 200 mg/ml, of tyloxapol or another alkylaryl
`polyether alcohol polymer per one ml of a diluent for nasal
`administration as a nasal and/or pharyngeal spray, nasal
`and/or pharyngeal solution, nasal and/or pharyngeal drops,
`lozenges, nasal aerosol or dry powder, administered directly,
`or by using a device for nasal or pharyngeal administration.
`
`[0051] Another aspect of the current invention is a meter-
`ing dose device for administration of the composition of the
`invention in predetermined dose.
`
`Page 7
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`

`
`US 2003/0053956 A1
`
`Mar. 20, 2003
`
`[0052] Definitions
`
`[0053] As used herein:
`
`“Alkylaryl” means alkylaryl polyether alcohol
`[0054]
`polymer depicted by formula
`
`“Tyloxapol” means a compound depicted by for-
`[0055]
`mula (II).
`
`or
`compound”
`“active
`component”,
`“Active
`[0056]
`“active ingredient” means one of the alkylaryl polyether
`alcohol polymers, preferably tyloxapol, as defined above.
`
`“CPAP” or “continuous positive airway pressure”
`[0057]
`means continuous positive airway pressure treatment for
`snoring and sleep apnea which is typically administered via
`the nose (nCPAP) or the mouth of the patient.
`
`[0058]
`
`“TNS” means tyloxapol nasal spray.
`
`[0059]
`drome.
`
`“SID” or “SIDS” means sudden infant death syn-
`
`[0060]
`
`“OSAS” means obstructive sleep apnea syndrome.
`
`“Normal saline” or “NS” means water solution
`[0061]
`contaiiing 0.9% (w/v) NaCl.
`
`“Diluted saline” means normal saline containing
`[0062]
`0.9% (w/v) NaCl diluted into its lesser strength from about
`0.1% to about 0.45%.
`
`“Half normal saline” or “1/2 NS” means normal
`[0063]
`saline diluted to its half strength containing 0.45% (w/v)
`NaCl.
`
`“Quarter normal saline” or “A: NS” means normal
`[0064]
`saline diluted to its quarter strength containing 0.225% (w/v)
`NaCl.
`
`[0074] FIG. 4 is a graph illustrating improvement of sleep
`in sleep apnea patients following treatment with 1% tylox-
`apol nasal spray, measured by number of arousals per hour
`(ArI).
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0075] The current invention concerns methods and com-
`positions for treatment and prevention of snoring and sleep
`apnea in humans, for prophylaxis of sudden infant death
`syndrome in infants, or for general improvement of sleep
`pattern and nasal breathing, for treatment, pretreatment and
`improvement of performance in a human or animal subjects
`prior to, during or following the physical performance.
`
`[0076] The methods for treatment of the above conditions
`are efficient, safe, non-invasive and convenient. The treat-
`ment is achieved by providing a subject with an easy to
`administer composition of the invention, said composition
`comprising one or a combination of several alkylaryl poly-
`ether alcohol polymers formulated as a spray, liquid or solid
`composition for nasal and/or pharyngeal administration.
`
`[0077] Upon nasal and/or pharyngeal application of the
`composition prior to or during sleep according to appropri-
`ate regimens, the incidence and severity of snoring and sleep
`apnea is reduced, sudden infant death in infants is prevented
`and nasal breathing is improved in mammals with anatomi-
`cally or functionally obstructed nasal passageway or before,
`during or following a physical activity or competitive sports,
`such as diving, high altitude climbing, hiking or flying in
`humans, or horse or dog racing, etc. in animals. Additionally,
`the method according to the current invention substantially
`improves daytime alertness and performance.
`
`[0078]
`
`I. Compounds of the Invention
`
`“One tenth normal saline” or “1/1o NS” means
`[0065]
`normal saline diluted to its one tenth strength containing
`0.09% (w/v) NaCl.
`
`[0079] Compounds of the invention are known for their
`activity as dispersants, mucolytics, antioxidants, anti-in-
`flammatories and free radical scavengers.
`
`[0066]
`
`“AHI” means apnea/hypopnea index.
`
`[0067]
`
`“VAS” means visual analog scale.
`
`[0068]
`
`“RDI” means respiratory distress index.
`
`[0069_
`0.14 ml
`
`[0070_
`0.015 ml
`
`“Squirt” means a volume dose of approximately
`
`“Drop” means a volume dose of approximately
`
`BRIEF DESCRIPTION OF FIGURES
`
`[0071] FIG. 1 is a graph illustrating decrease in snoring
`loudness following treatment with tyloxapol as determined
`by the visual analog scale (VAS).
`
`[0072] FIG. 2 is a graph showing decrease in occurrence
`of apneic/hypopneic episodes in sleep apnea patients fol-
`lowing treatment with tyloxapol as determined by apnea
`hypopnea index
`
`[0080] A. Chemical Characterization
`
`[0081] Active compounds of the invention are alkylaryl
`polyethers alcohol polymers represented by the general
`chemical formula
`
`O(RO)yH
`
`O(RO)yH
`
`(1)
`
`R1
`
`R1
`
`[0082] wherein R is ethylene, R1 is tertiary octyl, X
`is greater than 1, and Y is an integer from 8 to 18, or
`a pharmaceutically acceptable salt thereof.
`
`[0073] FIG. 3 is a graph illustrating improvement in sleep
`following treatment with nasal spray containing 1% of
`tyloxapol in sleep apnea patients, determined as sleep effi-
`ciency
`
`[0083] Alkylaryl polyether alcohol polymers are a well
`known group of mucolytic dispersants. Representative com-
`pounds are tyloxapol, Triton WR-1352, Triton M-3610,
`Triton N-100, Triton N-155, Triton WR-1360, Triton
`
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`
`US 2003/0053956 A1
`
`Mar. 20, 2003
`
`WR-1363, Triton WR-1369, WR-1364. Processes for prepa-
`ration of these compounds are known in the art.
`
`[0084]
`
`B. Pharmacological Characterization
`
`[0085] Alkylaryl polyether alcohol polymers of the inven-
`tion have a pharmacological activity as dispersants, muco-
`lytics, antioxidants, anti-inflammatories and free radical
`scavengers when topically applied to the epithelium of the
`upper airways.
`
`[0086] The mode of action of alkylaryl polyether alcohol
`polymers resulting in a decrease or cessation of snoring and
`sleep apnea can be described in both physical and pharma-
`cological terms.
`
`the alkylaryls dispersant action was
`Physically,
`[0087]
`found to reduce the collapse of muscular and epithelial
`structi res in the nose and throat, thereby improving upper
`airway patency during inspiration.
`
`[0088] The pharmacological activity of alkylaryls was
`found to result in reduction of inflammation and in protec-
`tion o the nasal and pharyngeal epithelium from swelling
`and damage. Since alkylaryls are not well absorbed systemi-
`cally, 3harmacological activity of alkylaryls affecting snor-
`ing and sleep apnea is due to a direct topical effect on the
`collapsing epithelium of the upper airways.
`
`[0089]
`
`C. Tyloxapol—Chemical Characterization
`
`[0090] The most preferred alkylaryl polyether alcohol
`polymer is tyloxapol, represented by the chemical formula
`(11)
`
`OH
`
`OH
`
`OH
`
`(H)
`
`(CH2CH2O)m
`
`(CH2CH2O)m
`
`(CH2CH2O)m
`
`O
`
`O
`
`O
`
`O
`
`O
`
`I
`
`O
`
`I
`
`1:
`
`CH3
`
`X:C:Y X:C:Y X:C:Y
`
`Z
`
`Z
`
`Z
`
`[0091] wherein X is hydrogen or methyl, Y is hydro-
`gen or methyl, Z is hydrogen or straight or branched
`hydrocarbon chain of 1-8 carbons m is an integer
`from 6-8 and n is equal or smaller than 5, or a
`pharmaceutically acceptable salt thereof.
`
`[0092] Tyloxapol is a known compound previously dis-
`closed in U.S. Pat. No. 2,454,541 as a mucolytic dispersant.
`Tyloxapol, also known and available under the trade names
`Triton WR-1339, Triton A-20, Superinone, Alevaire®, or
`Tacholiquin® is listed in Merck Index under a chemical
`
`name as an oxyethylated tertiary octylphenol formaldehyde
`polymer, an oxyethylated tertiary octyl-phenol-polymethyl-
`ene polymer or a p-isooctylpolyoxyethylenephenol formal-
`dehyde polymer. Tyloxapol is a blend of alkylaryl polyether
`alcohol polymers fitting within the formula II. Tyloxapol
`USP can be purchased from Ruger Chemical Company, Inc.,
`Irvington, N.J. 07111 and is also commercially available
`from Organichem, Rensselaer, N.Y.
`
`[0093] Tyloxapol is a viscous compound, miscible with
`water at all concentrations and soluble in the majority of
`organic solvents. Tyloxapol is a chemically stable compound
`unaffected by boiling, sterilization, extensive length storage
`or prolonged standing and is compatible with various buff-
`ers, buffer salts and a wide variety of organic compounds
`without changing its chemical characteristics.
`
`[0094] Tyloxapol has a dispersant and mucolytic activity
`on mucosal tissuc.
`
`[0095] Tyloxapol has been used in humans as a treatment
`for a variety of pulmonary disorders, primarily for treatment
`of tuberculosis and as an aerosolized agent for treatment of
`bronchitis, asthma, respiratory distress and bronchiectasis,
`or as a dispersant for other pharmacologically active sub-
`stances. Tyloxapol has been shown to be poorly absorbed
`from the gastrointestinal tract and its intravenous adminis-
`tration results in hyperlipemia.
`
`[0096] Tyloxapol has never before been used for nasal or
`pharyngeal administration to treat snoring or sleep apnea or
`other conditions as described herein.
`
`[0097] D. Tyloxapol—Pharmacological Characterization
`
`[0098] Tyloxapol, as an example of alkylaryl polyether
`alcohol polymers, is known as a mucolytic compound reduc-
`ing epithelial secretions, viscosity and tenacity of the spu-
`tum.
`
`It has been used for a number of years as an
`[0099]
`aerosolized tyloxapol, available under a product name
`Alevaire®, administered in an inhalable nebulized form for
`treatment of bronchitis and tracheitis. The current pharma-
`ceutical utility for tyloxapol, which is now marketed and
`approved for use only in Japan and Germany, is only for
`aerosol administration to the lung by a nebulizer.
`
`[0100] The use of tyloxapol as a nasal spray for treatment
`of snoring and sleep apnea, prevention of sudden infant
`death syndrome or improvement of nasal breathing and
`sleep pattern has never before been disclosed.
`
`It has now been discovered that a composition
`[0101]
`comprising tyloxapol is suitable for treatment and preven-
`tion of snoring, sleep apnea, sudden infant death syndrome
`or for general improvement of nasal breathing during physi-
`cal activity or medical conditions when used as a nasal
`and/or pharyngeal spray,
`liquid, lozenge, dry powder or
`nasal aerosol.
`
`[0102]
`
`II. Compositions of the Invention
`
`[0103] Composition of the invention consist essentially of
`an active ingredient and covers all pharmaceutically accept-
`able formulations containing alkylaryl polyether alcohol
`polymers, preferably tyloxapol, as an active ingredient for
`the treatment of snoring and/or sleep apnea and/or other
`conditions described herein.
`
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`
`formulations
`[0104] The pharmaceutically acceptable
`comprise a selected alkylaryl or tyloxapol at concentrations
`ranging from 0.01% to 20% (0.1 to 200 mg/ml) with the
`preferable range for each condition being from about 0.2%
`to about 10% (2 to 100 mg/ml) for treatment of snoring,
`from about 0.5% to about 15% (5 to 150 mg/ml) for
`treatment of sleep apnea, from about 0.01% to about 5% (0.1
`to 50 mg/ml) for prevention of sudden infant death syn-
`drome, and from about 0.2% to about 20 (2 to 200 mg/ml)
`for improvement of alertness and physical performance.
`
`[0105] The composition of the invention is typically
`administered as a nasal or pharyngeal spray although it may
`be administered as a liquid, liquid drops, lozenge, tablet,
`nasal aerosol or dry powder.
`
`[0106] The composition comprises one or a combination
`of two or more compounds selected from the group of
`alkylaryl polyether alcohol polymer compounds depicted by
`formula
`The most preferred alkylaryl
`is tyloxapol
`depicted by the formula (II).
`
`[0107] The selected alkylaryl is present in from about 0.01
`to about 20%, that is from about 0.1 to about 200 mg/ml,
`depending on the intended use.
`
`[0108] The composition intended for treatment of snoring
`comprises from about 0.2 to about 20%, preferably from
`about 1 to about 10%, and for treatment of sleep apnea from
`about 0.5 to about 20%, preferably from about 1 to about
`15%, of alkylaryl, preferably tyloxapol up to a maximum of
`3 grams per day.
`
`[0109] The composition intended for treatment and pre-
`vention of sudden infant death syndrome comprises from
`about 0.01 to about 5% of alkylaryl, preferably tyloxapol up
`to a maximum of 1 gram per day.
`
`[0110] The alkylaryl of the invention is formulated as a
`spray, liquid, drops, lozenge, nasal aerosol or dry powder
`alone or in admixture with any suitable pharmaceutically
`acceptable excipient and, when appropriate, is diluted in a
`pharmaceutically suitable diluent, such as a sterile water,
`normal or half or quarter diluted saline or another, preferably
`aqueous, diluent.
`
`[0111] The alkylaryl polyether alcohol polymers may also
`be used in combination with other topically active agents
`alone, as a combination of the alkylaryl and the topically
`act