(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`1 August 2002 (01.08.2002)
`
`
`
`PCT
`
`(10) International Publication Number
`WO 02/058610 A1
`
`(51) International Patent Classificationlz
`A61K 9/50
`
`A61F 13/02,
`
`(21) International Application Number:
`
`PCT/US02/02240
`
`(22) International Filing Date: 23 January 2002 (23.01.2002)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/264,166
`
`24 January 2001 (24.01.2001)
`
`US
`
`(71) Applicants: SUMMANUS PHARMA, INC. [US/US];
`Suite 800, 2025 First Avenue, Seattle, WA 98121 (US).
`HOFMANN, Thomas [DE/US]; 5526 28th Avenue NE,
`Seattle, WA 98105 (US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK,
`SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR,
`GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OAPI patent
`(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR,
`NE, SN, TD, TG).
`
`Published:
`
`with international search report
`
`(74) Agent: VERNY, Hana; Peters, Verny, Jones & Schmitt,
`LLP, Suite 6, 385 Sherman Avenue, Palo Alto, CA 94306
`(US).
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`(54) Title: ALKYL ARYL POLYETHER ALCOHOL POLYMERS FOR IMPROVEMENT OF NASAL BREATHING
`
`02/058610A1
`
`(57) Abstract: A method 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
`O 100 ug/ml to about 200 mg/ml, or tyloxapol or another alkylaryl polyether alcohol polymer alone or in admixture with pharmaceu-
`g tically acceptable excipients and additives. The composition is administered as a spray, liquid, liquid drops, lozenges or powder
`suitable for nasal and/or pharyngeal application.
`
`IPRZO1 5-01 099 |PR2015-O1 O97
`|PR2015-O1 100 |PR2015-O1 105
`
`Lupin EX1098
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`PCT/US02/02240
`
`ALKYL ARYL POLYETHER ALCOHOL POLYMERS FOR IMPROVEMENT OF NASAL
`BREATHING
`
`BACKGROUND OF THE INVENTION
`
`Field of the invention
`
`The
`
`current
`
`invention.
`
`concerns
`
`a
`
`method
`
`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.
`
`In particular,
`
`the present
`
`invention provides a spray,
`
`liquid or solid composition
`
`comprising from about 0.01 to about 20% (w/V), equivalent
`
`to about 100 ug/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.
`
`Background of the Invention
`
`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
`
`sleepiness and decreased alertness and work performance.
`
`As a consequence of snoring and sleep apnea, normal
`
`10
`
`15
`
`20
`
`25
`
`sleep
`
`rhythm is disturbed and
`
`oxygen
`
`saturation is
`
`30
`
`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.
`Sleep apnea is defined as cessation of air flow for
`
`35
`
`Page2
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`
`2
`
`more than ten seconds,
`
`occurring at
`
`least
`
`ten times per
`
`hour at night
`
`(Clinics in Chest Medicine,
`
`19:1 (1998) and
`
`Diagnostic
`
`and
`
`Coding Manual,
`
`The
`
`International
`
`Classification System of Sleep Disorders, Rochester, MN
`
`(1990)).
`
`Sleep apnea often leads to increased blood pressure,
`
`EKG changes, arrhythmia, neurologic changes,
`
`and even to
`
`increased risk for stroke (Clinics in Chest Medicine 19:1
`
`(1998).
`
`10
`
`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
`
`15
`
`(1995).
`
`Pathophysiologically,
`
`snoring and sleep apnea are
`
`characterized km! a
`
`recurrent closure «of
`
`the pharyngeal
`
`airway during sleep. Upper airway patency is influenced by
`
`muscle activity,
`
`anatomical
`
`features,
`
`vasomotor
`
`tone,
`
`mucosal adhesive forces and inflammation (Clinics in Chest
`
` ,
`
`19:1 (1998)).
`
`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
`
`20
`
`25
`
`other people,
`
`it is typically not dangerous to the snorer
`
`30
`
`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.
`
`35
`
`The current treatments of sleep apnea and snoring are
`
`Page3
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`
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`
`dominated by both pharmacological and non—pharmacological
`
`treatments, however, none of these have been found entirely
`
`satisfactory.
`
`Examples
`
`of
`
`nonpharmacological
`
`treatment
`
`include
`
`positive pressure therapy,
`
`such as nocturnal ventilation,
`
`continuous positive airway pressure, oral apparatuses, 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(l):55-68 (1998); Clinics in
`
`Chest Medicine,
`
`l9(l):69—76
`
`(1998); and Clinics in Chest
`
`Medicine,
`
`19(1):77-86 (1998),
`
`among others.
`
`Numerous other non—pharmaceutical treatmentimodalities
`
`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
`
`triggered by microphones or mild electrical shock devices,
`
`or mechanical devices used to manipulate the head position.
`
`Other treatments utilize such conservative measures as
`
`10
`
`15
`
`20
`
`weight loss, reduction of alcohol consumption and avoidance
`
`25
`
`of medications which influence muscular tone.
`
`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.
`
`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
`
`30
`
`35
`
`Page4
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`
`snoring.
`
`Phosphocholinamine
`
`as
`
`a
`
`topical
`
`spray
`
`(Am.
`
`J.
`
`Otolaryngol:,
`
`8:
`
`236
`
`(1987)),
`
`topical administration of
`
`methylsulfonylmethane to the nasal epithelium (US Patent
`
`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.
`
`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 "US patents 2,989,437 and
`
`4,668,513 and
`
`in German patent 3,046,125.
`
`The patent
`
`application WO 98/46245 proposes use of phospholipid lung
`
`surfactants for treatment of sleep apnea.
`
`Other proposed treatment for snoring include the use
`
`of mucopolysaccharides
`
`(US Patent 5,516,765),
`
`use of
`
`surfactant, preservatives and microbiocides (DE 3,917,109),
`
`pilocarpine (US 5,502,067), a mixture of herbal enzymes (US
`
`5,618,543)
`
`and use of ubidecarone,
`
`a lipid existing in
`
`mitochondria (JP 1,165,522).
`
`US patent 5,569,679 proposes
`
`using a solution of 1-20% methylsulfonylmethane along with
`
`an analgesic compound.
`
`The inventors of US patent 5,618,543 propose a mixture
`
`of natural enzymes and herbs as a remedy for snoring and
`
`allergies,
`
`given. preferably as
`
`tablets.
`
`The US patent
`
`2,989,437 describes a combination of an anti—inflammatory
`
`and an anti—bacterial substance as a nasal decongestant
`
`which could decrease snoring.
`
`The US patent 4,668,513
`
`proposes,
`
`as
`
`a
`
`treatment
`
`for
`
`snoring,
`
`a
`
`composition
`
`comprising a surface active substance, a preservative, and
`
`a bactericidal or fungicidal substance in the form of a
`
`10
`
`15
`
`20
`
`25
`
`30
`
`nasal spray.
`
`None of
`
`the above treatments have been found to be
`
`35
`
`effective for treatment of snoring and thus far none have
`
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`
`5
`
`been routinely utilized in practice.
`
`Thus
`
`the
`
`need
`
`for
`
`effective,
`
`practical
`
`and
`
`non—invasive treatment of snoring persist.
`
`Alkylaryl polyether alcohol polymers and particularly
`
`tyloxapol are compounds which are known for their mucolytic
`
`activity and have been previously used for
`
`inhalation
`
`treatment of
`
`lung inflammation.
`
`These
`
`compounds
`
`are
`
`generally classified as dispersants.
`
`The
`
`US patent 5,849,263 describes a pharmaceutical
`
`10
`
`composition. containing from. 0.125%
`
`to 5%
`
`of
`
`tyloxapol
`
`15
`
`20
`
`25
`
`useful for inhalation purposes, and suggests strategies 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
`
`associated with cystic fibrosis (Australian Patent AU 717
`
`537), pulmonary inflammation (WO 97/38 699),
`
`and as an
`
`anti—oxidant
`
`(US patent 5,512,270).
`
`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 inflammatory
`
`parameters. These factors,
`
`in combination with hyperviscous
`
`mucous production, play a role in cystic fibrosis.
`
`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,
`
`rhinosinusitis or other inflammation,
`
`they do not describe,
`
`30
`
`disclose or
`
`suggest
`
`a possible use of
`
`tyloxapol’ for
`
`treatment of snoring, sleep apnea or improvement of nasal
`
`breathing.
`
`The compounds which are subject of this invention have
`
`never before been used or their use suggested for treatment
`
`35
`
`of snoring and/or sleep apnea and/or sudden infant death
`
`Page6
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`
`syndrome and/or improvement of nasal breathing.
`
`W098/46245 proposes administration of phospholipid
`
`lung surfactants containing minute amounts of dispersant
`
`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.
`
`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
`
`therewifln in humans as well as
`
`improve nasal breathing
`
`following
`
`physical
`
`exertion,
`
`impaired
`
`breathing
`
`or
`
`post—surgical breathing trauma in mammals.
`
`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.
`
`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,
`
`antioxidants,
`
`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.
`
`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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Page?
`
`Page 7
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`
`nasal breathing.
`
`All patents, patent applications
`
`and publications
`
`described herein are hereby incorporated by reference.
`
`SUMMARY
`
`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
`
`improvement 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.
`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
`
`polyether alcohol polymer or a combination thereof.
`
`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
`
`10
`
`15
`
`20
`
`25
`
`prior to or during sleep.
`
`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 from about 0.045
`
`to about 3 ml of a nasal/pharyngeal spray comprising from
`
`30
`
`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.
`
`Yet another aspect of
`
`the current
`
`invention is a
`
`35
`
`method.
`
`for
`
`treatment
`
`and. prevention of sleep apnea in
`
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`
`8
`
`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.
`
`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
`
`10
`
`acceptable excipient and/or additive administered nasally
`
`and/or pharyngeally prior to or during sleep.
`
`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
`
`15
`
`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
`
`20
`
`grams.
`
`Another aspect of the current
`
`invention is a method
`
`for prevention of sudden infant death in infants comprising
`
`administering
`
`a
`
`composition
`
`comprising
`
`alkylaryl
`
`in
`
`concentration from about 0.01 to about
`
`5% of selected
`
`25
`
`alkylaryl administered to a nostril of an infant before
`
`sleep one or several times a day.
`
`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
`
`30
`
`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
`
`35
`
`a daily dose of 1 gram.
`
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`9
`
`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 pharmaceutically
`
`acceptable excipients and/or additives.
`
`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
`
`or
`anatomically
`having
`in mammals
`breathing
`nasal
`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 performance up to a daily dose of 3
`
`grams for humans and more than 10 grams for large animals.
`
`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(R0)yH
`
`0(RO)yH
`
`x
`
`R‘
`
`R‘
`
`(I)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`wherein R is ethylene,
`
`R1
`
`is tertiary octyl, X is
`
`greater than 1, and Y is an integer from 8
`
`to 18, or a
`
`35
`
`pharmaceutically acceptable salt thereof.
`
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`10
`
`Yet another aspect of
`
`the current
`
`invention is a
`
`composition comprising tyloxapol having a general formula
`OH
`OH
`OH
`
`Acmcmom /cmcmom Acmcmom
`
`°
`90
`
`?
`E
`0
`d
`O O n
`
`10
`
`x—-o—N
`I
`2
`
`x——o—w
`I
`z
`
`x——c—w
`I
`. 2
`
`(II)
`
`wherein X is hydrogen or methyl,
`
`Y is hydrogen or
`
`Z is hydrogen or straight or branched hydrocarbon
`methyl,
`chain of 1-8 cargons, m is an integer from 6-8 and n is an
`
`integer equal to or smaller than 5, or a pharmaceutically
`
`15
`
`acceptable salt thereof.
`
`Still another aspect of
`
`the current
`
`invention is a
`
`spray,
`
`liquid or solid nasal or pharyngeal composition
`
`comprising from about 0.01 to about 20%, that is from about
`
`0.1 to about 200 mg/ml,
`
`of tyloxapol or another alkylaryl
`
`20
`
`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
`
`25
`
`administration.
`
`Another aspect of the current invention is a metering
`
`dose device for administration of the composition of the
`
`invention in predetermined dose.
`
`Definitions
`
`30
`
`As used herein:
`
`“Alkylaryl” means alkylaryl polyether alcohol polymer
`
`depicted by formula (I).
`
`“Tyloxapol” means a compound depicted by formula (II).‘
`
`“Active
`
`component”,
`
`“active
`
`compound” or
`
`"active
`
`35
`
`ingredient” means one of the alkylaryl polyether alcohol
`
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`11
`
`polymers, preferably tyloxapol, as defined above.
`
`“CPAP” or “continuous positive airway pressure” 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.
`
`“TNS” means tyloxapol nasal spray.
`
`“SID” or “SIDS” means sudden infant death syndrome.
`
`“OSAS” means obstructive sleep apnea syndrome.
`
`“Normal
`
`saline”
`
`or
`
`“NS”
`
`means
`
`water
`
`solution
`
`10
`
`containing 0.9%
`
`(w/v) Nacl.
`
`“Diluted saline” means normal saline containing 0.9%
`
`(w/v) NaCl diluted into its lesser strength from about 0.1%
`
`to about 0.45%.
`
`“Half normal saline” or “ % NS” means normal saline
`
`diluted to its half strength containing 0.45% (w/v) NaCl.
`
`“Quarter normal
`
`saline” or
`
`“l/4 NS” means normal
`
`saline diluted to its quarter strength containing 0.225%
`
`(w/v) NaCl.
`
`“One tenth normal saline” or “l/10 NS” means normal
`
`saline diluted to its one tenth strength containing 0.09%
`
`(w/v) Nacl.
`
`“AHI” means apnea/hypopnea index.
`
`“VAS” means visual analog scale.
`
`“RDI” means respiratory distress index.
`
`“Squirt” means a volume dose of approximately 0.14 ml.
`
`“Drop” means a volume dose of approximately 0.015 ml.
`
`BRIEF DESCRIPTION OF FIGURES
`
`15
`
`20
`
`25
`
`Figure 1 is a graph illustrating decrease in snoring
`
`loudness following treatment with tyloxapol as determined
`
`30
`
`by the visual analog scale
`
`(VAS).
`
`Figure 2 is a graph showing decrease in occurrence of
`
`apneic/hypopneic episodes in sleep apnea patients following
`
`treatment with tyloxapol as determined by apnea hypopnea
`
`index
`
`(AHI).
`
`35
`
`Figure 3 is a graph illustrating improvement in sleep
`
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`12
`
`following treatment with. nasal
`
`spray containing 1% of
`
`tyloxapol
`
`in sleep apnea patients, determined as sleep
`
`efficiency (SE).
`
`Figure 4 is a graph illustrating improvement of sleep
`
`in sleep apnea patients
`
`following treatment with 1%
`
`tyloxapol nasal spray, measured by number of arousals per
`
`hour
`
`(ArI).
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The
`
`current
`
`invention
`
`concerns
`
`methods
`
`and
`
`compositions 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.
`
`The methods for treatment of the above conditions are
`
`efficient,
`
`safe,
`
`non-invasive
`
`and
`
`convenient.
`
`The
`
`treatment 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 polyether alcohol polymers formulated as a spray,
`
`liquid or solid composition for nasal and/or pharyngeal
`
`administration.
`
`Upon nasal
`
`and/or pharyngeal application of
`
`the
`
`composition prior
`
`to
`
`or
`
`during
`
`sleep
`
`according
`
`to
`
`appropriate regimens,
`the incidence and severity of snoring
`and sleep apnea is reduced, sudden infant death in infants
`
`10
`
`15
`
`20
`
`25
`
`is prevented and nasal breathing is improved in mammals
`
`30
`
`with
`
`anatomically
`
`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
`
`35
`
`according to the current invention substantially improves
`
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`13
`
`daytime alertness and performance.
`
`I.
`
`Compounds of the Invention
`
`Compounds of
`
`the
`
`invention are
`
`known
`
`for
`
`their
`
`activity
`
`as
`
`dispersants, mucolytics,
`
`antioxidants,
`
`5
`
`anti—inflammatories and free radical scavengers.
`
`A.
`
`Chemical Characterization
`
`Active
`
`compounds of
`
`the
`
`invention are alkylaryl
`
`polyethers alcohol polymers
`
`represented kn]
`
`the general
`
`chemical formula
`
`0(R0)yH
`
`O(RO)yH
`
`(I)
`
`10
`
`15
`
`wherein R is ethylene,
`
`R1
`
`is tertiary octyl, X is
`
`greater than 1, and Y is an integer from 8
`
`to 18, or a
`
`20
`
`pharmaceutically acceptable salt thereof.
`
`Alkylaryl polyether alcohol polymers are a well known
`
`group of nmcolytic dispersants. Representative compounds
`
`are tyloxapol, Triton WR-1352, Triton M-3610, Triton N-100,
`
`Triton. N—155,
`
`Triton WR—1360, Triton WR-1363, Triton
`
`25
`
`WR—1369, WR—1364.
`
`Processes
`
`for preparation of
`
`these
`
`compounds are known in the art.
`
`B.
`
`Pharmacological Characterization
`
`Alkylaryl polyether alcohol polymers of the invention
`
`have a pharmacological activity as dispersants, mucolytics,
`
`30
`
`antioxidants,
`
`anti—inflammatories
`
`and
`
`free
`
`radical
`
`scavengers when topically applied to the epithelium of the
`
`upper airways.
`
`The nwde of action of alkylaryl polyether alcohol
`
`polymers resulting in a decrease or cessation of snoring
`
`35
`
`and sleep apnea can be described in both physical and
`
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`pharmacological terms.
`
`14
`
`Physically,
`
`the alkylaryls dispersant action was found
`
`to
`
`reduce
`
`the
`
`collapse
`
`of
`
`muscular
`
`and
`
`epithelial
`
`structures in the nose and throat,
`
`thereby improving upper
`
`airway patency during inspiration.
`
`The'pharmacological activity of alkylaryls was found
`
`to result in reduction of inflammation and in protection of
`
`the nasal
`
`and pharyngeal epitheliunt
`
`from swelling and
`
`damage.
`
`Since
`
`alkylaryls
`
`are
`
`not
`
`well
`
`absorbed
`
`systemically,
`
`pharmacological
`
`activity of
`
`alkylaryls
`
`affecting snoring and sleep apnea
`
`is due
`
`to a direct
`
`topical effect on the collapsing epithelium of the upper
`
`airways.
`
`C.
`
`Tyloxapol - Chemical Characterization
`
`The most preferred alkylaryl polyether alcohol polymer
`
`is tyloxapol, represented by the chemical
`
`formula (II)
`
`OH
`
`OH
`
`OH
`
`/(CH2CH2O)m /(CH2CH2O)m /(CH2CH2O)m
`
`O
`
`0
`
`O
`
`t t ‘ CH2
`
`11
`
`X—-('3—-Y
`Z
`
`X-Ci?—Y
`Z
`
`X--Cl}--Y
`Z
`
`(II)
`
`wherein m is an integer from 6-8 and n is equal or
`
`smaller
`
`than 5, or
`
`a pharmaceutically' acceptable salt
`
`thereof.
`
`Tyloxapol is a known compound previously disclosed in
`
`2,454,541
`as
`a
`U.S.
`patent
`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
`
`Page15
`
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`
`15
`
`20
`
`25
`
`30
`
`35
`
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`
`;>o]_yn1er',
`
`”aI1
`
`o:<ye3tI1yJ.at<3d
`
`‘te:rt:iaJ:y
`
`octyl—phenol—polymethylene
`
`polymer
`
`or
`
`a
`
`p—isooctylpolyoxyethylenephenol
`
`formaldehyde
`
`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..
`
`Tyloxapol is a viscous compound, miscible with water
`
`10
`
`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 buffers, buffer salts and a wide variety of organic
`
`compounds without changing its chemical characteristics.
`
`Tyloxapol has a dispersant and mucolytic activity on
`
`mucosal tissue.
`
`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 substances. Tyloxapol has been
`
`15
`
`20
`
`shown to be poorly absorbed from the gastrointestinal tract
`
`25
`
`and
`
`its
`
`intravenous
`
`administration
`
`results
`
`in
`
`hyperlipemia.
`
`Tyloxapol has never before been used for nasal or
`
`pharyngeal administration to treat snoring or sleep apnea
`
`or other conditions as described herein.
`
`D.
`
`Tyloxapol — Pharmacological Characterization
`
`Tyloxapol,
`
`as
`
`an
`
`example of alkylaryl polyether
`
`alcohol polymers, is known as a mucolytic compound reducing
`
`epithelial
`
`secretions, viscosity and
`
`tenacity of
`
`the
`
`sputum.
`
`It has been used for
`
`a number of years
`
`as
`
`an
`
`30
`
`35
`
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`16
`
`aerosolized tyloxapol,
`
`available under
`
`a product name
`
`Alevaire®, administered in an inhalable nebulized form for
`
`treatment of bronchitis
`
`and tracheitis.
`
`The current
`
`pharmaceutical 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.
`
`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
`
`comprising
`
`tyloxapol
`
`is
`
`suitable
`
`for
`
`treatment
`
`and
`
`prevention of snoring,
`
`sleep apnea,
`
`sudden infant death
`
`syndrome or‘
`
`for general
`
`improvement
`
`cxf nasal breathing
`
`during physical activity or medical conditions when used as
`
`a nasal and/or pharyngeal
`
`spray,
`
`liquid,
`
`lozenge, dry
`
`powder or nasal aerosol.
`
`II. Compositions of the Invention
`
`Composition.of the invention consist essentially of an
`
`active
`
`ingredient
`
`and
`
`covers
`
`all
`
`pharmaceutically
`
`acceptable
`
`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.
`
`The pharmaceutically acceptable formulations 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 syndrome, and from about
`
`0.2% to about
`
`20
`
`(2
`
`to 200 mg/ml)
`
`for
`
`improvement of
`
`alertness and physical performance.
`
`The
`
`composition
`
`of
`
`the
`
`invention
`
`is
`
`typically
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
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`17
`
`administered as a nasal or pharyngeal spray although it may
`
`be administered as a liquid,
`
`liquid drops,
`
`lozenge, tablet,
`
`nasal aerosol or dry powder.
`
`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
`
`(I). The most preferred alkylaryl is tyloxapol depicted by
`
`the formula
`
`(II).
`
`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.
`
`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.
`
`The composition intended for treatment and prevention
`
`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.
`
`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
`