CA2285574C - Method and composition for treating sleep apnea - Google Patents
Method and composition for treating sleep apnea Download PDFInfo
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- CA2285574C CA2285574C CA002285574A CA2285574A CA2285574C CA 2285574 C CA2285574 C CA 2285574C CA 002285574 A CA002285574 A CA 002285574A CA 2285574 A CA2285574 A CA 2285574A CA 2285574 C CA2285574 C CA 2285574C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/42—Respiratory system, e.g. lungs, bronchi or lung cells
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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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Application of synthetic or naturally occurring lung surfactant to the posterior pharyngeal region prior to a period of sleep significantly reduces episodes of sleep disturbance resulting in apnea or hypopnea. The present invention provides lung surfactant in a convenient applicator container for easy use and storage. Incidents of oxygen desaturation are reduced, thereby lowering the risks of apnea-associated pathologies.
Description
METHOD AND COMPOSITION FOR TREATING SLEEP APNEA
FIELD OF THE INVENTION
The present invention relates to a treatment for sleep apnea using natural or synthetic lung surfactant to coat the pharyngeal mucosa. The invention thereby provides therapeutic relief for a medical condition having serious adverse health effects. An apparatus is also provided for therapeutic administration of the surfactant.
BACKGROUND OF THE INVENTION
Among the most troublesome of sleep impairing ailments is persistent snoring and associated sleep apnea during which normal breathing is interrupted for a sufficient time to produce anoxia. Episodes of apnea occur with sufficient frequency that the subject is deprived of the normal benef_Lts of restful sleep, and frequently suffers from profound daytime drowsiness, mental fatigue, and weakness. Snoring occurs in the collapsible part of the airway from the epiglottis to the choanae involving the so:=t palate, uvula, tonsils, tonsillar pillars, and the pharyngeal muscles and mucosa. In apnea., the air passage becomes completely occluded, interrupting breathing. Typically periods of loud snoring are punctuated with silent episodes in which the airway is occluded, followed by a loud resuscitative snort which restores breathing and partially wakes the sleeper.
Mild cases of snoring and apnea are nuisances easily tolerated, but more severe cases entail health risks that are only beginning to be studied and understood. A pathological condition exists when apnea episodes extend longer than 10 seconds and occur more than 7-10 times in an hour. When airflow is reduced to 30% of normal, hypopnea or a hypopneic episode ensues.
The number of apneas and hypopneas together are taken
FIELD OF THE INVENTION
The present invention relates to a treatment for sleep apnea using natural or synthetic lung surfactant to coat the pharyngeal mucosa. The invention thereby provides therapeutic relief for a medical condition having serious adverse health effects. An apparatus is also provided for therapeutic administration of the surfactant.
BACKGROUND OF THE INVENTION
Among the most troublesome of sleep impairing ailments is persistent snoring and associated sleep apnea during which normal breathing is interrupted for a sufficient time to produce anoxia. Episodes of apnea occur with sufficient frequency that the subject is deprived of the normal benef_Lts of restful sleep, and frequently suffers from profound daytime drowsiness, mental fatigue, and weakness. Snoring occurs in the collapsible part of the airway from the epiglottis to the choanae involving the so:=t palate, uvula, tonsils, tonsillar pillars, and the pharyngeal muscles and mucosa. In apnea., the air passage becomes completely occluded, interrupting breathing. Typically periods of loud snoring are punctuated with silent episodes in which the airway is occluded, followed by a loud resuscitative snort which restores breathing and partially wakes the sleeper.
Mild cases of snoring and apnea are nuisances easily tolerated, but more severe cases entail health risks that are only beginning to be studied and understood. A pathological condition exists when apnea episodes extend longer than 10 seconds and occur more than 7-10 times in an hour. When airflow is reduced to 30% of normal, hypopnea or a hypopneic episode ensues.
The number of apneas and hypopneas together are taken
-2-into account when assessing the severity of the problem. The sum of apneas and hypopneas occurring in an hour is termed the apnea-hypopnea index or the respiratory disturbance index.
Sleep apnea has been associated with arterial hypertension, electrocardiographic changes and arrhythmias, and even sudden death. For a general review of the pathologies associated with sleep apnea by statistical evaluation, see Sleep and Breathing, ed.
N.A. Saunders, 2 ed., Marcel Dekker, N.Y.: 1994. There are other correlations between brain asthma, brain infarction, and other neurological pathologies. In one Finnish study, 68% of stroke victims studied had a history of severe snoring and sleep apnea. There is a further correlation between habitual sleep apnea and arterial hypertension, another condition associated with stroke prevalence.
Cahan, et al., Chest, 1990; 98: 122s reported a significant correlation between a moderate apnea-hypopnea index (>15) and elevation in insulin levels.
At index values greater than 40, fasting hyperglycemia and hyperinsulinemia were observed. Cushing's disease and acromegaly are two further diseases associated with both sleep apnea and insulin resistance, as described in Fairbanks, et al., Snoring and Obstructive Sleep Apnea, 2ed., Raven Press, Ltd., New York: 1994.
There have been many modes of treatment proposed for snoring and sleep apnea. Over three hundred devices and treatment methods have received patents in the U.S. Patent and Trademark Office. These include body appurtenances as disclosed, for example, in U.S.
Patent Nos. 1,216,679 (a snore ball designed to discourage sleeping on the back), 2,339,998 (a chin strap), 3,696,377 (a snore activated microphone),
Sleep apnea has been associated with arterial hypertension, electrocardiographic changes and arrhythmias, and even sudden death. For a general review of the pathologies associated with sleep apnea by statistical evaluation, see Sleep and Breathing, ed.
N.A. Saunders, 2 ed., Marcel Dekker, N.Y.: 1994. There are other correlations between brain asthma, brain infarction, and other neurological pathologies. In one Finnish study, 68% of stroke victims studied had a history of severe snoring and sleep apnea. There is a further correlation between habitual sleep apnea and arterial hypertension, another condition associated with stroke prevalence.
Cahan, et al., Chest, 1990; 98: 122s reported a significant correlation between a moderate apnea-hypopnea index (>15) and elevation in insulin levels.
At index values greater than 40, fasting hyperglycemia and hyperinsulinemia were observed. Cushing's disease and acromegaly are two further diseases associated with both sleep apnea and insulin resistance, as described in Fairbanks, et al., Snoring and Obstructive Sleep Apnea, 2ed., Raven Press, Ltd., New York: 1994.
There have been many modes of treatment proposed for snoring and sleep apnea. Over three hundred devices and treatment methods have received patents in the U.S. Patent and Trademark Office. These include body appurtenances as disclosed, for example, in U.S.
Patent Nos. 1,216,679 (a snore ball designed to discourage sleeping on the back), 2,339,998 (a chin strap), 3,696,377 (a snore activated microphone),
3,998,209 (a snore trainer delivering an electric shock), 5,284,829 (a mouth held appliance), and 5,154, 184 (adjustable snore device). One device of interest is a tongue-retaining device, which pulls the superior aspect of the tongue forward, thereby keeping the tongue away from the posterior wall of the pharynx.
Most of these devices have limited value, as they only superficially address the actual anatomical bases of snoring and windpath occlusion, or create uncomfortable wearing conditions worse than the snoring and apnea.
The most successful treatment device has been the use of continuous positive airway pressure, as described in Sanders, et al., Chest, 1984; 86: 839.
However, very few patients are tolerant of the device, because of the continuous presence of tubes within the mouth and pharyngeal passages. As a last resort, this approach has proven efficacious for some patients, but is often poorly tolerated and compliance may be difficult.
Surgical intervention has been utilized extensively, either by bypassing the obstructive area by tracheostomy or eliminating the obstruction by excision. The latter excision can involve removal of excessive oropharyngeal issues such as an edematous uvula, redundant mucosal folds of the pharyngeal wall, excessive tissue in the soft palate, overly large tonsils, and redundant pillar mucosa. Depending on the particular structures implicated in the airway obstruction, many surgical strategies have been developed. For a general description of such strategies, see Fujita, "Pharyngeal Surgery for Obstructive Sleep Apnea and Snoring," in Snoring and Obstructive Sleep Apnea, 2ed., supra. The drawbacks to surgical intervention include the usual risks of invasive procedures in addition to creating problems with swallowing, speaking, and other daytime activities without relieving the snoring and apnea. The observed anatomical defects usually do not deviate much from normal, so that the benefits of surgery are often insignificant.
Good medical practice also recommends reducing known risk factors for sleep apnea, which are sometimes
Most of these devices have limited value, as they only superficially address the actual anatomical bases of snoring and windpath occlusion, or create uncomfortable wearing conditions worse than the snoring and apnea.
The most successful treatment device has been the use of continuous positive airway pressure, as described in Sanders, et al., Chest, 1984; 86: 839.
However, very few patients are tolerant of the device, because of the continuous presence of tubes within the mouth and pharyngeal passages. As a last resort, this approach has proven efficacious for some patients, but is often poorly tolerated and compliance may be difficult.
Surgical intervention has been utilized extensively, either by bypassing the obstructive area by tracheostomy or eliminating the obstruction by excision. The latter excision can involve removal of excessive oropharyngeal issues such as an edematous uvula, redundant mucosal folds of the pharyngeal wall, excessive tissue in the soft palate, overly large tonsils, and redundant pillar mucosa. Depending on the particular structures implicated in the airway obstruction, many surgical strategies have been developed. For a general description of such strategies, see Fujita, "Pharyngeal Surgery for Obstructive Sleep Apnea and Snoring," in Snoring and Obstructive Sleep Apnea, 2ed., supra. The drawbacks to surgical intervention include the usual risks of invasive procedures in addition to creating problems with swallowing, speaking, and other daytime activities without relieving the snoring and apnea. The observed anatomical defects usually do not deviate much from normal, so that the benefits of surgery are often insignificant.
Good medical practice also recommends reducing known risk factors for sleep apnea, which are sometimes
-4-completely effective for diminishing the problem to tolerable levels. These include eliminating obesity (Smith, et al.,.-Ann. Int. Med., 1985, 102: 850), curtailing alcohol consumption (Issa, et al., J.
Neurol. Neurosurg. Psychiatry 1982, 45: 353.), avoiding certain drugs known to exacerbate the problem such as flurazepam and other benzodiazepines, and manipulating sleep position. The use of many devices noted above reflects an attempt to constrain the body in a posture which reduces or eliminates snoring and sleep apnea.
Finally, there have been efforts to reduce or eliminate snoring and sleep apnea by the administration of therapeutic agents. In several studies protriptyline, a nonsedating, tricyclic antidepressant was administered. Although some reduction in apnea episodes was noted, there was a corresponding increase in hypopneas corresponding to the shorting of REM sleep associated with apnea. In addition, side effects are observed including urinary hesitancy, impotence, rash, and ataxia. Medroxyprotesterone acetate has also been used, but without statistically significant benefit.
Similarly, administration of tryptophan, a serotonin precursor, has shown little efficacy.
Some reduction in snoring utilizing phophocholinamin as a topical lubricant was noted in human subjects, as described in Am. J. Otolaarygol., 8:
236 (1987). U.S. Patent No. 5,569,679 discloses topical use of methylsulfonylethane applied to nasal passages from a dispenser to relieve snoring.
Widdlcombe, et al. Eur. Respir. J., 1:785 (1988) reported that Sonarex , a commercial preparation of surface active agents, reduced the sound of snoring and decreased upper airway resistance in dogs. However, to date no effective drug therapy specifically for sleep apnea has been demonstrated in humans.
Neurol. Neurosurg. Psychiatry 1982, 45: 353.), avoiding certain drugs known to exacerbate the problem such as flurazepam and other benzodiazepines, and manipulating sleep position. The use of many devices noted above reflects an attempt to constrain the body in a posture which reduces or eliminates snoring and sleep apnea.
Finally, there have been efforts to reduce or eliminate snoring and sleep apnea by the administration of therapeutic agents. In several studies protriptyline, a nonsedating, tricyclic antidepressant was administered. Although some reduction in apnea episodes was noted, there was a corresponding increase in hypopneas corresponding to the shorting of REM sleep associated with apnea. In addition, side effects are observed including urinary hesitancy, impotence, rash, and ataxia. Medroxyprotesterone acetate has also been used, but without statistically significant benefit.
Similarly, administration of tryptophan, a serotonin precursor, has shown little efficacy.
Some reduction in snoring utilizing phophocholinamin as a topical lubricant was noted in human subjects, as described in Am. J. Otolaarygol., 8:
236 (1987). U.S. Patent No. 5,569,679 discloses topical use of methylsulfonylethane applied to nasal passages from a dispenser to relieve snoring.
Widdlcombe, et al. Eur. Respir. J., 1:785 (1988) reported that Sonarex , a commercial preparation of surface active agents, reduced the sound of snoring and decreased upper airway resistance in dogs. However, to date no effective drug therapy specifically for sleep apnea has been demonstrated in humans.
5 PCT/L'S98/07735 SUMMARY OF THE INVENTION
Tne relatien between snari:zg anci slaep apr.ea =s associational but not necessarily causative.
Therefore, therapies rocuss:.ng on reduction in snoring may not decrease by as significant an extent ep_scdes of hynopnea and apnea. Snoring per se, while bothersome to the sleeper and annovir.g to companions, is not necessarily pathoiocrical or seri ously harmful.
It is therefore an object of the present _nver.tic~ tc develoD a therapy for sleep aonea and hypcp.~.ea _ead ir.~
to significant reduction in such episodes, whether cr not there is a concomitant reeiuctioz in snoring.
Another cbject is to orovide a conve::wen~ metlcd and IS apparatus of using the therapy which is not invasive or distracting, or which produces seriol,:s discomforz. h still further object is to provide an effective therapy for all-eviating sleep hypopnea and apnea episodes in a singie pre-sleep treatment without distur::.ng the 23 sleeper during a normal 7-9 hour per-od of rest.
In accordance with the present invenzion, a nulmonarv alveolar surfactant preparation in a physiologically compatible liquid vehicle is apUlied t::
the posterior pharyngeal region of a patient in a 25 pharmacologically effective dose prior to a period of sleep. Such pharmacologically effective dose may range from 0.25 to 2.75 mg, generally administered in 0.75 tc 1.25 ml, a volume sufficient to coat the affected region without excessive draining to the throat. The 30 method further provides for such application of a surfactant substance containing phospho].ivid-containing ingredients capable of lowering the surface tension of water to about 15-50 millinewtons/meter. The surfactant' preparation of the present method may optionally include 35 apoproteins selected from SP-A, SP-B, SP-C, and SP-D in a pharmacologically effective dose, and further optionally, neutral lipids. A pharmacologically effective dbse of the apoproteins will be a level from
Tne relatien between snari:zg anci slaep apr.ea =s associational but not necessarily causative.
Therefore, therapies rocuss:.ng on reduction in snoring may not decrease by as significant an extent ep_scdes of hynopnea and apnea. Snoring per se, while bothersome to the sleeper and annovir.g to companions, is not necessarily pathoiocrical or seri ously harmful.
It is therefore an object of the present _nver.tic~ tc develoD a therapy for sleep aonea and hypcp.~.ea _ead ir.~
to significant reduction in such episodes, whether cr not there is a concomitant reeiuctioz in snoring.
Another cbject is to orovide a conve::wen~ metlcd and IS apparatus of using the therapy which is not invasive or distracting, or which produces seriol,:s discomforz. h still further object is to provide an effective therapy for all-eviating sleep hypopnea and apnea episodes in a singie pre-sleep treatment without distur::.ng the 23 sleeper during a normal 7-9 hour per-od of rest.
In accordance with the present invenzion, a nulmonarv alveolar surfactant preparation in a physiologically compatible liquid vehicle is apUlied t::
the posterior pharyngeal region of a patient in a 25 pharmacologically effective dose prior to a period of sleep. Such pharmacologically effective dose may range from 0.25 to 2.75 mg, generally administered in 0.75 tc 1.25 ml, a volume sufficient to coat the affected region without excessive draining to the throat. The 30 method further provides for such application of a surfactant substance containing phospho].ivid-containing ingredients capable of lowering the surface tension of water to about 15-50 millinewtons/meter. The surfactant' preparation of the present method may optionally include 35 apoproteins selected from SP-A, SP-B, SP-C, and SP-D in a pharmacologically effective dose, and further optionally, neutral lipids. A pharmacologically effective dbse of the apoproteins will be a level from
-6-l0ug to 150ug, but functionally in a range to achieve anchoring of the phospholipid moieties contained in the surfactant to the pharyngeal tissue. The phospholipids are typically selected from saturated phosphatidylcholine, unsaturated phosphatidylcholine, phosphatidylglycerol, dipalmitoylphosphatidylcholine, and combinations.
In the apparatus of the present invention, the liquid containing the above ingredients is placed in a dispensing vessel capable of propelling a liquid in an aerosol, having a reservoir portion for holding the liquid, a nozzle means portion capable of being aligned to direct the aerosol towards the posterior pharyngeal region of a subject throat, and a label affixed to the reservoir potion of the vessel giving directions for use. The nozzle or delivery means may be a conventional inhaler tip or a pressured flow valve aperture.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In the present invention, application of alveolar surfactant preparations to the posterior pharyngeal region in human subjects significantly reduces the sleep disturbance index (sum of hourly hypopneic and apnoeic episodes during sleep), and decreases the incidence of oxygen desaturation. The surfactant preparations may be any of those naturally occurring or artificially compounded compositions commercially available and licensed by the Food & Drug Administration for use in treating infant respiratory distress syndrome or its adult counterparts. Table 1 gives the tradename, source, manufacturer, and active ingredients of the principal commercial products. A
preferred composition is Survanta (berectant), a modified natural bovine lung extract containing phospholipids, neutral lipids, fatty acids, surfactant-associated proteins including SP-B and SP-C, and supplemented with colfosceril palmitate (dipalmitoylphosphatidylchol.ine, DPPC), palmitic acid, and tripalmitin-to mimic the surface-tension reducing properties of natural lung surfactant. The performance of these products in respiratory distress syndrome is evaluated in Merrit, et al., Pediatric Pulmonology, 14:
1 (1992).
TABI,E 1 Surfac:tants Name Source Maker Active components Exosurf artificial G:Laxo- phospholipid Wellcome (DPPC) cetyl alcohol tyloxapol Infasurf calf lung phospholipid Curosurf porcine Laboratoire phospholipid lung Slaron France Survanta adult Ross phospholipids (berectant) bovine Laboratories (DPPC,others) lung SP-B
SP-C
KL4- artificial Johnson & synthetic surfactant Johnson peptide phospholipid (DPPC,POPG) Lung surfactant may also be synthetically compounded of purified phospholipids, fatty acids, and apoproteins which through their highly hydrophobic properties, aid in anchoring the phospholipid ingredients to the mucosal surfaces of the pharynx.
SUBSTITUTE SHEE7' (RULE 26) Various chemistries have been devised for effecting an ionic or eve.n covalent association of these surfactar.t components . Canadian pazenru Nc:;.2,042,635 (Sarin, et a=. ) discloses fa4t,v acid/SP-C ' on.,Eugates which may be used in conjunction with phospholipids and other surfactant i..gredie.;-it;_,. The c a:;u gat:e has the advantage of providing the hydronhobic moiety which lowers and st.api? izes surface te:-.siozl values,, and at t h a same t i r;:.e p rc> vi. de s a c:, oiar solv e n t. E?.~.o t:. he r synthetic s=u'"Lactar.t c:oMpos.iz:l.ori useful in 'he pra~tice of the uresai:t invention sd:i.sclosed in U.S. Patent.
~
111:~ 4 , 6G~r Q2.._ , and comprises dy.pr,:1.GT1l.tJy1 l;i. ospnatiQy_ choline, a C; 4 to C- 18 iazty alcoroi and a 2:cr_icnic .surface act i.re agenu, pr eferably tyloxapol.
Analysis of the phosoho_Li.pid fraction of naturally occurring surfaccant reveals a complex compos_ziori containing :.:.asrr:enylcho:i.ine, phosphatidylcholine, choline alycerophosphol i pi.ds ,sphLngornyel in, phosphatidylinositol, phosphati.dyLserine and.
lysophophat i dylet.hanolamine, frequently appearing in aifficult tc separacf:s pairs. See Dugan, ." al., J.
C:romatoaraohv, 3 7 8: 317 (1986) and U.S. Pate nt No.
4,826,821. The use of any of these phospholipids in purified form in low percentage amounts (about 0.5 to about 15 percent w/w) in combination with the major surfactant component, dipalmitoyl phosphatidyl choline (about 28 to 53 perceno iw/ w) , and includ.ing or omitting SB-A, SP-B or SP-C is a synthetic form of surfactant applicable to the present invention. Preparat::G..on of the purified hydrophobic protein, as SP-:, may be carried out according to the procedures disclosed in W087/06943, Use of surfactant: p.rOte:i.n fragcttents is also efficacious, as the fragments exhibit unusual.
surface tension properties, as disclosed in U.S. patent No. 5,547,937 Sar:in), and other patents :in the related series. A
pharmacologically effective dose of a hydrophillical WO 98/45245 PCT/L'S9810773;
aoo protein SP-A and the hydrophobic apo protein SP-=, C is 0.25 to 2.5 percent of each and a total com.b_r.ed percentage of 476 percent. Ar:y combination of t:-Ia foreQoi:;g ingred-ents wi.1i have efficacv the preCa::t invention so long as the tissue coating and ad'nesive properties of natural surfactant are mimicked, and most importantly, there is an effective lowerinG of surface tension of the fiim to values cf 10 miyiinewtons/meter or less (preferably from about 0.5 to 7 millinewtons/meter).
The therapeut:.c use of these substances is =._ contrast to oil-nased lubricants, which have some effect in reducing snoring, such as pnospho cholin a-:i n, the trade name for a mixture of lecithir~ comnlexe~ wi=r a lig~t hydrocarbon fraction, described in Hoffs-e;n, et al., Am. J. Otoiarvaol., 8:236 (1987). The prese::=
method is also in contrast to other human therace=,;tic approaches to reduce snoring specifically, such as the use of inetnysulfonylmethane ir. combination with a mil;
ar.esthetic, as taught in U.S. Patent No. 5,569,675.
T:e surfactant solucion is delivered in a convenient dose volume of about 0.5 to 1.5 ml. f a fine aerosol spray is used, the volume may be decreased to as little as 0.2 ml. Any amount will be effective so long as there is uniform continuous coating of the posterior pharyngeal surfaces. Volumes greater than about 1.5 ml are to be avoided as the excess will pocl or drain off and be swallowed. The concentration of various ingredients generally simulates the naturai surfactant, in that dipalmitoyl phospnatidyl choline is the predominant ingredient at 37 to 48 percent, in a preferred embodiment. A pharmacologically effective dose is an amount of surfactant containing 0.25 to 2.75 mg total ingredients dispersed in 0.75 to 1.5 m~
solution. The cornposition is not diluted.
In one embodiment of the present invention, the surfactant composition is contained in a vessel adapted to deliver a surfactant aerosol to the posterior WO 98/46245 ['CTIUS98/07735 1r pharyngeal region. T~:e ~,,essel may be of three types : a pressurized aerosol. c..~r:, s~xu~.,:eZt. bottle, ~Cr a pump bottle. Th<U sur.factanr: will be applied through the oral tvavi.ty, but _...r may lr:;e deli~,ered 3 nasally when the sub; eCt i,5 s',x:Dint:~ , Examples of containers saitabie f o:,: :.ze::~ i..very are depict-Vd in U.S. Patent No. 5,569,679. F()~.::- oral ad.m.inistration, a pump or squeeze bottle may be equipped with an elongated tapered nozzle (t.:ireE::~ to S1X inches i:i 1''.nCi~i1} ~'C1r zC~C:~.~. direG:t appl '~ca.I'.lon C~
surfactar_t t,.--) the p>haryngeai. Conveniently, the spray bottle containina a pre-7,easured auant;.t.y of surfactant, -.o w;.i.ch anpropr.i.at-e 1a'a:)e:i d:irer.::ti.ons are affixed, may be dist:..-ibut.ed aE an a ticvle ol:: commerce.
When packed under- steri.a Ea cond:..tions, ':-he s{.:rf:actant may be stored refx=ig rated or a.-_ rc>o~: temperature.
Further, advant.a(ges <-)f the: present inventi_on will be apparent from the Exa.mp i e w"nic h fo:' :iows .
EXA:'w'1.?I.aE
Six individuals wit.l: varying degrees of sleep apnea were studied or, t_wc) differenr... r;.? ghts at least 5 davs apart under a research ~:)rotc:cal apprcved by the University cDf Wisconsin Humarr Subjects Commi.tt:ee. These volunteer ,ubjects werf~~~. gi..ven saline (control) on one night and berectant ;Survantd; nat::ural bovine surfactant i on the other night. Onc:e the suhjects had f:allen asleep as demonstrated by their EEC, they were monitored fcr 60 minutes without an- i.r.terver :tion. One ml volumes of either saline or berectant were then delivered into the posterior pharynx -~,ria a small catheter (::.' . 5 mm outer diameter and placed transnasaliy) after the subjects had fallen asleep as verified 1ay je:i.ectroencephalic (EEGi monitori.ng. For the 60 minutes prior to iristillation of saline or berectant azid the subsequent 60 minutes followirig instillation, sl.ee~) s .~age (1, II:, III, IV, or REM) was monitored ~jia Ei:G, iri:ipiratory an.d expiratory air flow was monitored via a pneumotachometer attached to a close-fitting nasal mask, inspiratory muscle activity was monitored ._vi_a electromyography with two surface electrodes placed 2 to 4 cm above the right costal margin in the anterior axillary line, arterial oxyhemoglobin saturation was continuously monitored via ear oximetry, and end-tidal COz was measure:d breath to breath.
Hypopnea was defined as a 2016 decrease in tidal volume in three or more consecutive breaths compared to the preceding breath, apnea as cessation of flow for >5 seconds, and desaturation as >26 decrease in oxygen saturation from baseline. A Respiratory Disturbance Index (RDI) was defined as the number of hypopneas, apneas, and desaturations per hour of sleep. The degree of desaturation for each event (ASpOZo) was also computed. For a detailed discussion of sleep scoring techniques, see Mitler, et al., "Sleep Scoring Technique", in Sleep Disturbances, Yancy Press, NY: 1991.
The RDI for Stage II, III, and IV sleep combined, or for Stage II alone, significantly decreased following instillation of berectant but not following saline (Tables 2 and 3) Episodes of desaturation during Stage II, III, and IV sleep combined, or for Stage II sleep alone, also decreased (Tables 4 and 5). Additionally, the degree of desaturatior.L for each event (OSpOzo) diminished with berectant but not with saline, although this change did not reach statistical significance (p=0.09, Table 6).
Instillation of artifici.al surfactant into the upper airway of volunteer subjects with sleep-disordered breathing (sleep apnea/hypopnea) was associated with a modest but statistically significant reduction in RDI.
Mucosal surface factors may modulate upper airway patency in patients with sleep apnea/hypopnea, and interventions to reduce mucosal surface tension may serve as an adjunctive therapy in many patients with sleep apnea/hypopnea syndromes.
Respiratory Disturbance Index (Stage II, III, & IV sleep) Subject Pre- Post- Pre- Post-saline saline berectant berectant 1 109.6 112.1 133.9 131.2 2 31.6 15.8 22.7 19.3 3 52.4 110.4 72.0 15.0 4 37.1 28.0 48.0 25.3 5 137.1 121.1 157.5 132.9 6 83.8 91.8 120.0 90.3 Mean SEM 75t17 80 19 92 22 69 23*
*p<0.05 Respiratory Disturbance Index (Stage II sleep) Subject Pre- Post- Pre- Post-saline saline berectant berectant 1 115.6 112.1 126.7 131.4 2 45.7 18.2 26.3 13.0 3 56.5 110.4 72.0 15.0 4 37.6 25.8 48.4 25.6 5 137.1 121.1 157.5 132.9 6 83.3 90.9 120.0 90.3 Mean+SEM 79 16 80 19 92 21 68 23 SUBSTITUTE SHEET (RULE 26) Desaturations (.Stage II, III, & IV sleep) Subject Pre.- Post- Pre- Post-saline saline berectant berectant 1 106.1 105.8 126.2 125.6 2 17.4 7.4 17.7 12.4 3 8.7 4.8 4.0 5.0 4 12.0 17.9 5.5 8.0 5 131.4 105.6 132.5 45.7 6 49.3 71.1 81.6 67.1 Mean SEM 54 22 52 20 61t24 44 19 Desaturations (Stage II sleep) Subject Pre-- Post- Pre- Post-saline saline berectant berectant 1 113.3 105.8 126.7 125.7 2 17.1 10.9 22.5 7.8 3 9.4 4.8 4.0 5.0 4 12.1 16.8 5.5 8.1 5 131.4 105.6 132.5 45.7 6 48.3 71.5 81.6 67.1 Mean SEM 55t22 53 19 62 24 43t19 SUBSTITUTE SHEET (RULE 26) A SpOz Intervention Pre Post Berectant 3.7 2.0 2.4 1.5*
Saline 3.5+2.2 3.7+1.5 SUBSTITUTE SHEET (RULE 26)
In the apparatus of the present invention, the liquid containing the above ingredients is placed in a dispensing vessel capable of propelling a liquid in an aerosol, having a reservoir portion for holding the liquid, a nozzle means portion capable of being aligned to direct the aerosol towards the posterior pharyngeal region of a subject throat, and a label affixed to the reservoir potion of the vessel giving directions for use. The nozzle or delivery means may be a conventional inhaler tip or a pressured flow valve aperture.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In the present invention, application of alveolar surfactant preparations to the posterior pharyngeal region in human subjects significantly reduces the sleep disturbance index (sum of hourly hypopneic and apnoeic episodes during sleep), and decreases the incidence of oxygen desaturation. The surfactant preparations may be any of those naturally occurring or artificially compounded compositions commercially available and licensed by the Food & Drug Administration for use in treating infant respiratory distress syndrome or its adult counterparts. Table 1 gives the tradename, source, manufacturer, and active ingredients of the principal commercial products. A
preferred composition is Survanta (berectant), a modified natural bovine lung extract containing phospholipids, neutral lipids, fatty acids, surfactant-associated proteins including SP-B and SP-C, and supplemented with colfosceril palmitate (dipalmitoylphosphatidylchol.ine, DPPC), palmitic acid, and tripalmitin-to mimic the surface-tension reducing properties of natural lung surfactant. The performance of these products in respiratory distress syndrome is evaluated in Merrit, et al., Pediatric Pulmonology, 14:
1 (1992).
TABI,E 1 Surfac:tants Name Source Maker Active components Exosurf artificial G:Laxo- phospholipid Wellcome (DPPC) cetyl alcohol tyloxapol Infasurf calf lung phospholipid Curosurf porcine Laboratoire phospholipid lung Slaron France Survanta adult Ross phospholipids (berectant) bovine Laboratories (DPPC,others) lung SP-B
SP-C
KL4- artificial Johnson & synthetic surfactant Johnson peptide phospholipid (DPPC,POPG) Lung surfactant may also be synthetically compounded of purified phospholipids, fatty acids, and apoproteins which through their highly hydrophobic properties, aid in anchoring the phospholipid ingredients to the mucosal surfaces of the pharynx.
SUBSTITUTE SHEE7' (RULE 26) Various chemistries have been devised for effecting an ionic or eve.n covalent association of these surfactar.t components . Canadian pazenru Nc:;.2,042,635 (Sarin, et a=. ) discloses fa4t,v acid/SP-C ' on.,Eugates which may be used in conjunction with phospholipids and other surfactant i..gredie.;-it;_,. The c a:;u gat:e has the advantage of providing the hydronhobic moiety which lowers and st.api? izes surface te:-.siozl values,, and at t h a same t i r;:.e p rc> vi. de s a c:, oiar solv e n t. E?.~.o t:. he r synthetic s=u'"Lactar.t c:oMpos.iz:l.ori useful in 'he pra~tice of the uresai:t invention sd:i.sclosed in U.S. Patent.
~
111:~ 4 , 6G~r Q2.._ , and comprises dy.pr,:1.GT1l.tJy1 l;i. ospnatiQy_ choline, a C; 4 to C- 18 iazty alcoroi and a 2:cr_icnic .surface act i.re agenu, pr eferably tyloxapol.
Analysis of the phosoho_Li.pid fraction of naturally occurring surfaccant reveals a complex compos_ziori containing :.:.asrr:enylcho:i.ine, phosphatidylcholine, choline alycerophosphol i pi.ds ,sphLngornyel in, phosphatidylinositol, phosphati.dyLserine and.
lysophophat i dylet.hanolamine, frequently appearing in aifficult tc separacf:s pairs. See Dugan, ." al., J.
C:romatoaraohv, 3 7 8: 317 (1986) and U.S. Pate nt No.
4,826,821. The use of any of these phospholipids in purified form in low percentage amounts (about 0.5 to about 15 percent w/w) in combination with the major surfactant component, dipalmitoyl phosphatidyl choline (about 28 to 53 perceno iw/ w) , and includ.ing or omitting SB-A, SP-B or SP-C is a synthetic form of surfactant applicable to the present invention. Preparat::G..on of the purified hydrophobic protein, as SP-:, may be carried out according to the procedures disclosed in W087/06943, Use of surfactant: p.rOte:i.n fragcttents is also efficacious, as the fragments exhibit unusual.
surface tension properties, as disclosed in U.S. patent No. 5,547,937 Sar:in), and other patents :in the related series. A
pharmacologically effective dose of a hydrophillical WO 98/45245 PCT/L'S9810773;
aoo protein SP-A and the hydrophobic apo protein SP-=, C is 0.25 to 2.5 percent of each and a total com.b_r.ed percentage of 476 percent. Ar:y combination of t:-Ia foreQoi:;g ingred-ents wi.1i have efficacv the preCa::t invention so long as the tissue coating and ad'nesive properties of natural surfactant are mimicked, and most importantly, there is an effective lowerinG of surface tension of the fiim to values cf 10 miyiinewtons/meter or less (preferably from about 0.5 to 7 millinewtons/meter).
The therapeut:.c use of these substances is =._ contrast to oil-nased lubricants, which have some effect in reducing snoring, such as pnospho cholin a-:i n, the trade name for a mixture of lecithir~ comnlexe~ wi=r a lig~t hydrocarbon fraction, described in Hoffs-e;n, et al., Am. J. Otoiarvaol., 8:236 (1987). The prese::=
method is also in contrast to other human therace=,;tic approaches to reduce snoring specifically, such as the use of inetnysulfonylmethane ir. combination with a mil;
ar.esthetic, as taught in U.S. Patent No. 5,569,675.
T:e surfactant solucion is delivered in a convenient dose volume of about 0.5 to 1.5 ml. f a fine aerosol spray is used, the volume may be decreased to as little as 0.2 ml. Any amount will be effective so long as there is uniform continuous coating of the posterior pharyngeal surfaces. Volumes greater than about 1.5 ml are to be avoided as the excess will pocl or drain off and be swallowed. The concentration of various ingredients generally simulates the naturai surfactant, in that dipalmitoyl phospnatidyl choline is the predominant ingredient at 37 to 48 percent, in a preferred embodiment. A pharmacologically effective dose is an amount of surfactant containing 0.25 to 2.75 mg total ingredients dispersed in 0.75 to 1.5 m~
solution. The cornposition is not diluted.
In one embodiment of the present invention, the surfactant composition is contained in a vessel adapted to deliver a surfactant aerosol to the posterior WO 98/46245 ['CTIUS98/07735 1r pharyngeal region. T~:e ~,,essel may be of three types : a pressurized aerosol. c..~r:, s~xu~.,:eZt. bottle, ~Cr a pump bottle. Th<U sur.factanr: will be applied through the oral tvavi.ty, but _...r may lr:;e deli~,ered 3 nasally when the sub; eCt i,5 s',x:Dint:~ , Examples of containers saitabie f o:,: :.ze::~ i..very are depict-Vd in U.S. Patent No. 5,569,679. F()~.::- oral ad.m.inistration, a pump or squeeze bottle may be equipped with an elongated tapered nozzle (t.:ireE::~ to S1X inches i:i 1''.nCi~i1} ~'C1r zC~C:~.~. direG:t appl '~ca.I'.lon C~
surfactar_t t,.--) the p>haryngeai. Conveniently, the spray bottle containina a pre-7,easured auant;.t.y of surfactant, -.o w;.i.ch anpropr.i.at-e 1a'a:)e:i d:irer.::ti.ons are affixed, may be dist:..-ibut.ed aE an a ticvle ol:: commerce.
When packed under- steri.a Ea cond:..tions, ':-he s{.:rf:actant may be stored refx=ig rated or a.-_ rc>o~: temperature.
Further, advant.a(ges <-)f the: present inventi_on will be apparent from the Exa.mp i e w"nic h fo:' :iows .
EXA:'w'1.?I.aE
Six individuals wit.l: varying degrees of sleep apnea were studied or, t_wc) differenr... r;.? ghts at least 5 davs apart under a research ~:)rotc:cal apprcved by the University cDf Wisconsin Humarr Subjects Commi.tt:ee. These volunteer ,ubjects werf~~~. gi..ven saline (control) on one night and berectant ;Survantd; nat::ural bovine surfactant i on the other night. Onc:e the suhjects had f:allen asleep as demonstrated by their EEC, they were monitored fcr 60 minutes without an- i.r.terver :tion. One ml volumes of either saline or berectant were then delivered into the posterior pharynx -~,ria a small catheter (::.' . 5 mm outer diameter and placed transnasaliy) after the subjects had fallen asleep as verified 1ay je:i.ectroencephalic (EEGi monitori.ng. For the 60 minutes prior to iristillation of saline or berectant azid the subsequent 60 minutes followirig instillation, sl.ee~) s .~age (1, II:, III, IV, or REM) was monitored ~jia Ei:G, iri:ipiratory an.d expiratory air flow was monitored via a pneumotachometer attached to a close-fitting nasal mask, inspiratory muscle activity was monitored ._vi_a electromyography with two surface electrodes placed 2 to 4 cm above the right costal margin in the anterior axillary line, arterial oxyhemoglobin saturation was continuously monitored via ear oximetry, and end-tidal COz was measure:d breath to breath.
Hypopnea was defined as a 2016 decrease in tidal volume in three or more consecutive breaths compared to the preceding breath, apnea as cessation of flow for >5 seconds, and desaturation as >26 decrease in oxygen saturation from baseline. A Respiratory Disturbance Index (RDI) was defined as the number of hypopneas, apneas, and desaturations per hour of sleep. The degree of desaturation for each event (ASpOZo) was also computed. For a detailed discussion of sleep scoring techniques, see Mitler, et al., "Sleep Scoring Technique", in Sleep Disturbances, Yancy Press, NY: 1991.
The RDI for Stage II, III, and IV sleep combined, or for Stage II alone, significantly decreased following instillation of berectant but not following saline (Tables 2 and 3) Episodes of desaturation during Stage II, III, and IV sleep combined, or for Stage II sleep alone, also decreased (Tables 4 and 5). Additionally, the degree of desaturatior.L for each event (OSpOzo) diminished with berectant but not with saline, although this change did not reach statistical significance (p=0.09, Table 6).
Instillation of artifici.al surfactant into the upper airway of volunteer subjects with sleep-disordered breathing (sleep apnea/hypopnea) was associated with a modest but statistically significant reduction in RDI.
Mucosal surface factors may modulate upper airway patency in patients with sleep apnea/hypopnea, and interventions to reduce mucosal surface tension may serve as an adjunctive therapy in many patients with sleep apnea/hypopnea syndromes.
Respiratory Disturbance Index (Stage II, III, & IV sleep) Subject Pre- Post- Pre- Post-saline saline berectant berectant 1 109.6 112.1 133.9 131.2 2 31.6 15.8 22.7 19.3 3 52.4 110.4 72.0 15.0 4 37.1 28.0 48.0 25.3 5 137.1 121.1 157.5 132.9 6 83.8 91.8 120.0 90.3 Mean SEM 75t17 80 19 92 22 69 23*
*p<0.05 Respiratory Disturbance Index (Stage II sleep) Subject Pre- Post- Pre- Post-saline saline berectant berectant 1 115.6 112.1 126.7 131.4 2 45.7 18.2 26.3 13.0 3 56.5 110.4 72.0 15.0 4 37.6 25.8 48.4 25.6 5 137.1 121.1 157.5 132.9 6 83.3 90.9 120.0 90.3 Mean+SEM 79 16 80 19 92 21 68 23 SUBSTITUTE SHEET (RULE 26) Desaturations (.Stage II, III, & IV sleep) Subject Pre.- Post- Pre- Post-saline saline berectant berectant 1 106.1 105.8 126.2 125.6 2 17.4 7.4 17.7 12.4 3 8.7 4.8 4.0 5.0 4 12.0 17.9 5.5 8.0 5 131.4 105.6 132.5 45.7 6 49.3 71.1 81.6 67.1 Mean SEM 54 22 52 20 61t24 44 19 Desaturations (Stage II sleep) Subject Pre-- Post- Pre- Post-saline saline berectant berectant 1 113.3 105.8 126.7 125.7 2 17.1 10.9 22.5 7.8 3 9.4 4.8 4.0 5.0 4 12.1 16.8 5.5 8.1 5 131.4 105.6 132.5 45.7 6 48.3 71.5 81.6 67.1 Mean SEM 55t22 53 19 62 24 43t19 SUBSTITUTE SHEET (RULE 26) A SpOz Intervention Pre Post Berectant 3.7 2.0 2.4 1.5*
Saline 3.5+2.2 3.7+1.5 SUBSTITUTE SHEET (RULE 26)
Claims (14)
1. Use of an effective amount of a pulmonary alveolar surfactant preparation onto the posterior pharyngeal region of a patient prior to a period of sleep, as a sleep apnea or hypopnea preventive agent.
2. Use of an effective amount of a pulmonary alveolar surfactant preparation as claimed in claim 1, wherein the surfactant comprises a phospholipid capable of lowering the surface tension of water to about 15 to 50 millinewtons/meter.
3. Use of an effective amount of a pulmonary alveolar surfactant preparation as claimed in claim 2, wherein the surfactant preparation further includes a protein portion selected from the group consisting of surfactant apoprotein A, surfactant apoprotein B, surfactant apoprotein C, and surfactant apoprotein D in pharmacologically effective doses.
4. Use of an effective amount of a pulmonary alveolar surfactant preparation as claimed in claim 2, wherein the phospholipid is selected from the group consisting of saturated phosphatidylcholine, unsaturated phosphatidylcholine, phosphatidylglicerol, dipalmitoylphosphatidylcholine, and combinations thereof.
5. Use of an effective amount of a pulmonary alveolar surfactant preparation as claimed in claim 2, wherein the surfactant preparation further includes neutral lipids.
6. An inhaler for treating sleep apnea or hypopnea comprising:
an inhaler vessel having a reservoir portion and a nozzle portion, and being adapted to propel a liquid in an aerosol;
a liquid contained in the inhaler vessel having the composition of a phospholipid surfactant; and a label providing direction for use in treating sleep apnea or hypopnea wherein the nozzle portion is adapted to direct the aerosol to provide a coating onto the posterior pharyngeal region of a patient.
an inhaler vessel having a reservoir portion and a nozzle portion, and being adapted to propel a liquid in an aerosol;
a liquid contained in the inhaler vessel having the composition of a phospholipid surfactant; and a label providing direction for use in treating sleep apnea or hypopnea wherein the nozzle portion is adapted to direct the aerosol to provide a coating onto the posterior pharyngeal region of a patient.
7. An inhaler for treating sleep apnea or hypopnea comprising:
an inhaler vessel adapted to propel a liquid in an aerosol, the inhaler vessel comprising:
a reservoir portion adapted to hold the liquid;
a nozzle portion adapted to direct the aerosol toward the posterior pharyngeal region of a patient;
a liquid having the composition of a phospholipid surfactant; and a label providing direction for use in treating sleep apnea or hypopnea.
an inhaler vessel adapted to propel a liquid in an aerosol, the inhaler vessel comprising:
a reservoir portion adapted to hold the liquid;
a nozzle portion adapted to direct the aerosol toward the posterior pharyngeal region of a patient;
a liquid having the composition of a phospholipid surfactant; and a label providing direction for use in treating sleep apnea or hypopnea.
8. A pharmaceutical composition of a pulmonary alveolar surfactant preparation in a pharmacologically effective dose used as a sleep apnea or hypopnea preventive agent, wherein the pulmonary alveolar surfactant preparation is carried by a physiologically compatible liquid vehicle and is adapted to coat the posterior pharyngeal region of a patient prior to a period of sleep.
9. A pharmaceutical composition of a phospholipid-containing pulmonary alveolar surfactant preparation in a physiologically compatible liquid and capable of lowering the surface tension of water to about 15 to 50 millinewtons/meter in a pharmacologically effective dose, wherein the pulmonary alveolar surfactant preparation is adapted to coat the posterior pharyngeal region of a patient prior to a period of sleep, as a sleep apnea or hypopnea preventive agent.
10. A pharmaceutical composition as claimed in claim 9, wherein the surfactant preparation further includes a protein portion selected from the group consisting of surfactant apoprotein a, surfactant apoprotein B, surfactant apoprotein C, and surfactant apoprotein D in pharmacologically effective doses.
11. A pharmaceutical composition as claimed in claim 9, wherein the phospholipid is selected from the group consisting of saturated phosphatidylcholine, unsaturated phosphatidylcholine, phosphatidylglicerol, dipalmitoylphosphatidylcholine, and combinations thereof.
12. The pharmaceutical composition as claimed in claim 9, wherein the surfactant preparation further includes neutral lipids.
13. The use according to claim 1, wherein the pulmonary alveolar surfactant preparation further comprises phospholipids effective in lowering a surface tension of the preparation to a maximum of 10 millinewtons/meter.
14. The use according to claim 1, wherein the pulmonary alveolar surfactant preparation further comprises phospholipids effective in lowering a surface tension of the preparation from 0.5 to 7 millinewtons/meter.
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| US08/834,369 US5958902A (en) | 1997-04-16 | 1997-04-16 | Method and composition for treating sleep apnea |
| PCT/US1998/007735 WO1998046245A1 (en) | 1997-04-16 | 1998-04-16 | Method and composition for treating sleep apnea |
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| EP0458167B1 (en) * | 1990-05-21 | 1997-04-23 | Abbott Laboratories | Fatty acid-pulmonary surfactant conjugates |
| AU3662593A (en) * | 1992-04-10 | 1993-11-18 | Abbott Laboratories | Pulmonary surfactant protein fragments |
| US5569679A (en) * | 1994-12-30 | 1996-10-29 | Russell A. Krueger Pharmaceuticals, Inc. | Pharmacologic management of snoring |
| US6129934A (en) * | 1995-06-07 | 2000-10-10 | Ony, Inc. | Modification of animal lung surfactant for treating respiratory disease due to lung surfactant deficiency or dysfunction |
| US5925334A (en) * | 1997-08-27 | 1999-07-20 | Rubin; Bruce K. | Use of surface active agents to promote mucus clearance |
-
1997
- 1997-04-16 US US08/834,369 patent/US5958902A/en not_active Expired - Fee Related
-
1998
- 1998-04-02 CO CO98018668A patent/CO4940399A1/en unknown
- 1998-04-15 TW TW087105709A patent/TWI221771B/en not_active IP Right Cessation
- 1998-04-15 AR ARP980101739A patent/AR012221A1/en unknown
- 1998-04-16 KR KR10-1999-7009471A patent/KR100381643B1/en not_active IP Right Cessation
- 1998-04-16 TR TR1999/02577T patent/TR199902577T2/en unknown
- 1998-04-16 NZ NZ337969A patent/NZ337969A/en unknown
- 1998-04-16 ID IDW991220A patent/ID29298A/en unknown
- 1998-04-16 IL IL13213398A patent/IL132133A0/en unknown
- 1998-04-16 CN CN98804244A patent/CN1252727A/en active Pending
- 1998-04-16 HU HU0002645A patent/HUP0002645A3/en unknown
- 1998-04-16 AU AU69755/98A patent/AU722866B2/en not_active Ceased
- 1998-04-16 BR BR9809090-9A patent/BR9809090A/en not_active Application Discontinuation
- 1998-04-16 AT AT98915618T patent/ATE298241T1/en not_active IP Right Cessation
- 1998-04-16 DE DE69830660T patent/DE69830660T2/en not_active Expired - Fee Related
- 1998-04-16 CA CA002285574A patent/CA2285574C/en not_active Expired - Fee Related
- 1998-04-16 WO PCT/US1998/007735 patent/WO1998046245A1/en not_active Application Discontinuation
- 1998-04-16 JP JP54431498A patent/JP2001507364A/en not_active Ceased
- 1998-04-16 PL PL98336326A patent/PL336326A1/en unknown
- 1998-04-16 SK SK1431-99A patent/SK143199A3/en unknown
- 1998-04-16 EP EP98915618A patent/EP1009411B1/en not_active Expired - Lifetime
-
1999
- 1999-05-17 US US09/313,110 patent/US6329352B1/en not_active Expired - Fee Related
- 1999-09-23 NO NO19994613A patent/NO994613L/en not_active Application Discontinuation
- 1999-09-29 IL IL132133A patent/IL132133A/en not_active IP Right Cessation
- 1999-10-12 BG BG103800A patent/BG103800A/en unknown
-
2000
- 2000-08-29 HK HK00105378A patent/HK1026141A1/en not_active IP Right Cessation
-
2001
- 2001-12-10 US US10/016,474 patent/US20020099033A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| NZ337969A (en) | 2001-12-21 |
| DE69830660D1 (en) | 2005-07-28 |
| IL132133A0 (en) | 2001-03-19 |
| AU722866B2 (en) | 2000-08-10 |
| NO994613D0 (en) | 1999-09-23 |
| BG103800A (en) | 2000-03-31 |
| EP1009411B1 (en) | 2005-06-22 |
| IL132133A (en) | 2008-12-29 |
| NO994613L (en) | 1999-10-28 |
| KR20010006384A (en) | 2001-01-26 |
| EP1009411A1 (en) | 2000-06-21 |
| DE69830660T2 (en) | 2006-05-04 |
| JP2001507364A (en) | 2001-06-05 |
| US20020099033A1 (en) | 2002-07-25 |
| AR012221A1 (en) | 2000-09-27 |
| ATE298241T1 (en) | 2005-07-15 |
| US5958902A (en) | 1999-09-28 |
| CN1252727A (en) | 2000-05-10 |
| CA2285574A1 (en) | 1998-10-22 |
| PL336326A1 (en) | 2000-06-19 |
| ID29298A (en) | 2001-08-16 |
| AU6975598A (en) | 1998-11-11 |
| HUP0002645A2 (en) | 2001-06-28 |
| KR100381643B1 (en) | 2003-04-26 |
| HUP0002645A3 (en) | 2002-12-28 |
| TWI221771B (en) | 2004-10-11 |
| WO1998046245A1 (en) | 1998-10-22 |
| EP1009411A4 (en) | 2002-10-09 |
| BR9809090A (en) | 2002-12-03 |
| CO4940399A1 (en) | 2000-07-24 |
| TR199902577T2 (en) | 2000-02-21 |
| SK143199A3 (en) | 2001-01-18 |
| HK1026141A1 (en) | 2000-12-08 |
| US6329352B1 (en) | 2001-12-11 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed |