U.S. patent application number 10/016474 was filed with the patent office on 2002-07-25 for method and composition for treating sleep apnea.
This patent application is currently assigned to Wisconsin Alumni Research Foundation. Invention is credited to Badr, M. Safwan, Meyer, Keith C..
Application Number | 20020099033 10/016474 |
Document ID | / |
Family ID | 25266775 |
Filed Date | 2002-07-25 |
United States Patent
Application |
20020099033 |
Kind Code |
A1 |
Meyer, Keith C. ; et
al. |
July 25, 2002 |
Method and composition for treating sleep apnea
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.
Inventors: |
Meyer, Keith C.; (Middleton,
WI) ; Badr, M. Safwan; (West Bloomfield, MI) |
Correspondence
Address: |
MICHAEL BEST & FRIEDRICH, LLP
ONE SOUTH PINCKNEY STREET
P O BOX 1806
MADISON
WI
53701
|
Assignee: |
Wisconsin Alumni Research
Foundation
Madison
WI
|
Family ID: |
25266775 |
Appl. No.: |
10/016474 |
Filed: |
December 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10016474 |
Dec 10, 2001 |
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09313110 |
May 17, 1999 |
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09313110 |
May 17, 1999 |
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08834369 |
Apr 16, 1997 |
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Current U.S.
Class: |
514/76 ;
424/45 |
Current CPC
Class: |
A61K 9/006 20130101;
A61K 38/1709 20130101; A61P 11/00 20180101; A61K 31/685 20130101;
A61P 43/00 20180101 |
Class at
Publication: |
514/76 ;
424/45 |
International
Class: |
A61K 031/685; A61L
009/04 |
Claims
What is claimed is:
1. A method for treating sleep apnea comprising applying a
pulmonary alveolar surfactant preparation in a pharmacologically
effective dose to the posterior pharyngeal region of a patient
prior to a period of sleep.
2. A method for treating sleep apnea comprising applying a
phospholipid-containing surfactant preparation capable of lowering
the surface tension of water to about 15-50 mN*.sup.-1 in a
pharmacologically effective dose to the posterior pharyngeal region
of a patient prior to a period of sleep.
3. The method of claim 2 wherein said surfactant preparation
further includes a protein portion selected from the group
consisting of SP-A, SP-B, SP-C, and SP-D in pharmacologically
effective doses.
4. The method of claim 2 wherein said phospholipid is selected from
the group consisting of saturated phosphatidylcholine, unsaturated
phosphatidylcholine, phosphatidylglycerol,
dipalmitoylphosphatidylchloine- , and combinations thereof.
5. The method of claim 2 wherein said surfactant preparation
further includes neutral lipids.
6. An article of manufacture for treating sleep apnea comprising an
inhaler vessel having a reservoir portion and a nozzle portion,
said inhaler vessel being capable of propelling a liquid in an
aerosol; a liquid contained in said vessel having the composition
of a phospholipid surfactant; and a label affixed to said inhaler
vessel providing direction for use in treating sleep apnea whereby
when said nozzle portion is aligned to direct said aerosol to
provide a coating of the posterior pharyngeal region of a
patient.
7. An apparatus for treating sleep apnea comprising: an inhaler
vessel capable of propelling a liquid in an aerosol, said inhaler
vessel comprising: a reservoir portion capable of holding a liquid;
a nozzle portion capable of being aligned to direct the aerosol
toward the posterior pharyngeal region of a patient; a liquid
having the composition of a phospholipid surfactant; and a label
affixed to said reservoir providing direction for use in treating
sleep apnea.
Description
FIELD OF THE INVENTION
[0001] 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
[0002] 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 benefits 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 soft 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.
[0003] 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 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.
[0004] 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.
[0005] 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.
[0006] 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.
Pat. No. 1,216,679 (a snore ball designed to discourage sleeping on
the back), U.S. Pat. No. 2,339,998 (a chin strap), U.S. Pat. No.
3,696,377 (a snore activated microphone), U.S. Pat. No. 3,998,209
(a snore trainer delivering an electric shock), U.S. Pat. No.
5,284,829 (a mouth held appliance), and U.S. Pat. No. 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.
[0007] 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.
[0008] 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.
[0009] Good medical practice also recommends reducing known risk
factors for sleep apnea, which are sometimes 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.
[0010] 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.
[0011] 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. Pat. 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.RTM., 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.
SUMMARY OF THE INVENTION
[0012] The relation between snoring and sleep apnea is
associational but not necessarily causative. Therefore, therapies
focussing on reduction in snoring may not decrease by as
significant an extent episodes of hypopnea and apnea. Snoring per
se, while bothersome to the sleeper and annoying to companions, is
not necessarily pathological or seriously harmful. It is therefore
an object of the present invention to develop a therapy for sleep
apnea and hypopnea leading to significant reduction in such
episodes, whether or not there is a concomitant reduction in
snoring. Another object is to provide a convenient method and
apparatus of using the therapy which is not invasive or
distracting, or which produces serious discomfort. A still further
object is to provide an effective therapy for alleviating sleep
hypopnea and apnea episodes in a single pre-sleep treatment without
disturbing the sleeper during a normal 7-9 hour period of rest.
[0013] In accordance with the present invention, a pulmonary
alveolar surfactant preparation in a physiologically compatible
liquid vehicle is applied to the posterior pharyngeal region of a
patient in a 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 to 1.25 ml, a volume
sufficient to coat the affected region without excessive draining
to the throat. The method further provides for such application of
a surfactant substance containing phospholipid-containing
ingredients capable of lowering the surface tension of water to
about 15-50 nM*.sup.-1. The surfactant preparation of the present
method may optionally include 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 dose of
the apoproteins will be a level from 10 ug to 150 ug, 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.
[0014] 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
[0015] 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 (dipalmitoylphosphatidylcholine, 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).
1TABLE 1 Surfactants Active Name Source Maker components Exosurf
artificial Glaxo- phospholipid Wellcome (DPPC) cetyl alcohol
tyloxapol Infasurf calf lung phospholipid Curosurf porcine lung
Laboratoire phospholipid Seron France Survanta adult bovine Ross
phospholipids (berectant) lung Laboratories (DPPC, others) SP-B
SP-C KL4- artificial Johnson & synthetic surfactant Johnson
peptide phospholipid (DPPC, POPG)
[0016] 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.
Various chemistries have been devised for effecting an ionic or
even covalent association of these surfactant components. Canadian
patent No. 2,042,635 (Sarin, et al.) discloses fatty acid/SP-C
conjugates which may be used in conjunction with phospholipids and
other surfactant ingredients. The conjugate has the advantage of
providing the hydrophobic moiety which lowers and stabilizes
surface tension values, and at the same time provides a polar
solvent. Another synthetic surfactant composition useful in the
practice of the present invention is disclosed in U.S. Pat. No.
4,826,821, and comprises dipalmitoyl phosphatidyl choline, a C-14
to C-18 fatty alcohol and a nonionic surface active agent,
preferably tyloxapol.
[0017] Analysis of the phospholipid fraction of naturally occurring
surfactant reveals a complex composition containing
plasmenylcholine, phosphatidylcholine, choline
glycerophospholipids, sphingomyelin, phosphatidylinositol,
phosphatidylserine and lysophophatidylethanolamine, frequently
appearing in difficult to separate pairs. See Dugan, et al., J.
Chromatography, 378: 317 (1986) and U.S. Pat. No. 4,826,821, hereby
incorporated by reference. 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 percent (w/w), and
including or omitting SP-A, SP-B or SP-C is a synthetic form of
surfactant applicable to the present invention. Preparation of the
purified hydrophobic protein, as SP-C, may be carried out according
to the procedures disclosed in WO87/06943, hereby incorporated by
reference. Use of surfactant protein fragments is also efficacious,
as the fragments exhibit unusual surface tension properties, as
disclosed in U.S. Pat. No. 5,547,937 Sarin), and other patents in
the related series. A pharmacologically effective dose of a
hydrophillical apo protein SP-A and the hydrophobic apo protein
SP-B, C is 0.25 to 2.5 percent of each and a total combined
percentage of 4-6 percent. Any combination of the foregoing
ingredients will have efficacy in the present invention so long as
the tissue coating and adhesive properties of natural surfactant
are mimicked, and most importantly, there is an effective lowering
of surface tension of the film to values of 10 millinewtons or less
(preferably from about 0.5 to 7 millinewtons).
[0018] The therapeutic use of these substances is in contrast to
oil-based lubricants, which have some effect in reducing snoring,
such as phosphocholinamin, the trade name for a mixture of lecithin
complexed with a light hydrocarbon fraction, described in
Hoffstein, et al., Am. J. Otolarygol., 8:236 (1987). The present
method is also in contrast to other human therapeutic approaches to
reduce snoring specifically, such as the use of
methysulfonylmethane in combination with a mild anesthetic, as
taught in U.S. Pat. No. 5,569,679.
[0019] The surfactant solution is delivered in a convenient dose
volume of about 0.5 to 1.5 ml. If 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 pool or drain off and be
swallowed. The concentration of various ingredients generally
simulates the natural surfactant, in that dipalmitoyl phosphatidyl
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 ml solution. The composition is not
diluted.
[0020] In one embodiment of the present invention, the surfactant
composition is contained in a vessel adapted to deliver a
surfactant aerosol to the posterior pharyngeal region. The vessel
may be of three types: a pressurized aerosol can, a squeeze bottle,
or a pump bottle. The surfactant will typically be applied through
the oral cavity, but it may be delivered nasally when the subject
is supine. Examples of containers suitable for nasal delivery are
depicted in U.S. Pat. No. 5,569,679 incorporated by reference. For
oral administration, a pump or squeeze bottle may be equipped with
an elongated tapered nozzle (three to six inches in length) for
local direct application of surfactant to the pharyngeal region.
Conveniently, the spray bottle containing a pre-measured quantity
of surfactant, to which appropriate label directions are affixed,
may be distributed as an article of commerce. When packed under
sterile conditions, the surfactant may be stored refrigerated or at
room temperature.
[0021] Further advantages of the present invention will be apparent
from the Example which follows.
EXAMPLE
[0022] Six individuals with varying degrees of sleep apnea were
studied on two different nights at least 5 days apart under a
research protocol approved by the University of Wisconsin Human
Subjects Committee. These volunteer subjects were given saline
(control) on one night and berectant (Survanta; natural bovine
surfactant) on the other night. Once the subjects had fallen asleep
as demonstrated by their EEG, they were monitored for 60 minutes
without any intervention. One ml volumes of either saline or
berectant were then delivered into the posterior pharynx via a
small catheter (2.5 mm outer diameter and placed transnasally)
after the subjects had fallen asleep as verified by
electroencephalic (EEG) monitoring. For the 60 minutes prior to
instillation of saline or berectant and the subsequent 60 minutes
following instillation, sleep stage (I, II, III, IV, or REM) was
monitored via EEG, inspiratory and expiratory air flow was
monitored via a pneumotachometer attached to a close-fitting nasal
mask, inspiratory muscle activity was monitored via
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 CO.sub.2 was measured breath to breath.
[0023] Hypopnea was defined as a 20% decrease in tidal volume in
three or more consecutive breaths compared to the preceding breath,
apnea as cessation of flow for .gtoreq.5 seconds, and desaturation
as .gtoreq.2% 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 (.DELTA.SpO.sub.2%) 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.
[0024] 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 desaturation for each event
(.DELTA.SpO.sub.2%) diminished with berectant but not with saline,
although this change did not reach statistical significance
(p=0.09, Table 6).
[0025] Instillation of artificial 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.
2TABLE 2 Respiratory Disturbance Index (Stage II, III, & IV
sleep) Subject Pre-saline Post-saline Pre-berectant Post-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 75 .+-. 17 80 .+-. 19 92 .+-. 22 69 .+-.
23* *p < 0.05
[0026]
3TABLE 3 Respiratory Disturbance Index (Stage II sleep) Subject
Pre-saline Post-saline Pre-berectant Post-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
[0027]
4TABLE 4 Desaturations (Stage II, III, & IV sleep) Subject
Pre-saline Post-saline Pre-berectant Post-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 61 .+-. 24 44 .+-. 19
[0028]
5TABLE 5 Desaturations (Stage II sleep) Subject Pre-saline
Post-saline Pre-berectant Post-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 55 .+-. 22 53
.+-. 19 62 .+-. 24 43 .+-. 19
[0029]
6TABLE 6 .DELTA.SpO.sub.2% Intervention Pre Post Berectant 3.7 .+-.
2.0 2.4 .+-. 1.5* Saline 3.5 .+-. 2.2 3.7 .+-. 1.5
* * * * *