U.S. patent application number 10/193081 was filed with the patent office on 2002-12-26 for aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis.
Invention is credited to Hale, Mary Anne, Leivo, Frederick T., Munk, James D., Osbakken, Robert S..
Application Number | 20020197212 10/193081 |
Document ID | / |
Family ID | 27584535 |
Filed Date | 2002-12-26 |
United States Patent
Application |
20020197212 |
Kind Code |
A1 |
Osbakken, Robert S. ; et
al. |
December 26, 2002 |
Aerosolized anti-infectives, anti-inflammatories, and decongestants
for the treatment of sinusitis
Abstract
Pharmaceutical compositions are described that comprise one or
more active ingredients selected from the group consisting of
anti-infective, anti-inflammatory and mucolytic agents, and
particularly to compositions formulated as a solution in a unit
dose for aerosol administration to treat chronic sinusitis.
Inventors: |
Osbakken, Robert S.;
(Camarillo, CA) ; Hale, Mary Anne; (Woodland
Hills, CA) ; Leivo, Frederick T.; (Carpinteria,
CA) ; Munk, James D.; (Camarillo, CA) |
Correspondence
Address: |
ELLER EHRMAN WHITE & MCAULIFFE LLP
4350 LA JOLLA VILLAGE DRIVE
7TH FLOOR
SAN DIEGO
CA
92122-1246
US
|
Family ID: |
27584535 |
Appl. No.: |
10/193081 |
Filed: |
July 9, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10193081 |
Jul 9, 2002 |
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09577623 |
May 25, 2000 |
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60142618 |
Jul 6, 1999 |
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60142620 |
Jul 6, 1999 |
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60142621 |
Jul 6, 1999 |
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60142622 |
Jul 6, 1999 |
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60142624 |
Jul 6, 1999 |
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60142741 |
Jul 6, 1999 |
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60142881 |
Jul 6, 1999 |
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60193507 |
Apr 3, 2000 |
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60193508 |
Apr 3, 2000 |
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60193509 |
Apr 3, 2000 |
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60193510 |
Apr 3, 2000 |
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60194078 |
Apr 3, 2000 |
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Current U.S.
Class: |
424/45 |
Current CPC
Class: |
A61P 11/02 20180101;
A61K 31/573 20130101; A61P 31/04 20180101; Y10S 514/853 20130101;
A61M 11/06 20130101; A61K 9/0078 20130101; A61K 9/0043 20130101;
A61P 31/00 20180101 |
Class at
Publication: |
424/45 |
International
Class: |
A61L 009/04 |
Claims
What is claimed is:
1. A method of treating a patient suspected or diagnosed as having
chronic sinusitis, comprising nasally administering an
aerosolized/atomized composition comprising an agent for treatment
of sinusitus, wherein the composition has a surface tension that
results in penetration or adhesion of the agent in the sinuses.
2. The method of claim 1, wherein the surface tension is about 10
to about 70 dynes/cm.
3. The method of claim 1, wherein the composition comprises a
surfactant.
4. The method of claim 1, wherein the agent is an anti-infective,
an anti-inflammatory or a mucolytic agent.
5. The method of claim 1, wherein the composition is administered
via a nebulizer.
6. The method of claim 1, wherein the agent is selected from the
group consisting of anti-infective, anti-inflammatory and mucolytic
agents; the surface tension of the composition is between about 10
to about 70 dynes/cm; and the composition is formulated as a
solution in a unit dose for aerosol administration to the nasal
sinuses by aerosolization using a nebulizer that delivers aerosol
particles of between about 1 to about 5 .mu.m in average
diameter.
7. The method of claim 1, herein the composition is packaged with
directions for its use in the treatment of sinusitis.
8. The method of claim 5, wherein the nebulizer is a nebulizer with
a nasal adapter.
9. The method of claim 5, wherein the nebulizer is connected to a
compressor.
10. The method of claim 5, wherein the nebulizer delivers a
majority of aerosolized particles in the size range of about 3.0 to
about 3.5 .mu.m in diameter.
11. The method claim 1, wherein the pharmaceutical composition is
administered to the patient 1-3 times a day for a total of 14-21
days.
12. The method of claim 1, wherein the composition has a pH in the
range of about 3.0 to about 8.5.
13. The method of claim 1, wherein the osmotic pressure of the
composition is between about 300 mOsm/kg to about 880 mOsm/kg.
14. The method of claim 1, wherein the NaCl equivalency to the
composition is between about 0.9% NaCl to about 3.0% NaCl.
15. The method of claim 1, wherein the composition further
comprises a decongestant.
16. The method of claim 1, wherein the composition, when
administered as an aerosolized spray, has minimal systemic side
effects.
17. The method of claim 1, wherein said active ingredient is an
anti-infective agent and the sinusitis is caused by a pathogen
selected from the group consisting of Alpha Hemolytic streptococci,
Beta Hemolytic streptococci, Branhamella Catarrhalis, Diptheroids,
Haemophilis influenzae (beta-lactamase positive and negative),
Moraxella species, Pseudomonas aeruginosa, Pseudomonas maltophilia,
Serratia marcescens, Staphylococcus aureus, Streptococcus
pneumonia, Aspergillosis, Mucor and Candida Albicans, Fusarium,
Curvularia, cryptococcus, coccidioides and histoplasma.
18. The method of claim 17, wherein said anti-infective agent is
selected from the group consisting of Penicillins, Cephalosporins,
Macrolides, Sulfonamides, Quinolones, Aminoglycosides, BetaLactam
antibiotics, Linezolid, Vancomycin, Amphotericin B, and Azole
antifungals.
19. The method of claim 2, wherein said surfactant is a
polysorbate.
20. The method of claim 5, wherein the nebulizer delivers a
majority of aerosolized particles in the size range of about 1.0 to
about 4.0 .mu.m in diameter.
21. The method of claim 5, wherein the nebulizer delivers a
majority of aerosolized particles in the size range of about 0.5 to
about 5.0 .mu.m in diameter.
22. The method of claim 5, wherein the nebulizer delivers a
majority of aerosolized particles in the size range of about 2.0 to
about 3.5 .mu.m in diameter.
23. The method of claim 5, wherein the maximum number of particles
delivered by the nebulizer over about 5.0 microns is less that 20%
of the total particles.
24. The method of claim 1, wherein the surface tension of the
composition is between about 20 to about 60 dynes/cm.
25. The method of claim 1, wherein the surface tension of the
composition is between about 30 to about 50 dynes/cm.
26. The method of claim 1, wherein the osmotic pressure of the
composition is between about 150 mOsm/kg to about 880 mOsm/kg.
27. The method of claim 1, wherein the osmotic pressure of the
composition is between about 400 mOsm/kg to about 700 mOsm/kg.
28. The method of claim 1, wherein the osmotic pressure of the
composition is between about 500 mOsm/kg to about 600 mOsm/kg.
29. The method of claim 1, wherein the NaCl equivalency to the
composition is between about 1.1 % NaCl to about 1.8% NaCl.
30. The method of claim 1, wherein the NaCl equivalency to the
composition is between about 1.3% NaCl to about 1.7% NaCl.
31. The method of claim 4, wherein the anti-inflammatory agent is a
glucocorticoid, disodium cromoglycate or nedcromil sodium.
32. The method of claim 4, wherein the mucolytic agent is
acetylcysteine or dornase alpha.
33. The method of claim 15, wherein the decongestant is
phenylephrine, naphazoline, oxymetazoline, tetrahydrozoline or
xylometoazoline.
34. The method of claim 1, wherein the agent is amikacin,
amphotericin B, azithromycin, aztreonam, cefazolin, cefepime,
cefonicid, cefoperazone, cefotaxime, cefotetan, cefoxitin,
ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cephapirin,
ciprofloxacin, clindamycin, doxycycline, fluconazole, gentamycin,
itraconazole, levofloxacin, meropenem, meziocillin, miconazole,
nafcilin, oflaxacin, piperacillin, rifampin,
ticarcillin+clavulanate, tobramycin or vancomycin.
35. The method of claim 2, wherein the surfactant is PEG 400,
sodium lauryl sulfate, span 20, span 40, span 60, Tween 20, Tween
40, Tween 60 or benzalkonium chloride.
36. The method of claim 2, wherein the surfactant has a
hydrophile-lipophile-balance (HLB) of between about 1.8 to about
8.6.
37. The method of claim 2, wherein the surfactant has a
hydrophile-lipophile-balance (HLB) of between about 9.6 to about
16.7.
38. The method of claim 2, wherein the surfactant is Tween 20.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 09/577,623, to Osbakken et al., entitled "AEROSOLIZED
ANTI-INFECTIVES, ANTI-INFLAMMATORIES, AND DECONGESTANTS FOR THE
TREATMENT OF SINUSITIS." This application claims priority under 35
U.S.C. .sctn.119(e) to U.S. provisional application Ser. Nos.
60/142,618, 60/142,620, 60/142,621, 60/142,622, 60/142,624,
60/142,741, and 60/142,881, all filed on Jul. 6, 1999, and to U.S.
provisional application Ser. Nos. 60/194,078, 60/193,509,
60/193,508, 60/193,507 and 60/193,510, all filed Apr. 3, 2000. The
disclosures of the above-referenced utility and provisional
applications are hereby incorporated by reference in their
entireties.
FIELD
[0002] The present invention relates to pharmaceutical compositions
comprising one or more active ingredients selected from the group
consisting of anti-infective, anti-inflammatory and anti-mucolytic
agents, and particularly to compositions formulated as a solution
in a unit dose or multi-dose vials for aerosol administration to
treat chronic sinusitis.
BACKGROUND
[0003] There are a number of air-filled cavities called sinuses in
the skull (Stedman's Medical Dictionary, 27th Edition, page 1644,
(1999), Lippincott Williams & Wilkins, Baltimore, Md.). Four
pairs of sinuses known as the paranasal sinuses, connect the space
(known as the nasal passage) running from the nostrils and up
through the nose. These four pairs of paranasal sinuses are the
frontal sinuses, the maxillary sinuses, the ethmoid sinuses, and
the sphenoid sinuses. They are located, respectively, in the
forehead, behind the cheekbones, between the eyes, and behind the
eyes. A membrane lining the sinuses secretes mucus, which drains
into the nasal passage from a small channel in each sinus. Healthy
sinuses are sterile and contain no bacteria. In contrast, the nasal
passage, normally contains many bacteria that enter through the
nostrils as a person breathes.
[0004] A number of factors and/or processes are involved in
maintaining healthy sinuses. The mucus secreted by the membrane
lining must be fluid but sticky, in order to flow freely yet absorb
pollutants and entrap bacteria. It must also contain sufficient
amounts of bacteria-fighting substances, such as antibodies.
Additionally, small hair-like projections called cilia, located in
the nostril, must beat in unison to propel mucus outward, in order
to expel bacteria and other particles. Moreover, the mucous
membranes themselves must be intact, and the sinus passages must be
open to allow drainage and the circulation of air through the nasal
passage. When one or more of these processes or factors are amiss,
causing obstruction of the sinus passage, an infection called
sinusitis develops.
[0005] Sinusitis is an inflammation of the membrane lining one or
more paranasal sinuses. There are three different types of
sinusitis: acute, recurrent acute, and chronic. Acute sinusitis is
characterized as lasting less than three weeks or occurring less
than four times a year. Acute sinusitis can be successfully treated
using antibiotics, leaving no damage to the linings of the sinus
tissue. Recurrent acute sinusitis occurs more often but leaves no
significant damage. Chronic sinusitis lasts longer than three weeks
and often continues for months. In cases of chronic sinusitis,
there is usually tissue damage. According to the Center for Disease
Control (CDC), thirty seven million cases of chronic sinusitis are
reported annually.
Causes of Sinusitis
[0006] The most common cause for sinusitis is a viral cold or flu
that infects the upper respiratory tract and causes obstruction.
Obstruction creates an environment that is hospitable for bacteria,
the primary cause of acute sinusitis (Etkins et al., 1999 Nidus
Information Services, Inc. Well-Connected Report. Sinusitis. June
1999. (Online) www.well-connected.com.). The bacteria most commonly
found in acute sinusitis are Streptococcus pneumoniae (also called
pneumococcal pneumonia or pneumococci), H. influenzae (a common
bacteria associated with many respiratory infections in young
children), and Moraxella (or Branhamella) catarrhalis. Less common
bacterial culprits include other streptococcal strains including
Staphylococcus aureus.
[0007] Fungi are an uncommon cause of sinusitis, but its incidence
is increasing. The fungus Aspergillus is the common cause of fungal
sinusitis. Others include Curvularia, Bipolaris, Exserohilum, and
Mucormycosis. Fungal infections can be very serious and should be
suspected in people with sinusitis who also have diabetes,
leukemia, AIDS, or other conditions that impair the immune systems.
Fungal infections can also occur in patients with healthy immune
systems. There have been a few reports of fungal sinusitis caused
by Metarrhizium anisopliae which is used in biological insect
control.
[0008] Chronic or recurrent acute sinusitis can be a lifelong
condition and may result from untreated acute sinusitis that causes
damage to the mucous membranes, medical disorders that cause
chronic thickened stagnant mucus, or abnormalities in the nasal
passage such as polyps, enlarged adenoids, cleft palate, or tumors.
The same organisms that cause acute sinusitis are often present in
chronic sinusitis. In addition, about 20% of chronic sinusitis
cases (Etkins et al., 1999, Id.) are caused by Staphylococcus
aureus (commonly called Staph infection). Along with these
bacteria, certain anaerobic bacteria, particularly the species
Peptostreptococcus, Fusobacterium, and Prevotella, are found in 88%
of cultures in chronic sinusitis cases (Etkins et al., 1999, Id.).
Fungi can also cause chronic and recurrent sinusitis. An uncommon
form of chronic and highly recurrent sinusitis is caused by an
allergic reaction to fungi, usually, aspergillus, growing in the
sinus cavities. Fungal sinusitis usually occurs in younger people
with healthy immune systems and is more likely to be found in warm
climates.
Symptoms of Sinusitis
[0009] In acute sinusitis, symptoms almost always present are nasal
congestion and discharge which is typically thick and contains pus
that is yellowish to yellow-green. Severe headache occurs, and
there is pain in the face. A persistent cough occurs particularly
during the day. Other upper respiratory symptoms and fever may be
present. Sneezing, sore throat, muscle aches, and fatigue are
rarely caused by sinusitis itself, but may result from symptoms or
causes, such as muscle aches caused by fever, sore throat caused by
post-nasal drip, and sneezing resulting from allergies.
[0010] The symptoms of recurrent acute and chronic sinusitis tend
to be vague and generalized, last longer than eight weeks, and
occur throughout the year, even during nonallergy seasons. Nasal
congestion and obstruction are common. Yellowish discharge, chronic
cough, bad breath, and postnasal drip may occur. Sufferers do not
usually experience facial pain unless the infection is in the
frontal sinuses, which results in a dull, constant ache. However,
facial tenderness or pressure may be present.
[0011] Site-specific symptoms depend on the location of the
infection. Frontal sinusitis causes pain across the lower forehead.
Maxillary sinusitis causes pain over the cheeks and may travel to
the teeth, and the hard palate in the mouth sometimes becomes
swollen. Ethmoid sinusitis causes pain behind the eyes and
sometimes redness and tenderness in the area across the top of the
nose. Sphenoid sinusitis rarely occurs by itself. When it does, the
pain may be experienced behind the eyes, across the forehead, or in
the face. Rare complications of sinusitis can produce additional
symptoms which may be severe or even life threatening.
Treatments of Sinusitis
[0012] The primary objectives for treatment of sinusitis are
reduction of swelling, eradication of infection, draining of the
sinuses, and ensuring that the sinuses remain open. Less than half
of patients reporting symptoms of sinusitis need aggressive
treatment and can be cured using home remedies and decongestants
alone. Steam inhalation and warm compresses applied over the sinus
are often sufficient to relief discomfort. Many over-the-counter
decongestants are available, either in tablet form or as sprays,
drops, or vapors, which bring the medication into direct contact
with nasal tissue.
[0013] Antibiotics are prescribed if decongestants fail to relieve
symptoms or if other problems exist, including signs of infection
(such as yellowish nasal discharge). They prevent complications,
relieve symptoms, and reduce the risk of chronic sinusitis. Most
patients with sinusitis caused by bacteria can be successfully
treated with antibiotics used along with a nasal or oral
decongestant.
[0014] Chronic sinusitis is often difficult to treat successfully,
however, as some symptoms persist even after prolonged courses of
antibiotics. The usefulness of antibiotics in treating chronic
sinusitis is debated. Steroid nasal sprays are commonly used to
treat inflammation in chronic sinusitis. For patients with severe
chronic sinusitis, a doctor may prescribe steroids, such as
prednisone. Since oral steroids can have serious side effects, they
are prescribed only when other medications have not been
effective.
[0015] When medical treatment fails, surgery may be the only
alternative in treating chronic sinusitis. Studies suggest that the
most patients who undergo surgery have fewer symptoms and better
life. Presently, the most common surgery done is functional
endoscopic sinus surgery, in which the diseased and thickened
tissues from the sinuses are removed to allow drainage. This type
of surgery is less invasive than conventional sinus surgery, and
serious complications are rare.
Considerations and Concerns of Treatments
[0016] Sprays, drops, and vapors work quickly but often require
frequent administration. Nasal decongestants may dry out the
affected areas and damage tissues. With prolonged use, nasal
decongestants become ineffective. The tendency is to then increase
the frequency of use to as often as once an hour. Withdrawal from
the drugs after three to five days of over-frequent use can itself
cause symptoms of sinusitis and the return of nasal congestion
phenomenon known as rebound effect. Short-acting nasal
decongestants may cause rebound effect after only eight hours.
Rebound effect leads to dependency when the patient takes the
decongestant to treat the rebound effect, the drug becomes
ineffective, the patient withdraws, and the condition rebounds
again, with the nasal passages becoming swollen and burning.
Eventually, the condition can become worse than before the
medication was taken. Nasal decongestants are generally recommended
for no more than one to three days of use because of this risk.
[0017] Some oral decongestants may cause constriction of other
vessels in the body, temporarily raising blood pressure in people
with hypertension. Other side effects of oral decongestants include
insomnia, agitation, abnormal heart rhythms (particularly in people
with existing cardiac problems), and urinary retention in men with
enlarged prostates. Decongestant sprays and drops, too, are
absorbed into the body and can sometimes cause these side
effects.
[0018] The most common side effect for nearly all antibiotics is
gastrointestinal distress. Antibiotics also double the risk for
vaginal infections in women. Certain drugs, including some
over-the-counter medications, interact with antibiotics, and all
antibiotics carry the risk for allergic reactions, which can be
serious in some cases. Thus, patients should inform their physician
of all medications they are taking and of any drug allergies.
[0019] Oral antibiotics are usually prescribed for 7 to 10 days.
Patients must take all of the tablets prescribed; failure to do so
may increase the risk for reinfection and also for development of
antibiotic-resistant bacteria. It should be noted, however, that
even after antibiotic treatments, between 10% and 25% of patients
still complain of symptoms.
[0020] Of major concern to physicians and the public is the
emergence of bacterial strains that have become resistant to common
antibiotics due to frequent exposure. It should be noted that the
average person is not yet endangered by this problem. The risk is
greatest in hospitals and nursing homes, but it is still not high.
Nonetheless, the prevalence of such antibiotic-resistant bacteria
has increased dramatically worldwide, and caution should be
exercised.
Nebulization Therapy
[0021] Nebulization is a conventional treatment for pulmonary
infections related to cystic fibrosis, because it is relatively
easy and safe to use, and because it delivers antibiotics topically
to the site of infection, with little systemic absorption of the
antibiotics. Nebulization has also been known to have been used for
sinus infections and pulmonary infections, related to
bronchiectasis. Thus, there are few systemic side effects.
Small Aerosolized Particles for Treating Sinusitis
[0022] Yokota et al., Japanese Journal of Antibiotics 609(15):48
(1995) reports administration of cefmenoxime using a nebulizer to
treat sinusitis patients. These authors evaluated cefmenoxime
against clinical isolates from sinusitis patients, and found that
minimum inhibitory concentrations were lower when a one percent
(1%) solution was used with a nebulizer. The paper speculates that
sufficient concentrations exceeding such minimum inhibitory
concentrations would be obtained by nebulizer treatment using a
cefmenoxime nasal solution.
[0023] Guevara et al., Anales O.R.L. Iber. -Amer. XVIII, 3:231-238
(1991), describes aerosol therapy for treating patients suffering
from chronic sinusitis. The disclosed aerosol therapy involves
delivery of a therapeutic composition comprising 500 mg of
Cefotaxime, 5 mg metilprednisolone, and 1.5 ml N-acetilcisteina
using an air-jet nebulizer for 15-20 minutes, every 8 hours, over a
total period of 15 days. The air-jet nebulizer produces aerodynamic
particle diameters of average mass of four microns. Guevara et al.
reports a success rate of 96%. However, Guevara et al. does not
disclose adding a surfactant to assist deposition, penetration, and
retention of the antibiotic in the sinuses. It is also noted that
the aerosol therapy of Guevara et al. requires frequent treatments
over a long period of time.
[0024] Kondo et al., Acta Otolaryngol Suppl. 525:64-67 (1996),
reports treatment of paranasal sinusitis using fosfomycin (FOM)
aerosol. Kondo et al. describes delivery of 4 ml of 3% FOM solution
using either a jet-type nebulizer or a ultrasonic nebulizer. The
jet-type nebulizer produces aerosol particles having about 0.5 to
0.7 .mu.m in diameter, while the ultrasonic-type nebulizer produces
particles having about 2-4 .mu.m in diameter. The results of Kondo
et al. indicate that the ultrasonic-type nebulizer delivers a
higher concentration of FOM to the maxillary sinus surface and is
therefore more effective in treating paranasal sinusitis than the
jet-type nebulizer. Although Kondo et al. suggests that the
preferred aerosol particle size is about 2-4 .mu.m in diameter for
deposition of a higher level of antibiotic in the maxillary sinus,
Kondo et al. does not disclose an administration schedule or the
addition of a surfactant to the FOM solution to further increase
the deposition of FOM in the sinuses.
Small Aerosolized Particles for Pulmonary Treatment
[0025] Smith et al., U.S. Pat. No. 5,508,269, discloses the use of
aminoglycoside aerosol formulations to treat patients suffering
from endobronchial infection. Smith et al. describes delivery of
the aminoglycoside formulation using a jet or ultrasonic nebulizer
that produces aerosol particle size between 1 and 5 .mu.m. The
formulation comprises 200 to 400 mg of aminoglycoside dissolved in
about 5 ml of solution containing 0.225% sodium chloride and it has
a pH between 5.5 to 6.5. Although Smith teaches delivery of
aminoglycoside to the endobronchial space using a nebulizer for the
treatment endobronchial infection, Smith does not teach an aerosol
formulation for treatment of sinusitis and does not disclose a
treatment schedule. It is also noted that the aerosol particle size
disclosed in Smith et al. is a broad range. It is not predictable
what fraction of the aerosol particles between 1 to 5 .mu.m will
deposit in the sinuses, and what fraction of the aerosol particles
will have a diameter of 1 .mu.m, 2 .mu.m, etc.
[0026] Rubin et al., U.S. Pat. No. 5,925,334, describes the use of
aerosolized surfactant to promote pulmonary airway clearance. The
method of Rubin et al. comprises administering a formulation
containing a surfactant using a PARI LC Jet nebulizer for 15
minutes, 3 times a day for 14 consecutive days, to patients
suffering from bronchitis or cystic fibrosis. However, Rubin does
not teach the use of aerosolized antibiotic or aerosolized
antibiotic and surfactant combination to treat sinusitis.
[0027] Schmitt et al., U.S. Pat. No. 4,950,477, teaches a method of
preventing and treating pulmonary infection by fungi using
aerosolized polyenes. The method comprises administering to a
patient suffering from pulmonary infection by Asperigillus about
0.01 mg/kg to 6.0 mg/kg of a polyene in an aerosol of particles
having an aerodynamic diameter between about 0.5 .mu.m to about 8
.mu.m. Schmitt et al. specifically discloses the administration of
amphotericin B. Although Schmitt et al. teaches aerosolized
polyenes for treatment of pulmonary infection, Schmitt et al. does
not provide guidance for using aerosolized polyenes for treating
sinusitis.
[0028] O'Riordan et al., Journal of Aerosol Medicine, 20(1):13-23
(1997), reports the effect of nebulizer configuration on delivery
of aerosolized tobramycin to the lung. O'Riordan et al. discloses
the delivery of tobramycin using either an ultrasonic nebulizer
delivering aerosol particles having between 1.45 to 4.3 .mu.m or a
jet nebulizer delivering aerosol particles having between 1.25
.mu.m. The results of O'Riordan et al. show that nebulizer
configuration affects both the amount of aerosolized tobramycin
inhaled as well as the particle size. Specifically, nebulizers that
produce large particles are prone to considerable deposition on
tubing and connections. O'Riordan et al. recommends that nebulizer
configuration be specified in treatment protocols.
Large Particle Aerosolization
[0029] In contrast to the references discussed above, Negley et
al., ENT Jounal, 78(8):550-554 (1999), and Desrosiers et al.,
(presented at the ENT Academy Meeting, May 1999) teach large
particle nebulization therapy for treatment of sinusitis. Negley
observes that deposition of medication into the sinuses is best
achieved when the aerosolized particles are 1 6 to 25 .mu.m in
size. Desrosiers et al. reports that large particle saline aerosol
therapy alone is effective in treating refractory sinusitis and
that the addition of tobramycin to the saline solution had minimal
benefit.
[0030] The journal articles and patents discussed above teach
various aerosol therapies for the treatment of sinusitis. However,
there does not appear to be agreement among the various authors as
to the optimal size or size distribution of the aerosolized
particles or even whether antibiotics are effective in treating
sinusitis. What has been needed is a clinically effective
anti-infective treatment protocol for sinusitis, a more optimal
therapy schedule, and an appropriate nebulizer configuration for
the deposition of aerosolized anti-infective particles into the
sinuses for the successful and consistent treatment of chronic
sinusitis.
SUMMARY
[0031] Provided are pharmaceutical compositions that include one or
more active ingredients such as anti-infective, anti-inflammatory
and mucolytic agents. Such compositions preferably are formulated
as a solution in a unit dose or multi-dose vial for aerosol
administration to the nasal sinuses. It is contemplated that such
formulations are packaged with labels or inserts or other forms of
directions for their use in the treatment of sinusitis.
[0032] In a preferred embodiment, the surface tension of the
solution is between about 10 to 70 dynes/cm, in order to yield an
aerosol having a preferred Mass Median Aerodynamic Diameter within
the range of about 1.0 to 4.0 microns. The use of such an
aerosolized spray has minimal systemic side effects. Surface
tension of a given formulation may be adjusted by adding a
surfactant in addition to the active ingredients in order to bring
it into the preferred range.
[0033] Generally, it is contemplated that formulations according to
the present invention will preferably have a pH in the range of
about 3.0 to 8.5; an osmotic pressure of the solution between about
150 mOsm/kg to 880 mOsm/kg; and a NaCl equivalency to the solution
is preferably between about 0.9% NaCl to 3.0% NaCl.
[0034] Preferred anti-infective agents include Penicillins,
Cephalosporins, Macrolides, Sulfonamides, Quinolones,
Aminoglycosides, BetaLactam antibiotics, Linezolid, Vancomycin,
Amphotericin B, and Azole antifungals. Preferred anti-inflammatory
agents include Glucocorticoids, Disodium Cromoglycate and Nedcromil
Sodium. Preferred mucolytic agents are Acetylcysteine and Dornase
Alpha. Preferred decongestant agents are Phenylephrine,
Naphazoline, Oxymetazoline, Tetrahydrozoline and
Xylometoazoline.
[0035] In a preferred embodiment of the invention, a kit is
described that provides the various equipment and attachments
useful in administering the formulations of the present invention
by using the disclosed nebulizer devices.
[0036] Preferred administration protocols also are described.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIG. 1 discloses the preferred equipment for aerosolized
delivery of pharmaceutical solutions. This nebulizer, manufactured
by Pari Respiratory Equipment, Inc., for the inventors, produces
the desired particle size for effective administration of the
solutions in this invention to the sinuses. To use this nebulizer
preferably medication is placed in the nebulizer at A. The
nebulizer is then connected to a compressor or other source at B
with tubing supplied. When the airflow is turned on the patient
places the nose piece C under their nostrils and breathes normally
until the medication solution in the nebulizer begins to sputter
and no mist comes out at C.
DETAILED DESCRIPTION
[0038] I. General Description
[0039] The present invention involves the topical delivery of
medications to the nasal cavity and sinuses by aerosolizing aqueous
solutions of these medications. The present invention is based in
part on the surprising finding that aerosolized ant-infective
particles are surprisingly effective therapeutically when they have
a mass median aerodynamic diameter (MMAD) of about 3.0 to 3.5 .mu.m
for deposition in the sinuses in a preferred size range. The
present invention provides an apparatus for delivery of such
optimally sized anti-infective particles into the sinuses. The
present invention is also based in part on the finding that the
addition of a surfactant to formulations increases the deposition,
retention, and penetration of anti-infectives or other active
ingredients into the sinuses. The present invention provides
guidance for therapy schedule and dosage as discussed in detail
below.
[0040] As described in greater detail below, the pharmaceutical
formulations will be aerosolized/atomized prior to administration
to a patient to form an aerosol cloud with particles of
aerosolized/atomized H.sub.2O and medication that have a MMAD (Mass
Median Aerodynamic Diameter) of preferably between about 0.5 and
5.0 microns, more preferably between about 1.0 to 4.0 microns and
most preferably between about 2.0 to 3.5 microns. It is also
preferable to have the maximum number of particles over 5.0 microns
be less than 20% of the total particles.
[0041] A surprising discovery made by the inventors was that the
surface tension of the solution prepared for inhalation needed to
be adjusted to achieve optimal results. To achieve effective
deposition of medication within the sinuses it is preferable to
have the surface tension of the solution for aerosolization be
adjusted with surfactants to between 10 dynes/cm and 70 dynes/cm,
more preferably between about 20 to 60 dynes/cm, and most
preferably between about 30 to 50 dynes/cm.
[0042] Contemplated pharmaceutical compositions will include one or
more active ingredients such as anti-infective, anti-inflammatory
and mucolytic agents. Appropriate medications to be used in the
methods according to the present invention are listed in Table 1.
These medications may be administered for the treatment of
sinusitis, particularly chronic sinusitis, by resolving infection,
reducing inflammation or reducing congestion in the nasal cavity
and sinuses.
[0043] These compositions ideally will be formulated as a solution
in a unit dose or multi-dose vial for aerosol administration to the
nasal cavity and sinuses and packaged with directions for its use
in the treatment of sinusitis. Appropriate compositions for this
purpose will be formulated by using surfactants, NaCl or other
chemicals entities to adjust the solution for administration to
have the following properties:
[0044] surface tension preferably between about 10 to 70 dynes/cm,
more preferably between about 20 to 60 dynes/cm, and most
preferably between about 30 to 50 dynes/cm.
[0045] osmotic pressure between about 300 mOsm/kg to 880 mOsm/kg,
more preferably between about 400 mOsm/kg to 700 mOsm/kg and most
preferably between about 500 mOsm/kg to 600 mOsm/kg.
[0046] NaCl equivalency of the solution preferably between about
0.9% NaCl and 3.0% NaCl, more preferably between about 1.1% NaCl
and 1.8% NaCl and most preferably between about 1.3% NaCl and 1.7%
NaCl.
[0047] pH preferably between about 3.0 and 8.5, but may vary
according to the properties of the medication used.
[0048] A. Surface Tension
[0049] The present inventors have found that the surface tension
and, to a lesser degree, particle size are critical factors in
getting optimal deposition of the formulation in the nasal cavity
and sinuses. For example, particles that are too large will deposit
in the nasal cavity, but are unlikely to enter the sinuses. Having
too low a surface tension increases an aerosolized particle's
chance of deposition on the first surface that it comes in contact
with, which generally would be tissue or structures in the nasal
cavity proximal to the sinuses. In contrast, if the surface tension
is too high much of the aerosolized medication is not deposited
within the patient's sinuses and ultimately is deposited in the
lungs. If the surface tension is too low most of the aerosolized
medication is deposited in the nasal cavity and does not reach the
sinuses.
[0050] For purposes of preparing formulations according to the
present invention, surface tension may be measured by using a Ring
Tensiometer or the capillary rise measure method which consists of
a capillary tube of known diameter placed into the solution and a
measurement of capillary rise taken to provide surface tension.
Surface tension will then be adjusted using surfactants to fall
within a preferred range in dynes/cm.
[0051] B. Osmotic Pressure
[0052] Optimal osmotic pressure helps to reduce damage to the
epithelia cilia of the sinuses. Although often not present in
chronic sinusitis patients, epithelia cilia perform a useful
function in the sinuses by moving mucosal fluid out of the
sinuses.
[0053] For purposes of preparing formulations according to the
present invention, osmotic pressure may be measured by using an
Osmometer. If necessary, osmotic pressure may then be raised to
fall within a preferred range by adding NaCl to the solution.
[0054] C. Sodium Chloride Equivalency
[0055] Optimal NaCl equivalency (tonicity) works to reduce swelling
in the sinuses and nasal cavity by drawing water from the nasal and
sinus epithelia, reducing swelling. NaCl equivalency below 0.9%
(hypotonic) may cause swelling in the epithelia of the nasal cavity
and sinuses. NaCl equivalency above 3.0% would raise the tonicity
and osmotic pressure above desirable levels and may cause a burning
sensation.
[0056] For purposes of preparing formulations according to the
present invention, NaCl equivalency will closely follow osmotic
pressure and can be measured using the methods described in section
B above.
[0057] D. pH
[0058] In general, the pH would be adjusted if a given medication
is either more stable or more effective at a certain pH. American
Hospital Formulary Service (AFHS) published yearly or the Hand Book
of Injectable Drugs by Lawrence A. Trissel, .RTM. 1994 American
Society of Hospital Pharmacists, Inc., which are herein
incorporated by reference, provide information regarding the
stability or effectiveness of a medication at certain pH.
[0059] For the purposes of preparing formulations according to the
present invention the pH of the various solutions may need to be
adjusted to achieve stability or increase effectiveness. A pH
meter, where a probe is placed into the solution and the device
gives the pH, will be used to measure pH or pH paper will be used
to estimate pH by placing solution on the tape and then comparing
to a predeveloped chart of pH colorations. When necessary pH will
then be adjusted to arrive at the most preferable range of pH
needed for nasal aerosolization by adding buffering agents.
[0060] E. General Preparation of a Unit Dose and Production of
Aerosol with Optimal Particle Diameter
[0061] After determining the medications to be used in the
formulation, each ingredient is weighed/measured out individually,
added together and dissolved in sterile water for injection. The
preparation is then tested to ensure that it is within the
parameters established for surface tension, osmolarity, pH, and
sodium chloride equivalency. This is done by using the appropriate
equipment for each test as noted in Sections A to D above. To
prepare a unit dose, the ingredients of such formulations generally
will be dissolved in a solvent such as water or saline solution, in
a volume between about 0.5 and 6.0 mis, more preferably between
about 2 and 4 mis and most preferably between about 2.5 and 3.5
mis.
[0062] F. Surfactants
[0063] The surface tension of a fluid is the tendency of the fluid
to "stick" to itself when there is a surface between the liquid and
the vapor phase (known as an interface). A good example is a drop
of water falling in air. The drop assumes a spherical shape due to
surface tension forces, which minimize its surface given the
volume. Molecules at the surface of a liquid exert strong
attractive forces on other molecules within their vicinity. The
resultant force acting perpendicular to a line of unit length in
the surface is known as surface tension, usually measured in
Dynes/Centimeter.
[0064] Surfactants can be used as dispersing agents, solubilizing
agents and spreading agents. Some examples of surfactants are: PEG
400, Sodium lauryl sulfate, Spans (20-40-60 etc), Tweens
(polysorbates, 20-40-60 etc), and Benzalkonium chloride. The
purpose of using surfactants in the preferred formulations of the
present invention is to adjust the surface tension of the
aerosolized particles so that the maximum amount of medication is
deposited in or near the middle meatus ostea. If the surface
tension is reduced too much, the majority of the particles will
deposit in the nasal cavity, conversely if the surface tension is
too high the particles go directly to the lungs without depositing
in the nasal sinuses.
[0065] The HLB (hydrophille-lipophile-balance) is used to describe
the characteristics of a surfactant. The system consists of an
arbitrary scale to which HLB values are experimentally determined
and assigned. If the HLB value is low, the number of hydrophilic
groups on the surfactant is small, which means it is more
lipophilic (oil soluble).
[0066] Surfactants can act as a solubilizing agent by forming
micelles. For example, a surfactant with a high HLB would be used
to increase the solubility of an oil in an aqueous medium. The
lipophilic portion of the surfactant would entrap the oil in the
lipophilic portion of the surfactant would entrap the oil in the
lipophilic (interior) portion of the micelle. The hydrophilic
portion of the surfactant surrounding of oil globule would, in
turn, be exposed to the aqueous phase.
[0067] An HLB value of 10 or higher means that the agent is
primarily hydrophilic, while an HLB value of less than 10 means it
would be lipophilic. For example, spans have HLB values ranging
from 1.8 to 8.6, which is indicative of oil soluble for oil
dispersible molecules. Consequently, the oil phase will predominate
and a water/oil emulsion will be formed. Tweens have HLB values
that range from 9.6 to 16.7, which is characteristic of
water-soluble or water dispersible molecules. Therefore, the water
phase will predominate and oil/water emulsions will be formed.
[0068] Emulsifying agents are surfactants that reduce the
interfacial tension between oil and water, thereby minimizing the
surface energy through the formation of globules. Wetting agents,
on the other hand, aid in attaining intimate contact between solid
particles and liquids.
[0069] Detergents are also surfactants that reduce the surface
tension and wet the surface as well as the dirt. When a detergent
is used, the dirt will be emulsified, foaming may occur and the
dirt will then wash away.
[0070] G. Pathogens Known to Produce Acute and Chronic Sinus
Infections
[0071] A retrospective review of sinus cultures obtained over a
4-year period from a consecutive series of patients who underwent
endoscopic sinus surgery (ESS) was conducted by Niel Bhattacharyya
M.D. et al.; Archives of Otolaryngology-Head and Neck surgery Vol.
125 No. 10, October 1999. A wide range of bacteria may be present
in the infected post-ESS sinus cavity, with a considerable
population of gram-negative organisms, including Pseudomonas
species. Fungal infections of the sinuses have a nonspecific
clinical presentation, is refractory to standard medical treatment
and may produce expansion and erosion of the sinus wall. Various
factors have been implicated in the development of fungal
sinusitis: anatomical factors in the osteomeatal complex, tissular
hypoxia, traumatic factors, massive exposure to fungal spores,
allergy and immunosuppression.
[0072] The most common bacterial organisms found are the following:
Alpha Hemolytic streptococci, Beta Hemolytic streptococci,
Branhamella Catarrhalis, Diptheroids, Haemophilis influenzae
(beta-lactamase positive and negative), Moraxella species,
Pseudomonas aeruginosa, Pseudomonas maltophilia, Serratia
marcescens, Staphylococcus aureus and Streptococcus pneumonia.
[0073] The most common fungal organisms found are the following:
Aspergillosis, Mucor and Candida Albicans, Fusarium, Curvularia,
cryptococcus, coccidioides, and histoplasma.
[0074] The optimum treatment modality is for the physician to
obtain a culture from the sinus cavities via endoscope. The culture
is sent to a laboratory where it is tested for minimum inhibitory
concentration for several antibiotics and then the correct
antibiotic can be chosen based on the sensitivities provided by the
laboratory. Current therapy by most Otolaryngologists is to
determine the best antibiotic by using their clinical experience in
treating sinus infections. This is called empiric therapy.
[0075] The anti-fungal therapy is done similarly in that it can
also be cultured and sent to the lab for identification allowing
the most effective agent to be prescribed, or empiric therapy is
performed by the physician.
[0076] The kill rate is determined by the susceptibility of the
organism to the antibiotic or antifungals. If culture and
sensitivities are performed and the correct antibiotic is
prescribed the kill rate occurs between a period of one to three
weeks. The kill is determined/measured by a repeat culture and
sensitivity test showing no bacterial or fungal growth (as
appropriate).
[0077] II. Specific Embodiments
[0078] A. Pharmaceutical Compositions and Formulations
[0079] Preferred anti-infective agents include Penicillins,
Cephalosporins, Macrolides, Sulfonamides, Quinolones,
Aminoglycosides, BetaLactam antibiotics, Linezolid, Vancomycin,
Amphotericin B, and Azole antifungals. Preferred anti-inflammatory
agents include Glucocorticoids, Disodium Cromoglycate and Nedcromil
Sodium. Preferred mucolytic agents are Acetylcysteine and Dornase
Alpha. Preferred decongestant agents are Phenylephrine,
Naphazoline, Oxymetazoline, Tetrahydrozoline and Xylometoazoline.
These agents may be found in the American Hospital Formulary
Service published by American Society of Hospital Pharmacists,
Inc., which is incorporated herein by reference.
[0080] As an example of a contemplated formulation, Cefuroxime is
formulated in dosages of 285 mg in 3 ml sterile water for injection
per dose, to produce an antibiotic for aerosol administration. This
formulation may be compounded under a Laminar Flow hood by
performing the following steps: 1) weigh out sufficient cefuroxime
to provide 21 doses of 285 mg each (5985 mg), with 5% overage to
account for that lost in compounding; 2) QS ad (add up to) to 63 ml
with sterile water, with 5% overfill for loss in compounding; and
3) adding 0.1 ml of polysorbate 20 per 100 ml solution.
[0081] The formulation is tested using a Ring Tensiometer or the
Capillary Rise test to determine the surface tension of the
solution. The preferable range is 10 to 70 dynes/cm. The
formulation may be adjusted with a surfactant if necessary using,
for example, polysorbate 20. Using a pH meter, the formulation is
tested for the desirable pH, preferably in the range of about 3.0
to 8.5. The pH is adjusted with appropriate acids, bases and
appropriate buffers as needed according to conventional compounding
practices.
[0082] Preferably the formulation will also be evaluated using E
tables from sources known to practitioners skilled in the
pharmaceutical arts, such as Remington: The Science and Practice of
Pharmacy or other suitable pharmaceutical text to calculate its
sodium chloride equivalence to ensure that it is in the preferred
range of 0.9% to 3.0%. Similarly, the Osmolarity is checked to
ensure that it falls within the preferred range of about 300 to 880
mOsm/kg. If Osmolarity falls outside of this range, the polysorbate
20 component may be decreased until the preferred conditions are
met.
[0083] As a second example, Ciprofloxacin is formulated in dosages
of 90 mg unit dose in 3 ml of sterile water for injection per dose.
Because compounds of this antibiotic class (i.e., Fluoroquinolones)
do not have inherent surfactant activities, a surfactant preferably
is added to lower the surface tension of the final product.
[0084] This formulation may be compounded under a Laminar Flow hood
by performing the following steps: 1) weighing out a sufficient
quantity of Ciprofloxacin powder to prepare 28 doses (2520 mg) with
5% overage to account for loss during compounding; 2) QS ad to 74
ml sterile water for injection (add 5% overage for loss in
compounding); and 3) adding 0.25 ml polysorbate 20 for every 100 ml
of solution.
[0085] The formulation is tested as described above and adjustments
made to bring surface tension, pH, sodium chloride equivalence and
osmolarity within preferred ranges or to preferred levels.
[0086] As a third example, Amphotericin B is formulated in 10 mg
unit doses along with Hydrocortisone sodium succinate in 50 mg unit
doses in 3 ml sterile water to provide an antifungal agent together
with an anti-inflammatory agent.
[0087] This formulation may be compounded under a Laminar Flow hood
by performing the following steps: 1) weighing out sufficient
powder of Amphotericin B to make 28 doses (280 mg) of 10 mg each
allowing 5% overage for loss in compounding; 2) weighing out
sufficient powder of Hydrocortisone sodium succinate to make 28
doses (1400 mg) of 50 mg each allowing 5% overage for loss of
compounding; 3) combining powders; and 4) QS ad sterile water for
injection to 84 ml plus 5% for loss in compounding. The formulation
is tested as described above and adjustments made to bring surface
tension, pH, sodium chloride equivalence and osmolarity within
preferred ranges or to preferred levels.
[0088] As a fourth example, Ofloxacin is formulated in 90 mg unit
doses along with Acetylcystiene in 100 mg unit doses in 3 ml of
sterile water to provide an antibiotic together with a mucolytic
agent for injection.
[0089] This formulation is compounded under a Laminar Flow Hood by
performing the following steps: 1) weighing out sufficient powder
of Ofloxacin to make 28 doses (2520 mg) of 90 mg each allowing 5%
overage for loss in compounding; 2) weighing out sufficient powder
of Acetylcysteine to make 28 doses (2800 mg) of 100 mg each
allowing 5% overage for loss in compounding; and 3) combining the
powders and QS ad to 84 ml with sterile water for injection
allowing 5% overage for loss during compounding. The formulation is
tested as described above and adjustments made to bring surface
tension, pH, sodium chloride equivalence and osmolarity within
preferred ranges or to preferred levels.
[0090] As a fifth example, Tobramycin is formulated in 100 mg unit
doses in 2.5 ml of saline solution to provide an alternative
antibiotic formulation. The formulation is compounded under a
Laminar Flow hood by performing the following steps: 1) weighing
out the tobramycin powder sufficient to provide 42 doses of 100 mg
per dose (4200 mg), allowing for 5% overage due to losses during
compounding; 2) QS ad with 105 ml of sterile water for injection,
allowing for 5% overage due to losses during compounding; and 3)
adding 0.15 ml polysorbate 20 to adjust surface tension. The
formulation is tested as described above and adjustments made to
bring surface tension, pH, sodium chloride equivalence and
osmolarity within preferred ranges or to preferred levels.
[0091] As a sixth example, Cefoperazone and Oxymetazoline are
formulated in 3 ml of Sterile water for injection to provide an
antibiotic formulated with a decongestant. This formulation is
prepared under a Laminar Flow Hood by following these steps: 1)
weighing out sufficient powder of Cefoperazone to make 28 doses of
600 mg each (16.8 .mu.m) allowing 5% overage for compounding loss;
2) weighing out sufficient powder of Oxymetazonline to make 28
doses of 0.5 mg each (14 mg) allowing 5% overage for compounding
loss; 3) combining the powders together; 4) QS ad with sterile
water to 84 ml allowing 5% overage for compounding loss; 5) adding
Benzalkonium Chloride 0.02% (0.02 .mu.m/100 ml of solution). The
formulation is tested as described above and adjustments made to
bring surface tension, pH, sodium chloride equivalence and
osmolarity within preferred ranges or to preferred levels.
[0092] B. Determination of the Course of Treatment
[0093] In general, the course of treatment for any given patient
will be determined by his or her physician. Thus, if the organisms
found in a patient's sinuses are cultured by known techniques and
their sensitivities are determined, the most appropriate antibiotic
will be ordered. However, if no cultures and sensitivities are
done, then the patient also may be treated empirically with the
antibiotic chosen by the physician using his or her experience
based on what bacteria or fungus is suspected. If the anatomical
structures inside the nasal passageways are swollen or inflamed due
to allergy or flu symptoms, an anti-inflammatory agent or a
decongestant agent also may be administered if the patient is not
otherwise using nasal sprays or oral medication separately.
Example of a Patient Treatment Scenario
[0094] 1. Patient contracts what they feel is a sinus infection and
goes to their Otolaryngologist for diagnosis. After determining the
diagnosis of sinusitis, a culture is obtained endoscopically and
sent to the laboratory.
[0095] 2. The laboratory determines the bacteria/fungus
sensitivities by drug and reports its findings to the
physician.
[0096] 3. The physician faxes the report to the pharmacy along with
a prescription for the antibiotic most appropriate for the
infection. The formulation is prepared as described above and
dispensed in 2.5 ml containers. Generally, the container will be
labeled: "Store in Refrigerator."
[0097] 4. The physician will call patient and discuss the treatment
and any pertinent data necessary to enhance the treatment
outcome.
[0098] C. Contemplated and Preferred Treatment Regimens
[0099] The preferred treatment is the antibiotic (adjusted for the
proper surface tension, pH, sodium chloride equivalence, and
osmolarity) that most effectively kills the bacteria or fungus as
determined by culture and sensitivity, administered once to three
times per day for a duration of 5 to 10 minutes per each treatment
(See Table 1).
[0100] The total number of days needed to rid the infection
preferably is determined by reculturing until no growth is noted.
However, when the physician does not do culturing, the conventional
standard of practice is two weeks of therapy until patient
generally would be expected to have become asymptomatic plus an
additional 7 days of therapy.
[0101] D. Monitoring Efficacy
[0102] The typical Otolaryngologist when treating chronic sinusitis
prescribes antibiotics until the patient is symptom free by
physical exam plus an additional seven days. The problem that
occurs with respect to sinus infections is that, if the infection
is not completely resolved, the patient will have a recurrence the
next time their immune system is challenged, i.e., they contract
the flu, go through a stressful time in their life or need
chemotherapy treatments. Thus, the preferred method of determining
resolution of the infection is to reculture the sinuses
endoscopically and have the laboratory report come back negative,
i.e., reporting no growth of pathogenic microorganisms. The present
inventors have discovered that aerosolization should lead to less
resistance exhibited by bacteria due to the fewer times they are
exposed to the antibiotic, and such exposure occurs at lower
dosages and for shorter periods of time of aerosolized
administration (typically 1-3 weeks) as compared to oral (typically
3 weeks to several months) and intravenous treatment (typically 3-6
weeks).
[0103] E. Equipment for Aerosolized Delivery of Pharmaceutical
Composition
[0104] Equipment for aerosolized delivery of pharmaceutical
compositions are well known to the skilled artisan. O'Riordan et
al., Journal of Aerosol Medicine, 20(1):13-23 (1997), reports the
delivery of aerosolized tobramycin by a jet nebulizer and an
ultrasonic nebulizer. U.S. Pat. No. 5,508,269, issued Apr. 16,
1996, compares the characteristics of three different nebulizers:
the Ultraneb 99 (DeVilbiss) ultrasonic nebulizer, the Medicaid
Sidestream jet nebulizer, and the Pari LC jet nebulizer.
[0105] The preferred equipment for aerosolized delivery of
pharmaceutical solutions is depicted in FIG. 1. This nebulizer
manufactured by Pari Respiratory Equipment, Inc for the inventors
produces the desired particle size for effective administration of
the solutions in this invention to the sinuses. To use this
nebulizer preferably 1 ml to 5 ml of medication solution, more
preferably 2 ml to 4 ml and most preferably 2.5 ml to 3.5 ml of
medication solution is placed in the nebulizer at A. The nebulizer
is then connected to a compressor or other source of 4 liter/minute
airflow at B with tubing supplied. When the airflow is turned on
the patient places the nose piece C under their nostrils and
breathes normally until the medication solution in the nebulizer
begins to sputter and no mist comes out at C. This will usually
take 8 to 10 minutes.
[0106] In light of the foregoing general discussion, the specific
examples presented below are illustrative only and are not intended
to limit the scope of the invention. Other generic and specific
configurations will be apparent to those persons skilled in the
art.
EXAMPLES
Example 1
[0107] Patient A
[0108] A female in her forty's had been suffering from sinusitis
for most of her adult life. These sinusitis episodes seemed to be
triggered by allergies. She historically had three-four (3-4)
episodes of sinusitis each year, which were treated with oral
antibiotics for four-eight (4-8) weeks per episode. These oral
antibiotic regimens produced yeast infections, which were treated
with Diflucan.RTM. (fluconazole). Relief from the headaches,
malaise, facial pressure and pain, yellow-green nasal discharge,
coughing and fever took up to six weeks and were treated with
narcotic and non narcotic analgesics, decongestants, decongestant
nasal sprays, cough suppressants, and nasal rinses. Her allergies
were treated with antihistamines and anti-inflammatory agents.
[0109] In an effort to reduce the duration of her sinusitis
episodes, a nose drop of tobramycin 80 mg/ml was administered. This
treatment did not seem to work. The medication was irritating; and
in order to administer the drops and try to get them into the sinus
cavity, the patient had to hold her head back. This caused
intolerable pain resulting in the discontinuation of the therapy. A
nose drop of Bactoban.RTM. was tried. It was not efficacious; it
was very viscous. The administration of this drop produced similar
pain on administration, and this therapy was also discontinued.
[0110] In order to eliminate the pain caused by holding her head
back when administering nose drops, a nose drop of tobramycin was
administered after the patient had been on oral antibiotics for a
period of time. This did not seem to work. The drop did not seem to
penetrate into the sinus cavities.
[0111] Thereafter, a preparation of tobramycin 80 mg/ml was
administered using 3 ml in a Pari LC Star.RTM. nebulizer cup with
adult mask attached and a Pari Proneb.RTM. compressor. The
medication was nebulized three (3) times daily. After four days of
therapy, the patient experienced a "dumping" of green, purulent
nasal discharge. The therapy was continued for a total of seven (7)
days. It seemed at this point that the sinus infection had been
eliminated, but a relapse was experienced within a month. Another
seven (7) day regimen of nebulized tobramycin was given to the
patient. Again the sinus infection seemed to be eliminated, but it
reoccurred within two (2) months.
[0112] A preparation of cefuoxime 285 mg in 2.5 ml sterile water
for injection was administered three (3) times daily using a Pari
LC Star.RTM. nebulizer cup with adult mask attached and a Pari
Proneb.RTM. compressor. The time of nebulization was extensive and
the medication did not seem to be completely nebulized. After one
day of therapy, a Pari Turbo.RTM. compression was substituted for
the Pari Proneb.RTM. compressor. The patient experienced a
"dumping" of green, purulent nasal discharge after (3) days of
therapy. The therapy was continued for a total of seven (7) days,
again she contracted a yeast infection and was given
Diflucan.RTM..
[0113] After the seven (7) days of treatment with nebulized
cefuroxime using the Pari Turbo.RTM. compressor and the Pari LC
Star.RTM. nebulizer cup with mask, the patient has remained free of
sinus infections for nine (9) months. She has continued to
experience problems with her allergies, and while in the past these
allergies triggered sinus infections, this time no such infection
has recurred.
Example 2 Patient B
[0114] A male in his forty's had been experiencing sinus infections
off and on during his adult life. He was treated with cefuoxime 285
mg in 2.5 ml of sterile water for injection three (3) times daily
using a Pari LC Star.RTM. nebulizer cup with adult mask attached
and a Pari Turbo.RTM. compressor. The patient experienced a
"dumping" of green, purulent nasal discharge after eight (8)
treatments. The therapy was continued for a total of seven (7)
days. No other antibiotics were given. This patient has been free
from sinus infections for six (6) months.
Example 3 Patient C
[0115] A female aged mid-50s had been suffering from sinusitis off
and on for most of her adult life. These sinusitis episodes seemed
to be triggered by allergies. The patient took antihistamines and
decongestants when allergies triggered headaches and/or a clear
nasal discharge. Historically, she would have one or more sinus
infections a year requiring twenty or more days of oral
antibiotics.
[0116] She was treated with cefuoxime 285 mg in 2.5 ml of sterile
water for injection three (3) times daily using a Pari LC Star.RTM.
nebulizer cup with adult mask attached and a Pari Turbo.RTM.
compressor. The patient experienced a "dumping" of green, purulent
nasal discharge after eight (8) treatments. The therapy was
continued form a total of seven (7) days. No other antibiotics were
given. This patient has been free from sinus infections for six (6)
months.
[0117] It should be understood that the foregoing discussion and
examples merely present a detailed description of certain preferred
embodiments. It therefore should be apparent to those of ordinary
skill in the art that various modifications and equivalents can be
made without departing from the spirit and scope of the invention.
All journal articles, other references, patents and patent
applications that are identified in this patent application are
incorporated by reference in their entirety.
1TABLE 1 Agents and Dosages More Most Most Brand Preferable
Preferable Preferable Preferable Generic Name Name Class Range
Range Range Dose Amikacin Amikin Aminoglycoside 50- 75-300 mg 100-
166 mg 500 mg 200 mg Q8-12H Amphptericin B Fungizone Antifungal
2.5-45 mg 4-30 mg 7.5-15 mg 10 mg Q12H Azithromycin Zithromax
Macrolide 50- 75-300 mg 150- 167 mg 400 mg 200 mg Q12H Aztreonam
Azactam Monobactam 250- 300- 475- 450 mg 1000 mg 900 mg 750 mg Q8H
Cefazolin Ancef, Cephlasporin 250- 300- 575- 650 mg Kefzol (Gen I)
1000 mg 900 mg 700 mg Q8H Cefepime Maxipime Cephlasporin 125- 200-
575- 650 mg (Gen IV) 1000 mg 900 mg 700 mg Q12H Cefonicid Moniacid
Cephlasporin 250- 300- 575- 600 mg (Gen II) 1000 mg 900 mg 700 mg
Q24H Cefoperazone Cefobid Cephlasporin 250- 300- 575- 600 mg (Gen
III) 1000 mg 900 mg 700 mg Q12H Cefotaxime Claforan Cephlasporin
250- 300- 575- 600 mg (Gen III) 1000 mg 900 mg 700 mg Q8-12H
Cefotetan Cefotan Cephlasporin 250- 300- 575- 600 mg (Cephamycin)
1000 mg 900 mg 700 mg Q8-12H Cefoxitin Mefoxin Cephlasporin 250-
300- 575- 600 mg (Cephamycin) 1000 mg 900 mg 700 mg Q12H
Ceftazidime Fortaz, Cephlasporin 250- 300- 475- 550 mg Ceptaz (Gen
III) 1000 mg 900 mg 750 mg Q12H Ceftizoxime Cefizox Cephlasporin
250- 300- 575- 600 mg (Gen III) 1000 mg 900 mg 700 mg Q8-12H
Ceftriaxone Rocephin Cephlasporin 250- 300- 575- 650 mg (Gen III)
1000 mg 900 mg 700 mg Q12H Cefuroxime Ceftin Cephlasporin 100- 200-
250- 285 mg (Gen II) 600 mg 520 mg 400 mg Q8H Cephapirin Cefadyl
Cephlasporin 250- 300- 575- 650 mg (Gen I) 1000 mg 900 mg 700 mg
Q12H Ciprofloxacin Cipro Quinolone 25- 50-175 mg 75-110 mg 90 mg
200 mg Q12H Clindamycin Cleocin Lincosamide 50- 75-500 mg 125- 225
mg 600 mg 300 mg Q12H Doxycycline Vibramycin Tetracycline 10- 15-80
mg 25-65 mg 27 mg 100 mg Q12H Fluconazole Diflucan Antifungal 12.5-
20-70 mg 25-50 mg 30 mg 150 mg Q12H Gentamycin Garamycin
Aminoglycoside 10- 30-150 mg 80-120 mg 95 mg Q8- 200 mg 12H
Itraconzaole Sporanox Antifungal 12.5- 20-70 mg 25-50 mg 30 mg 150
mg Q12H Levofloxacin Levaquin Quinolone 40- 50-150 mg 60-80 mg 70
mg 200 mg Q12H Meropenem Merrin Carbapenem 200- 250- 300- 333 mg
750 mg 700 mg 500 mg Q8H Mezlocillin Mezlin Penicillin 300- 375-
750- 833 mg 1500 mg 1000 mg 950 mg Q6H Miconazole Monistat
Antifungal 12.5- 30-200 mg 50-100 mg 60 mg 300 mg Q12H Nafcilin
Nafcil Penicillin 100- 125- 250- 460 mg 1000 mg 750 mg 600 mg Q6H
Ofloxacin Floxin Quinolone 25- 50-175 mg 75-110 mg 90 mg 200 mg
Q12H Piperacillin Pipracil Penicillin 100- 125- 250- 460 mg 1000 mg
750 mg 600 mg Q6H Rifampin Rafadin Miscellaneous 500- 1000- 1500-
2250 mg 5000 mg 4000 mg 3500 mg Q12H Ticarcillin + Timentin
Penicillin 500- 1000- 1500- 2250 mg Clavulanate 5000 mg 4000 mg
3500 mg Q6-8H Tobramycin Nebcin Aminoglycoside 10- 30-150 mg 80-120
mg 95 mg Q8- 200 mg 12H Vancomycin Vancocin Antifungal 50- 75-325
mg 125- 166 mg 400 mg 250 mg Q6-8H
* * * * *
References