U.S. patent application number 10/660841 was filed with the patent office on 2004-03-18 for novel composition and method for treatment of upper respiratory conditions.
Invention is credited to Smith, C. Steven.
Application Number | 20040053902 10/660841 |
Document ID | / |
Family ID | 31994174 |
Filed Date | 2004-03-18 |
United States Patent
Application |
20040053902 |
Kind Code |
A1 |
Smith, C. Steven |
March 18, 2004 |
Novel composition and method for treatment of upper respiratory
conditions
Abstract
Provided are compositions and methods useful for the
non-addictive treatment and prevention of upper respiratory
conditions in man and animals, e.g., allergic, non-allergic and
mixed rhinitis in man or pharyngitis and IAD in horses.
Compositions of the invention comprise effective amounts of a
suitable nasal decongestant; a suitable corticosteroid; and a
suitable anticholinergic agent. The compositions and methods
provided are especially useful for long term use in patients with
mixed rhinitis and substantially reduce or eliminate the risk of
rhinitis medicamentosa. The compositions and methods of treatment
provided also eliminate the risk of adverse sequella seen from
therapeutic regimens which employ systemic use of decongestants.
The compositions provided can further comprise a suitable aromatic
and/or a suitable antihistamine and may also comprise optional
suitable antimicrobials, cytokine modulators, leukotriene
antagonists, cromolyn sodium, or a suitable NDAID agent.
Inventors: |
Smith, C. Steven;
(Louisville, KY) |
Correspondence
Address: |
STOCKWELL & ASSOCIATES, PSC
861 CORPORATE DRIVE, SUITE 201
LEXINGTON
KY
40503
US
|
Family ID: |
31994174 |
Appl. No.: |
10/660841 |
Filed: |
September 12, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60410661 |
Sep 13, 2002 |
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Current U.S.
Class: |
514/171 |
Current CPC
Class: |
A61K 31/573 20130101;
A61K 45/06 20130101 |
Class at
Publication: |
514/171 |
International
Class: |
A61K 031/573 |
Claims
What is claimed is:
1. A composition useful for the non-addictive treatment and/or
prevention of an upper airway condition in a subject, the
composition comprising effective amounts of a suitable nasal
decongestant; a suitable corticosteroid; and a suitable
anticholinergic agent.
2. The composition of claim 1, wherein the subject is a human.
3. The composition of claim 2, wherein the upper airway condition
is rhinitis.
4. The composition of claim 3, wherein the rhinitis is selected
from the group consisting of allergic rhinitis, non-allergic
rhinitis and mixed rhinitis.
5. The composition of claim 1, wherein the subject is an
animal.
6. The composition of claim 5, wherein the animal is selected from
the group consisting of a horse, a dog and a cat.
7. The composition of claim 6, wherein the animal is a horse and
the upper airway condition is pharyngitis.
8. The composition of claim 1, wherein the composition is a
liquid.
9. The composition of claim 8, wherein the composition is a liquid
and at least a selected one of the suitable nasal decongestant, the
suitable corticosteroid or the suitable anticholinergic agent is in
solution in the composition.
10. The composition of claim 1, wherein the suitable nasal
decongestant is selected from the group consisting of oxymetazoline
hydrochloride, phenylephrine hydrochloride, phenylpropolamine
hydrochloride, pseudophedrine and combinations thereof.
11. The composition of claim 10, wherein the suitable nasal
decongestant is oxymetazoline hydrochloride and the effective
amount is from between about 0.25 ml to about 4.0 ml of a 0.05%
solution of oxymetazoline hydrochloride.
12. The composition of claim 11, wherein the effective amount is
about 2.0 ml of a 0.05% solution of oxymetazoline
hydrochloride.
13. The composition of claim 1, wherein the suitable corticosteroid
is selected from the group consisting of betamethazone
dipropionate, flunisolide, triamcinolone acetate, fluticasone
propionate and hydrocortisone.
14. The composition of claim 13, wherein the suitable
corticosteroid is triamcinolone acetate and the effective amount is
from between about 3.0 ml to about 24.0 ml of a 0.25 gram/ml
solution of triamcinolone acetate.
15. The composition of claim 14, wherein the effective amount is
about 6.0 ml of a 0.25 gram/ml solution of triamcinolone
acetate.
16. The composition of claim 13, wherein the suitable
corticosteroid is betamethasone dipropionate and the effective
amount is from between about 3.0 ml to about 24.0 ml of a 84
meq/0.1 ml solution of betamethasone dipropionate.
17. The composition of claim 16, wherein the effective amount is
about 6 ml of a 84 meq/0.1 ml solution of betamethasone
dipropionate.
18. The composition of claim 13, wherein the suitable
corticosteroid is budesonide and the effective amount is from
between about 3.0 ml to about 24.0 ml of a 384 meq/ml solution of
budesonide.
19. The composition of claim 18, wherein the effective amount is
about 5 ml of a 384 meq/ml solution of budesonide.
20. The composition of claim 13, wherein the suitable
corticosteroid is flunisolide and the effective amount is from
between about 3.0 ml to about 24.0 ml of a 0.025% solution of
flunisolide.
21. The composition of claim 20, wherein the effective amount is
about 11 ml of a 0.025% solution of flunisolide.
22. The composition of claim 13, wherein the suitable
corticosteroid is fluticasone propionate and the effective amount
is from between about 3.0 ml to about 24.0 ml of a 100 meq/ml
solution of fluticasone propionate.
23. The composition of claim 22, wherein the effective amount is
about 10 ml of a fluticasone propionate solution such that the
final concentration of fluticasone propionate in the composition is
about 100 meq/0.10 ml.
24. The composition of claim 13, wherein the suitable
corticosteroid is mometasone furonate monohydrate and the effective
amount is from between about 5.0 ml to about 40.0 ml of a 0.05%
solution of mometasone furonate monohydrate.
25. The composition of claim 24, wherein the effective amount is
about 10 ml of a 0.05% solution of mometasone furonate monohydrate
such that the final concentration of mometasone furonate
monohydrate in the composition is about 100 meq/0.10 ml.
26 The composition of claim 1, wherein the suitable anticholinegic
agent is selected from the group consisting of atropine,
scopolomine, ipratropium bromide and combinations thereof.
27. The composition of claim 26, wherein the suitable
anticholinergic agent is ipratropium bromide and the effective
amount is from between about 1.25 ml to about 12.0 ml of a 42
meq/ml solution of ipratropium bromide.
28. The composition of claim 27, wherein the effective amount is
about 5 ml of a 42 meq/ml solution of ipratropium bromide.
29. The composition of claim 1, further comprising an effective
amount of a suitable antihistamine.
30. The composition of claim 30, wherein the suitable antihistamine
is selected from the group consisting of cetirizine,
chlorpheniramine, diphenhydramine, dexchloropheniramine,
astemizole, azelastine hydrochloride, acrivastine, loratadine,
terfenadine, cyproheptidine and combinations thereof.
31. The composition of claim 30, wherein the suitable antihistamine
is azelastine hydrochloride and the effective amount is from
between about 1.25 ml to about 7.5 ml of a 0.1% solution of
azelastine hydrochloride.
32. The composition of claim 31, wherein the effective amount is
about 5 ml of a 0.1% solution of azelastine hydrochloride.
33. The composition of claim 1, further comprising an effective
amount of a suitable antimicrobial agent.
34. The composition of claim 33, wherein the suitable antimicrobial
agent is selected from the group consisting of an antibiotic, an
antibacterial, an antifungal, an antiviral and combinations
thereof.
35. The composition of claim 1, further comprising an effective
amount of a suitable cytokine modulator.
36 The composition of claim 35, wherein the cytokine modulator is
selected from the group consisting of pimecrolimus, tacrolimus,
zileuton and combinations thereof.
37. The composition of claim 1, further comprising an effective
amount of a suitable antileukotriene or a leukotriene receptor
antagonist.
38. The composition of claim 37, wherein the suitable leukotriene
receptor antagonist is selected from the group consisting of
montelukast sodium, zafirulakast and combinations thereof.
39. The composition of claim 1, further comprising an effective
amount of cromolyn sodium.
40. The composition of claim 1, further comprising an effective
amount of nedocromil sodium.
41. The composition of claim 1, further comprising an effective
amount of a suitable non-steroidal anti-inflammatory agent.
42. The composition of claim 41, wherein the suitable non-steroidal
anti-inflammatory agent is selected from the group consisting of
acetominophen, ibuprofen, ketofen, rofecoxib, celecoxib, flunixin
meglumine and combinations thereof.
43. The composition of claim 1, wherein a suitable non-steroidal
anti-inflammatory agent is substituted for the suitable
corticosteroid in the composition.
44. The composition of claim 1, further comprising an effective
amount of a suitable aromatic agent.
45. The composition of claim 44, wherein the suitable aromatic
agent is selected from the group consisting of camphor, menthol,
eucalyptus and combinations thereof.
46. A method for the non-addictive treatment and/or prevention of
an upper airway condition in a subject comprising administering to
the subject an effective amount of a composition comprised of
effective amounts of a suitable nasal decongestant; a suitable
corticosteroid; and a suitable anticholinergic agent.
47. The method of claim 46, wherein the subject is a human.
48. The method of claim 47, wherein the upper airway condition is
rhinitis.
49. The method of claim 48, wherein the rhinitis is selected from
the group consisting of allergic rhinitis, non-allergic rhinitis
and mixed rhinitis.
50. The method of claim 46, wherein the subject is an animal.
51. The method of claim 50, wherein the animal is selected from the
group consisting of a horse, a dog and a cat.
52. The method of claim 51, wherein the animal is a horse and the
upper airway condition is pharyngitis.
53. The method of claim 46, wherein the composition is administered
topically.
54. The method of claim 46, wherein the composition is administered
intranasally.
55. The method of claim 46, wherein the composition further
comprises an effective amount of a suitable antihistamine.
56. The method of claim 46, wherein the composition further
comprises an effective amount of a suitable antimicrobial
agent.
57. The method of claim 46, wherein the composition further
comprises an effective amount of a suitable cytokine modulator.
58. The method of claim 46, wherein the composition further
comprises an effective amount of a suitable antileukotriene or a
leukotriene receptor antagonist.
59. The method of claim 46, wherein the composition further
comprises an effective amount of cromolyn sodium.
60. The method of claim 46, wherein the composition further
comprises an effective amount of nedocromil sodium.
61. The method of claim 46, wherein the composition further
comprises an effective amount of a suitable non-steroidal
anti-inflammatory agent.
62. The method of claim 46, wherein a suitable non-sterioidal
anti-inflammatory agent is substituted for the suitable
corticosteroid in the composition.
63. The method of claim 46, wherein the composition further
comprises an effective amount of a suitable aromatic agent.
Description
[0001] This application claims the benefit of priority in
provisional application serial No. 60/410,661 filed on Sep. 13,
2002.
FIELD OF THE INVENTION
[0002] The present invention generally relates to the treatment
and/or prevention of upper respiratory pathology and/or disease in
humans (and other susceptible animals). In particular, the present
invention relates to novel compositions, for the acute treatment
and also the long term treatment and/or prevention of mixed
rhinitis in man and in animals which does not predispose the
patient to development of rhinitis medicamentosa.
BACKGROUND OF THE INVENTION
[0003] Rhinitis is a term used to describe the symptom complex
related to irritation and inflammation of the nasal passageways
(see, e.g., Middleton's Allergy Principles & Practice Volume II
Fifth Edition Copyright 1998). Rhinitis affects 50 to 60 million
Americans and the prevalence of allergic rhinitis has increased
dramatically over the past 30 years.
[0004] Patients with rhinitis may experience a variety of symptoms
including sneezing, rhinorrhea, nasal itching, congestion, and/or
postnasal drainage. As a result, patients with these symptoms often
experience headaches, fatigue, impaired concentration, reduced
productivity, loss of sleep, increased occupational risk, increase
in asthma, sinusitis, and otitis, and decreased emotional well
being and social functioning (see, e.g., "Advice From Your
Allergist" published by American College of Allergy, Asthma &
Immunology, revised July 2000). Occasionally, children with chronic
rhinitis develop altered facial growth and orthodontic problems.
(See Table 1)
1TABLE 1 Symptoms and Complications of Rhinitis Symptoms Rhinorrhea
Nasal congestion Sneezing Pruritus Postnasal drip Additional
Symptoms Headache Fatigue Cognitive impairment Complications
Disturbances of facial growth and development Dental malocclusions
Otitis media Sinusitis Disturbance of taste and smell Sleep apnea
and sleep interruption Activation of nasal-bronchial reflexes Table
Source. "Clinician's Manual on Rhinitis: Both Allergic and
Nonallergic", Published by Science Press, Copyright 2001
[0005] The financial impact is also very significant. Health care
expenditures in 1996 were estimated to be 6 billion dollars and
this figure does not include the indirect cost of the 3.5 million
loss work days and 2 million loss school days (See, Tables
2-3).
2TABLE 2 Direct and Indirect Cost Estimates for Allergic Rhinitis
(1994) Direct Costs Ambulatory visits 301,371,342 Emergency
department 17,730,879 Total Direct Costs $1,147,258,636 Office and
clinic 648,341,417 Hospital outpatient 179,814,998 Indirect Costs
Work-associated productivity loss 46,793,667 School-associated
productivity loss 16,656,697 Restricted-activity-associated
productivity loss 22,959,642 Total Indirect Costs $86,410,006 Total
Costs $1,233,668,642 Table Source. Clinician's Manual on Rhinitis.
Both Allergic and Nonallergic, Published by Science Press,
Copyright 2001
[0006]
3TABLE 3 Medical Expenditures Attributable to Allergic
Rhinitis/Conjuctivitis and Related Airway Disorders (1996
US$/Millions) Allergic rhinitis/ +514 937.1 260.5 .sctn. 72.6 593.2
1863.4 conjunctivitis Chronic otitis media and 49.6 540.1 232.8
14.7 326.4 320.2 1483.5 eustachian tube disorder Sinusitis 88.2
436.0 117.1 3.0 78.3 294.6 1017.3 Asthma 523.4 156.3 84.4 .sctn.
86.0 156.5 1006.7 Acute upper respiratory 12.8 82.3 30.7 .sctn.
36.4 49.1 211.8 infection Phyaryngitis and 7.8 63.7 21.4 0.1 36.8
35.9 165.7 tonsilitis Other conjunctivitis .sctn. 33.2 16.0 0.3
20.3 18.2 88.0 Chronic rhinitis .sctn. 30.1 8.9 .sctn. 3.7 19.6
62.3 Rhinorrhea .sctn. 19.7 .sctn. 1.0 .sctn. 11.4 32.0 TOTAL 681.8
2299.0 771.8 19.1 660.5 1498.5 5930.7 *Included prescribed and
over-the-counter medications ordered during visits to the
physician's office, hospital outpatient department or emergency
department. Did not include refills. .sctn. Nonsignificant
expenditures according to criteria of the National Center for
Health Statistics. Table Source: "Clinican's Manual on Rhinitis:
Both Allergic and Nonallergic" Published by Science Press,
Copyright 2001
[0007] Chronic rhinitis, (rhinitis of greater than 6 weeks
duration), is among the most common problem presenting to primary
care physicians. Rhinitis can be caused by an allergy to inhalants,
i.e., pollen, mold, animal dander and allergy to foods (58 million
Americans). Non-allergic causes including strong odors, sudden
temperature changes, alcohol ingestion, airborne irritants,
skiing/jogging, pregnancy, spicy foods, and certain medications
(e.g., topical agents such as certain alpha-adrenergic
vasoconstrictors, cocaine, eye drops and oral agents such as
antihypertensives, birth control pills, and certain phenothiazines)
affect approximately 19 million Americans. Forty-four percent of
the patients with allergic rhinitis have concomitant non-allergic
rhinitis. This later group of patients with mixed rhinitis
represents an estimated 26 million people in the United States.
Prior to the present invention, however, there has not been an
effective single entity medication for treatment and/or prevention
of mixed rhinitis in patients.
[0008] The attached flowchart (See, FIG. 1) is useful in
establishing a pattern for pharmacalogic therapy for mixed
rhinitis, which embraces an integrated approach (Figure Source:
"Middleton's Allergy Principles & Practice", Vol. II, 5.sup.th
Edition, Copyright 1998). Currently, there are many single entry
topical medications for treatment of allergic rhinitis. Nasal
steroids, which top the list, (See, Table 5 below) help both the
immediate and late phase response by modulating the production and
effects of the ever-growing family of cytokines. Recently,
cytokines have been shown to play a role in non-allergic rhinitis
pathophysiology as well.
[0009] The diagnosis of mixed rhinitis is made when patients are
known to have allergic rhinitis but their symptoms are clearly
worsened by non-allergic triggers. Mixed rhinitis is one of the
more difficult entities to treat, probably because of the great
variety of provocative stimuli and its unremittingly perennial
nature. Patients with mixed rhinitis may also already have an
iatrogenic addiction to topical decongestants (rhinitis
medicamentosa), chronic sinusitis, and/or nasal polyps as a result
of their long-standing illness.
[0010] Empiric treatment with a topical broad based agent that is
indicated for allergic rhinitis and non allergic rhinitis is a
reasonable choice for first line therapy, but most patients need
immediate relief of their symptoms to reinforce their long term
plan with short term relief (see, e.g., Clinician's Manual on
Rhinitis: Both Allergic and Nonallergic, published by Science
Press, Copyright 2001). Topical decongestants fit this need, but
used alone, they can induce rhinitis medicamentosa (iatrogenic
rhinitis). Botanical agents which cool the nasal membranes such as
menthol, camphor and eucalyptus give an immediate sensation of
improved airflow. Interestingly, this sensation occurs without any
actual change in nasal airway diameter or restriction. Thus, there
is a subjective feeling of improvement with immediate results from
the patient's perspective gives the patient the "security" of being
able to breathe more easily (see, e.g., "Asthma and Rhinitis"
edited by William W. Busse, & Stephen T. Holgate, published by
Blackwell Science, Copyright 1995).
[0011] When it is not possible to definitively diagnose the type of
rhinitis present (i.e, allergic vs. non-allergic), emphasis on
broad based treatment should be considered. At present all of these
broad based treatment components are available only as single
entity formulations, i.e., single entity topical steroids, single
entity topical decongestants (some with cooling aromatic
components), single entity topical antihistamines or topical
anticholinergic agents. Thus, there is a need in the art for a
fixed integrated pharmacotherapy composition which can effectively
treat the allergic as well as the non-allergic components of mixed
rhinitis without harmful sequella, e.g., rhinitis medicamentosa.
Prior to the present invention there had been no formulation useful
for treatment of acute mixed rhinitis which combined effective
amounts of a suitable nasal decongestant and a suitable
corticosteroid that can also be used on a long term basis without
inducing long term use complications such as rhinitis
medicamentosa. The cost and compliance benefits of a such a
composition are also of undeniable importance.
[0012] Presently, when long-term decongestant use is indicated,
physicans must rely on systemic decongestants to avoid the adverse
effects of long term topical use. Systemic therapy with
decongestants can also produce adverse effects including;
nervousness, insomnia, irritability headache, palpitations,
tachycardia, hypertension, glaucoma, and decreased urinary flow as
well as sexual dysfunction in males which greatly limits the use of
oral decongestants. One of the only three alpha-adrenergic agonists
available, phenylpropanolomine, was recently removed from the
market because of fatal cardiovascular events related to its use,
further limiting this choice of therapy. With only two systemic
decongestants left, the therapy dilemma is even more complicated.
Accordingly, there is a need in the art for a topical composition
(as provided by the present invention) which can immediately
alleviate congestion and can also be used on a long term basis
without the risk of developing rhinitis medicamentosa or the risk
adverse effects encountered with systemic decongestant therapy. The
novel compositions provided by the present invention combine the
use of topical nasal decongestant with an anti-inflammatory agent
(topical steroid) and substantially eliminates the risk of rhinitis
medicamentosa and concomitantly eliminates the risk of systemic
decongestant use.
[0013] Likewise, in animals, especially companion animals such as
dogs, cats and horses, there exists a need in the art for a
composition adapted for topical administration and or nebulization
which can effectively treat upper respiratory conditions in
patients suffering from allergies, and/or infectious/inflammatory
disorders such as inflammatory airway disease (IAD) and/or mixed
rhinitis and that also may be used for treatment of lower
respiratory conditions, e.g., recurrent airway obstruction
(heaves). In horses, especially competition animals such as racing
thoroughbreds, for example, inflammatory airway disease and/or
upper respiratory inflamation can be troublesome and economically
devastating. Pharyngitis, sinusitis and guttural pouch inflammation
and/or infection if not properly treated can become a chronic
manifestation in training animals and decrease performance.
Inflammatory airway disease and pharyngitis or mixed rhinitis is
often observed in young athletic horses, e.g., in two year olds in
training. Mechanical irritation from breathing cold air in
conjunction with environmental contaminants (dust, mold spores and
the like) with or without an infectious component can predispose
the animal to a lingering bout with upper airway inflammation such
as pharyngitis or inflammatory airway disease. Clinical signs may
be subtle and are often manifested as a chronic cough, excess mucus
in the trachea and poor performance. Otherwise, the animal may have
a normal attitude and appetite.
[0014] Treatment approaches to upper airway disease in the horse
have largely been directed at treatment of the inflammation and
broncho constriction which manifest especially with IAD.
Aerosolized therapy with anti-inflammatory agents such as
corticosteroids has been tried via nebulization or metered dose
inhalation (MDI). In addition, bronchodilators such as albuterol
have been used with some measure of success and also
immunostimulants and antibiotic have been advocated. Treatment of
pharangitis and gutteral pouch inflammation has been directed to
various throat washes and lavages such as e.g., sodium iodide with
or without DMSO. These may be used in conjunction with systemic
antibiotic and or corticosteroid or other systemic
anti-inflammatory agents such as NSAIDs, e.g., phenylbutazone or
flunixin megulamine. However, prior to the present invention there
has not been a single entity medication adapted for direct topical
application which utilizes a unique combination of active agents
for the effective treatment of upper airway disease in animals.
SUMMARY OF THE INVENTION
[0015] The present invention provides compositions and methods
useful for the non-addictive treatment and/or prevention of
allergic, non-allergic and mixed rhinitis. In one embodiment, the
compositions of the invention are comprised of effective amounts of
a suitable nasal decongestant; a suitable synthetic or
non-synthetic corticosteroid; and a suitable anticholinergic
agent.
[0016] The compositions and methods provided by the invention may
be used for relief of acute symptoms of allergic as well as
non-allergic rhinitis, but are especially useful for long term use
in patients with mixed rhinitis. The compositions and methods of
the invention can be used for treatment and/or prevention of mixed
rhinitis on a long term basis and substantially reduce or eliminate
the risk of the patient developing rhinitis medicamentosa (e.g., as
currently is frequently seen with long term use of the presently
available topical nasal decongestant formulations). The
compositions and methods of treatment provided by the invention
also eliminate the risk of adverse sequella seen from therapeutic
regimens which employ the systemic use of decongestants.
[0017] In one embodiment of the invention, the compositions
provided can further comprise a suitable aromatic, e.g., a
Botanical agent such as camphor, menthol or eucalyptus. Yet another
embodiment of the invention, provides the compositions for
treatment and/or prevention of allergic, non-allergic and/or mixed
rhinitis which may further comprise an effective amount of a
suitable antihistamine.
[0018] Another embodiment of the invention provides compositions
comprised of effective amounts of a suitable nasal decongestant; a
suitable corticosteroid; a suitable anticholinergic agent and a
suitable antihistamine with or without the addition of a suitable
aromatic agent. The core compositions of the invention comprised of
a suitable nasal decongestant; a suitable corticosteroid and a
suitable anticholinergic agent may further comprise optional
suitable antimicrobials (antibiotics and/or antifungal and/or
antiviral agents); cytokine modulators and/or inhibitors;
leukotriene antagonists cromolyn sodium and/or a suitable NSAID
agent.
[0019] The compositions of the invention are also useful for the
long term treatment of sequella (e.g., constricted upper airway) in
patients suffering from sleep apnea and receiving treatment with a
constant positive pressure airway (CPAP) machine.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The present invention provides compositions and methods for
the treatment and/or prevention of upper respiratory pathology
and/or disease in man and in animals. The compositions provided
herein can be used to treat and/or prevent any of a variety of
upper respiratory conditions in man and animals including, but not
limited to, allergic, non-allergic and mixed conditions having both
allergic and non-allergic components (See, e.g., Table 4). In
particular, the methods and compositions provided herein are useful
in man for treatment and prevention of both acute and chronic
manifestations of allergic, non-allergic and mixed rhinitis.
4TABLE 4 Differential Diagnosis of Rhinitis Allergic Rhinitis
Seasonal Perennial Non-allergic Rhinitis Vasomotor NARES Rhinitis
medicamentosa Topical agents (alpha-adrenergic vasoconstrictors,
cocaine, eye drops) Oral agents (antihypertensives, birth control
pills, phenothiazines) Endocrine-induced Pregnancy Hypothyroidism
Acromegaly Acute cholinergic-induced Gustatory Skier's/jogger's
nose Chronic sinusitis Nasal polyposis Anatomical obstruction
Tumors, granulomas, sarcoid Wegener's Septal deviation Septal
perforation Cerebrospinal leakage Atrophic Mixed Rhinitis (allergic
and non-allergic) Table Source. "Clinician's Manual on Rhinitis:
Both Allergic and Nonallergic", Published by Science Press,
Copyright 2001
[0021] In one embodiment, the compositions of the invention are
adapted for topical, e.g., intranasal use and may be used in
patients on a long term basis (for therapy of chronic or recurring
upper respiratory conditions requiring daily or as needed, PRN,
treatment) with a substantially reduced risk of adverse side
effects such as rhinitis medicamentosa. Thus, the present invention
also particularly provides methods of use for the novel
compositions, for acute as well as long term treatment and/or
prevention of upper respiratory conditions (e.g., mixed rhinitis in
man and pharyngitis in animals) which does not predispose the
patient to development of iatrogenic rhinitis (rhinitis
medicamentosa).
[0022] In one embodiment, the present invention provides a
composition that is useful for the non-addictive treatment and/or
prevention of allergic, non-allergic and/or mixed rhinitis
comprised of effective amounts of a suitable nasal decongestant; a
suitable synthetic or non-synthetic corticosteroid; and a suitable
anticholinergic agent. Examples of suitable nasal decongestants
include, but are not limited to, any of a number of nasal
decongestants that are currently used in prescription and over the
counter preparations. Specific examples of suitable nasal
decongestants include, but are not limited to, oxymetazoline,
phenylephrine hydrochloride, phenylpropolamine hydrochloride,
pseudophedrine and the like. Other examples of suitable
decongestants (as well as other required agents, i.e., suitable
corticosteroids and anticholinergic agents) that are adaptable for
topical intranasal use can be found e.g., in Middleton, Elliott,
Jr. et al., "Allergy Principles and Practice", 5.sup.th Ed.,
Volumes I & II, Mosby-Year Book, Inc. (1988)) (ISBN
0-8151-0072-8) the contents of which are incorporated herein by
reference in its entirety. (See also, The Physicians Desk Reference
56.sup.th Ed., Medical Economics, Inc. (2002) (ISBN: 156363-411-2)
and also, The Physicians Desk Reference For Nonprescription Drugs
And Dietary Supplements, 21.sup.st Ed., Medical Economics, Inc.
(2000) (ISBN: 156363-341-8) also incorporated herein by reference
in their entirety).
[0023] Examples of suitable corticosteroids (or
glucocorticosteroids) include, but are not limited to,
betamethazone dipropionate, flunisolide, triamcinolone acetonide,
fluticasone propionate, hydrocortisone, and the like. It is
contemplated that any of the class of cortisone agents that are
adaptable to localized (e.g., topical, intranasal) delivery can be
utilized in the compositions set forth herein. (See Table 5 below)
Anticholinegic agents which are suitable for use in the
compositions provided by the present invention included, but are
not limited to atropine, scopolomine, ipratropium bromide and the
like.
5TABLE 5 Intranasal Corticosteroids for Rhinitis Available in the
United States Formu- Age Molecule Trade Name lation (Years) Dosage
Beclomethasone Beconase, MDI 6-12 1 spray/nostril Vancenase 3 x/day
12+ 1 spray/nostril 2-4 x/day Belcomethasone Beconase AQ, Aqueous
6+ 1-2 spray/ Vancenase AQ nostril 2 x/day Budesonide Rhinocort MDI
6+ * 4 spray/nostril 1 x/day or 2 spray/nostril 2 x/day
Dexamethasone Dexacort in MDI 6-12 1-2 spray/ Turbinaire ** 12+
nostril 2 x/day 2 spray/nostril 2/3 x/day Flunisolide
Nasarel{circumflex over ( )} Solution 6+ 2 spray/nostril 2 x/day or
1 spray/nostril 3 x/day Fluticasone Flonase Aqueous 12+ 2
spray/nostril once/day Mometasone Nasonex Aqueous 12+ 2
spray/nostril once/day Triamcinolone Nasacort MDI 12+ 2
spray/nostril once/day Triameinolone Nasacort AQ Aqueous 6+ 2
spray/nostril once/day Triamcinolone Trinasal Solution 6+ 2
spray/nostril once/day MDI- Metered Dose Inhaler {circumflex over (
)} Reformulation of Nasalide with less propylene glycol * Not
recommended for perennial nonallergic rhinitis in children **
Indicated for "allergic or inflammatory nasal conditions and nasal
polyps" Table Source: "Middleton's Allergy Principles &
Practice", Vol. II, 5.sup.th Edition, Copyright 1998
[0024] In general, it is preferable that the compositions of the
invention be adapted for localized, e.g., intranasal delivery, with
the active agents in a solution suitable for spraying or misting or
other direct topical application. However, as can be appreciated,
other variations such as powders and the like are possible and are
within the scope of the invention. A presently preferred method of
localized delivery of the compositions is via intranasal
administration of a fine mist utilizing a standard metered dose
pump, which can be calibrated to deliver an exact amount of the
solution per administration, e.g., 0.1 ml per pump. It can also be
appreciated that other forms of application are possible and are
within the scope of the invention.
[0025] Given the many possible combinations of the required classes
of active agents that are possible, it can be appreciated by one of
skill in the art that the effective amount for any particular
component of the compositions of the invention can vary depending
upon the agent and/or the combination of agents selected, the
condition being treated and the therapeutic regimen that is
desired. However, given the teachings set forth herein one of skill
in the art can optimize the effective amount of a given active
agent given the identity of the other required agents of the
combination for the compositions of the invention, the subject and
condition being treated and the desired therapeutic regimen.
[0026] Thus, in one embodiment, a core combination of effective
amounts of a suitable nasal decongestant; a suitable synthetic or
non-synthetic corticosteroid; and a suitable anticholinergic agent
are provided for the treatment of upper respiratory conditions in
man and in animals. It is contemplated that other active agents may
be added to the core compositions as desired. In particular, in
another embodiment of the invention, the compositions for treatment
and/or prevention of allergic, non-allergic and/or mixed rhinitis
set forth above may further comprise an effective amount of a
suitable aromatic agent such as e.g., camphor, eucalyptus, menthol
or the like.
[0027] In another embodiment of the invention, the compositions for
treatment and/or prevention of allergic, non-allergic and/or mixed
rhinitis set forth above may further comprise an effective amount
of a suitable antihistamine. Examples of suitable antihistamines
include, but are not limited to, cetirizine, chlorpheniramine,
diphenhydramine, dexchloropheniramine, astemizole, azelastine,
acrivastine, loratadine, terfenadine, cyproheptidine and the
like.
[0028] Also contemplated by the present invention are the optional
addition of suitable antibiotics and/or suitable antifungal agents
and/or antiviral agents to the core compositions, as desired. The
antibiotic and or antifungal agents can be selected from any of the
currently available antimicrobial agents useful for treatment of
upper respiratory infections. Examples of suitable antibiotics
include any of the antibiotics commonly used to treat upper
respiratory infections, e.g., penicillins, cephalosporins,
sulfonamides, neosporin, polysporin, mupirocin and the like. In
humans, it may be less desirable to utilize penicillin derivatives
due to allergic problems associated with their use. Examples of
suitable antifungal agents include, but are not limited to
miconazole, ketaconazole and the like. One of skill in the art may
also appreciate that other natural antimicrobial agents may be
utilized including but not limited to, e.g., pentisols such as
xylitol. Antimicrobial, e.g., antibiotic selection and dosage may,
of course, vary depending upon physician or veterinarian preference
and the infectious agent to be treated and the desired therapeutic
regimen.
[0029] Other agents which may be added to the core compositions of
the invention include, cytokine modulators or inhibitors and/or
antileukotrienes or leukotriene receptor antagonists. Examples of
cytokine modulators can include pimecrolimus, tacrolimus, zileuton
and the like. Examples of suitable leukotriene receptor antagonists
include, but are not limited to montelukast sodium, and
zafirulakast.
[0030] Cromolyn sodium (also known as sodium cromoglycrate (SCG))
and/or pryanoquinolones such as, e.g., nedocromil sodium, and other
mast cell stabilizers may also be added to the core compositions
set forth herein. Likewise, in certain instances, non-steroidal
anti-inflammatory agents such as, e.g., acetominophen, ibuprofen,
ketofen and/or Cox-2 inhibitors such as, e.g., rofecoxib or
celecoxib may be added to the core compositions of the invention.
To further reduce inflammation and in certain embodiments these
NDAID agents may be used in place of corticosteroid agents in the
core formulations. Anti-serotonin agents may also be utilized as an
adjunct to the core formulations.
[0031] In another embodiment, the invention provides a method for
the non-addictive treatment and/or prevention of allergic,
non-allergic and/or mixed rhinitis comprised of administering a
therapeutic and/or a preventative amount of a composition comprised
of a suitable nasal decongestant; a suitable synthetic or
non-synthetic corticosteroid; and a suitable anticholinergic agent.
In a presently preferred embodiment, the method comprises the
intranasal administration of the compositions set forth herein.
Depending upon the severity of the rhinitic condition, the
compositions may be administered 1.times./day or 2.times./day or as
needed for symptomatic relief.
[0032] In a presently preferred therapeutic regimen for treatment
of rhinitis, e.g., mixed rhinitis, the compositions of the
invention can be administered, e.g. as an intranasal spray, in a
split dosage fashion wherein a first treatment can be administered
to relieve the acute nasal congestion and decrease swelling of
nasal passages. The first administration is followed up by a second
administration of the nasal spray at a preselected time after the
first administration to provide a more long term and effective
relief of the mixed rhinitis being treated. For example, a first
administration of the composition is administered to the subject
and a second administration is followed at between about 5 and
about 45 minutes but preferably at about 10-15 minutes following
the first administration. This split dosage regimen can be repeated
daily or 2.times./day or as needed to control or provide
symptomatic relief of the rhinitic condition being treated.
EXAMPLE OF A PRESENTLY PREFERRED EMBODIMENT
[0033] A Novel Composition for the Treatment of Allergy
Symptoms:
[0034] Allergy-Sinus Total Coverage Nasal Spray
[0035] An Allergy-Sinus "Total Control" Nasal Spray composition is
provided which is comprised of:
[0036] 1. 2.0 cc of 0.05% Oxymetazoline HCl with
[0037] Q/S Camphor &/or
[0038] Q/S Eucalyptol &/or
[0039] Q/S Menthol for desired Aromatic Cooling Affect
[0040] (the volume, and thus the concentration of Oxymetazoline HCl
in the final composition can range from about 0.25 cc to about 4 cc
of a 0.05% solution);
[0041] 2. 5 cc Ipratropium Bromide @ 42 meq/0.1 cc
[0042] (the volume, and thus the concentration of Ipratropium
Bromide in the final composition can range from about 1.25 cc to
about 12 cc of a 42 meq/0.1 cc solution); and
[0043] 3. Add only one of the items listed below:
[0044] 1. 6 cc of 0.25 gm/cc Triamcinolone Acetate with buffers,
stabilizers & surfactants (the volume, and thus the
concentration of Triamcinolone Acetate in the final composition can
range from about 3 cc to about 24 cc of a 0.25 gm/cc solution);
or
[0045] 2. 6 cc of Betamethasone Dipropionate @ 84 meq/0.1 cc with
buffers, stabilizers & surfactants (the volume, and thus the
concentration of Betamethasone Dipropionate in the final
composition can range from about 3 cc to about 24 cc of a 84
meq/0.1 cc solution); or
[0046] 3. 5 cc Budesonide 384 meq/cc with buffers, stabilizers
& surfactants (the volume, and thus the concentration of
Budesonide in the final composition can range from about 3 cc to
about 24 cc of a 384 meq/cc solution); or
[0047] 4. 11 cc Flunisolide in 0.025% solution with buffers,
stabilizers & surfactants (the volume, and thus the
concentration of Flunisolide in the final composition can range
from about 3 cc to about 24 cc of a 0.025% solution); or
[0048] 5. 10 cc Fluticasone Propionate @ solution to allow 100 meq
per 0.10 cc (the volume, and thus the concentration of Fluticasone
Propionate in the final composition can range from about 3 cc to
about 24 cc of a 100 meq per 0.10 cc solution); and or
[0049] 6. 10 grams of 0.05% Mometasone Furoate Monohydrate to allow
100 meq per 0.10 cc (the volume, and thus the concentration of
Mometasone Furoate Monohydrate in the final composition can range
from about 5 cc to about 40 cc of a of 0.05% Mometasone Furoate
Monohydrate solution at 100 meq per 0.10 cc).
[0050] Optional:
[0051] 4. 5 cc Azelastine HCl in a 0.1% solution (0.137 mg) an
antihistamine helpful for extra allergy and vasomotor rhinitis
control may be added (the volume, and thus the concentration of
Azelastine HCl in the final composition can range from about 1.25
cc to about 7.5 cc of a of 0.1% Azelastine HCl solution)
[0052] The above composition, for example, can be useful for the
methods of treatment and or prevention of upper respiratory
conditions in man and in animals provided herein. However, it can
be appreciated by one of skill in the art that other of the
embodiments provided by the invention are, likewise, useful in the
methods set forth herein. For example, in one embodiment the
invention provides a composition useful in a method for the
non-addictive treatment and/or prevention of an upper airway
condition in a subject, comprising administering to the subject a
composition comprising effective amounts of a suitable nasal
decongestant; a suitable corticosteroid; and a suitable
anticholinergic agent. The subject can be a human or animal subject
and the upper airway condition can be, e.g., rhinitis (allergic,
non-allergic and mixed) in man or pharyngitis in horses. The
compositions set forth herein are also useful in methods of
treatment of other upper respiratory and respiratory conditions,
e.g., for treatment of inflammatory airway disease, heaves,
guttural pouch inflammation and/or infection and sinusitis in
horses.
[0053] In one embodiment, the compositions of the invention are
adapted for intranasal administration such as via spraying,
misting, or other direct topical application to the membranes or
the compositions can be adapted for inhalation via a metered dose
inhalation device or nebulization of the composition. The condition
being treated, will likely dictate the choice of administration.
For example, in humans suffering from mixed rhinitis, the
compositions may be administered by a metered dose inhaler or spray
or mist intranasal applicator. Whereas, in a horse, for example,
the route of administration for pharyngitis may be via direct
topical administration of the composition to the oropharynx via the
use of a catheter (e.g., a canine urinary catheter or the like) or
nasal cannula that is passed up the nasal passages such that the
tip of the catheter or cannula is adjacent the target pharyngeal
tissue and the composition is sprayed on topically. If, for
example, the condition being treated is an inflamed guttural pouch,
the catheter may be passed into the opening of the guttural pouch
and the composition delivered directly into the pouch such that the
membranous lining of the pouch is treated. Likewise, for IAD or
heaves, nebulization or a commercially available inhaler may be
employed. Examples of metered dose inhalers include the Equine
AeroMask (Canadian Monaghan, Ontario, Canada) or the Equine Haler
(Equine Healthcare APS, Hillerod, Denmark).
[0054] The frequency of administration for the methods set forth
herein will, of course, vary according to the subject being
treated, the condition and severity of the condition being treated
and the particular combination of active agents within the
composition. Given the teachings set forth herein and elsewhere,
the skilled artisan will be able to tailor a therapeutic regimen
suited to the individual being treated.
[0055] As set forth above, in one embodiment of the compositions of
the invention, the suitable nasal decongestant is oxymetazoline
hydrochloride and the effective amount of is oxymetazoline
hydrochloride is from between about 0.25 ml to about 4.0 ml of a
0.05% solution of oxymetazoline hydrochloride. Most preferably, the
effective amount of is oxymetazoline hydrochloride is about 2.0 ml
of a 0.05% solution of oxymetazoline hydrochloride added to the
composition.
[0056] Any of a number of suitable corticosteriods may be utilized
in the compositions of the invention. For example, in another
embodiment, the suitable corticosteroid is triamcinolone acetate
and the effective amount of triamcinolone acetate is from between
about 3.0 ml to about 24.0 ml of a 0.25 gram/ml solution of
triamcinolone acetate. Most preferably, the effective amount of
triamcinolone acetate is about 6.0 ml of a 0.25 gram/ml solution of
triamcinolone acetate added to the composition.
[0057] In yet another embodiment, the suitable corticosteroid of
the composition is betamethasone dipropionate and the effective
amount of betamethasone dipropionate is from between about 3.0 ml
to about 24.0 ml of a 84 meq/0.1 ml solution of betamethasone
dipropionate. More preferably, the effective amount of
betamethasone dipropionate is about 6 ml of a 84 meq/0.1 ml
solution of betamethasone dipropionate added to the composition. In
still another embodiment, the suitable corticosteroid is budesonide
and the effective amount of budesonide is from between about 3.0 ml
to about 24.0 ml of a 384 meq/ml solution of budesonide, but, most
preferrably, the effective amount of budesonide is about 5 ml of a
384 meq/ml solution of budesonide added to the composition. Still
another embodiment of the compositions of the invention comprises
the utilization of flunisolide as the suitable corticosteroid and
the effective amount of flunisolide is from between about 3.0 ml to
about 24.0 ml of a 0.025% solution of flunisolide, but, more
preferably the effective amount of flunisolide is about 11 ml of a
0.025% solution of flunisolide added to the composition.
[0058] In one embodiment, the suitable corticosteroid is
fluticasone propionate and the effective amount of fluticasone
propionate is from between about 3.0 ml to about 24.0 ml of a 100
meq/ml solution of fluticasone propionate. More preferably, the
effective amount of fluticasone propionate is about 10 ml of a
fluticasone propionate solution such that the final concentration
of fluticasone propionate in the composition is about 100 meq/0.10
ml. In another embodiment, the suitable corticosteroid is
mometasone furonate monohydrate and the effective amount of
mometasone furonate monohydrate is from between about 5.0 ml to
about 40.0 ml of a 0.05% solution of mometasone furonate
monohydrate. Preferably the effective amount of mometasone furonate
monohydrate is about 10 ml of a 0.05% solution of mometasone
furonate monohydrate such that the final concentration of
mometasone furonate monohydrate in the composition is about 100
meq/0.10 ml. One of skill in the art can appreciate that the
effective amount of corticosteroid will vary depending upon the
choice of corticosteroid, the subject and condition being treated
and the severity of the condition and the like. Given the teachings
she forth herein, the effective amounts and dosage can be optimized
by one of skill in the art.
[0059] In another embodiment, the suitable anticholinegic agent is
ipratropium bromide and the effective amount of ipratropium bromide
in the composition is from between about 1.25 ml to about 12.0 ml
of a 42 meq/ml solution of ipratropium bromide, but, more
preferably the effective amount of ipratropium bromide is about 5
ml of a 42 meq/ml solution of ipratropium bromide added to the
composition. In a presently preferred embodiment, the compositions
of the invention may further comprise an effective amount of
suitable antihistamine such as, e.g., an antihistamine selected
from the group consisting of cetirizine, chlorpheniramine,
diphenhydramine, dexchloropheniramine, astemizole, azelastine
hydrochloride, acrivastine, loratadine, terfenadine, cyproheptidine
or a combination thereof. In one preferred embodiemnt, the suitable
antihistamine is azelastine hydrochloride and the effective amount
of azelastine hydrochloride is from between about 1.25 ml to about
7.5 ml of a 0.1% solution of azelastine hydrochloride added to the
composition. More preferably, the effective amount of azelastine
hydrochloride is about 5 ml of a 0.1% solution of azelastine
hydrochloride added to the composition.
[0060] Contained herein are several citations to literature
references, the contents of which are hereby incorporated herein in
their entirety by reference. The foregoing descriptions of novel
and preferred embodiments of the invention have been presented for
purposes of illustration and description. The descriptions are not
intended to be exhaustive or to limit the invention to the precise
form disclosed. Obvious modifications or variations are possible in
light of the above testing. The embodiment was chosen and described
to provide the best illustration of the principles of the invention
and its practical application to thereby enable one of ordinary
skill in the art to utilize the invention in various embodiments
and with various modifications as are suited to the particular use
contemplated. All such modifications and variations are within the
scope of the invention as determined by the claims made in this
application when interpreted in accordance with the breadth to
which they are fairly, legally and equitably entitled.
* * * * *