# Patent

## Title
Formulations and methods for treating rhinosinusitis

## Abstract

The invention involves methods and formulations for treating or preventing rhinosinusitis, including fungus-induced rhinosinusitis in mammals. In one embodiment, the formulation of the present invention comprises a steroidal anti-inflammatory agent having a specific particle size distribution profile. The formulation may also comprise an antifungal agent, antibiotic or antiviral agent.

## Background
I. RELATED APPLICATIONS
The present application is a continuation-in-part of application Ser. No. 10/414,682 and application Ser. No. 10/414,756 now U.S. Pat. No. 7,811,606. Both applications were filed Apr. 16, 2003. Each application is incorporated herein by reference in its entirety.


II. FIELD OF THE INVENTION
The present invention relates to formulations and methods for treating rhinosinusitis in mammals (e.g., humans), including but not limited to fungus induced rhinosinusitis. The formulations of the present invention comprise a steroidal agent, such as fluticasone or beclomethasone, wherein the steroidal agent has a specific particle size distribution profile. The formulations may also comprise an antibiotic, antifungal agent or an antiviral agent, or any combination thereof. While the formulations of the present invention may take any form, preferably they are provided as a sterile, aqueous suspension or solution which can be administered intranasally to the nasal-paranasal mucosa via spray pump. Also, the steroidal agent may be administered alone or in conjunction with an antifungal agent, antibiotic or antiviral agent.
III. BACKGROUND OF THE INVENTION
Rhinosinusitis is generally described as an inflammation of the nasal cavity and/or paranasal sinuses and involves the nasal mucosa. Chronic rhinosinusitis (CRS) is diagnosed when signs or symptoms of inflammation persist for 8-12 weeks or longer. It is estimated that one out of every seven Americans suffers from chronic rhinosinusitis (CRS). Symptoms of CRS include nasal obstruction, loss of sense of smell, nasal or postnasal discharge, nasal congestion, and facial pain/pressure (typically over the affected sinus area).
CRS impairs normal physical and social functioning, and patients with CRS typically suffer from an overall poor quality of life. Moreover, CRS is often associated with other co-morbid conditions such as asthma, eczema and other media. Asthma is found in 20-35% of patients with CRS, and CRS is found in up to 75% of moderate-to severe asthmatics.
It is now known that rhinosinusitis may be caused by fungi found in mucus. It is believed that some persons have an immunologic response to certain fungi found in most, if not all, persons' mucus. This immunologic response causes activated white blood cells, eosinophils, to enter the mucus. The activated eosinophils release a major basic toxic protein into the mucus which attacks and kills the fungi, but damages the nose and sinus membranes as well. The major basic protein also injures the epithelium, which allows bacteria to infect the tissues.
One type of fungus-induced rhinosinusitis is allergic fungus rhinosinusitis (AFS). AFS is generally diagnosed by: (1) the presence of nasal polyps; (2) allergic mucin; (3) CRS evidenced by CT scan; (4) positive fungal culture or histology; and/or (5) allergy to fungi by history, skin prick test or serology. AFS often leads to or is associated with CRS.
Current treatments for fungus induced rhinosinusitis include antifungal medications to remove the antigenic burden. A topical or systemic corticosteroid may also be prescribed to control inflammation of the mucosal tissue associated with CRS. This inflammation is thought to contribute to tissue and bone destruction associated with CRS. Recently, it has been discovered that steroidal anti-inflammatories such as fluticasone propionate (FP) and beclomethasone dipropionate (BDP) having a particular particle size distribution profile provide increased bioavailability, increased efficacy and/or prolonged therapeutic effect when administered intranasally.
CRS may also be characterized by or associated with a chronic bacterial infection of the sinuses (nasal-paranasal region) which is often superimposed upon a self-perpetuating, eosinophil-rich inflammatory process in the sinuses. Currently, antibiotic therapy is indicated for up to six weeks or more for the treatment and elimination of the bacterial infection associated with CRS.
IV. SUMMARY OF INVENTION
The present invention relates generally to formulations and methods for treating rhinosinusitis in mammals (e.g., humans), including, but not limited to fungus-induced rhinosinusitis. In one embodiment, the formulations of the present invention comprise a steroid, alone or in combination with an antifungal agent or antibiotic. It is believed that treating the patient with an antifungal agent will sufficiently reduce the level of fungal organisms in the patient's mucus such that the one ore more of the symptoms of rhinosinusitis are prevented from developing, or are lessened, or are prevented from worsening.
In an embodiment, the present formulations comprise about 4 mg to about 30 mg of the anti-fungal agent amphotericin β. In an alternative embodiment, the formulation of the present invention comprises about 20 to about 70 mg of the anti-fungal agent fluconazole or itraconazole.
The present invention is also based on the realization that a patient or individual may have already developed one or more symptoms of rhinosinusitis, possibly CRS, when he or she first seeks the help of a physician or by the time that treatment is started. Thus, it would also be beneficial to provide an anti-inflammatory steroid to the patient to treat inflammation of the mucosal tissue associated with rhinosinusitis, since such inflammation might lead to or contribute to tissue and bone destruction in the nasal-paranasal region.
It has recently been discovered that certain steroidal anti-inflammatories having a specific particle size distribution profile provide increased bioavailability, increased efficacy or prolonged therapeutic effect when administered intranasally. In one embodiment, the formulation of the present invention comprises about 25 to about 400 mcg of the steroidal anti-inflammatory agent, including but not limited to, fluticasone, or a pharmaceutically acceptable derivative thereof, having the following particle size distribution profile: about 10% of the drug substance particles have a particle size of about 0.90 microns; about than 25% of the drug substance particles have a particle size of less than 1.6 microns; about 50% of the drug substance particles have a particle size of less than 3.2 microns; about 75% of the drug substance particles have a particle size of less than 6.10 microns; about 90% of the drug substance particles have a particle size of less than 10.0 microns.
In an alternative embodiment, the formulation of the present invention comprises about 0.2 to about 3 mg of the steroidal anti-inflammatory beclomethasone, or a pharmaceutically acceptable derivative thereof, having the following particle size distribution profile: about 10% of the drug substance particles have a particle size of about 0.75 microns; about than 25% of the drug substance particles have a particle size of less than 1.5 microns; about 50% of the drug substance particles have a particle size of less than 2.0 microns; about 75% of the drug substance particles have a particle size of less than 3.5 microns; about 90% of the drug substance particles have a particle size of less than 5.0 microns; and, greater than 90% or about 100% of the drug substance particles have a particle size of less than 10 microns.
In many instances the fungus-induced rhinosinusitis may be accompanied by, or associated with, a bacterial infection of the nasal-paranasal mucosa. In one embodiment, the formulations of the present invention comprise an antibiotic. In an alternative embodiment, the present formulations comprise about 1 to about 800 mg of the antibiotic neomycin sulfate.
The formulations of the present invention may be provided in any form which directly contacts the formulation with the nasal-paranasal mucosa. In one embodiment, the present formulation is provided as a sterile aqueous solution or suspension. In an alternative embodiment, the formulation is in a metered dose spray pump.
The present invention also generally relates to methods for treating rhinosinusitis, including fungus-induced rhinosinusitis. In one alternative embodiment, an individual suffering from rhinosinusitis may be administered a steroidal agent of the present invention alone, or in combination or conjunction with an anti-fungal agent, antibiotic or antiviral agent. For example, the steroidal agent may be administered separately from the anti-fungal agent or antibiotic, or each of these ingredients may be administered simultaneously (e.g., in a single formulation) or individually, concurrently, in tandem or subsequently relative to each other, or in any combination thereof.



BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 shows the change from baseline in AM and PM reflective TNSS over time in the ITT population over a 14 day study period.
FIG. 2 shows the change from baseline in AM and PM reflective TNSS over time in the PP population over a 14 day study period.
FIG. 3 shows the change from baseline in AM reflective TNSS over time in the PP population over a 14 day study period.
FIG. 4 shows the change from baseline in PM reflective TNSS over time in the PP population over a 14 day study period.



V. DETAILED DISCUSSION OF THE INVENTION
The present invention is directed to formulations for the treatment of one or more symptoms of rhinosinusitis in an individual. Rhinosinusitis occurs in the nasal-paranasal region. Symptoms of rhinosinusitis include, without limitation, facial pain, pressure, and/or fullness; loss of smell; nasal obstruction or blockage; nasal or postnasal discharge; rhinorrhea; hyposimia/ansomnia; fever; headaches; halitosis; fatigue; dental pain; cough; and ear pain, pressure, and/or fullness. Upon examination, the presence of thick mucus or the visual identification of nasal or paranasal obstruction with mucus or polyps often indicates a rhinosinusitis condition.
Nasal polyps may also be associated with or indicative of rhinosinusitis. Nasal polyps are outgrowths from the nasal-paranasal mucosa that are typically smooth, gelatinous, semitranslucent, round or pear shaped, and pale. In general, nasal polyps are located on the lateral wall of the nose, usually in the middle meatus or along the middle and superior turbinates. Most nasal polyps arise from the ethmoid sinus but some polyps originate in the maxillary sphenoid sinuses. The mass of a nasal polyp is composed mainly of edematous fluid with sparse fibrous cells and a few mucous glands. The surface epithelium of nasal and paranasal polyps generally reveals squamous metaplasia. Eosinophils are usually present in polyps in moderate to large numbers, and it is now known that nasal polyp fluid contains greater than normal concentrations of IgA, IgE, IgG, and IgM antibodies as well as abnormally high concentrations of IL-5, a cytokine that contributes to eosinophil activation and survival.
It is understood that the scope of the invention is directed to the treatment of rhinosinusitis including, but not limited to, any rhinosinusitis condition, including, but not limited to, acute, subacute, recurrent acute and chronic rhinosinusitis, which may be accompanied by, aggravated by, associated with or caused by (in whole or in part) fungi, viruses, or microorganisms in the mucosa. For example, rhinosinusitis may include fungus-induced rhinosinusitis caused by, for example, an immunologic response to mucosal fungi or other organism. In one alternative embodiment, the fungus-induced rhinosinusitis is allergic fungal rhinosinusitis, or AFS.
Formulation
In one alternative embodiment, the present invention is directed to formulations for the treatment of rhinosinusitis. In one embodiment, the formulations comprise a steroidal anti-inflammatory, alone or in combination with an antifungal agent, antibiotic or antiviral agent. As used herein, treatment means the prophylaxis, prevention or amelioration of one or more symptoms of, or associated with, rhinosinusitis, or any manner in which one or more of the symptoms of, or associated with, rhinosinusitis are beneficially altered or are prevented from worsening. As used herein, amelioration means any lessening, whether permanent or temporary, lasting or transient, of one or more symptoms of rhinosinusitis, including but not limited to fungus-induced rhino sinusitis.
Antifungal Agent
Antifungal agents for use herein include any agent effective in treating rhinosinusitis, including fungus-induced rhinosinusitis. Preferably, the antifungal agent of the present formulations reduces the presence of fungal organisms within mucus to a level such that the characteristic inflammatory responses and resulting damages associated with fungal induced rhinosinusitis are lessened, whether permanent or temporary, lasting or transient, stopped, treated, or prevented.
For example, in one alternative embodiment of the present invention, an antifungal agent for use herein may include any agent that prevents the growth of or kills a fungal organism such as antifungal polyene macrolides, tetraene macrolides, pentaenic macrolides, fluorinated pyrimidines, imidazoles, triazoles, azoles, halogenated phenolic ethers, thiocarbamates, and allylamines, and other. In addition, antifungal agents can be agents that interpolate fungal cell wall components or act as sterol inhibitors. Specific antifungal agents within the scope of the invention include, without limitation, amphotericin β, flucytosine, ketoconazole, miconazole, itraconazole, fluconazole, griseofulvin, clotrimazole, econazole, terconazole, butoconazole, oxiconazole, sulconazole, saperconazole, voriconazole, ciclopirox olamine, haloprogin, tolnaftate, naftifine, nystatin, natamycin, terbinafine hydrochloride, morpholines, butenafine undecylenic acid, Whitefield's ointment, propionic acid, and caprylic acid as well as those agents that can be identified as antifungal agents using methods well known in the art. Preferably, the antifungal agent of the present formulations is amphotericin β or fluconazole.
It is noted that a particular patient may possess a fungal organism acting as the etiological agent that is resistant to a particular antifungal agent. In such a case, an embodiment of this invention involves treating that patient with an effective antifungal agent (e.g., an antifungal agent that prevents the growth of, or kills, the fungal organism acting as the etiological agent). Such fungal organisms acting as etiological agents can be identified using collection and culture methods known in the art.
In one alternative embodiment, the formulation of the present invention may comprise any amount of antifungal agent that reduces, prevents, or eliminates one or more symptoms of, or associated with, fungus-induced rhinosinusitis without producing significant toxicity. In one embodiment, an effective amount may be any amount greater than or equal to the minimum inhibitory concentration (MIC) for a fungal organism or isolate present within a particular individual's mucus that does not induce significant toxicity to the individual upon administration. Some antifungal agents may have a relatively large concentration range that is effective while others may have a relatively narrow effective concentration range. In addition, the effective amount can vary depending upon the specific fungal organism or isolate since certain organisms and isolates are more or less susceptible to particular antifungal agents. Such effective amounts can be determined for individual antifungal agents using commonly available or easily ascertainable information involving antifungal effectiveness concentrations, animal toxicity concentrations, and tissue permeability rates.
For example, non-toxic antifungal agents typically can be directly or indirectly administered in any amount that exhibits antifungal activity within mucus. In addition, antifungal agents that do not permeate mucosal epithelium typically can be directly administered to the mucus in any amount that exhibits antifungal activity within mucus. Using the information provided herein, such effective amounts also can be determined by routine experimentation in vitro or in vivo. For example, a patient having a fungus-induced rhinosinusitis can receive direct administration of an antifungal agent in an amount close to the MIC calculated from in vitro analysis. If the patient fails to respond, then the amount can be increased by, for example, ten fold. After receiving this higher concentration, the patient can be monitored for both responsiveness to the treatment and toxicity symptoms, and adjustments made accordingly.
In one embodiment, the present formulations comprise about 0.01 ng to about 1000 mg per kg of body weight of the mammal per administration of formulation, where the formulation is administered directly to the nasal-paranasal mucose. Antifungal agent particularly suitable for administration are itraconazole, ketoconazole, or voriconazole. The MIC values for voriconazole range from about 0.003 .mu.g/mL to about 4 .mu.g/mL depending upon the specific fungal organism or isolate tested. For fluconazole, the MIC values range from about 0.25 .mu.g/mL to greater than about 64 .mu.g/mL.
Various factors can influence the actual amount of antifungal agent in the formulations provided herein. For example, the frequency of administration of the formulations, duration of treatment, combination of other antifungal agents, site of administration, degree of inflammation, and the anatomical configuration of the treated area may require an increase or decrease in the actual amount of antifungal agent in the present formulations.
Table 1 sets forth preferable ranges and dosages of the antifungal agent of the present invention.







TABLE 1







Antifungal Agents and Dosages

















More
Most
Most



Brand

Preferable
Preferable
Preferable
Preferable


Generic Name
Name
Class
Range
Range
Range
Dose





Amphotericin β
Fungizone
Antifungal
0.5-150 mg
 4-30 mg
7.5-15 mg 
10 mg Q12H


Fluconazole
Diflucan
Antifungal
0.5-150 mg
20-70 mg
25-50 mg
10 mg Q12H


Itraconazole
Sporanox
Antifungal
0.5-150 mg
20-70 mg
25-50 mg
30 mg Q12H









Steroidal Anti-Inflammatory
Steroidal anti-inflammatories for use herein include fluticasone, beclomethasone, any pharmaceutically acceptable derivative thereof, and any combination thereof. As used herein, a pharmaceutically acceptable derivative includes any salt, ester, enol ether, enol ester, acid, base, solvate or hydrate thereof. Such derivatives may be prepared by those of skill in the art using known methods for such derivatization.
In one alternative embodiment, the steroidal anti-inflammatory agents have a specific particle size distribution profile. As used herein, particle size refers to an average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as, for example, sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation, among other techniques.
Fluticasone
Preferably, the intranasal steroid of the present formulations is fluticasone propionate. Fluticasone propionate is a synthetic corticosteroid and has the empirical formula C25H31F3O5S. It has the chemical name S-(fluromethyl)6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate. Fluticasone propionate is a white to off-white powder with a molecular weight of 500.6 and is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.
In an embodiment, the formulations of the present invention may comprise a steroidal anti-inflammatory (e.g., fluticasone propionate) having the following particle size distribution profile: about 10% or less of the steroid particles have a particle size of less than 0.90 microns; about 25% or less of the steroid particles have a particle size of less than 1.6 microns; about 50% or less of the steroid particles have a particle size of less than 3.2 microns; about 75% or less of the steroid particles have a particle size of less than 6.10 microns; about 90% or less of the steroid particles have a particle size of less than 10 microns.
In another alternate embodiment, the formulation of the present invention is an aqueous suspension comprising about 0.005% to about 5%, or about 0.01% to about 2.5%, or about 0.01% to about 0.2%, or about 0.01% to about 0.1%, or about 0.1% to about 0.75% by weight of a drug substance. In a preferred embodiment, the formulation is an aqueous suspension comprising about 0.025% to about 1.0% of a drug substance, wherein the drug substance is preferably fluticasone. Even more preferably, the formulation is an aqueous suspension comprising about 0.04% to about 0.06% by weight of a drug substance wherein the drug substance is preferably fluticasone propionate. In a preferred embodiment, the formulation of the present invention is an aqueous suspension comprising about 0.045% by weight of fluticasone propionate, wherein the fluticasone propionate has the following particle size distribution profiles disclosed herein.
In an alternative embodiment, the formulation of the present invention comprises a steroidal anti-inflammatory having the following particle size distribution profile: about 10% of the steroid particles have a particle size of less than 0.70 microns; about 25% of the steroid particles have a particle size of less than 1.30 microns; about 50% of the steroid particles have a particle size of less than 2.5 microns; about 75% of the steroid particles have a particle size of less than 4.0 microns; about 90% of the steroid particles have a particle size of less than 6.0 microns; and greater than 90% or about 100% of the steroid particles have a particle size of less than 10 microns. Preferably, the steroid is fluticasone propionate.
In one preferred embodiment, the formulation of the present invention comprises a steroid having the following particle size distribution profile: about 10% of the steroid particles have a particle size less than 0.50 microns; about 25% of the steroid particles have a particle size less than 0.90 microns; about 50% of the steroid particles have a particle size less than 1.7 microns; about 75% of the steroid particles have a particle size less than 3.5 microns; about 90% of the steroid particles have a particle size less than 5.5 microns.
In another alternative embodiment, greater than 90% or about 100% of the steroid particles have a particle size less than 15 microns, preferably less than 10 microns, more preferably less than 8 microns, most preferably less than 7 microns.
Beclomethasone
Also preferably, the steroidal anti-inflammatory of the present formulations is beclomethasone dipropionate or its monohydrate. Beclomethasone dipropionate has the chemical name 9-chloro-11b,17,21-trih-ydroxy-16b-methylpregna-1,4-diene-3,20-doine17,21-dipropionate. The compound may be a white powder with a molecular weight of 521.25; and is very slightly soluble in water (PHYSICIAN'S DESK REFERENCE®), very soluble in chloroform, and freely soluble in acetone and in alcohol.
The formulations of the present invention may comprise a steroidal anti-inflammatory (e.g., beclometasone diproprionate) having the following particle size distribution profile: about 10% or less of the steroid particles have a particle size of less than 0.75 microns; about 25% or less of the steroid particles have a particle size of less than 1.5 microns; about 50% or less of the steroid particles have a particle size of less than 2.0 microns; about 75% or less of the steroid particles have a particle size of less than 3.5 microns; about 90% or less of the steroid particles have a particle size of less than 5.0 microns; and greater than 90% or about 100% of the steroid particles have a particle size of less than 10 microns.
In an alternative embodiment, the formulation of the present invention comprises a steroidal anti-inflammatory having the following particle size distribution profile: about 10% of the steroid particles have a particle size of less than 0.35 microns; about 25% of the steroid particles have a particle size of less than 0.70 microns; about 50% of the steroid particles have a particle size of less than 1.25 microns; about 75% of the steroid particles have a particle size of less than 2.0 microns; about 90% of the steroid particles have a particle size of less than 3.0 microns; and greater than 90% or about 100% of the steroid particles have a particle size of less than 6.5 microns. Preferably, the steroid is beclomethasone dipropionate.
In one preferred embodiment, the formulation of the present invention comprises a steroidal anti-inflammatory having the following particle size distribution profile: about 10% of the steroid particles have a particle size less than 0.40 microns; about 25% of the steroid particles have a particle size less than 0.70 microns; about 50% of the steroid particles have a particle size less than 1.3 microns; about 75% of the steroid particles have a particle size less than 2.0 microns; about 90% of the steroid particles have a particle size less than 3.0 microns; greater than 90% or about 100% of the steroid particles have a particle size less than 6.0 microns.
In another alternative embodiment, the formulation of the present invention comprises a steroidal anti-inflammatory having the following particle size distribution profile: about 10% of the steroid particles have a particle size less than 0.60 microns; 25% of the steroid particles have a particle size less than 0.90 microns; about 50% of the steroid particles have a particle size less than 1.5 microns; about 75% of the steroid particles have a particle size less than 2.5 microns; about 90% of the steroid particles have a particle size less than 3.5 microns; greater than 90% or about 100% of the steroid particles have a particle size less than 6.0 microns.
In another alternative embodiment, greater than 90% or about 100% of the steroid particles have a particle size less than 15 microns, preferably less than 10 microns, more preferably less than 8 microns, most preferably less than 7 microns. In another preferred embodiment, greater than 90% or about 100% of the steroid particles have a particle size between 4 and 7 microns or 5 and 6 microns. In another embodiment, greater than 90% or about 100% of the steroid particles have a particle size less than 10 microns, preferably less than 7 microns; less than 6 microns; less than 5 microns, or less than 4 microns.
Providing steroidal anti-inflammatories according to the present invention is believed to be a more effective way to provide the medication to the nasal-paranasal region, thereby increasing bioavailability and efficacy of the steroid. It is understood that each of the particle size distribution profiles described in application Ser. Nos. 10/414,682 and 10/414,756 may be suitable for any of the anti-inflammatory agents described herein. The preferred anti-inflammatory agents are fluticasone and beclomethasone. Also, the dosages described in these applications may also be suitable for use in the present invention. Each of these applications are incorporated herein by reference in their entirety.
Additionally, the formulations of the present invention may comprise fluticasone or beclomethasone alone or in combination with one or more other steroidal anti-inflammatories. Examples of steroidal anti-inflammatories for use herein include, but are not limited to, betamethasone, triamcinolone, dexamethasone, prednisone, mometasone, flunisolide and budesonide. Other anti-inflammatory for use herein are listed below in Table 2.







TABLE 2







Steroidal Anti-inflammatory Agents and Dosages
















Preferable
More Preferable




Generic Name
Brand Name
Class
Range
Range
Most Preferable Range
Most Preferable Dose




















Acetylcysteine
Mucomist Mucosil
Mucolytics
125-500
mg
150-450
mg
200-400
mg
300
mg Q12H


Amikacin
Amikin
Aminoglycoside
50-500
mg
75-300
mg
100-200
mg
166
mg Q8-












12H


Amphotericin B
Fungizone
Antifungal
2.5-45
mg
4-30
mg
7.5-15
mg
10
mg Q12H


Atropine

Anticolinergic
10-700
mcg
25-400
mcg
75-30
mcg
200
mcg Q12H


Azelastine
Astelin
Antihistamine
137-1096
mcg
204-822
mcg
382-616
mcg
411
mcg Q12H


Azithromycin
Zithromax
Macrolide
50-400
mg
75-300
mg
150-200
mg
167
mg Q12H


Aztreonan
Azactam
Monobactam
250-1000
mg
300-900
mg
475-750
mg
450
mg Q8H


Beclamethasone
Vanceril Beclovent
Steroidal Anti-
0.1-4
mg
0.2-3
mg
0.2-2
mg
0.8
mg Q12H




inflammatory










Betamethasone
Celestone
Steroidal Anti-
0.1-4
mg
0.2-3
mg
0.2-2
mg
0.8
mg Q12H




inflammatory










Cefazolin
Ancef, Kefzol
Cephlasporin
250-1000
mg
300-900
mg
575-700
mg
650
mg Q8H




(Gen I)










Cefepine
Maxipime
Cephlasporin
125-1000
mg
200-900
mg
575-700
mg
650
mg Q12H




(Gen IV)










Cefonicid
Moniacid
Cephlasporin
250-1000
mg
300-900
mg
575-700
mg
600
mg Q24H




(Gen II)










Cefaperazone
Cefobid
Cephlasporin
250-1000
mg
300-900
mg
575-700
mg
600
mg Q12H




(Gen III)










Cefotaxime
Claforan
Cephlasporin
250-1000
mg
300-900
mg
575-700
mg
600
mg Q8-




(Gen III)







12H


Cefotetan
Cefotan
Cephlasporin
250-1000
mg
300-900
mg
575-700
mg
600
mg Q8-




(Cephamycin)







12H


Cefoxitin
Mefoxin
Cephlasporin
250-1000
mg
300-900
mg
575-700
mg
600
mg Q12H




(Cephamycin)










Ceftazidime
Fortaz, Ceptaz
Cephlasporin
250-1000
mg
300-900
mg
475-750
mg
550
mg Q12H




(Gen III)










Ceftizoxime
Cefizox
Cephlasporin
250-1000
mg
300-900
mg
575-700
mg
600
mg Q8-




(Gen III)







12H


Ceftriaxone
Rocephin
Cephlasporin
250-1000
mg
300-900
mg
575-700
mg
650
mg Q12H




(Gen III)










Cefuroxime
Ceftin
Cephlasporin
100-600
mg
200-520
mg
250-400
mg
285
mg Q8H




(Gen II)










Cephapirin
Cefadyl
Cephlasporin
250-1000
mg
300-900
mg
575-700
mg
650
mg Q12H




(Gen I)










Ciprofloxacin
Cipro
Quinolone
25-200
mg
50-175
mg
75-110
mg
90
mg Q12H


Clindamycin
Cleocin
Lincosamide
50-600
mg
75-500
mg
125-300
mg
225
mg Q12H


Cromolyn Sodium
Intal/Nasalcrom
Mast cell
5-100
mg
7.5-75
mg
10-50
mg
20
mg Q12H




stabilizer










Dexamethasone
Decadron
Steroidal Anti-
0.1-4
mg
0.2-3
mg
0.2-2
mg
0.8
mg Q12H




inflammatory










Dornase alpha
Pulmozyme
Mucolytic
0.5-5
mg
1-4
mg
2-3
mg
1.5
mg Q12H


Doxycycline
Vibramycin
Tetracycline
10-100
mg
15-80
mg
25-65
mg
27
mg Q12H


Erythromycin
Erythrocin
Macrolide
50-600
mg
60-350
mg
100-300
mg
150
mg Q8H


Lactobionate












Fluconazole
Diflucan
Antifungal
12.5-150
mg
20-70
mg
25-50
mg
30
mg Q12H


Flunisolide
Aerobid Nasalide
Steroidal Anti-
0.1-4
mg
0.2-3
mg
0.2-2
mg
0.8
mg Q12H




inflammatory










Flurbiprofen
Ocufen
Nonsteroidal
0.01-2
mg
0.05-1
mg
0.1-0.5
mg
0.15
mg Q12H




Anti-












inflammatory










Fluticasone
Flonase
Steroidal Anti-
10-700
mcg
25-400
mcg
75-300
mcg
200
mcg Q24H




inflammatory










Gentamycin
Garamycin
Aminoglycoside
10-200
mg
30-150
mg
80-120
mg
95
mg Q8-12H


Ibuprofen
Motrin
Nonsteroidal
25-400
mg
30-300
mg
50-150
mg
100
mg Q12H




Anti-












inflammatory










Ipratropium
Atrovent
Anticholinergic
10-700
mcg
25-400
mcg
75-300
mcg
200
mcg Q12H


Itraconazole
Sporanox
Antifungal
12.5-150
mg
20-70
mg
25-50
mg
30
mg Q12H


Ketorolac
Acular
Nonsteroidal
0.05-4
mg
0.1-2
mg
0.3-1
mg
0.5
mg Q12H




Anti-












inflamattory










Levofloxacin
Levaquin
Quinolone
40-200
mg
50-150
mg
60-80
mg
70
mg Q12H


Linezolid
Zyvox
Miscellaneous
50-600
mg
75-450
mg
100-300
ng
200
mg Q12H




anti-bacterial










Loratidine
Claritin
Antihistamine
0.5-10
mg
1-7.5
mg
1-5
mg
2
mg Q12H


Meropenem
Merrin
Carbapenem
200-75
mg
250-700
mg
300-500
mg
33
mg Q8H


Mezlocillin
Mezlin
Penicillin
300-1500
mg
375-1000
mg
750-950
mg
833
mg Q6H


Miconazole
Monistat
Antifungal
12.5-300
mg
30-200
mg
50-100
mg
60
mg Q12H


Montelukast
Singulair
Antileukotriene
0.5-15
mg
2-25
mg
3-15
mg
10
mg Q12H


Mupirocin
Bactroban
Antibacterial
1-25
mg
1.5-20
mg
2-15
mg
10
mg Q6-8H


Nafcillin
Unipen
Penicillin
250-1000
mg
300-900
mg
575-700
mg
600
mg Q8H


Nedocromil
Tilade
Mast cell
1-25
mg
3-15
mg
5-12
mg
7
mg Q12H




stabilizer










Ofloxacin
Floxin
Quinolone
25-200
mg
50-175
mg
75-110
mg
90
mg Q12H


Oxacillin
Prostaphin
Penicillin
250-1000
mg
300-900
mg
575-700
mg
600
mg Q8H


Oxymetazoline
Afrin
Decongestant
0.05-0.5
mg
0.075-0.4
mg
0.1-0.3
mg
0.2
mg Q12H


Phenylepherine
Neo-Synephine
Decongestant
5-50
mg
10-35
mg
15-20
mg
10
mg Q12H


Piperacillin
Pipracil
Penicillin
100-1000
mg
125-750
mg
250-600
mg
460
mg Q6H


Potassium Iodide
—
Antiseptic
30-200
mg
40-150
mg
50-80
mg
60
mg Q12H


Rifampin
Rifadin
Miscellaneous
500-5000
mg
1000-4000
mg
1500-3500
mg
2250
mg Q12H


Taurolin
Taurolidine
Non antibiotic
5-200
mg
20-150
mg
40-120
mg
80
mg Q12H




antimicrobial










Tetrahydrozolidine
Tizine
Decongestant
0.05-0.5
mg
0.06-0.4
mg
0.1-0.3
mg
0.15
mg Q12H


Ticarcillin +
Timentin
Penicillin
500-5000
mg
1000-4000
mg
1500-3500
mg
2250
mg Q6-8H


Clavulanatc












Tobramycin
Nebcin
Aminoglycoside
10-200
mg
30-150
mg
80-120
mg
95
mg Q8-12H


Triamcinalone
Asthmacor
Steroidal Anti-
0.05-3
mg
0.2-2.5
mg
0.5-2
mg
0.6
mg Q12H



Aristocort
inflammatory










Vancomycin
Vancocin
Antibiotic-
50-400
mg
75-325
mg
125.250
mg
166
mg Q6-8H




miscellaneous










Xylometazoline
Otrivin
Decongestant
0.05-0.4
mg
0.075-03
mg
0.1-0.2
mg
0125
mg Q12H


Zafirlukast
Accolate
Antileukotriene
2-60
mg
4-50
mg
6-30
mg
20
mg Q12H









Antibiotic
The formulations of the present invention may further comprise an antibiotic. Additionally, since more than one bacterial organism may be associated with the bacterial infection of the nasal-paranasal region, the present formulations may comprise a broad-spectrum antibiotic such as amoxycillin, erythromycin, or cefadroxil. Alternatively, a combination of anti-bacterial agents with differing spectra of activity may also be used. Examples of antibiotics for use in the present invention are shown in Table 3.







TABLE 3







Antibiotic Agents and Dosages

















More
Most
Most





Preferable
Preferable
Preferable
Preferable


Generic Name
Brand Name
Class
Range
Range
Range
Dose




















Amikacin
Amikin
aminoglycoside
1-800
mg
5-500
mg
50-300
mg
150
mg Q8H


Azithromycin
Zithromax
Macrolide
25-400
mg
75-300
mg
150-200
mg
167
mg Q12H


Aztreonan
Azactam
Monobactam
150-1000
mg
300-900
mg
475-750
mg
450
mg Q8H


Cefazolin
Ancef, Kefzol
Cephlasporin (Gen
150-1000
mg
300-900
mg
575-700
mg
650
mg Q8H




I)










Cefepine
Maxipime
Cephlasporin (Gen
75-1000
mg
200-900
mg
575-700
mg
650
mg Q12H




IV)










Cefonicid
Moniacid
Cephlasporin (Gen
150-1000
mg
300-900
mg
575-700
mg
600
mg Q24H




II)










Cefaperazone
Cefobid
Cephlasporin (Gen
150-1000
mg
300-900
mg
575-700
mg
600
mg Q12H




III)










Cefotaxime
Claforan
Cephlasporin (Gen
150-1000
mg
300-900
mg
575-700
mg
600
mg Q8-




III)







12H


Cefotetan
Cefotetan
Cephlasporin
150-1000
mg
300-900
mg
575-700
mg
600
mg Q8-




(Cephamycin)







12H


Cefoxitin
Mefoxin
Cephlasporin
150-1000
mg
300-900
mg
575-700
mg
600
mg Q12H




(Cephamycin)










Ceftazidime
Fortaz, Ceptaz
Cephlasporin (Gen
150-1000
mg
300-900
mg
475-750
mg
550
mg Q12H




III)










Ceftizoxime
Cefizox
Cephlasporin (Gen
150-1000
mg
300-900
mg
575-700
mg
600
mg Q8-




III)







12H


Ceftriaxone
Rocephin
Cephlasporin (Gen
150-1000
mg
300-900
mg
575-700
mg
650
mg Q12H




III)










Cefuroxime
Ceftin
Cephlasporin (Gen
50-600
mg
200-520
mg
250-400
mg
285
mg Q8H




II)










Cephapirin
Cefadyl
Cephlasporin (Gen
150-1000
mg
300-900
mg
575-700
mg
650
mg Q12H




I)










Ciprofloxacin
Cipro
Quinolone
15-200
mg
50-175
mg
750110
mg
90
mg Q12H


Clindamycin
Cleocin
Lincosamide
25-600
mg
75-500
mg
125-300
mg
225
mg Q12H


Doxycycline
Vibramycin
Tetracycline
10-100
mg
15-80
mg
25-65
mg
27
mg Q12H


Erythromycin
Erythrocin
Macrolide
25-600
mg
60-350
mg
100-300
mg
150
mg Q8H


Lactobionate












Gentamicin
Garamycin
Aminoglycoside
1-800
mg
5-500
mg
50-300
mg
150
mg Q8H


Kanamycin
Kantrex
Aminoglycoside
1-800
mg
5-500
mg
50-300
mg
150
mg Q8H


Linezolid
Zyvox
Miscellaneous
25-600
mg
75-450
mg
100-300
mg
200
mg Q12H




anti-bacterial










Mezlocillin
Mezlin
Penicillin
100-1500
mg
375-1000
mg
750-950
mg
833
mg Q6H


Mupirocin
Bactroban
Antibacterial
1-25
mg
1.5-20
mg
2-15
mg
10
mg Q6-8H


Nafcillin
Unipen
Penicillin
150-1000
mg
300-900
mg
575-700
mg
600
mg Q8H


Netilmicin
Netromycin
Aminoglycoside
1-800
mg
5-500
mg
50-300
mg
150
mg Q8H


Neomycin
Mycifradin
Aminoglycoside
1-800
mg
5-500
mg
50-300
mg
150
mg Q8H


Oxacillin
Prostaphin
Penicillin
150-1000
mg
300-900
mg
575-700
mg
600
mg Q8H


Paromomycin
Humatin
Aminoglycoside
1-800
mg
5-500
mg
50-300
mg
150
mg Q8H


Piperacillin
Pipracil
Penicillin
50-1000
mg
125-750
mg
250-600
mg
460
mg Q6H


Streptomycin

Aminoglycoside
1-800
mg
5-500
mg
50-300
mg
150
mg Q8H


Ticarcillin +
Timentin
Penicillin
200-5000
mg
1000-4000
mg
1500-3500
mg
2250
mg Q6-


Clavulanaic









8H


Tobramycin

Aminoglycoside
1-800
mg
5-500
mg
50-300
mg
150
mg Q8H


Vancomycin
Vancocin
Antibiotic-
25-400
mg
75-325
mg
125.250
mg
166
mg Q6-8H




miscellaneous









Antiviral Agents
The formulations of the present invention may comprise a therapeutically effective amount of one or more antiviral agents. These agents can be administered individually or simultaneously with the steroidal agent of the present invention. The antiviral agent may also include Acyclovir, Famciclovir, Valacyclovir, edoxudine, ganciclovir, foscarnet, cidovir (vistide), Vitrasert, Formivirsen, HPMPA (9-(3-hydroxy-2-phosphonomethoxypropyl)adenine), PMEA (9-(2-phosphonomethoxyethyl)adenine), HPMPG (9-(3-Hydroxy-2-(Phosphonomethoxy)propyl)guanine), PMEG (9-[2-(phosphonomethoxy)ethyl]guanine), HPMPC (1-(2-phosphonomethoxy-3-hydroxypropyl)-cytosine), ribavirin, EICAR (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamine), pyrazofurin (3-[beta-D-ribofuranosyl]-4-hydroxypyrazole-5-carboxamine), 3-Deazaguanine, GR-92938X (1-beta-D-ribofuranosylpyrazole-3,4-dicarboxamide), LY253963 (1,3,4-thiadiazol-2-yl-cyanamide), RD3-0028 (1,4-dihydro-2,3-Benzodithiin), CL387626 (4,4′-bis[4,6-d][3-aminophenyl-N,N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazin-2-ylamino-biphenyl-2,2′-disulfonic acid disodium salt), BABIM (Bis[5-Amidino-2-benzimidazolyl]methane), and NIH351.
Other suitable dosages and methods of treatment of the ingredients described herein are described in US 2001/0006944A1, pub. date Jul. 5, 2001, which is incorporated herein by reference in its entirety.
Other Components
The formulation of the present invention may be in any form provided the formulation can be administered to a mammal in an amount, at a frequency, and for a duration effective to prevent, reduce, or eliminate one or more symptoms associated with Rhinosinusitis, including fungus induced Rhinosinusitis. For example, a formulation within the scope of the invention can be in the form of a solid, liquid, and/or aerosol including, without limitation, powders, crystalline substances, gels pastes, ointments, salves, creams, solutions, suspensions, partial liquids, sprays, nebulae, mists, atomized vapors, tinctures, pills, capsules, tablets, and gelcaps. In addition, the formulation can contain a cocktail of other ingredients, particularly those described herein. For example, a formulation within the scope of the invention can contain, without limitation, one, two, three, four, five, or more different antifungal agents, antibiotics, antiviral agents, or the other ingredients described herein. Further, formulations within the scope of the invention can contain additional ingredients including, without limitation, pharmaceutically acceptable aqueous vehicles, pharmaceutically acceptable solid vehicles, steroids, mucolytic agents, antibacterial agents, anti-inflammatory agents, immunosuppressants, dilators, vaso-constrictors, decongestants, leukotriene inhibitors, anti-cholinergics, anti-histamines, therapeutic compounds and combinations thereof. Such antiviral agents may include IMPDH inhibitors, inhibitors of virus adsorption entry, inhibitors of fusion with host cells, antisense oligonucleotides, and nucleoside analogues.
In one embodiment, the present formulations may be provided in any form suitable for intranasal administration. In another alternative embodiment, the formulations of the present invention are in solution or suspension form suitable for intranasal administration.
In an embodiment, the formulation of the present invention may comprise a preservative, suspending agent, wetting agent, tonicity agent and/or diluent. In one embodiment, the formulations provided herein may comprise from about 0.01% to about 95%, or about 0.01% to about 50%, or about 0.01% to about 25%, or about 0.01% to about 10%, or about 0.01% to about 5% of one or more pharmacologically suitable suspending fluids which is physiologically acceptable upon administration. Pharmacologically suitable fluids for use herein include, but are not limited to, polar solvents, including, but not limited to, compounds that contain hydroxyl groups or other polar groups. Solvents include, but are not limited to, water or alcohols, such as ethanol, isopropanol, and glycols including propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol and polyoxyethylene alcohols. Polar solvents also include protic solvents, including, but not limited to, water, aqueous saline solutions with one or more pharmaceutically acceptable salt(s), alcohols, glycols or a mixture there of. In one alternative embodiment, the water for use in the present formulations should meet or exceed the applicable regulatory requirements for use in drugs.
In certain embodiments herein, the formulations of the present invention have a pH of about 2.0 to about 9.0. Optionally, the formulations of the present invention may contain a pH buffer. For example, a buffer may comprise any known pharmacologically suitable buffers which are physiologically acceptable upon administration intranasally. The buffer may be added to maintain the pH of the formulation between about 3.0 and about 7.0, for example.
Sterility or adequate antimicrobial preservation may be provided as part of the present formulations. Since certain formulations of the present invention are intended to be administered intranasally, it is preferred that they be free of pathogenic organisms. A benefit of a sterile liquid suspension is that it reduces the possibility of introducing contaminants into the individual when the suspension formulation is administered intranasally, thereby reducing the chance of an opportunistic infection. Processes which may be considered for achieving sterility may include any appropriate sterilization steps known in the art.
In one embodiment, the formulation of the present invention is produced under sterile conditions, and the micronization of the steroidal anti-inflammatory is performed in a sterile environment, and the mixing and packaging is conducted under sterile conditions. In one alternative embodiment, one or more ingredients in the present formulation may be sterilized by steam, gamma radiation or prepared using or mixing sterile steroidal powder and other sterile ingredients where appropriate. Also, the formulations may be prepared and handled under sterile conditions, or may be sterilized before or after packaging.
In addition to or in lieu of sterilization, the formulations of the present invention may contain a pharmaceutically acceptable preservative to minimize the possibility of microbial contamination. Additionally, a pharmaceutically-acceptable preservative may be used in the present formulations to increase the stability of the formulations. It should be noted, however, that any preservative must be chosen for safety, as the treated tissues may be sensitive to irritants. Preservatives suitable for use herein include, but are not limited to, those that protect the solution from contamination with pathogenic particles, including phenylethyl alcohol, benzalkonium chloride, benzoic acid, or benzoates such as sodium benzoate. Preferably, the preservative for use in the present formulations is benzalkonium chloride or phenylethyl alcohol. In certain embodiments, the formulations herein comprise from about 0.01% and about 1.0% w/w of benzalkonium chloride, or from about 0.01% and about 1% v/w phenylethyl alcohol. Preserving agents may also be present in an amount from about 0.01% to about 1%, preferably about 0.002% to about 0.02% by total weight or volume of the formulation.
The formulations provided herein may also comprise from about 0.01% to about 90%, or about 0.01% to about 50%, or about 0.01% to about 25%, or about 0.01% to about 10%, or about 0.01% to about 1% w/w of one or more emulsifying agent, wetting agent or suspending agent. Such agents for use herein include, but are not limited to, polyoxyethylene sorbitan fatty esters or polysorbates, including, but not limited to, polyethylene sorbitan monooleate (Polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate; lecithins; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propane-1,2-diol alginate; agar; carrageenan; locust bean gum; guar gum; tragacanth; acacia; xanthan gum; karaya gum; pectin; amidated pectin; ammonium phosphatides; microcrystalline cellulose; methylcellulose; hydroxypropylcellulose; hydroxypropylmethylcellulose; ethylmethylcellulose; carboxymethylcellulose; sodium, potassium and calcium salts of fatty acids; mono- and di-glycerides of fatty acids; acetic acid esters of mono- and di-glycerides of fatty acids; lactic acid esters of mono- and di-glycerides of fatty acids; citric acid esters of mono- and di-glycerides of fatty acids; tartaric acid esters of mono- and di-glycerides of fatty acids; mono- and diacetyltartaric acid esters of mono- and di-glycerides of fatty acids; mixed acetic and tartaric acid esters of mono- and di-glycerides of fatty acids; sucrose esters of fatty acids; sucroglycerides; polyglycerol esters of fatty acids; polyglycerol esters of polycondensed fatty acids of castor oil; propane-1,2-diol esters of fatty acids; sodium stearoyl-2lactylate; calcium stearoyl-2-lactylate; stearoyl tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; extract of quillaia; polyglycerol esters of dimerised fatty acids of soya bean oil; oxidatively polymerised soya bean oil; and pectin extract. In certain embodiments herein, the present formulations comprise polysorbate 80, microcrystalline cellulose, carboxymethylcellulose sodium and/or dextrose.
The present formulations may further comprise from about 0.01% to about 90%, or about 0.01% to about 50%, or about 0.01% to about 25%, or about 0.01% to about 10%, or about 0.01% to about 1% w/w of one or more excipients and additives which are pharmacologically suitable. Excipients and additives generally have no pharmacological activity, or at least no undesirable pharmacological activity. The concentration of these may vary with the selected agent, although the presence or absence of these agents, or their concentration is not an essential feature of the invention. The excipients and additives may include, but are not limited to, surfactants, moisturizers, stabilizers, complexing agents, antioxidants, or other additives known in the art. Complexing agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) or a salt thereof, such as the disodium salt, citric acid, nitrilotriacetic acid and the salts thereof. In another embodiment, particularly in the suspension formulations provided herein, the complexing agent is sodium edetate. In one embodiment, the compositions contain sodium edetate at a concentration of about 0.05 mg/mL to about 0.5 mg/mL, or about 0.1 mg/mL to about 0.2 mg/mL. Also, for example, the formulations of the present invention may comprise from about 0.001% to about 5% by weight of a humectant to inhibit drying of the mucous membrane and to prevent irritation. Any of a variety of pharmaceutically-acceptable humectants can be employed, including sorbitol, propylene glycol, polyethylene glycol, glycerol or mixtures thereof, for example.
The formulations provided herein also may comprise about 0.01% to about 90%, or about 0.01% to about 50%, or about 0.01% to about 25%, or about 0.01% to about 10%, or about 0.01% to about 10% w/w of one or more solvents or co-solvents to increase the solubility of any of the components of the present formulations. Solvents or co-solvents for use herein include, but are not limited to, hydroxylated solvents or other pharmaceutically-acceptable polar solvents, such as alcohols including isopropyl alcohol, glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, and polyoxyethylene alcohols. In another embodiment, the formulations of the present invention may comprise one or more conventional diluents known in the art. The preferred diluent is purified water.
Tonicity agents may include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other osmotic adjusting agents may also include, but are not limited to, mannitol, glycerol, and dextrose or mixtures thereof. In an alternative embodiment, the present formulation may comprise about 0.01% to about 10% w/w, or about 1% to about 8% w/w, or 1% to about 6% w/w, preferably about 5.0% w/w. The preferred tonicity agent is anhydrous dextrose.
In one alternative embodiment, the formulations of the present invention are stable. As used herein, the stability of formulations provided herein refers to the length of time at a given temperature that greater than 80%, 85%, 90% or 95% of the initial amount of the active ingredients is present in the formulation. For example, the formulations provided herein may be stored between about 15° C. and about 30° C., and remain stable for at least 1, 2, 12, 18, 24 or 36 months. Also, the formulations may be suitable for administration to a subject in need thereof after storage for more than 1, 2, 12, 18, 24 or 36 months at 250. Also, in another alternative embodiment, using Arrhenius Kinetics, more than 80%, or more than 85%, or more than 90%, or more than 95% of the initial amount of active ingredients remains after storage of the formulations for more than 1, 2, 12, 18, 24 or 36 months between about 15° C. and about 30° C.
The formulations of the present invention may be manufactured in any conventional manner known in the art, or by minor modification of such means. For example, the formulations may be manufactured by thoroughly mixing the ingredients described herein at ambient or elevated temperatures in order to achieve solubility of ingredients where appropriate.
The preparation of the steroidal inflammatory of the present invention, e.g., fluticasone propionate and beclomethasone dipropionate, having a specific particle size distribution profile may be obtained by any conventional means known in the art, or by minor modification of such means. For example, suspensions of drug particles can rapidly undergo particulate size reduction when subjected to “jet milling” (high pressure particle in liquid milling) techniques. Other known methods for reducing particle size into the micrometer range include mechanical milling, the application of ultrasonic energy and other techniques.
In addition, the formulations of the present invention may comprise any of the following components: (i) antihistamine: (ii) non-steroidal anti-flammatories; (iii) decongestants; (iv) mucolytics; (v) anticholinergics; or (vi) mass cell stabilizers. Examples of such components are found in U.S. 2002/0061281 A1, published May 23, 2002. This reference is incorporated herein by reference in its entirety.
In one alternative embodiment, the present invention is directed to a pharmaceutical composition that may be useful in treating rhinosinusitis caused by Alpha Hemolytic Sreptococci, Beta Hemolytic Streptococci, Branhamella Catarrhalis, Diptheroids, Heaemophilis influenza (beta-lactamase positive and negative), Moraxella species, Psuedomonas aeroguinosa, Pseudomas maltophilia, Serratia marcesns, Staphylococcus aureus, Streptococcus pheumonia, Aspergillosis, Mucor and Candida albicans, Flusarium, Curvularia, crytococcus, coccidiodes, and histoplasma. 
Mode of Administration
Administration of the present formulations can be any type of administration that places the present formulations in contact with nasal-paranasal mucosa. Direct intranasal administration includes, without limitation, nasal irrigations, nasal sprays, nasal inhalations, and nasal packs with, for example, saturated gauze provided the administered agent contacts nasal-paranasal mucosa prior to crossing epithelium. In addition, injections into the nasal-paranasal cavities using, for example, a needle or catheter tube is considered a direct intranasal administration provided the administered agent contacts nasal-paranasal mucosa after leaving the needle or catheter tube and prior to crossing epithelium. Any device can be used to directly administer the present formulations intranasally including, without limitation, a syringe, bulb, inhaler, canister, spray can, nebulizer, and mask.
Indirect administration to the nasal-paranasal anatomies can include, without limitation, oral, intravenous, intradermal, and intraperitoneal administrations provided the administered agent contacts nasal-paranasal mucosa. In addition, any device can be used to indirectly administer an agent to the nasal-paranasal anatomy including, without limitation, a syringe and regulated release capsule.
The present formulations may be packaged in any conventional manner suitable for administration of the present formulations. Spray administration containers for various types of nasal formulations have been known in the past and substantially all will be equally suitable for the present formulations, provided that the container materials is compatible with the formulation. In an embodiment, the formulation of the present invention herein is packaged in a container such that it can be dispersed as a mist to be directed into each nostril. For example, the container may be made of flexible plastic such that squeezing the bottle's sides impels the spray out through the nozzle into the nasal cavity. Alternatively, a small pump button may pump air into the container and cause the liquid spray to be emitted on the return stroke when pressed.
In an alternative embodiment, the formulations of the present invention are packaged in a container pressurized with a gas which is inert to the user and to the ingredients of the solution. The gas may be dissolved under pressure in the container or may be generated by dissolution or reaction of a solid material which forms the gas as a product of dissolution or as a reaction product. Suitable inert gases which can be used herein include nitrogen, argon, and carbon dioxide. Also, the formulations herein may be administered as a spray or aerosol wherein the formulation is packaged in a pressurized container with a liquid propellant such as dicholorodifluoro methane or chlorotrifluoro ethylene, or other propellant.
Preferably, the present formulations are packaged in a metered dose spray pump, or metering atomizing pump, such that each actuation of the pump delivers a fixed volume of the formulation (i.e. per spray-unit). For administration in drop or other topical form, the formulations herein may suitably be packaged in a container provided with a conventional dropper/closure device, comprising a pipette or the like, preferably delivering a substantially fixed volume of the formulation.
Method of Treatment
The present invention is also directed to a method for treating rhinosinusitis, including fungus-induced rhinosinusitis. In one embodiment, the method of treating rhinosinusitis of the present invention comprises the step of administering a therapeutically effective amount of the formulation of the present invention to a mammal in need thereof. The formulation may comprise the steroidal agent of the present invention alone or in combination with an anti-fungal agent, an antibiotic or antiviral agent. The formulation is preferably administered intranasally. In one embodiment, the formulation is administered directly to the nasal-paranasal mucosa. In an alternative embodiment, the formulation is administered intranasally via a metered dose spray pump. In general, the course of treatment for any individual with respect to any of the active ingredients described herein can be readily determined by his or her physician.
The method of the present invention may further comprise administering the formulation of the present for a duration or frequency sufficient to treat one or more symptoms of rhinosinusitis, including fungus-induced rhinosinusitis. For example, the formulation may be administered one time to about 10 times a day for about one day to about 100 days or more, or until such fungus-induced rhinosinusitis is treated. In an embodiment, the method of the present invention comprises administering to a mammal diagnosed with fungus-induced rhinosinusitis a formulation comprising a therapeutically effective amount of an antifungal agent and a steroidal anti-inflammatory intranasally via a metered dose spray pump one to three times a day for up to two weeks. In an alternative embodiment, the administration of the present formulations may comprise 1, 2, 3, 4, 5, 6, 7 or 8 applications of the present formulation to the nasal-paranasal mucosa one, two, three, four or five times a day.
In an alternative embodiment, the formulation of the method of the present invention further comprises an antibiotic. However, when administering antibiotics, physicians must keep in mind the incidence of drug-resistant bacteria in their community and consider the patient's overall health status. Special attention should be given to diseases that could impede normal recovery from infection and/or predispose to complications (e.g., diabetes mellitus, chronic pulmonary disease, asthma, cystic fibrosis and immune deficiencies). Additionally, physicians should consider whether or not the patient is immunocompromised in selecting an antibiotic. In one embodiment, the antibiotic is administered for a period of 1 day to about 10 weeks. In an alternative embodiment, the antibiotic is administered for about 1 day to about 28 days.
Accordingly, the present invention provides a method of treating fungus-induced rhinosinusitis associated with a bacterial infection in the nasal-paranasal region, comprising the steps of administering a formulation comprising an antifungal agent, steroidal anti-inflammatory, and antibiotic until said bacterial infection is cured, and then administering a formulation comprising an antifungal agent and steroidal anti-inflammatory.
In an alternative embodiment, the present invention provides a method of treating fungus-induced rhinosinusitis, comprising the steps of administering a formulation comprising a steroidal anti-inflammatory alone or in combination or in conjunction with an antifungal agent, antibiotic or antiviral agent. For example, the steroidal agent may be administered separately from the antifungal agent or antibiotic, or each ingredient can be administered simultaneously (e.g., in a single formulation) concurrently, subsequently, or in tandem. In another embodiment, each ingredient is administered individually in its own formulation and pursuant to an appropriate dosage regimen for that particular ingredient. Suitable dosage regimens for steroidal agents, fungal agents, antibiotics or antiviral agents are known by those skilled in the art.
V. EXAMPLES
Examples 1-5 herein are prophetic examples provided to illustrate, but not to limit, the formulations and methods of the present invention. They are presented with the understanding that changes can be and may need to be made to a specific composition in order to obtain or optimize the formulation. Such modifications to the following prophetic examples, if needed, are normal and understandable to those of ordinary skill in the art, and shall not be used to limit the invention.
It is believed that prophetic examples 1-5 would be suitable for administration to the nasal-paranasal mucosa of an individual suffering from fungus-induced rhinosinusitis associated with a bacterial infection. The formulations may be sterile. It is understood that the steroid, antibiotic, antifungal agent or the other ingredients described herein may be administered in the same formulation, or may be administered individually, or in any combination thereof.
Example 1
















Amphotericin B
2.0-100.0
mg/ml



Neomycin Sulfate
5.0-100.0
mg/ml



Phenylethyl Alcohol
0.5-10.0
mg.ml



Fluticasone Propionate
0.25-1.0
mg/ml



Microcrystalline Cellulose
5.0-15.0
mg/ml



Polysorbate 80
0.1-1.0
mg/ml










Purified Water
q.s.









Example 1 is a prophetic example of a formulation of the present invention, wherein about 10% of the fluticasone propionate particles have a particle size of less than 0.70 microns; about 25% of the fluticasone propionate particles have a particle size of less than 1.30 microns; about 50% of the fluticasone propionate particles have a particle size of less than 2.5 microns; about 75% of the fluticasone propionate particles have a particle size of less than 4.0 microns; about 90% of the fluticasone propionate particles have a particle size of less than 6.0 microns; and greater than 90% or about 100% of the fluticasone propionate particles have a particle size of less than 10 microns. The solution of Example 1 may be made by methods known to those of ordinary skill in the art.
Example 2
















Fluconazole
1.0-20.0
mg/ml



Neomycin Sulfate
5.0-100.0
mg/ml



Phenylethyl Alcohol
0.5-10.0
mg/ml



Fluticasone Propionate
0.25-1.0
mg/ml



Microcrystalline Cellulose
5.0-15.0
mg/ml



Polysorbate 80
0.1-1.0
mg/ml










Purified Water
q.s.









Example 2 is a prophetic example of a formulation of the present invention, wherein about 10% of the fluticasone propionate particles have a particle size of less than 0.70 microns; about 25% of the fluticasone propionate particles have a particle size of less than 1.30 microns; about 50% of the fluticasone propionate particles have a particle size of less than 2.5 microns; about 75% of the fluticasone propionate particles have a particle size of less than 4.0 microns; about 90% of the fluticasone propionate particles have a particle size of less than 6.0 microns; and greater than 90% or about 100% of the fluticasone propionate particles have a particle size of less than 10 microns. The solution of Example 2 may be made by methods known to those of ordinary skill in the art.
Example 3
















Amphotericin B
2.0-100.0
mg/ml



Neomycin Sulfate
5.0-100.0
mg/ml



Benzalkonium Chloride
0.1-0.5
mg/ml










Dextrose
20.0-100.0











Phenylethyl Alcohol
0.5-10.0
mg · ml



Beclomethasone Dipropionate
0.25-1.0
mg/ml










Purified Water
q.s.









Example 3 is a prophetic example of a formulation of the present invention, wherein about 10% of the beclomethasone dipropionate particles have a particle size less than 0.40 microns; about 25% of the beclomethasone dipropionate particles have a particle size less than 0.70 microns; about 50% of the beclomethasone dipropionate particles have a particle size less than 1.3 microns; about 75% of the beclomethasone dipropionate particles have a particle size less than 2.0 microns; about 90% of the beclomethasone dipropionate particles have a particle size less than 3.0 microns; and greater than 90% or about 100% of the beclomethasone dipropionate particles have a particle size less than 6.0 microns. Example 3 may be made by methods known to those of ordinary skill in the art.
Example 4
















Fluconazole
1.0-20.0
mg/ml



Neomycin Sulfate
5.0-100.0
mg/ml



Benzalkonium Chloride
0.1-0.5
mg/ml










Dextrose
20.0-100.0











Phenylethyl Alcohol
0.5-10.0
mg · ml



Beclomethasone Dipropionate
0.25-1.0
mg/ml










Purified Water
q.s.









Example 4 is a prophetic example of a formulation of the present invention, wherein about 10% of the beclomethasone dipropionate particles have a particle size less than 0.40 microns; about 25% of the beclomethasone dipropionate particles have a particle size less than 0.70 microns; about 50% of the beclomethasone dipropionate particles have a particle size less than 1.3 microns; about 75% of the beclomethasone dipropionate particles have a particle size less than 2.0 microns; about 90% of the beclomethasone dipropionate particles have a particle size less than 3.0 microns; and greater than 90% or about 100% of the beclomethasone dipropionate particles have a particle size less than 6.0 microns. Example 4 may be made by methods known to those of ordinary skill in the art.
Example 5
















Fluconazole
1.0-20.0
mg/ml



Benzalkonium Chloride
0.1-0.5
mg/ml










Dextrose
20.0-100.0











Phenylethyl Alcohol
0.5-10.0
mg · ml



Beclomethasone Dipropionate
0.25-1.0
mg/ml










Purified Water
q.s.









Example 5 is a prophetic example of a formulation of the present invention, wherein about 10% of the beclomethasone dipropionate particles have a particle size less than 0.40 microns; about 25% of the beclomethasone dipropionate particles have a particle size less than 0.70 microns; about 50% of the beclomethasone dipropionate particles have a particle size less than 1.3 microns; about 75% of the beclomethasone dipropionate particles have a particle size less than 2.0 microns; about 90% of the beclomethasone dipropionate particles have a particle size less than 3.0 microns; and greater than 90% or about 100% of the beclomethasone dipropionate particles have a particle size less than 6.0 microns. Example 5 may be made by methods known to those of ordinary skill in the art.
The Examples herein are presented for illustrative purposes only. They are not intended to limit the scope of the invention. Further, it should be understood that various changes and modifications to the embodiment described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be covered by the appended claims. Also, the invention may suitably comprise, consist of or consist essentially of the elements or steps described herein. Further, the invention described herein suitably may comprise or be practiced in the absence of any element or step which is not specifically disclosed herein. Further, one or more step described herein may be performed simultaneously with another step.
Example 6
The following example is included for illustrative purposes only and is not intended to limit the scope of the invention.
A blinded, randomized, placebo-controlled, multicenter study to assess the safety and efficacy of Dey Fluticasone Propionate Nasal Spray 50 mcg in adolescent and adult patients with seasonal allergic rhinitis was conducted. The primary objective of this study was to determine the safety and efficacy of Dey fluticasone propionate nasal spray 50 mcg (Dey-FP) compared with Placebo during 2 weeks of treatment in adult and adolescent patients with seasonal allergic rhinitis (SAR) due to mountain cedar pollen. The secondary objective was to establish the comparability of Dey-FP with FLONASE® Nasal Spray 50 mcg during 2 weeks of treatment in adults and adolescent patients with SAR due to mountain cedar pollen.
The study was a randomized, multicenter (7 sites), 3 treatment (Dey-FP, FLONASE®, and Placebo), 2 level (high and low dose) placebo-controlled repeated measures study conducted in the U.S. during the 2001/2002 mountain cedar pollen allergy season. The study duration was 3 weeks and consisted of 2 phases: a 1-week baseline screening period for diary data followed by a 2-week randomized patient- and rater-blind treatment phase. Patients were seen on an outpatient basis on Day-7, Day 1, Day 7, and Day 14. The initial baseline screening period for diary data began 1 week (Day-7.+−.2 days) prior to randomization to treatment. Patients who met the eligibility criteria (inclusion/exclusion criteria and completion of baseline study procedures [within 30 days of Day-7]) were assigned a patient number, given standard oral antihistamine as a rescue medication, and a Patient Total Nasal Symptom Score (TNSS) Diary. Patients recorded daily TNSS (sum of the signs and symptoms for runny nose, nasal congestion, sneezing, and itchy nose) in their diaries rating each on a scale of 0 to 3 with 0 being no symptoms present and 3 being severe symptoms present. The amount of oral antihistamine taken was recorded as well.
One week later, at the conclusion of the baseline screening period, the patients returned to the study site and were re-evaluated for eligibility. Patients who did not complete the diaries or no longer met the entry criteria were discontinued. Patients who met all entry criteria were then randomized to 1 of 6 treatment groups: Dey-FP High Dose, Dey-FP Low Dose, FLONASE High Dose, FLONASE Low Dose, or Placebo High Dose or Placebo Low Dose. The patient- and rater-blind treatment phase (Day 1 through 14) consisted of once daily self-administered treatment (1-2 sprays into each nostril per administration). On Days 7 and 14 (or at early termination), patients returned to the study sites and were evaluated. Efficacy assessments included reflective and instantaneous TNSS daily diary information, patient and physician global evaluations, and use of rescue medication. Safety evaluations were the incidence of adverse events, clinical laboratory tests, physical examinations findings, vital signs measurements, and ECG results (see Study Flow Chart). Pollen counts, outside air temperature, rainfall, and humidity were also monitored and recorded by each study site.
A history of moderate-to-severe SAR due to mountain cedar pollen for at least 2 years individuals 12 years of age and older;
Confirmed IgE-mediated hypersensitivity to mountain cedar pollen within last 12 months (a positive result is required);
Minimum TNSS of 8 out of a maximum of 12 (either AM or PM 12-hour assessment) on at least 3 days during the baseline period, one of which must have been within 3 days of Day 1;
If receiving immunotherapy, a stable maintenance regimen for 30 days prior to study enrollment;
General good health and free of disease or concomitant treatment that could interfere with interpretation of study results;
Written informed consent/pediatric assent; and
Willingness to comply with study procedures.
Patients who met all criteria were then randomized to 1 of 6 treatment groups: (1) Dey-FP 50 mcg Low Dose (100 mcg)—1 spray in each nostril daily; (2) Dey-FP 50 mcg High Dose (100 mcg)—1 spray in each nostril twice daily; (3) FLONASE® Nasal Spray Low Dose (100 mcg)—1 spray in each nostril daily; (4) FLONASE® Nasal Spray High Dose (200 mcg)—1 spray in each nostril daily twice daily; (5) placebo—1 spray in each nostril once daily; and, (6) placebo-1-1 spray in each nostril twice daily.
The primary endpoint for this study was the change from baseline in a patient's combined (AM and PM) 12-hour reflective TNSS over a 2-week treatment period. The primary endpoint analysis was the comparison of Dey-FP Low Dose versus Placebo High and Low Dose overall (Days 2-14) and at Days 7 and 14. TNSS consisted of the sum of the combined AM plus PM 12-hour assessment scores for runny nose, nasal congestion, sneezing, and itchy nose recorded twice daily on the Patient's TNSS Diary card. Baseline was defined as the average of the run-in period of the combined (AM plus PM) 12-hour reflective TNSS from the 7 calendar days.+−.2 days preceding Day 1.
Secondary endpoints for this study included:
The change from baseline in a patient's combined (AM plus PM) 12-hour reflective TNSS overall (Days 2-14);
The change from baseline in a patient's combined (AM plus PM) 12-hour reflective TNSS at Days 7 and 14;
The change from baseline in a patient's AM 12-hour reflective TNSS;
The change from baseline in a patient's PM 12-hour reflective TNSS;
The percent change from baseline in a patient's combined (AM plus PM) 12-hour reflective TNSS;
The percent change from baseline in a patient's AM 12-hour reflective TNSS;
The percent change from baseline in a patient's PM 12-hour reflective TNSS;
The change from baseline to 1-week and 2-week postbaseline in area under the curve (AUC) of patient's combined (AM plus PM) 12-hour reflective TNSS;
The change from baseline to 1-week and 2-week postbaseline in area under the curve (AUC) of patient's AM 12-hour reflective TNSS;
The change from baseline to 1-week and 2-week postbaseline in area under the curve (AUC) of patient's PM 12-hour reflective TNSS;
The change from baseline in patient's combined (AM plus PM) instantaneous TNSS;
The change from baseline in patient's AM instantaneous TNSS;
The change from baseline inpatient's PM instantaneous TNSS;
Patient global evaluation of change in SAR signs and symptoms;
Physician global evaluation of change in SAR signs and symptoms; and
Use of rescue medication.
Secondary efficacy endpoints were compared across all treatment groups.
Both reflective and instantaneous change from baseline in 12-hour (AM plus PM, combined and individual) TNSS for primary and secondary variables were compared across treatment groups using a mixed effect analysis of variance (ANOVA) model with Treatment, day (Days 2-14) and the interaction of Treatment-by-Day as fixed effects and patients as random effect. Area under the curve (AUC) of the 12-hour (AM plus PM, combined and individual) reflective TNSS was calculated for the baseline period and Week 1 and Week 2 postbaseline using a trapezoidal method. The change from baseline in AUC was compared across the groups using a similar ANOVA model as described for the primary efficacy variable. Patient and physician global evaluations of change from baseline in SAR symptoms were compared between the groups using a one-way ANOVA model. Frequency of rescue medication use, as well as the percentage of patients needing rescue medication, was compared across the groups using the Pearson Chi-square test. The average number of tablets of rescue medication was compared using an ANOVA model. All statistical analyses were performed for both Intent-to-Treat (ITT) and Per Protocol (PP) Populations. TNSS missing observations in the ITT Population were imputed using the last observation carried forward (LOCF) method. All inferential statistics were conducted against a two-sided alternative hypothesis at 0.05 level of significance.
In all, 774 patients were enrolled and randomized to 1 of 6 treatment groups at 7 study centers located in the US during the 2001/2002 mountain cedar pollen allergy season, including 1 patient who enrolled at 2 separate sites (Patient 02-044 and 05-056 were the same patient). The data from Patient 02-044 were excluded from all analysis populations except the randomized patient population because the patient had received study drug. The data from Patient 05-056 were included in the analysis populations because enrollment at Site 5 preceded enrollment at the second site, Site 2. The Intent-to-Treat (ITT) Population, therefore, was composed of 773 patients (774 randomized patients minus Patient 02-044). The distribution was as follows: 129 patients in the Dey-FP High Dose group, 129 in the Dey-FP Low Dose group, 127 in the FLONASE High Dose group, 129 in the FLONASE Low Dose group, 131 in the Placebo High Dose group, and 128 patients in the Placebo Low Dose group. In total, 752 (97.3%) patients of the original 774 completed the study and 22 C2.8%) discontinued prematurely, 8 of these were due to Aes. Patients were predominantly White (>90%) and female (>59%). The mean age range was from 37.55 to 42.01 years (min-max range=12.1 to 78.9 years) across treatment groups. Patients had a mean skin antigen challenge score of between 7.5 to 8.5 mm. Over half of all patients (>58%) had no previous history of fluticasone usage.
All active treatment groups (Dey-FP and FLONASE) demonstrated reductions in TNSS over the 2-week treatment period. Regardless of which efficacy endpoint was examined (i.e., 12-hour reflective TNSS, instantaneous TNSS, change in AUC), the Treatment effect was highly significant as was the day (duration of treatment) effect (p=0.0000) indicating improvement in TNSS. Both Dey-FP and FLONASE Low Dose groups were statistically superior to Placebos for both primary and secondary efficacy endpoint analyses, as were Dey-FP High Dose and FLONASE High Dose treatment groups. Treatment-by-Day interaction (overall Days 2-14) and Treatment-by-Week interaction (Week 1 and Week 2) effects were not statistically significant indicating that the treatment groups behaved similarly for the duration of the study, except for the magnitude of improvement in TNSS. There was no statistically significant differences between Dey-FP and FLONASE High and Low Dose groups for any efficacy endpoint analysis (relief of signs and symptoms of SAR). Moreover, all active treatment groups were consistently statistically superior to both High and Low Dose Placebo groups. Results of analyses for the Per Protocol Population paralleled those of the ITT Population for all efficacy variables.
In FIGS. 1-4, the efficacy of the nasal formulations is expressed as the change from baseline (pretreatment) in a composite score of nasal symptoms (e.g. runny nose, sneezing, nasal itching and congestion) referred to as total nasal symptom scores (TNSS). The change from baseline in TNSS scores is expressed in absolute units (rather tan percent change from baseline). Using an analysis of variance model (ANOVA), the least square mean (LS Mean) for the baseline (positive value) and change from baseline (negative value if symptoms improve) are obtained. The higher the negative value seen in the LS Mean, the greater was the change (improvement) in TNSS. Table 1 shows a particle size distribution of the fluticasone particles in Dey-FP, wherein the particle size is in microns. Table 2 also shows the particle size distribution of fluticasone particles of another batch of Dey-FP, wherein the particle size is in microns. Table 3 shows the formulation of Dey-FP.







TABLE 1







Dey-FP 50 mcg


Particle Size Data - Batch 1














Run 1
Run 2
Run 3
Avg.







D (v, 0.10)
0.38
0.38
0.41
0.39



D (v, 0.25)
0.75
0.75
0.78
0.76



D (v, 0.50)
1.50
1.51
1.56
1.52



D (v, 0.75)
2.93
2.94
3.05
2.97



D (v, 0.90)
5.22
5.21
5.42
5.28

















TABLE 2







Dey-FP 50 mcg


Particle Size Data - Batch 2














Run 1
Run 2
Run 3
Avg.







D (v, 0.10)
0.38
0.42
0.37
0.39



D (v, 0.25)
0.76
0.79
0.72
0.76



D (v, 0.50)
1.53
1.57
1.40
1.50



D (v, 0.75)
3.00 
3.08 
2.64
2.91



D (v, 0.90)
5.34 
5.50
4.53
5.12

















TABLE 3







Formulation of Fluticasone Propionate Nasal Spray













Drug Product




Ingredient
Function
Concentration
Per Spray
Per Bottle

















Fluticasone Propionate USP
Active Ingredient
0.050% 
w/w
0.050 
mg
8.00 
mg


Benzalkonium Chloride
Preservative
0.020% 
w/w
0.0388 
mg
6.1 
mg











Solution, 50% NF


















Microcrystalline
Suspending Agent
1.50% 
w/w
1.50 
mg
240.0 
mg











Cellulose/Carboxy-






methylcellulose Sodium, NF


















Polysorbate 80, NF
Wetting Agent
0.0050%
w/w
0.005 
mg
0.80 
mg


Phenylethyl Alcohol, USP
Preservative
0.25% 
v/w
0.255 
mg
40.80 
mg


Dextrose, Anhydrous, USP
To adjust osmolality 
5.00% 
w/w
5.00 
mg
800.0 
mg











Hydrochloric Acid, 1N
To adjust pH
As required
As required 
As required













Purified Water, USP
Diluent
n/a
93.15 
mg
14.90 
g









The Figures and attachments herein are presented for illustrative purposes only. They are not intended to limit the scope of the invention. Further, it should be understood that various changes and modifications to the presently preferred embodiment described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be covered by the appended claims. Also, the invention may suitably comprise, consist of or consist essentially of the elements or steps described herein. Further, the invention described herein suitably may comprise or be practiced in the absence of any element or step which is not specifically disclosed herein. Further, one or more step described herein may be performed simultaneously with another step.

## Claims

1. A formulation for the treatment of fungus-induced rhinosinusitis in a mammal, said formulation comprising an aqueous suspension comprising:
(a) about 0.05% by weight of suspended solid steroidal anti-inflammatory particles, wherein the steroidal anti-inflammatory is fluticasone or a pharmaceutically acceptable salt, ester, enol ether, enol ester, acid, or base thereof, said suspended solid steroidal anti-inflammatory having the following particle size distribution profile:
i. about 10% of the solid steroidal anti-inflammatory particles have a particle size of less than 0.4 microns;
ii. about 25% of the solid steroidal anti-inflammatory particles have a particle size of less than 0.8 microns;
iii. about 50% of the solid steroidal anti-inflammatory particles have a particle size of less than 1.5 microns;
iv. about 75% of the solid steroidal anti-inflammatory particles have a particle size of less than 3.0 microns; and

v. about 90% of the solid steroidal anti-inflammatory particles have a particle size of less than 5.3 microns; and
(b) an antifungal agent;
wherein the formulation is sterile and has a relatively long period of stability such that after storage for 12 months at a temperature between 15 to 30° C., greater than 90% of the fluticasone originally present in the formulation still remains in the formulation.

2. The formulation of claim 1, wherein the antifungal agent comprises from 0.5 to 150 mg of amphotericin β.

3. The formulation of claim 1, wherein said formulation comprises about 7.5 to about 15 mg of amphotericin β.

4. The formulation of claim 1, wherein said formulation comprises about 10 mg of amphotericin β.

5. The formulation of claim 1, comprising about 50 mcg of said steroidal anti-inflammatory.

6. The formulation of claim 1, comprising about 75 to about 300 mcg of said steroidal anti-inflammatory.

7. The formulation of claim 1, wherein the formulation is sterile.

8. The formulation of claim 1, wherein the formulation further comprises a preservative.

9. The formulation of claim 8, wherein the preservative is benzalkonium chloride.

10. The formulation of claim 1, wherein the formulation is in a metered-dose spray pump bottle.

11. The formulation of claim 1, further comprising about 0.01% to about 90% by weight on a dried weight basis of one or more of the following compounds:
(a) microcrystalline cellulose;
(b) carboxymethyl cellulose sodium;
(c) dextrose;
(d) benzalkonium chloride;
(e) polysorbate 80; and
(g) phenylethyl alcohol.

12. The formulation of claim 1, further comprising an antibiotic.

13. The formulation of claim 12, wherein the antibiotic is one or more selected from the group consisting of amikacin, azithromycin, aztreonan, cefazolin, cefepine, cefonicid, cefaperazone, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cephapirin, ciprofloxacin, clindamycin, doxycycline, erythromycin lactobionate, gentamicin, kanamycin, linezolid, mezlocillin, mupirocin, nafcillin, netilmicin, neomycin, oxacillin, paromomycin, piperacillin, streptomycin, ticarcillin, tobramycin, and vancomycin.

14. The formulation of claim 1 further comprising at least one complexing agent wherein the at least one complexing agent is sodium edetate.

15. A formulation for the treatment of fungus-induced rhinosinusitis, said formulation comprising an aqueous suspension comprising:
(a) amphotericin β;
(b) about 0.045% to about 0.05% by weight of suspended solid steroidal anti-inflammatory fluticasone propionate particles having the following particle size distribution profile:
ii. about 10% of the solid steroidal anti-inflammatory particles have a particle size of less than 0.40 microns;
iii. about 25% of the solid steroidal anti-inflammatory particles have a particle size of less than 0.80 microns;
iv. about 50% of the solid steroidal anti-inflammatory particles have a particle size of less than 1.5 microns;
v. about 75% of the solid steroidal anti-inflammatory particles have a particle size of less than 3.0 microns;
vi. about 90% of the solid steroid particles have a particle size of less than 5.3 microns; and,

(c) at least one complexing agent selected from the group consisting of ethylenediaminetertraacetic acid, citric acid, nitrilotriacetic acid, salts thereof, and sodium edetate;
wherein said formulation comprises a pH from about 3 to about 7 and is suitable for administration to the nasal-paranasal mucosa, and wherein the formulation is sterile and has a relatively long period of stability such that after storage for 12 months at a temperature between 15 to 30° C., greater than 90% of the fluticasone originally present in the formulation still remains in the formulation.

16. The formulation of claim 15, wherein the at least one complexing agent is sodium edetate.

17. A formulation for the treatment of fungus-induced rhinosinusitis, said formulation comprising an aqueous suspension comprising:
(a) a therapeutic amount of an antiviral agent selected from the group consisting of Acyclovir, Famciclovir, Valacyclovir, edoxudine, ganciclovir, foscarnet, cidofovir (vistide), Vitrasert and Formivirsen
(b) about 7.5 to about 15 mg of amphotericin 13;
(c) about 10 to about 100 mg of doxycycline
(d) about 0.045% to about 0.05% by weight of suspended solid steroidal anti-inflammatory fluticasone propionate particles having the following particle size distribution profile:
ii. about 10% of the solid steroidal anti-inflammatory particles have a particle size of less than 0.4 microns;
iii. about 25% of the solid steroidal anti-inflammatory particles have a particle size of less than 0.8 microns;
iv. about 50% of the solid steroidal anti-inflammatory particles have a particle size of less than 1.5 microns;
v. about 75% of the solid steroidal anti-inflammatory particles have a particle size of less than 3.0 microns;
vi. about 90% of the solid steroid particles have a particle size of less than 5.3 microns; and,

(e) at least one complexing agent selected from the group consisting of ethylenediaminetertraacetic acid, citric acid, nitrilotriacetic acid, salts thereof, and sodium edetate;
wherein said formulation comprises a pH from about 3 to about 7 and is suitable for administration to the nasal-paranasal mucosa and wherein the formulation is sterile and has a relatively long period of stability such that after storage for 12 months at a temperature between 15 to 30° C., greater than 90% of the fluticasone originally present in the formulation still remains in the formulation.

18. The formulation of claim 17, wherein the antiviral agent is edoxudine.