Methods for treating infection and / or inflammation of nasal, paranasal sinus, and nasopharyngeal tissues

Abstract

To provide compositions for treating diseases and conditions of the nasal, paranasal sinus and nasopharyngeal tissues.SOLUTION: Provided is a composition for use in a method for treating a subject having a condition associated with paranasal sinus or nasopharyngeal tissues. The method comprises administering the composition topically to the subject's paranasal sinus or nasopharyngeal tissues not more than once in a 10-day period, the composition being a cream and comprising a steroid. The composition further comprises an ingredient selected from a group consisting of an agent having antimicrobial activity, cetostearyl alcohol, cetyl ester wax, sorbitan monostearate, benzyl alcohol, propylene glycol, 2-octyldodecanol, polysorbate 60, sodium hydroxide, carbomer 940 NF, and water.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 811,169, filed February 27, 2019, which is incorporated by reference in its entirety. [Background technology]

[0002] The nasal cavity, paranasal sinuses and nasopharynx are important components of the human respiratory system and can be affected by diseases or conditions that require medical intervention. Proper and effective treatment of these diseases and conditions is necessary to promote patient health and avoid complications from the disease or condition.

[0003] The current standard of care for diseases or conditions in these areas is saline sprays or rinses, and nasal sprays of corticosteroids, glucocorticoids, anticorticoids, and antihistamines, which are generally low viscosity (1-10 cPs), water-based solutions or suspensions applied multiple times per day for extended periods of time. While steroidal nasal sprays address the inflammation resulting from the condition, they may not address the underlying cause if it is an infection. These at-home therapies also require high levels of patient compliance for efficacy. Also, there are currently no U.S. Food and Drug Administration-approved antifungal drugs for nasal administration. Thus, there is a need for effective products that are administered topically to the sinuses or nasopharyngeal tissues for antifungal therapy.

[0004] With regard to the underlying cause of the condition, in some cases with fungal and / or bacterial infections, treatment can include intravenous administration, in clinic or hospital procedures, irrigation with a water-based suspension of antimicrobial or antifungal drugs, and anesthesia, but most often the patient is treated at home with a nasal spray, often multiple doses per day. Alternatively, or in addition, oral antibiotics and antifungals are prescribed. These treatments are often unsuccessful, and patients continue to suffer from chronic infection and inflammation without a viable alternative. Thus, there is a need for treatment options that address the above deficiencies. Summary of the Invention

[0005] The present disclosure is directed to methods for treating diseases and conditions of nasal, paranasal sinus and nasopharyngeal tissue.

[0006] In some embodiments, a method for treating a subject having a disease or condition associated with nasal, paranasal sinus or nasopharyngeal tissue comprises topically administering a composition to the paranasal sinus or nasopharyngeal tissue of the subject, wherein the composition is a thickened cream comprising a steroid and / or an agent having antimicrobial activity.

[0007] For a more complete understanding of the present invention, and the advantages thereof, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which: [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 is a bar graph showing the raw symptom severity scores of 11 patients (F indicates female and M indicates male) in Example 2, where the blue line represents the severity score before treatment and the red line represents the severity score after treatment.

[0009] [Figure 2A] FIG. 2A shows an endoscopic photograph of the sinuses of patient 7 of Example 2 prior to treatment with the cream composition described in Example 1.

[0010] [Figure 2B]FIG. 2B shows an endoscopic photograph of the sinuses of patient 7 of Example 2 prior to treatment with the cream composition described in Example 1, with rounded areas depicting mucus secretions.

[0011] [Figure 2C] FIG. 2C shows an endoscopic photograph of the sinuses of patient 7 of Example 2 prior to treatment with the cream composition described in Example 1, with a circular area depicting congestion.

[0012] [Figure 2D] FIG. 2D shows an endoscopic photograph of the sinuses of patient 7 of Example 2, two months after treatment with the cream composition described in Example 1.

[0013] [Figure 3A] FIG. 3A shows an endoscopic photograph of the sinuses of patient 11 of Example 2 prior to treatment with the cream composition described in Example 1.

[0014] [Figure 3B] FIG. 3B shows an endoscopic photograph of the sinuses of patient 11 of Example 2 two months after treatment with the cream composition described in Example 1.

[0015] [Figure 4A] FIG. 4A shows a histological specimen taken from the lateral aspect of the middle turbinate of patient 11 in Example 2 stained with hematoxylin and eosin immediately prior to the first application.

[0016] [Figure 4B] FIG. 4B is a tissue specimen taken from the lateral aspect of the middle turbinate of patient 11 in Example 2, stained with hematoxylin and eosin 2 months after initial application.

[0017] [Figure 5A] FIG. 5A depicts the SNOT-22 scores of patient 2 in Example 5 before and after treatment.

[0018] [Figure 5B]FIG. 5B depicts the SNOT-22 scores of patient 3 of Example 5 before and after treatment.

[0019] [Figure 5C] FIG. 5C represents the SNOT-22 scores of patient 6 of Example 5 before and after treatment.

[0020] [Figure 5D] FIG. 5D shows the mean SNOT-22 scores for each SNOT-22 metric for patients 1 to 8 in Example 5 before and after treatment (~30 days).

[0021] [Figure 6] FIG. 6 represents the total SNOT-22 scores of the patients in Example 5 before and after treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The present disclosure provides compositions and methods for treating diseases and conditions of the nasal, paranasal sinuses and nasopharyngeal tissues. definition

[0023] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0024] The use of the term "or" in the claims and this disclosure is used to mean "and / or" unless expressly stated to refer to alternatives only or the alternatives are mutually exclusive.

[0025] The use of the term "about" when used in conjunction with a numerical value is intended to include + / - 10%. By way of example and not limitation, if a number of amino acids is identified as about 200, this would include 180 to 220 (plus or minus 10%).

[0026] As used herein, "antimicrobial" should be understood to include anti-microorganisms such as anti-bacterial and anti-fungal agents.

[0027] As used herein, "effective amount" refers to an amount sufficient to produce a desired pharmacological and / or pharmacodynamic outcome.For example, an effective amount for treatment is an amount that can reduce or eliminate symptoms and / or pathology of infection or disease.Another example is an amount that is effective to destroy or eradicate the biofilm that protects the pathogen, so as to effectively eliminate the pathogen.

[0028] The terms "patient," "individual," and "subject" are used interchangeably herein to refer to a mammalian subject to be treated, with human patients being preferred. In some cases, the methods of the invention find use in laboratory animals, in veterinary applications, and in the development of animal models for disease, including rodents such as mice, rats, guinea pigs, and hamsters, as well as other animals, including, but not limited to, dogs, cats, horses, and primates.

[0029] "Treatment" refers to an intervention with the goal of preventing the occurrence of a disease or altering its pathology or symptoms. Thus, "treatment" can refer to both therapeutic and prophylactic or preventative measures. Those in need of treatment include those already with the disease as well as those wishing to prevent the disease.

[0030] As used herein, "cream" refers to a semi-solid formulation containing one or more medicinal agents dissolved or dispersed in either an oil-in-water emulsion or a water-in-oil emulsion. For the avoidance of doubt, "cream" does not include "gels," which are semi-solid systems consisting of a dispersion of small or large molecules in an aqueous liquid vehicle that has been made into a jelly by the addition of a gelling agent, and therefore "cream" does not include thermoreversible gels, thermoreversible polymers, or copolymers of polyoxyethylene and polyoxypropylene.

[0031] In some embodiments, a method for treating a disease or condition of the nasal, paranasal sinus, or nasopharyngeal tissue may comprise topically administering a composition to the nasal or nasopharyngeal tissue of a subject, the composition being a cream having a high viscosity that includes a steroid and / or an agent having antimicrobial activity.

[0032] In some embodiments, the step of applying the composition is performed as a single dose, which in some instances is sufficient to provide effective treatment of a disease or condition of the nasal, nasal or nasopharyngeal tissue. In certain other embodiments, the step of applying the cream composition is performed only once every 10-21 days, every 21-30 days, every 30-60 days, every 60-90 days, every 90-180 days, or every 180-365 days, by way of example and not limitation. It should be understood that in most cases, "single dose" refers to sequential bilateral administration via intranasal administration. In some embodiments, the step of applying the cream composition is performed no more than twice per 21, 30, 60, 90, 180, or 365 days, by way of example and not limitation.

[0033] In one embodiment, the step of administering the cream composition of the present disclosure comprises applying the cream composition to the sinus mucosa via a first intranasal administration. This first application can be performed using a syringe with a tube or other similar tool attached. The syringe with a tube or other similar tool attached can be guided by a surgical endoscope. The method can then further comprise the use of an instrument to spread the cream composition in a manner sufficient to cover the affected sinus mucosa. One or more of these steps can be repeated via a second intranasal administration to ensure bilateral coverage of the sinus.

[0034] The amount of cream composition applied varies based on the size of the area of ​​affected tissue and the size of the patient. In some embodiments, the composition can be administered in an amount of about 0.5 cubic centimeters (cc) to about 5 cc per intranasal application, or about 1 cc to about 10 cc total application to affected sinus tissue, more commonly about 2 cc to about 4 cc per intranasal application, or about 4 cc to about 8 cc total application to affected tissue of the nasal mucosa. By way of example and not of limitation, the amount of composition administered per intranasal application can be about 0.5 cc, 0.75 cc, 1 cc, 1.25 cc, 1.5 cc, 1.75 cc, 2 cc, 2.25 cc, 2.5 cc, 2.75 cc, 3 cc, 3.25 cc, 3.5 cc, 3.75 cc, 4 cc, 4.5 cc, or 5 cc. It should be understood that for total bilateral application to diseased sinus mucosa, these stated amounts are doubled unless otherwise specified.

[0035] In other embodiments, the composition can be administered to the affected tissue in an amount of about 0.5 grams (g) to about 5 g per intranasal administration, or about 1 g to about 10 g total application to the affected tissue, more typically about 2 g to about 4 g, or about 4 g to about 8 g total application to the affected tissue per intranasal administration. By way of example and not of limitation, the amount of the composition can be about 0.5 g, 0.75 g, 1 g, 1.25 g, 1.5 g, 1.75 g, 2 g, 2.25 g, 2.5 g, 2.75 g, 3 g, 3.25 g, 3.5 g, 3.75 g, 4 g, 4.5 g, or 5 g per intranasal administration. It should be understood that for total bilateral application to diseased paranasal sinus mucosa, these recited amounts are doubled unless otherwise specified.

[0036] The compositions and methods of the present disclosure can be used to treat various conditions of nasal, paranasal sinus, and nasopharyngeal tissues.By way of example and not limitation, such conditions of nasal, paranasal sinus, and nasopharyngeal tissues can include diseases, infections, symptoms, and combinations of the above.By way of example and not limitation, such diseases or infections can include chronic sinusitis, acute sinusitis mucormycosis, polymicrobial sinusitis, nasal polyps, bacterial sinusitis, allergic fungal sinusitis, chronic bacterial sinusitis, chronic allergic fungal sinusitis, and rhinosinusitis. By way of further example, and not by way of limitation, the methods of the present disclosure can be used to treat the following sinus symptoms: need to blow nose, stuffy nose, sneezing, runny nose, coughing, post nasal drip, thick nasal mucus, ear congestion, dizziness, ear pain, pain or pressure in the face, loss of smell or taste, difficulty falling asleep, waking at night, difficulty sleeping soundly, waking up tired, fatigue, loss of productivity, difficulty concentrating, frustration, restlessness or irritability, sadness, embarrassment, or combinations thereof. In some embodiments, the condition further comprises need to blow nose, stuffy nose, sneezing, runny nose, coughing, post nasal drip, thick nasal mucus, ear congestion, dizziness, ear pain, pain or pressure in the face, loss of smell or taste, difficulty falling asleep, waking at night, difficulty sleeping soundly, waking up tired, fatigue, loss of productivity, difficulty concentrating, frustration, restlessness or irritability, sadness, embarrassment, or combinations thereof. Thus, these sinus symptoms may occur in conjunction with disease, infection or other conditions, or may be conditions that should be treated in their own right. In some embodiments, the subject has previously undergone functional endoscopic sinus surgery (FESS) and subsequently developed a chronic inflammatory response. In some embodiments, the subject for whom the compositions and methods are effective suffers from chronic allergic fungal sinusitis following FESS. In some embodiments, the patient experiences an exacerbation of symptoms after a period of mild or no symptoms following FESS, with or without the use of nasal steroid sprays, oral antibiotics and / or nasal irrigation. In some embodiments, the subject has undergone FESS resulting in abnormal nasal tissue described as hypertrophic, inflammatory, and granular tissue.In further aspects of these embodiments, the subject's post-FESS sinusitis was treated with nasal steroid sprays, oral antibiotics and / or nasal irrigation for one year with minimal to no change in pathology prior to the implementation of the method. In some embodiments, the subject suffers from chronic sinusitis due to bacterial infection. In some embodiments, the method of the present disclosure can be implemented at the time of FESS. In some embodiments, the patient has not previously undergone FESS. In some embodiments, the method of the present disclosure can be implemented during balloon sinus dilation. In some embodiments, the composition of the present disclosure can be administered at the time of FESS. In some embodiments, the composition of the present disclosure can be administered during balloon sinus dilation. Even if the chronic inflammation is the result of bacterial infection, a cream composition containing clotrimazole may be useful, as this active agent has been shown to have antibacterial activity in addition to antifungal activity against both gram-positive and gram-negative microorganisms. In particular, clotrimazole has been shown to result in a reduction of Pseudomonas aeruginosa and to have antibacterial activity against Streptococcus, Staphylococcus, Gardnerella vaginalis, and Corynebacterium. However, other antibiotic active agents may be substituted in the cream composition of the present disclosure, as discussed in more detail below. In some embodiments, the patient does not have a detectable microbial infection. In other embodiments, the patient has a detectable microbial infection, such as a bacterial or fungal infection. Thus, the compositions and methods of the present disclosure may be useful in the absence or presence of a detectable microbial infection. In some embodiments, the pathology may include a bacterial infection. In some embodiments, the pathology is at least in part the result of a bacterial infection, and a biofilm is formed on the surface of the sinus or nasopharyngeal tissue. In some embodiments, the pathology may include a fungal infection. In some embodiments, the pathology may include a yeast infection. In some embodiments, the pathology may include a polymicrobial infection.

[0037] The cream composition of the present disclosure can include steroids.Various corticosteroids, glucocorticoids or combinations thereof can be used in the compositions and methods of the present disclosure.Without being limited thereto, corticosteroids that can be used in the compositions and methods of the present invention include cortisone, cortisol, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, betamethasone, ciclesonide, dexamethasone, 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, budesonide, chloroprednisone, Clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronaceto, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperone acetate, fluprednidene acetate, fluprednisolone, fludroxycortide, fluticasone propionate, formocortal, halcinonide , halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, meprednisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisolone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, etc. Esters, derivatives and salts, including hydrates and hydrochloride salts of corticosteroids, may also be used in the compositions and methods of the present disclosure. For example, betamethasone is available as betamethasone dipropionate (having the chemical name 9-fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate, C28 H 37 It is frequently administered as betamethasone, which has an empirical formula of FO7 and a molecular weight of 504.59 g / mol), and the doses of betamethasone shown in Table 1 below are based on this particular salt.

[0038] The amount of steroid in the compositions of the present disclosure can vary according to the desired dose to be delivered based on the patient's condition, the patient's sensitivity, the biological half-life of the steroid, the patient's age, systemic factors, and other factors. Additionally, the state of infection or disease and sensitivity to steroids can also be taken into consideration. Those skilled in the art can determine the appropriate dose, including determining the "effective amount" of the composition to be applied.

[0039] Exemplary, non-limiting dose ranges of specific steroids for use in the cream compositions of the present method are set forth below in Table 1. The values ​​set forth in Table 1 are for use in the present cream compositions and assume a total single dose (i.e., bilateral intranasal administration to the sinonasal mucosa) of 5-6 grams (i.e., 2.5-3 g per intranasal administration) of the cream composition. [Table 1]

[0040] In some embodiments, the steroid is betamethasone or betamethasone dipropionate, present in the compositions of the present disclosure at about 0.1 mg to about 0.5 mg per gram of cream composition or about 0.15 to about 0.64 mg per gram of cream composition, respectively, or more preferably about 0.25 mg per gram of cream composition or about 0.32 mg per gram of cream composition, respectively. In another embodiment, the total dose of betamethasone dipropionate administered in a single application (i.e., bilateral intranasal administration) is about 0.643 mg to about 3.25 mg, or more preferably about 0.80 mg to about 2.6 mg, or even more preferably about 0.95 mg to about 1.93 mg, and even more preferably about 1.28 mg to about 1.61 mg.

[0041] In some embodiments, the steroid is present in about 0.01 to about 1 weight percent of the composition. By way of example and not limitation, the steroid can be present in 0.01 to 0.5 weight percent of the composition, 0.02 to 0.4 weight percent of the composition, 0.03 to 0.3 weight percent of the composition, 0.04 to 0.2 weight percent of the composition, or 0.05 to 0.1 weight percent of the composition. In some embodiments, the steroid is betamethasone dipropionate and is present in about 0.03 weight percent of the composition.

[0042] Various antifungal agents can be used in the compositions and methods of the present disclosure.For example, but not limited to, such antifungal agents can include natamycin, ciclopirox, fluconazole, terbinafine, clotrimazole, ketoconazole, econazole, miconazole, nystatin, oxiconazole, terconazole, tolnaphthoate, efinaconazole, abafungin, terbinafine, butenafine, metronidazole, etc., and combinations thereof.In some embodiments, the antifungal agent is clotrimazole.

[0043] The antifungal agent can be present in the compositions of the present disclosure in an effective amount. In certain embodiments, the effective or total amount of antifungal agent per single dose (i.e., bilateral intranasal administration) is from about 20 mg to about 50 mg, and more preferably from about 25 mg to about 40 mg. In certain embodiments, the antifungal agent is in an amount of from about 2.5 mg per gram of cream composition to about 10 mg per gram of cream composition, and more preferably about 5 mg per gram of cream composition. In some embodiments, the antifungal agent is present in about 0.1 to about 5 weight percent of the composition. By way of non-limiting example, the antifungal agent is present in 0.1-5 weight percent of the composition, 0.5-4 weight percent of the composition, 0.5-3 weight percent of the composition, 0.5-2 weight percent of the composition, 0.5-1 weight percent of the composition, 1-5 weight percent of the composition, 2-5 weight percent of the composition, 3-5 weight percent of the composition, 4-5 weight percent of the composition, or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 weight percent of the composition. In some embodiments, the antifungal agent is clotrimazole and is present in about 0.5 weight percent of the composition.

[0044] In some embodiments, the compositions of the present disclosure can further include an antibiotic. For example, but not limited to, such antibacterial agents can include flucloxacillin, triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether), alcohol (including ethanol and isopropyl alcohol), peroxide (including benzoyl peroxide), iodine, benzethonium chloride, chloroxylenol, and aminoglycoside antibiotics, such as ciprofloxacin, and salts or derivatives thereof. Examples of other antibiotics include, but are not limited to, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromycin, geldanamycin, herbimycin, loracarbef, ertapenem, doripenem, imipenem, meropenem, cefaclor, cefamandole, cefotoxin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, vancomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, aztreonam, amoxicillin, ampicillin, azocillin, carbenicillin, and cloxacillin. , dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, peperacillin, ticarcillin, bacitracin, colistin, polymyxin B ciprofloxacin, clavulanic acid, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nonfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, AL-15469A, AL-38905, OP-145, mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, cotrimoxazole, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, linezolid, arsogebanuvem chloramphenicol, clindamycin,Lincomycin, Ethambutol, Fosfomycin, Fusidic acid, Furazolidone, Isoniazid, Linezolid, Metronidazole, Mupirocin, Nitrofurantoin, Platensimycin, Pyrazinamide, Quinupristin, Dalfopristin, Rifampicin, Thiamphenicol, Tinidazole, Amoxicillin / Clavulanic acid, Maximin H5, Dermcidin, Cecropin, Andropin, Moricin, Ceratotoxin, Melittin, Magainin, Dermaseptin, Bombinin, Brevinin-1, Esculentin, Buforin II, CAP18, LL37, Abaecin, Apidaecin, Prophenin, Indolicidin, Brevinin, Propylaeus ... rotegrin, tachyplesin, defensin, drosomycin, alamethicin, pexiganan or MSI-78, MSI-843, MSI-594, polyphemusin, colicin, pyocin, klebicin, subtilisin, epidermin, herbicolacin, brevicin, halocin, agrocin, albesin, camocin, curvaticin, diversin, enterocin, enterolysin, erwiniocin, glycinecin, lactococcin, lacticin, leucoccin, mesenterycin, pediocin, plantaricin, sakacin, sulfolobicin, vibriocin, warnerinand, nisin, and the like, and salts or derivatives thereof.

[0045] The therapeutically active agents (steroids and / or antimicrobial agents) contemplated within the scope of the present invention should be understood to include hydrophobic, hydrophilic and amphiphilic compounds. They may be in free acid, free base or pharma-ceutically acceptable salt form, including derivatives, esters or prodrugs. It should be understood that the cream composition of the present disclosure may include only steroids, antimicrobial agents (antifungal, antibacterial, or combinations thereof), or a combination of steroids and antimicrobial agents. The type of therapeutically active ingredient in the cream composition may be determined based on the condition being treated, in some cases only steroids are required, in other cases only antimicrobial agents are required, and in further examples both steroids and antimicrobial agents may be required. Thus, in some embodiments, the cream composition does not include antimicrobial agents. In other embodiments, the cream composition does not include steroids. In such cases, the cream composition may include, for example, but not limited to, only steroids as therapeutically active agents, i.e., the cream composition does not include antimicrobial agents. As another example, but not limited to, the cream composition may include only antimicrobial agents as therapeutic agents, i.e., the cream composition does not include steroids.

[0046] In some embodiments, the total amount of cream composition applied to the affected area of ​​the subject (i.e., bilateral intranasal administration) is about 4 grams to about 10 grams, more preferably about 5 grams to about 8 grams. It should therefore be understood that the amount of cream composition administered per intranasal administration is about 2 grams to about 5 grams, and more preferably about 2.5 grams to about 4 grams.

[0047] The compositions described herein are sufficiently viscous to maintain contact with the tissues of the nasal cavity, nasal cavity, and nasopharynx for a period of time sufficient to provide effective treatment of these tissues.

[0048] It should be understood by those skilled in the art that the viscosity value of a cream is highly dependent on the method of measuring the viscosity. Thus, the viscosity values ​​of the cream composition of the present disclosure, generated by Brookfield HBT with spindle 21 at room temperature, include the following viscosity values ​​under the corresponding recited conditions: (1) about 220,000 centipoise (cP) to about 260,000 cP at a shear rate of 0.5 RPM, 30% torque with a modulus of 8,000; (2) about 140,000 cP to about 170,000 cP at a shear rate of 1.0 RPM, 39% torque with a modulus of 4,000; (3) about 75,000 cP to about 90,000 cP at a shear rate of 2.0 RPM, 41% torque with a modulus of 2,000; (4) about 100,000 cP to about 150,000 cP at a shear rate of 2.5 RPM, 1,600% torque; (5) from about 32,000 cP to about 55,000 cP at a shear rate of 5.0 RPM and a 50% torque by a factor of 800; (6) from about 19,000 cP to about 32,000 cP at a shear rate of 10.0 RPM and a 60% torque by a factor of 400; (7) from about 10,000 cP to about 19,000 cP at a shear rate of 20.0 RPM and a 73% torque by a factor of 200; or (8) from about 5,000 cP to about 10,000 cP at a shear rate of 50.0 RPM and a 97% torque by a factor of 80 (collectively referred to herein as the "cream composition viscosity profile"). To avoid confusion, in this specification and any amended claims, the term "cream composition viscosity profile" refers to the viscosity values ​​recited above under the recited conditions using a Brookfield HBT with spindle 21 at room temperature.

[0049] Various topical analgesics may also be used in the compositions described herein, including, but not limited to, nonsteroidal anti-inflammatory drugs, lidocaine, capsaicin, amitriptyline, glyceryl nitrate, opioids, menthol, pimecrolimus, phenytoin, and the like.

[0050] Various other materials can be used in the compositions described herein. These include, but are not limited to, astringents such as aluminum acetate, and topical anti-infectives such as neomycin, clioquinol, or chloramphenicol. As a further example, but not limited to, the composition can further include cetostearyl alcohol, cetyl ester wax, sorbitan monostearate, benzyl alcohol, propylene glycol, 2-octyldodecanol, polysorbate 60, sodium hydroxide, carbomer 940NF, water, and any combination thereof.

[0051] The pharmaceutical compositions described herein preferably have a pH of less than about 7, as use of compositions having a higher pH may promote or inappropriately inhibit bacterial and / or fungal growth in target tissues. In some cases, the particular pH, or range of pH, formulated into the pharmaceutical composition may depend on the particular corticosteroid, or combination of corticosteroids, selected for the composition, as pH may affect the solubility and / or shelf life of these substances. The present invention also provides the following aspects. [1] 1. A method for treating a subject having a condition associated with paranasal sinus or nasopharyngeal tissue, comprising administering a composition locally to the paranasal sinus or nasopharyngeal tissue of the subject, the composition having a viscosity of from about 220,000 centipoise (cP) to about 260,000 cP at a shear rate of about 0.5 RPM and 30% torque with a factor of 8,000; (2) from about 140,000 cP to about 170,000 cP at a shear rate of about 1.0 RPM and 39% torque with a factor of 4,000; (3) from about 75,000 cP to about 90,000 cP at a shear rate of about 2.0 RPM and 41% torque with a factor of 2,000; or (4) from about 55,000 cP to about 74,990 cP at a shear rate of about 2.5 RPM and 42% torque with a factor of 1,600. 9 cP, (5) from about 32,000 cP to about 55,000 cP at 50% torque with a factor of 800 at a shear rate of about 5.0 RPM, (6) from about 19,000 cP to about 32,000 cP at 60% torque with a factor of 400 at a shear rate of about 10.0 RPM, (7) from about 10,000 cP to about 19,000 cP at a shear rate of about 20.0 RPM, and a 73% torque with a factor of 200, or (8) from about 5,000 cP to about 10,000 cP at 97% torque with a factor of 80 at a shear rate of about 50.0 RPM, as measured by a Brookfield HBT with spindle 21 at room temperature, said cream further comprising an agent having steroid and antimicrobial activity. [2] The method according to [1], wherein the steroid is selected from cortisone, cortisol, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, betamethasone, ciclesonide, dexamethasone, esters, derivatives and salts thereof, and combinations thereof. [3] The method according to [1], wherein the steroid is betamethasone or an ester, derivative or salt thereof. [4] The method according to [1], wherein the steroid is betamethasone dipropionate. [5] The method according to any of [1] to [4], wherein the steroid is present in the composition in an amount of about 0.1 to 100 milligrams per gram of the composition. [6] The method of [4], wherein the steroid is present at about 0.322 milligrams per gram of the composition. [7] The method according to [6], wherein the total amount of the composition administered to the patient is from about 4 grams to about 8 grams. [8] The method according to any of [1] to [7], wherein the drug having antimicrobial activity is selected from the group consisting of natamycin, ciclopirox, fluconazole, terbinafine, clotrimazole, ketoconazole, econazole, miconazole, nystatin, oxiconazole, terconazole, tolnaphthoate, efinaconazole, abafungin, terbinafine, butenafine, metronidazole, and any combination thereof. [9] The method according to any one of [1] to [7], wherein the drug having antimicrobial activity is clotrimazole.

[10] The method of [8], wherein the agent having antimicrobial activity is present in the composition at about 5 milligrams per gram of the composition.

[11] The method according to any of [1] to

[10] , wherein the disease or infection of the paranasal sinuses or nasopharyngeal tissue is selected from mucormycosis, chronic sinusitis, acute sinusitis, bacterial sinusitis, chronic bacterial sinusitis, polymicrobial sinusitis, nasal polyps, allergic fungal sinusitis, chronic allergic fungal sinusitis, and rhinosinusitis.

[12] The method according to any of [1] to

[11] , wherein the subject has undergone sinus surgery prior to application of the composition.

[13] The method according to any of [1] to

[10] , wherein the disease or infection is chronic allergic fungal sinusitis and the subject has undergone functional endoscopic sinus surgery prior to application of the composition.

[14] The method according to any of [1] to

[13] , wherein the administering step is carried out to the subject not more than once.

[15] The method according to any of [1] to

[13] , wherein the administering step is carried out not more than once every 10 days.

[16] The method according to any one of [1] to

[13] , wherein the administering step is carried out not more than once every 21 days.

[17] The method according to any one of [1] to

[13] , wherein the administering step is carried out not more than once every 30 days.

[18] The method according to any one of [1] to

[13] , wherein the administering step is carried out not more than once every 60 days.

[19] The method according to any one of [1] to

[13] , wherein the administering step is carried out not more than once every 90 days.

[20] The method according to any of [1] to

[13] , wherein the administering step is carried out not more than once every 180 days.

[21] The method according to any one of [1] to

[13] , wherein the administering step is carried out not more than once every 365 days.

[22] The method according to any of [1] to

[21] , wherein the composition further contains cetostearyl alcohol, cetyl ester wax, sorbitan monostearate, benzyl alcohol, propylene glycol, 2-octyldodecanol, polysorbate 60, sodium hydroxide, carbomer 940NF, and water.

[23] A method for treating a subject having a condition associated with paranasal sinus or nasopharyngeal tissue, comprising topically administering a composition to the paranasal sinus or nasopharyngeal tissue of the subject, wherein the composition is a cream, the cream further comprising a steroid and an agent having antimicrobial activity, the total amount of composition administered being from about 4 g to about 8 g, the amount of the steroid being from about 0.1 to 0.5 milligrams per gram of the composition, and the amount of the antimicrobial agent being from about 2.5 mg to about 10 mg per gram of the composition.

[24] The method according to

[23] , wherein the steroid is selected from cortisone, cortisol, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, betamethasone, ciclesonide, dexamethasone, esters, derivatives and salts thereof, and combinations thereof.

[25] The method according to

[23] , wherein the steroid is betamethasone or an ester, derivative or salt thereof.

[26] The method according to

[23] , wherein the steroid is betamethasone dipropionate.

[27] The method of

[26] , wherein the steroid is present at about 0.322 milligrams per gram of the composition.

[28] The method according to any of

[23] to

[27] , wherein the drug having antimicrobial activity is selected from the group consisting of natamycin, ciclopirox, fluconazole, terbinafine, clotrimazole, ketoconazole, econazole, miconazole, nystatin, oxiconazole, terconazole, tolnaphthoate, efinaconazole, abafungin, terbinafine, butenafine, metronidazole, and combinations thereof.

[29] The method according to any one of

[23] to

[27] , wherein the drug having antimicrobial activity is clotrimazole.

[30] The method according to any of

[23] to

[29] , wherein the disease or infection of the paranasal sinuses or nasopharyngeal tissue is selected from mucormycosis, chronic sinusitis, acute sinusitis, bacterial sinusitis, chronic bacterial sinusitis, polymicrobial sinusitis, nasal polyps, allergic fungal sinusitis, chronic allergic fungal sinusitis, and rhinosinusitis.

[31] The method according to any of

[23] to

[30] , wherein the subject has undergone sinus surgery prior to application of the composition.

[32] The method according to any of

[23] to

[29] , wherein the disease or infection is chronic allergic fungal sinusitis and the subject has undergone functional endoscopic sinus surgery prior to application of the composition.

[33] The method according to any of

[23] to

[32] , wherein the administering step is carried out to the subject not more than once.

[34] The method according to any one of

[23] to

[32] , wherein the administering step is carried out not more than once every 10 days.

[35] The method according to any one of

[23] to

[32] , wherein the administering step is carried out not more than once every 21 days.

[36] The method according to any one of

[23] to

[32] , wherein the administering step is carried out not more than once every 30 days.

[37] The method according to any one of

[23] to

[32] , wherein the administering step is carried out not more than once every 60 days.

[38] The method according to any one of

[23] to

[32] , wherein the administering step is carried out not more than once every 90 days.

[39] The method according to any one of

[23] to

[32] , wherein the administering step is carried out not more than once every 180 days.

[40] The method according to any one of

[23] to

[32] , wherein the administering step is carried out not more than once every 365 days.

[41] The method according to any of

[23] to

[32] , wherein the composition further contains cetostearyl alcohol, cetyl ester wax, sorbitan monostearate, benzyl alcohol, propylene glycol, 2-octyldodecanol, polysorbate 60, sodium hydroxide, carbomer 940NF, and water.

[42] The method of [1], wherein the pathology is the result of gram-negative bacteria.

[43] The method according to

[42] , wherein the drug having antimicrobial activity is clotrimazole.

[44] The method of [1], wherein the pathology is the result of gram-positive bacteria.

[45] The method according to

[44] , wherein the drug having antimicrobial activity is clotrimazole.

[46] The method of [1], wherein the condition is the result of a fungus.

[47] The method of [1], wherein the condition is the result of yeast.

[48] ​​The method of [1], wherein the condition is polymicrobial, including a combination of bacteria, fungi and / or yeasts.

[49] The method according to [1], wherein the pathology is the result of inflammation without an identified microbial infection.

[50] The method described in [1], wherein the condition is an exacerbation of sinusitis after sinus surgery.

[51] The method according to any one of

[23] to

[32] , wherein the administering step is carried out not more than twice within 60 days.

[52] The method according to any of

[23] to

[32] , wherein the subject has undergone FESS resulting in abnormal nasal tissue described as hypertrophied, inflammatory, and granular tissue.

[53] The method according to any of

[23] to

[32] , wherein the pathological condition is at least partially the result of a bacterial infection and a biofilm is formed on the surface of the paranasal sinus or nasopharyngeal tissue.

[54] A method for treating a subject having a condition associated with paranasal sinus or nasopharyngeal tissue, comprising administering a composition locally to the paranasal sinus or nasopharyngeal tissue of the subject, the composition having a viscosity of from about 220,000 centipoise (cP) to about 260,000 cP at a shear rate of about 0.5 RPM and 30% torque with a factor of 8,000; (2) from about 140,000 cP to about 170,000 cP at a shear rate of about 1.0 RPM and 39% torque with a factor of 4,000; (3) from about 75,000 cP to about 90,000 cP at a shear rate of about 2.0 RPM and 41% torque with a factor of 2,000; or (4) from about 55,000 cP to about 70,000 cP at a shear rate of about 2.5 RPM and 42% torque with a factor of 1,600. (5) from about 32,000 cP to about 55,000 cP at 50% torque with a factor of 800 at a shear rate of about 5.0 RPM, (6) from about 19,000 cP to about 32,000 cP at 60% torque with a factor of 400 at a shear rate of about 10.0 RPM, (7) from about 10,000 cP to about 19,000 cP at a shear rate of about 20.0 RPM, and a torque of 73% with a factor of 200, or (8) from about 5,000 cP to about 10,000 cP at 97% torque with a factor of 80 at a shear rate of about 50.0 RPM, as measured by a Brookfield HBT with spindle 21 at room temperature, wherein the cream further comprises an agent having antimicrobial activity.

[55] The method according to

[54] , wherein the total amount of the composition administered to the patient is from about 4 grams to about 8 grams.

[56] The method according to any of

[54] to

[55] , wherein the drug having antimicrobial activity is selected from the group consisting of natamycin, ciclopirox, fluconazole, terbinafine, clotrimazole, ketoconazole, econazole, miconazole, nystatin, oxiconazole, terconazole, tolnaphthoate, efinaconazole, abafungin, terbinafine, butenafine, metronidazole, and any combination thereof.

[57] The method according to any one of

[54] to

[55] , wherein the drug having antimicrobial activity is clotrimazole.

[58] The method of

[56] , wherein the antimicrobial agent is present in the composition at about 5 milligrams per gram of the composition.

[59] The method according to any of

[54] to

[58] , wherein the disease or infection of the paranasal sinuses or nasopharyngeal tissue is selected from mucormycosis, chronic sinusitis, acute sinusitis, bacterial sinusitis, chronic bacterial sinusitis, polymicrobial sinusitis, nasal polyps, allergic fungal sinusitis, chronic allergic fungal sinusitis, and rhinosinusitis.

[60] The method according to any of

[54] to

[59] , wherein the subject has undergone sinus surgery prior to application of the composition.

[61] The method according to any of

[54] to

[58] , wherein the disease or infection is chronic allergic fungal sinusitis and the subject has undergone functional endoscopic sinus surgery prior to application of the composition.

[62] The method according to any of

[54] to

[61] , wherein the administering step is carried out to the subject not more than once.

[63] The method according to any one of

[54] to

[61] , wherein the administering step is carried out not more than once every 10 days.

[64] The method according to any one of

[54] to

[61] , wherein the administering step is carried out not more than once every 21 days.

[65] The method according to any one of

[54] to

[61] , wherein the administering step is carried out not more than once every 30 days.

[66] The method according to any one of

[54] to

[61] , wherein the administering step is carried out not more than once every 60 days.

[67] The method according to any one of

[54] to

[61] , wherein the administering step is carried out not more than once every 90 days.

[68] The method according to any one of

[54] to

[61] , wherein the administering step is carried out not more than once every 180 days.

[69] The method according to any one of

[54] to

[61] , wherein the administering step is carried out not more than once every 365 days.

[70] The method according to any of

[54] to

[69] , wherein the composition further contains cetostearyl alcohol, cetyl ester wax, sorbitan monostearate, benzyl alcohol, propylene glycol, 2-octyldodecanol, polysorbate 60, sodium hydroxide, carbomer 940NF, and water.

[71] A method for treating a subject having a condition associated with nasal or nasopharyngeal tissue, comprising topically administering a composition to the nasal or nasopharyngeal tissue of the subject, wherein the composition is a cream, the cream further comprising an agent having antimicrobial activity, the total amount of composition administered is from about 4 g to about 8 g, and the amount of the agent having antimicrobial activity is from about 2.5 mg to about 10 mg per gram of composition.

[72] The method according to

[71] , wherein the drug having antimicrobial activity is selected from the group consisting of natamycin, ciclopirox, fluconazole, terbinazole, clotrimazole, ketoconazole, econazole, miconazole, nystatin, oxiconazole, terconazole, tolnaftate, efinaconazole, abafungin, terbinafine, butenafine, metronidazole, and combinations thereof.

[73] The method according to

[71] , wherein the drug having antimicrobial activity is clotrimazole.

[74] The method according to any of

[71] to

[73] , wherein the disease or infection of the paranasal sinuses or nasopharyngeal tissue is selected from mucormycosis, chronic sinusitis, acute sinusitis, bacterial sinusitis, chronic bacterial sinusitis, polymicrobial sinusitis, nasal polyps, allergic fungal sinusitis, chronic allergic fungal sinusitis, and rhinosinusitis.

[75] The method according to any of

[71] to

[74] , wherein the subject has undergone sinus surgery prior to application of the composition.

[76] The method according to any of

[71] to

[73] , wherein the disease or infection is chronic allergic fungal sinusitis and the subject has undergone functional endoscopic sinus surgery prior to application of the composition.

[77] The method according to any of

[71] to

[76] , wherein the administering step is performed not more than once to the subject.

[78] The method according to any one of

[71] to

[76] , wherein the administering step is carried out not more than once every 10 days.

[79] The method according to any one of

[71] to

[76] , wherein the administering step is carried out not more than once every 21 days.

[80] The method according to any one of

[71] to

[76] , wherein the administering step is carried out not more than once every 30 days.

[81] The method according to any one of

[71] to

[76] , wherein the administering step is carried out not more than once every 60 days.

[82] The method according to any one of

[71] to

[76] , wherein the administering step is carried out not more than once every 90 days.

[83] The method according to any one of

[71] to

[76] , wherein the administering step is carried out not more than once every 180 days.

[84] The method according to any one of

[71] to

[76] , wherein the administering step is carried out not more than once every 365 days.

[85] The method according to any of

[71] to

[76] , wherein the composition further contains cetostearyl alcohol, cetyl ester wax, sorbitan monostearate, benzyl alcohol, propylene glycol, 2-octyldodecanol, polysorbate 60, sodium hydroxide, carbomer 940NF, and water.

[86] The method of

[54] , wherein the pathology is the result of gram-negative bacteria.

[87] The method according to

[86] , wherein the drug having antimicrobial activity is clotrimazole.

[88] The method according to

[54] , wherein the pathological condition is the result of a gram-positive bacterium.

[89] The method according to

[88] , wherein the drug having antimicrobial activity is clotrimazole.

[90] The method of

[54] , wherein the condition is the result of a fungus.

[91] The method of

[54] , wherein the condition is the result of yeast.

[92] The method of

[54] , wherein the condition is polymicrobial, including a combination of bacteria, fungi and / or yeasts.

[93] The method according to

[54] , wherein the pathology is the result of inflammation without an identified microbial infection.

[94] The method according to

[54] , wherein the condition is an exacerbation of sinusitis following sinus surgery.

[95] The method according to any one of

[71] to

[76] , wherein the administering step is carried out not more than twice within 60 days.

[96] The method according to any of

[71] to

[76] , wherein the subject has undergone FESS resulting in abnormal nasal tissue described as hypertrophied, inflammatory, and granular tissue.

[97] The method of any of

[71] to

[76] , wherein the pathological condition is at least partially the result of a bacterial infection and a biofilm is formed on the surface of the paranasal sinus or nasopharyngeal tissue.

[98] A method for treating a subject having a condition associated with paranasal sinus or nasopharyngeal tissue, comprising administering a composition locally to the paranasal sinus or nasopharyngeal tissue of the subject, the composition having a viscosity of about (1) about 220,000 centipoise (cP) to about 260,000 cP at a shear rate of about 0.5 RPM and 30% torque with a factor of 8,000; (2) about 140,000 cP to about 170,000 cP at a shear rate of about 1.0 RPM and 39% torque with a factor of 4,000; (3) about 75,000 cP to about 90,000 cP at a shear rate of about 2.0 RPM and 41% torque with a factor of 2,000; or (4) about 75,000 cP to about 90,000 cP at a shear rate of about 2.5 RPM and 42% torque with a factor of 1,600. (5) from about 32,000 cP to about 55,000 cP at 50% torque with a factor of 800 at a shear rate of about 5.0 RPM; (6) from about 19,000 cP to about 32,000 cP at 60% torque with a factor of 400 at a shear rate of about 10.0 RPM; (7) from about 10,000 cP to about 19,000 cP at a shear rate of about 20.0 RPM and 73% torque with a factor of 200; or (8) from about 5,000 cP to about 10,000 cP at 97% torque with a factor of 80 at a shear rate of about 50.0 RPM, as measured by a Brookfield HBT with spindle 21 at room temperature. The cream further comprises a steroid.

[99] The method of

[98] , wherein the steroid is selected from cortisone, cortisol, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, betamethasone, ciclesonide, dexamethasone, esters, derivatives and salts thereof, and combinations thereof.

[0100] The method according to

[98] , wherein the steroid is betamethasone or an ester, derivative or salt thereof.

[0101] The method according to

[98] , wherein the steroid is betamethasone dipropionate.

[0102] The method according to any of

[98] to

[0101] , wherein the steroid is present in the composition in an amount of about 0.1 to 100 milligrams per gram of the composition.

[0103] The method of claim 0101, wherein the steroid is present at about 0.322 milligrams per gram of the composition.

[0104] The method according to

[0103] , wherein the total amount of the composition administered to the patient is from about 4 grams to about 8 grams.

[0105] The method according to any of

[98] to

[0104] , wherein the disease or infection of the paranasal sinuses or nasopharyngeal tissue is selected from mucormycosis, chronic sinusitis, acute sinusitis, bacterial sinusitis, chronic bacterial sinusitis, polymicrobial sinusitis, nasal polyps, allergic fungal sinusitis, chronic allergic fungal sinusitis, and rhinosinusitis.

[0106] The method according to any of

[98] to

[0105] , wherein the subject has undergone sinus surgery prior to application of the composition.

[0107] A method according to any of

[98] to

[0104] , wherein the disease or infection is chronic allergic fungal sinusitis and the subject has undergone functional endoscopic sinus surgery prior to application of the composition.

[0108] A method according to any of

[98] to

[0107] , wherein the administering step is carried out to the subject not more than once.

[0109] The method according to any one of

[98] to

[0107] , wherein the administering step is carried out not more than once every 10 days.

[0110] The method according to any one of

[98] to

[0107] , wherein the administering step is carried out not more than once every 21 days.

[0111] The method according to any one of

[98] to

[0107] , wherein the administering step is carried out not more than once every 30 days.

[0112] The method according to any one of

[98] to

[0107] , wherein the administering step is carried out not more than once every 60 days.

[0113] The method according to any one of

[98] to

[0107] , wherein the administering step is carried out not more than once every 90 days.

[0114] The method according to any one of

[98] to

[0107] , wherein the administering step is carried out not more than once every 180 days.

[0115] The method according to any one of

[98] to

[0107] , wherein the administering step is carried out not more than once every 365 days.

[0116] The method according to any one of

[98] to

[0115] , wherein the composition further contains cetostearyl alcohol, cetyl ester wax, sorbitan monostearate, benzyl alcohol, propylene glycol, 2-octyldodecanol, polysorbate 60, sodium hydroxide, carbomer 940NF, and water.

[0117] 1. A method for treating a subject having a condition associated with paranasal sinus or nasopharyngeal tissue, comprising topically administering a composition to the paranasal sinus or nasopharyngeal tissue of the subject, wherein the composition is a cream, the cream further comprising a steroid, the total amount of composition administered is from about 4 g to about 8 g, and the amount of steroid is from about 0.1 to 0.5 milligrams per gram of the composition.

[0118] The method according to

[0117] , wherein the steroid is selected from cortisone, cortisol, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, betamethasone, ciclesonide, dexamethasone, esters, derivatives and salts thereof, and combinations thereof.

[0119] The method according to

[0117] , wherein the steroid is betamethasone or an ester, derivative or salt thereof.

[0120] The method according to

[0117] , wherein the steroid is betamethasone dipropionate.

[0121] The method of claim 0120, wherein the steroid is present at about 0.322 milligrams per gram of the composition.

[0122] The method according to any one of

[0117] to

[0121] , wherein the disease or infection of the paranasal sinuses or nasopharyngeal tissue is selected from mucormycosis, chronic sinusitis, acute sinusitis, bacterial sinusitis, chronic bacterial sinusitis, polymicrobial sinusitis, nasal polyps, allergic fungal sinusitis, chronic allergic fungal sinusitis, and rhinosinusitis.

[0123] A method according to any one of

[0117] to

[0122] , wherein the subject has undergone sinus surgery prior to application of the composition.

[0124] The method described in any of

[0117] to

[0121] , wherein the disease or infection is chronic allergic fungal sinusitis and the subject has undergone functional endoscopic sinus surgery prior to application of the composition.

[0125] A method according to any one of

[0117] to

[0124] , wherein the administering step is performed on the subject not more than once.

[0126] A method according to any one of

[0117] to

[0124] , wherein the administering step is carried out not more than once every 10 days.

[0127] A method according to any one of

[0117] to

[0124] , wherein the administering step is carried out not more than once every 21 days.

[0128] A method according to any one of

[0117] to

[0124] , wherein the administering step is carried out not more than once every 30 days.

[0129] A method according to any one of

[0117] to

[0124] , wherein the administering step is carried out not more than once every 60 days.

[0130] A method according to any one of

[0117] to

[0124] , wherein the administering step is carried out not more than once every 90 days.

[0131] A method according to any one of

[0117] to

[0124] , wherein the administering step is carried out not more than once every 180 days.

[0132] A method according to any one of

[0117] to

[0124] , wherein the administering step is carried out not more than once every 365 days.

[0133] The method according to any one of

[0117] to

[0124] , wherein the composition further contains cetostearyl alcohol, cetyl ester wax, sorbitan monostearate, benzyl alcohol, propylene glycol, 2-octyldodecanol, polysorbate 60, sodium hydroxide, carbomer 940NF, and water.

[0134] The method according to

[98] , wherein the pathology is the result of gram-negative bacteria.

[0135] The method according to

[0134] , wherein the drug having antimicrobial activity is clotrimazole.

[0136] The method according to

[98] , wherein the pathology is the result of a Gram-positive bacterium.

[0137] The method according to

[0136] , wherein the drug having antimicrobial activity is clotrimazole.

[0138] The method according to

[98] , wherein the pathology is the result of a fungus.

[0139] The method according to

[98] , wherein the condition is the result of yeast.

[0140] The method according to

[98] , wherein the condition is polymicrobial, comprising a combination of bacteria, fungi and / or yeasts.

[0141] The method according to

[98] , wherein the pathology is the result of inflammation without an identified microbial infection.

[0142]

[98] The method described in claim 1, wherein the pathological condition is an exacerbation of sinusitis after sinus surgery.

[0143] A method according to any one of

[0117] to

[0124] , wherein the administering step is carried out no more than twice within 60 days.

[0144] The method described in any of

[0117] to

[0124] , wherein the subject has undergone FESS resulting in abnormal nasal tissue described as hypertrophied, inflammatory, and granular tissue.

[0145] A method according to any of

[0117] to

[0124] , wherein the pathological condition is at least in part the result of a bacterial infection and a biofilm is formed on the surface of the paranasal sinus or nasopharyngeal tissue.

[0146] The method according to any one of [1] to

[0145] , wherein the patient is suffering from one or more sinus conditions selected from the group consisting of the need to blow nose, nasal congestion, sneezing, runny nose, coughing, postnasal drip, thick nasal discharge, ear congestion, dizziness, ear pain, facial pain or pressure, decreased sense of smell or taste, difficulty falling asleep, waking at night, not being able to sleep soundly, waking up tired, fatigue, decreased productivity, decreased ability to concentrate, frustration, restlessness or irritability, sadness, embarrassment, and combinations thereof.

[0147] The condition associated with the paranasal sinus or nasopharyngeal tissue includes the need to blow your nose, nasal congestion, sneezing, runny nose, coughing, postnasal drip, thick nasal mucus, ear congestion, dizziness, ear pain, facial pain or pressure, decreased sense of smell or taste, difficulty falling asleep, waking at night, not being able to sleep soundly, waking up tired, lethargy, decreased productivity, decreased ability to concentrate, frustration, restlessness or irritability, sadness, embarrassment, or a combination thereof.

[0148] The method according to any one of

[98] to

[0145] , wherein the composition does not contain an agent having antimicrobial activity.

[0149] The method according to any one of

[54] to

[97] , wherein the composition does not contain a steroid.

[0052] Pharmaceutical compositions, and methodologies for their application, will now be described with reference to the following non-limiting examples. EXAMPLES

[0053] Example 1 A pharmaceutical composition in the form of a cream was prepared. The composition has as its first active ingredient betamethasone dipropionate, a synthetic glucocorticosteroid that is an analogue of prednisolone (betamethasone dipropionate is the 17,21-dipropionic acid ester of betamethasone). Betamethasone dipropionate has the empirical formula C 28 H37 FO7, with a molecular weight of 504.59 g / mol, has the following structural formula: [ka]

[0054] The cream composition further comprises a second active ingredient, clotrimazole, an antimicrobial agent.The cream composition further comprises various inactive ingredients as shown in Table 2 below, which shows the respective actives and inactives expressed as %wt based on the total weight of the cream composition. [Table 2]

[0055] The viscosity profile of the above cream composition was determined using a Brookfield HBT with spindle 21 at room temperature to give the following values ​​in Table 3 for the corresponding pathologies. [Table 3]

[0056] The density of the cream composition was determined to be 0.9 grams / cc.

[0057] The cream composition of Example 1 was used in the following Examples 2 to 5.

[0058] Example 2 This example demonstrates the efficacy of the cream composition described in Example 1 in eleven subjects (six females and five males, age range 17-72 years) who fit the following criteria: 1- History of endoscopic sinus surgery within the past year with a minimum of maxillary open sinus surgery and ethmoid sinus surgery. 2- Chronic severe nasal congestion and discharge that is not relieved by medical treatment, including nasal irrigation. 3- Visual or CT manifestations of inflammatory and chronic diseases.

[0059] The patients were treated by Dr. Patrick Slater at the Austin Ear Clinic in Austin, Texas. Before treatment, the severity of symptoms was assessed by physician observation (visual inspection for congestion, bloating, and inflammation) and by having patients rate the severity of congestion, bloating, and discharge on a scale of 1 to 10, with 10 being the most severe. The mean severity score for the 11 patients was 8.62.

[0060] Patients were not sedated during treatment application, but received a topical spray application of lidocaine followed by pontocaine. The cream composition of Example 1 was then applied topically to the sinus mucosa via bilateral intranasal application using a sinus suction tube attached to a syringe, and then spread over the inflamed area using a cue tip. The amount of cream composition applied was between 1.5g and 4.5g per intranasal application, for a total cream composition application of 3-9g. Approximately 4 weeks after treatment, patients returned to the clinic for a follow-up visit to assess the severity of symptoms according to the scale described above.

[0061] Results: All 11 patients noted increased congestion for the first 1-3 days after treatment, but this quickly resolved in all patients, with significant improvement in congestion and secretions approximately 4 weeks after initial application. The majority of patients reported breathability (lack of congestion) and secretions at levels not experienced in many years. The mean symptom severity improved to 2.53. Visual inspection after 2-6 months noted that the mucosa often returned to a normal appearance. Individual severity scores for each patient before and after treatment are shown in Figure 1, with a severity score of 1 meaning normal sinus health. Figures 2A-2D provide photographs of the sinus mucosa of patient 7 (from Figure 1) before (Figure 2A-2C) and 2 months after treatment (Figure 2D). As shown in Figure 2D, patient 7 showed complete resolution of inflammation (red mucosa (as shown in Figures 2A-C), mucus secretions (mucus circled in Figure 2B), and reduced congestion (hyperemia circled in Figure 2C). Figures 3A-B provide photographs of the sinonasal mucosa in patient 11 (from Figure 1) before treatment (Figure 3A) and 2 months after treatment (Figure 3B). Before treatment, Figure 3A shows the left nasal cavity with the middle turbinate circled. The middle turbinate shows granulation changes with significant congestion, edema, and small hemorrhages. The area lateral to the middle turbinate shows polypoid changes and mild mucopurulence from the middle meatus natural orifice root. After treatment, Figure 3B shows a reduction in all diseased changes observed before treatment with the most notable reduction in the general inflammatory response highlighted by the reduction in congestion, edema, and granulation changes.

[0062] Figures 4A-4B provide histological specimens taken from the lateral aspect of the middle turbinate of patient 11 (from Figure 1) immediately prior to initial application (Figure 4A) and 2 months after treatment (Figure 4B). Biopsies were taken using a pair of cup forceps, preserved in formalin and hematoxylin and eosin, and stained and photographed by a pathologist at high magnification using standard techniques. While pre-treatment tissue showed a significant presence of eosinophils (depicted in red), post-treatment tissue showed a significant decrease in the presence of eosinophils. Without being bound by theory, it is believed that a decrease in eosinophils may decrease inflammation in the sinuses by decreasing edema, thick mucus production and polyp formation caused by inflammatory mediators released from eosinophils.

[0063] This example demonstrates a virtually complete resolution of symptoms and inflammation previously rarely achieved by standard medical treatments.

[0064] Example 3 - Case Study Patient History: A 59-year-old male patient presented with a history of bilateral sinus congestion, foul odor, and shortness of breath for the past 3-4 months. The patient complained of greenish-yellow purulent discharge over the past few months along with sinus pressure. There was a history of recurrent sinus infections over the past 2-3 years. The patient had FESS surgery approximately 19 years ago, which resulted in the patient's sinus symptoms resolving after surgery. Symptoms began to recur approximately 3 years ago, and he has been on maximal allergy management ever since. The patient graded his sinus congestion as an 8 on the severity scale described above in Example 2. He also reported an episode of severe sinus infection and bronchitis approximately 2 months prior to visiting the clinic in Example 2, and was on a course of amoxicillin under the care of his primary care physician. He reported a significant increase in left nasal sinus congestion, shortness of breath, and purulent discharge following the infection.

[0065] Diagnosis: Endoscopy revealed mucin, mucosal inflammation, and crust formation. CT scan showed bilateral FESS surgery to the maxillary, ethmoid, and frontal sinuses, with mild mucosal thickening throughout. Cultures from crust specimens grew the fungus Fusarium species.

[0066] Treatment and Outcome: The cream composition of Example 1 was applied bilaterally to the ethmoid and maxillary sinus anastomosis areas as described in Example 2. Patients were instructed on the nasal spray for 2-3 days and invited to a follow-up visit after 2 weeks.

[0067] At the follow-up visit, the patient reported that his symptoms had improved by approximately 50%. Nasal odor, congestion and purulent discharge were significantly reduced and he rated the severity of his symptoms as 4 based on the scale described in Example 2. The cream composition of Example 1 was reapplied to the ethmoid and maxillomastoid sinus openings and he returned after 2 weeks.

[0068] At the 2-week visit after the second application, an 80-90% reduction in the dark green purulent discharge was reported, along with clear, frothy discharge. No congestion was present. Microscopic examination of the nasal passages was clear, without crusting or thick purulent mucin. The patient returned 3 months later.

[0069] Example 4 - Case Study Patient History: A 53-year-old female patient presented with a history of bilateral sinus congestion, ear and sinus pressure, shortness of breath, loss of smell, and constant mucus discharge from the nose. The severity of symptoms had increased over the past year. She complained of intense facial pressure, fever, upper toothache, purulent discharge along with bad breath. The patient had been treated with antibiotics in the past with no improvement in symptoms. She had a history of multiple FESS surgeries (mastoid sinusotomy, ethmoid sinusotomy, sphenoidectomy) over the past 9 years for chronic sinus disease. The patient was given Medrol dose packs and a nebulizer, but she still felt air hungry.

[0070] Endonasal Examination and Imaging: Endonasal examination revealed congested tissue with mucosal inflammation, suppuration, and crusting. The patient graded her sinus congestion as a 9 on the severity scale described in Example 2. CT sinus was recommended and demonstrated chronic total sinus disease with patent ethmoid sinuses and obstructed maxillary bilateral mastoid sinus openings.

[0071] Treatment: After informed consent, the patient was placed in a supine position. The nasal cavity was sprayed with tetracaine spray without epinephrine. The cream composition of Example 1 was applied to the maxillary sinus mucosa, middle meatus natural orifice route and nasal mucosa using a maxillary sinus suction tube attached to a syringe. The patient reported nasal stuffiness, pressure and congestion at the 24-hour follow-up. The patient was called back for a follow-up visit 10 days later.

[0072] At the 10th visit, the patient's symptoms had regressed to a 3 on the severity scale after the first application, and there was a decrease in active purulent discharge. The cream was reapplied, and the patient was called back in 4 weeks.

[0073] At 4-week follow-up, the patient noted improvement in her sinus congestion and discharge symptoms. Mucosal inflammation had resolved. She had mild facial pressure and upper dental pain. The cream was reapplied to the maxillary sinus area. Four weeks after the third application, the patient reported resolution of symptoms.

[0074] Example 5 This example further demonstrates the efficacy of the cream composition described in Example 1 in eight subjects who met the following inclusion criteria: 1. Men or non-pregnant, non-lactating women aged 18-80 2. Able to understand and provide signed informed consent. 3. FESS more than 6 months ago within the past 20 years 4. Clinical diagnosis of exacerbated sinusitis (suspected or confirmed due to bacterial, fungal, yeast, polymicrobial (bacterial, fungal and / or yeast)) with signs and symptoms such as congestion, discharge, nasal and / or sinus inflammation with a current episode lasting 1 month or more. If bilateral sinus disease is present, treat both sinuses. A congestion score of at least 3 on a scale of 5.5 (5 levels worsening) (no minimum secretions score required). 6. Willingness to submit to biopsy at baseline and discharge visits. 7. Willingness to submit to CT imaging at baseline and discharge visits. 8. Willing to submit to microbiological sampling of affected sinuses at baseline and discharge visits. 9. Willingness to self-report sinus signs and symptoms daily (Appendix 2) 10. Females of childbearing potential must have a negative urine pregnancy test at screening and agree to use one of the following acceptable methods of contraception: a. Surgical sterilization (hysterectomy or bilateral oophorectomy) b. Surgical sterility (bilateral tubal ligation by surgery at least 6 weeks prior to the start of the study) c. Intrauterine device (IUD) left in place for 3 months or more d. Abstinence (absence of sexual intercourse) e. Spermicidal barrier methods (condoms or diaphragms) for at least 14 days prior to screening and until the end of the study f. Stable hormonal contraception for at least 3 months prior to the study and until the end of the study 11. Agree to refrain from immersing the sinuses during the study. 12. Patients taking analgesics or other nonsteroid-containing maintenance medications (e.g., for arthritis) will be allowed to enter the study if their dose has been stable for at least 8 weeks prior to enrollment and must remain stable for the duration of the study. 13. Subject is normally active and otherwise in good general health as determined by the investigator based on medical history and physical examination. 14. Patient and / or caregiver able to comply with the visit schedule and protocol requirements and able to complete the entire study.

[0075] Patients were excluded if they met any of the following criteria: 1. Women who are pregnant, breastfeeding, or wish to become pregnant during the clinical trial period 2. Signs and symptoms of current sinusitis episodes in the affected sinus designated as the "study sinus" for less than 1 month 3. History of diabetes mellitus, immunodeficiency, allergy or intolerance to corticosteroids, oral steroid-dependent state, clinical evidence of acute bacterial sinusitis, or clinical evidence of invasive fungal sinusitis. 4. History or diagnosis of glaucoma or ocular hypertension, presence or absence of grade +3 or greater cataract, or presence or absence of posterior subcapsular cataract. 5. Clinically diagnosed sinus disease other than exacerbation of sinusitis (e.g., congenital anomalies in the paranasal sinus area, obstructive bone exostoses or tumors, upper respiratory tract infections including chickenpox and herpes simplex infections, cellulitis) 6. Grade 2 or greater glaucoma or cataract. 7. Known or suspected hypersensitivity or allergy to clotrimazole, betamethasone dipropionate, or any other component of the investigational drug 8. Localized sinus abnormalities such as abscesses or significant polyps in the affected sinus 9. Patients who are not willing to discontinue use of intranasal medications, rinses, or sprays for 3 days after application of the study drug. 10. History of sinus surgery in the affected sinus within 3 months of study enrollment 11. Use of systemic antibiotics within 2 weeks prior to enrollment 12. Patients with any type of device in the nose or sinuses (e.g. PROPEL) 13. Any nasal or sinus surgical procedure following application of the study drug during the study period unless prescribed by the PI after discontinuing the study 14. Previous enrollment in this study. 15. Taking steroids orally. 16. Systemic glucocorticosteroids other than inhaled asthma medications 17. Systemic or topical immunosuppressants or immunomodulatory agents (e.g. azathioprine, infliximab, calcineurin inhibitors). 18. Current enrollment in an investigational drug or device trial, or participation in such a trial within 30 days of enrollment in this study. 19. Any significant medical or mental / psychiatric condition that, in the judgment of the PI, may interfere with the ability to provide informed consent or comply with the instructions of the study, or that may confound the interpretation of the study results, or expose the patient to undue risk. (This includes: recent history (within the past 12 months) or strong likelihood of alcohol or drug abuse.

[0076] Upon presenting with a diagnosis of post-FESS exacerbation of sinusitis lasting more than one month, patients were screened, examined, and completed the Sino-Nasal Outcome Test (SNOT-22). The SNOT-22 assesses sinus health and is based on a scoring system of 0 to 5 (0 = no problem, 1 = very mild problem, 2 = mild or slight problem, 3 = moderate problem, 4 = severe problem, 5 = worst possible problem). The 22 metrics are as follows: 1. The need to blow your nose; 2. Stuffy nose; 3. Sneezing; 4. Runny nose; 5. Cough; 6. Postnasal drip; 7. Thick nasal discharge; 8. Sensation of ear fullness; 9. Dizziness; 10. Ear pain; 11. Pain or pressure in the face; 12. Decreased sense of smell and taste; 13. Difficulty falling asleep; 14. Waking up at night; 15. Having trouble sleeping; 16. Waking up tired; 17. Fatigue; 18. Reduced productivity; 19. Concentration decrease; 20. Frustration / restlessness / irritability; 21. Sadness; and 22. Perplexity.

[0077] Microbiological specimens from the sinuses were taken pre-treatment and at discharge visits in addition to biopsy specimens for evaluation of eosinophil counts for a subset of patients. Patients then underwent mechanical irrigation of the sinuses by standard techniques, if indicated. The composition of Example 1 was then applied to the sinuses to be treated with a 4-inch flexible-tip applicator attached to a syringe containing the composition of Example 1, administering 0.5cc to 5cc per sinus.

[0078] Patients were evaluated at the discharge visit 30 + / - 7 days after initial treatment, and for a subset of patients, CT scans were obtained for evaluation of the treated sinuses in addition to microbiological samples taken from the treated sinuses and biopsies from the maxilloethmoidal junction or lateral aspect of the middle turbinate. Patients also completed the SNOT-22 assessment at the visit. The discharge visits for patients 4 and 5 were 63 and 45 days after treatment, respectively.

[0079] The patients were administered the following amounts of the composition: [Table 4]

[0080] SNOT-22 results for patients 2, 3, and 6 are provided in Figure 5A-C, respectively. Patient 2 was evaluated on day 29 after treatment, patient 3 on day 35 after treatment, and patient 6 on day 27 after treatment. At baseline, patient 2 was positive for 2+ Pseudomonas aeruginosa (mucoid strains) and 2+ Pseudomonas aeruginosa (nonmucoid strains), as well as 1+ Nematode fungus. At baseline, patient 3 was positive for 1+ Staphylococcus aureus. No bacterial or fungal infections were detected in patient 6 at baseline. One case (patient 1) was found not to meet study criteria after study initiation, and this patient demonstrated good control of sinus symptoms with nasal spray. For each SNOT-22 metric, the mean results pre-treatment and up to 30 days post-treatment are shown in Figure 5D.

[0081] As demonstrated in these figures, the composition was effective in improving the sinus health of patients, as evidenced by the reduction in overall mean SNOT-22 scores, and the significant reduction in most of the 22 sinus health metrics. Figure 6 shows a summary of the overall SNOT-22 scores for patients 1-8 before and after treatment, as well as the effectiveness of treatment by the significant reduction in the total SNOT-22 scores for eligible patients (patients 2-8).

[0082] Example 6 - Case Study A 39-year-old woman reports 10 sinus infections over the past year. She had a very similar situation 4 years ago and had been treated with multiple courses of oral antibiotics, including Bactrim and erythromycin. She continues to use nasal steroids and antihistamines. She has not had any sinus surgery.

[0083] She had been scheduled for standard endonasal endoscopic sinus surgery 2 years ago, but the procedure was cancelled due to a move to Texas. Her symptoms for many years also included severe sinus pressure in the frontal and maxillary regions. A previous CT scan showed total sinus disease with prominent 4+ mm of mucosal changes, and physical examination noted mucopurulent discharge from bilateral sinus bones.

[0084] Approximately 2 years ago, the patient underwent bilateral 6-sinus balloon sinus dilation. Nasal symptoms and recurrent sinus infections resolved completely along with clearance of nasal congestion and secretions. This "normal state" persisted for approximately 1 year without evidence of infection. The patient then developed chronic sinus infections with facial pressure, pain, secretions, and mucopurulent discharge. These persisted for several months without resolution, including with antibiotic therapy. CT showed bilateral maxillary and frontal disease, which was reduced from the previous CT scan performed prior to balloon sinus dilation.

[0085] The betamethasone / clotrimazole cream of Example 1 was applied to both Omnibus Meatal Routes (OMC) under local anesthesia in the office, with approximately 2 cc of ointment placed in the OMC area. She received no antibiotics following application of the OMC, and at follow-up approximately 5 days after application, all symptoms had completely disappeared, including fullness, pressure, pain, congestion, discharge, and essentially all of the sinus complaints listed above. Before treatment, the patient reported her symptoms as 7-8 out of 10 for congestion and discharge, and 1 out of 10 for both after treatment.

[0086] She has returned to baseline medication with nasal sprays and antihistamines for her nasal symptoms. Her most recent evaluation showed that she was stable with complete resolution of nasal discharge, facial pain, nasal congestion, and rhinorrhea.

[0087] All references cited in this specification, including publications, patent applications, and patents, are herein incorporated by reference as if each reference was individually and specifically indicated to be incorporated by reference and as if set forth in its entirety herein.

[0088] The terms "comprise", "have", "include" and "include" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. The recitation of numerical ranges herein is intended merely to serve as a shorthand method for individually referring to each value falling within the range, unless otherwise noted herein, and each value is incorporated into the specification as if it were individually recited herein. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention, unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0089] Preferred embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of these preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect that such variations will be applied by those of ordinary skill in the art as appropriate, and intend that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the elements recited in the claims appended hereto as permitted by applicable law. Moreover, all combinations of the above-described elements in all possible variations thereof are encompassed by the invention unless otherwise indicated herein or clearly contradicted by context.

Claims

1. 1. A composition for use in a method for treating a subject having a condition associated with paranasal sinus or nasopharyngeal tissue, the method comprising administering a composition topically to the paranasal sinus or nasopharyngeal tissue of the subject not more than once every ten days, the composition being a cream and comprising a steroid.

2. 2. The composition of claim 1, wherein the steroid is selected from betamethasone, cortisone, cortisol, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, ciclesonide, dexamethasone, salts thereof, and combinations thereof.

3. The composition of claim 1 , wherein the steroid is betamethasone or a salt thereof.

4. 2. The composition of claim 1, wherein the steroid is betamethasone dipropionate.

5. 5. The composition of claim 1, wherein the steroid is present in the composition at 0.1 to 100 milligrams per gram of composition.

6. 6. The composition of claim 5, wherein said steroid is present at 0.322 milligrams per gram of said composition.

7. The composition of claim 6, wherein the total amount of the composition administered to the subject is between 1 gram and 10 grams.

8. 8. The composition of any one of claims 1 to 7, wherein the pathology associated with the paranasal sinus or nasopharyngeal tissue is selected from mucormycosis, chronic sinusitis, acute sinusitis, bacterial sinusitis, chronic bacterial sinusitis, polymicrobial sinusitis, nasal polyps, allergic fungal sinusitis, chronic allergic fungal sinusitis, and rhinosinusitis.

9. The composition of any one of claims 1 to 8, wherein the subject has undergone sinus surgery prior to application of the composition.

10. 8. The composition of any one of claims 1 to 7, wherein the condition associated with the paranasal sinuses or nasopharyngeal tissue is chronic allergic fungal sinusitis and the subject has undergone functional endoscopic sinus surgery prior to application of the composition.

11. The composition of any one of claims 1 to 10, wherein the administering step is performed not more than once to the subject.

12. The composition of claim 11 , wherein the administering step occurs after functional endoscopic sinus surgery.

13. The composition of any one of claims 1 to 10, wherein the administering step is performed not more than once every 21 days.

14. The composition of any one of claims 1 to 10, wherein the administering step is performed not more than once every 30 days.

15. The composition of any one of claims 1 to 10, wherein the administering step is performed not more than once every 60 days.

16. The composition of any one of claims 1 to 10, wherein the administering step is performed not more than once every 90 days.

17. The composition of any one of claims 1 to 10, wherein the administering step is carried out no more than once every 180 days.

18. The composition of any one of claims 1 to 10, wherein the administering step is performed not more than once every 365 days.

19. 19. The composition of any one of claims 1 to 18, further comprising an ingredient selected from the group consisting of an agent having antimicrobial activity, cetostearyl alcohol, cetyl esters wax, sorbitan monostearate, benzyl alcohol, propylene glycol, 2-octyldodecanol, polysorbate 60, sodium hydroxide, carbomer 940 NF, and water.

20. 1. A composition for use in a method for treating a subject having a condition associated with paranasal sinus or nasopharyngeal tissue, the method comprising administering a composition topically to the paranasal sinus or nasopharyngeal tissue of the subject not more than once every 21 days, the composition being a cream and comprising a steroid, and the subject having undergone functional endoscopic sinus surgery prior to applying the composition.

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