Compositions, devices, and methods for treating infections and / or inflammation of the nose, ears, and other tissues.

Abstract

Compositions, devices, and methods are provided for treating diseases and symptoms of the nose, sinuses, nasopharynx, ear, and other tissues.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 070,812, filed August 26, 2020, which is incorporated herein by reference in its entirety. Background Technology

[0003] An emulsion is a two-phase emulsion prepared by combining two immiscible liquids, in which droplets of one liquid are uniformly dispersed in the other. The liquid dispersed into small droplets is usually called the dispersed phase or internal phase. The other liquid is called the external phase or continuous phase. When oil is the dispersed phase and the aqueous solution is the continuous phase, the system is designated as an oil-in-water (O / W) emulsion. Conversely, when water or an aqueous solution is the dispersed phase and oil or an oily material is the continuous phase, the system is designated as a water-in-oil (W / O) emulsion.

[0004] Creams are typically thermodynamically unstable due to a significant increase in surface energy resulting from a combination of interfacial tension, the large surface area of ​​the dispersed phase, and the density difference between the two phases. Internal phase droplets can coalesce, and surface free energy decreases significantly. Therefore, creams tend to separate – the less dense phase rises, and the more dense phase sinks. When exposed to heat, uniformly distributed droplets begin to aggregate and eventually coalesce into large spheres, and the cream becomes unstable, often resulting in phase separation. This disclosure addresses this problem by providing a cream that does not separate upon autoclaving or other sterilization methods.

[0005] The nasal cavity, sinuses, and nasopharynx are important components of the human respiratory system and can be affected by diseases or conditions requiring medical intervention. Appropriate and effective treatment of these diseases and conditions is essential for promoting patient health and preventing complications arising from them.

[0006] Currently, the standard of care for treating diseases or symptoms in these areas is saline nasal sprays or rinsing solutions, as well as nasal sprays containing corticosteroids, glucocorticoids, anticholinergics, and antihistamines. These are typically low-viscosity (1-10 cP), water-based solutions or suspensions, applied multiple times daily for extended periods. Simple nasal delivery methods, such as drops, sprays, aerosols, nebulizers, and nebulizers, provide good nasal contact but poor sinus delivery. The entry of low-viscosity liquids into the sinuses and short residence times contribute to poor delivery. Furthermore, while steroid nasal sprays can address inflammation caused by the symptoms, they may not address the underlying cause of an infection. These home remedies also require high levels of patient compliance to be effective. Currently, there are no FDA-approved antifungal medications for nasal administration. Therefore, there is a need for an effective product that can be applied topically to the sinuses or nasopharyngeal tissue for antifungal therapy.

[0007] Regarding the underlying cause of the symptoms, in some cases, it is a fungal and / or bacterial infection. Treatment involves rinsing with a water-based antimicrobial agent or antifungal suspension during a clinical or hospital procedure, which may include intravenous administration and may involve anesthesia, but is most commonly administered at home by the patient using a nasal spray, typically in multiple daily doses. Alternatively or alternatively, oral antibiotics and antifungal medications are prescribed. These treatments are often unsuccessful, and the patient continues to suffer from chronic infection and inflammation with no viable alternatives. Therefore, a treatment solution that addresses the aforementioned shortcomings is needed.

[0008] Regarding the adverse effects of delivering steroids to the sinus mucosa, a treatment option is needed to overcome the shortcomings and inconveniences of delivering liquid-based steroids to the sinuses.

[0009] Otitis externa is a disease of the external ear characterized by inflammation of the meatal skin of the external auditory canal. Over 90% of otitis externa cases can be traced back to bacterial and / or fungal infections. In the early stages, symptoms include itching and pain in the ear canal, often accompanied by tenderness in the area surrounding the external auditory canal and pain when pulling the earlobe or moving the jaw. In the later stages, suppuration occurs in the ear canal and may be accompanied by hearing loss. Treatment of otitis externa becomes complicated because the infected skin of the external auditory canal is relatively difficult to access, making it challenging to effectively apply treatment to the affected area.

[0010] One of the most common types of otitis externa encountered by doctors is designated as "swimmer's ear." Swimmer's ear has long been understood in the medical community as a bacterial infection and has been treated accordingly. Therefore, current medical practice for treating swimmer's ear prescribes a multi-dose bolus of antibiotic ear drops to treat the condition. In some cases, these drops may contain small doses of steroids or organic acids, such as acetic acid. Typically, the ear drops are applied twice daily to the affected ear for 10 days. Alternatively or concurrently, oral antibiotics and analgesics are prescribed. This approach aligns with standard medical practice for treating bacterial infections, which aims to eradicate the causative bacteria by (a) maintaining high levels of antibiotics in the patient's blood through daily administration and (b) prolonged local contact.

[0011] While ear drop regimens can be effective in some cases for swimmer's ear and offer considerable convenience for patient administration, any interruption of treatment leading to missed doses or application can result in an incurable condition. Furthermore, topical application of ear drops often results in insufficient physical contact with the treated surface, and even when proper contact is achieved, the duration of this contact may be insufficient to achieve the desired physiological effect. In addition, current ear drop formulations have been found to be ineffective in a considerable number of cases, even when applied correctly.

[0012] Typically, when an infection is present in the ear, the eardrum ruptures. As a result, the ear drop clump can enter the middle and inner ear through the rupture, exposing these sensitive tissues and organs to the components of the ear drop clump. This is problematic because many antimicrobial agents and inactive ingredients are ototoxic and can damage the middle ear, hair cells, cochlea, auditory nerve, and sometimes the vestibular system, leading to permanent hearing loss. For example, aminoglycoside antibiotics, such as gentamicin, neomycin, and tobramycin, are ototoxic. Many inactive ingredients used in topical drops, such as ethanol, acetic acid, chlorhexidine, and propanol, are also ototoxic. Therefore, non-ototoxic compositions are needed to treat ear diseases.

[0013] Furthermore, sterile compositions are required to treat infections of the ear, sinuses, and similar tissues. Non-sterile compositions can introduce additional pathogens into diseased or infected tissues. Autoclaving is one of the commonly used techniques for sterilizing pharmaceutical preparations. Creams are thermodynamically unstable. When exposed to the heat conditions of autoclaving, creams typically flocculate, then coalesce, eventually separating back into oil and water.

[0014] Diseased and infected tissues are sensitive and often painful. In addition to treating the underlying infection, treatments and compositions are needed to address this sensitivity and maintain or improve patient comfort. Tonometry refers to the ability of a solution to allow cells to gain or lose water. Isotonic solutions do not cause a net increase or decrease in cell water. Hypertonic solutions cause water to leave the cells, while hypotonic solutions cause water to enter the cells. Drugs that are far from isotonic can cause pressure on tissues and rupture cells. Therefore, isotonic therapy is required.

[0015] The effectiveness of ear drop regimens, or any other treatment requiring regular application of a pharmaceutical composition, can generally be optimized when practiced by a skilled physician. However, as a practical problem, many patients are reluctant to undergo treatments that require multiple visits to a hospital or healthcare provider. Consequently, many such patients avoid initial or subsequent treatment, resulting in easily treatable otitis externa maturing into a more acute condition requiring serious medical intervention. Similar outcomes can occur if there is any significant delay between the onset of initial symptoms and subsequent treatment, such as delays in scheduling appointments. In this regard, it is worth noting that the growth rate of the infectious organism in the diseased tissue is typically exponential.

[0016] Alternative methods for treating swimmer's ear and other types of otitis externa have been developed in the art, often with the aim of overcoming one or more of the aforementioned drawbacks. Some of these treatments can be used in conjunction with ear drop regimens. For example, one method involves introducing a strip of gauze soaked in antibacterial ear drops (which may contain a small dose of steroids) or an astringent (such as aluminum acetate solution) into the infected area. While this method can be very effective in some cases, it is impractical in many more acute cases of otitis externa because the contact between the inserted gauze and the inflamed external auditory canal tissue can be very painful. Furthermore, this method cannot be administered by the patient and therefore requires the patient to see a doctor for treatment.

[0017] Therefore, there is a need in the art for a method for treating otitis externa that does not require multiple applications, is suitable for treatment without delay, and is effective in treating swimmer's ear and other types of otitis externa. There is also a need in the art for a method for treating otitis externa that is non-invasive and effectively contacts the infected skin of the external auditory canal. A sterile composition without ototoxicity is required. These and other needs are met by the apparatus and methods disclosed herein and below. Summary of the Invention

[0018] This disclosure provides compositions, devices, and methods for treating diseases and symptoms of the nose, sinuses, nasopharynx, ear, and other tissues. More generally, this disclosure provides compositions, devices, and methods for delivering therapeutic active ingredients to mucous membranes or other tissues via isotonic and / or, in some cases, sterilizable creams (e.g., by autoclaving without phase separation).

[0019] In some embodiments, a composition comprising a tension agent and an emulsifier is provided, wherein the composition is a cream and has an osmotic pressure of about 270 mOsm / kg to about 360 mOsm / kg.

[0020] In some embodiments, a method is provided for treating a disease or symptom of said tissue by applying the composition of the present disclosure to the nose, sinuses, nasopharynx, ear or other tissues.

[0021] In some embodiments, an apparatus is provided having a section of pipe having a first end having an outer diameter; a tip at a second end having a maximum diameter greater than the outer diameter of the first end and an arcuate shape; and, optionally, a structural support element.

[0022] In some embodiments, the treatment method may use the apparatus of this disclosure to apply a composition, which may be a composition of this disclosure applied to the nasal, sinus, nasopharyngeal, or ear tissue to treat a disease or symptom of said tissue.

[0023] In some embodiments, a kit is provided that includes the compositions and devices disclosed herein. Attached Figure Description

[0024] To gain a more complete understanding of the invention and its advantages, reference is now made to the following description taken in conjunction with the accompanying drawings.

[0025] Figure 1A A workflow for an exemplary method of manufacturing the cream of this disclosure is described.

[0026] Figure 1B A workflow for another exemplary method for manufacturing the cream of this disclosure is described.

[0027] Figure 2 Exemplary apparatuses of this disclosure are depicted.

[0028] Figure 3A An exemplary apparatus of this disclosure is depicted.

[0029] Figure 3B An exemplary apparatus of this disclosure is depicted.

[0030] Figure 3C An exemplary apparatus of this disclosure is depicted.

[0031] Figure 3D An exemplary apparatus of this disclosure is depicted.

[0032] Figure 3E An exemplary apparatus of this disclosure is depicted.

[0033] Figure 4A An exemplary apparatus of this disclosure is depicted.

[0034] Figure 4B An exemplary apparatus of this disclosure is depicted.

[0035] Figure 4C An exemplary apparatus of this disclosure is depicted.

[0036] Figure 4D An exemplary apparatus of this disclosure is depicted.

[0037] Figure 5A The results of autoclaving the cream composition prepared in the examples of this disclosure are described.

[0038] Figure 5B The results of autoclaving the cream composition prepared in the examples of this disclosure are described.

[0039] Figure 5C The results of autoclaving the cream composition prepared in the examples of this disclosure are described.

[0040] Figure 5D The results of autoclaving the cream composition prepared in the examples of this disclosure are described.

[0041] Figure 5E The results of autoclaving the cream composition prepared in the examples of this disclosure are described.

[0042] Figure 6 A graph depicting the relationship between the osmotic pressure and the amount of glycerin in the cream compositions prepared in the examples of this disclosure is shown.

[0043] Figure 7A A graph depicting the relationship between viscosity and shear rate for the cream compositions prepared in the examples of this disclosure is presented.

[0044] Figure 7B A graph depicting the relationship between the viscosity of the cream composition prepared in the examples of this disclosure and the autoclaving temperature is presented.

[0045] Figure 8 It depicts both oblique needle tips and non-oblique needle tips.

[0046] Figure 9A An injection setup for an example used in ototoxicity studies is described.

[0047] Figure 9B An injection setup for an example used in ototoxicity studies is described.

[0048] Figure 10 The results of the ABR used in the ototoxicity study are described.

[0049] Figure 11 The average hair cell counts in different frequency regions of guinea pig ears treated with test samples or saline were depicted.

[0050] Figure 12 Images depicting the middle ear of a guinea pig treated with the compositions of this disclosure or physiological saline.

[0051] Figure 13A The mean sheep plasma concentrations of betamethasone-17-propionate and betamethasone were depicted.

[0052] Figure 13B A plot depicting average and individual betamethasone-17-propionate plasma concentrations was created.

[0053] Figure 13C A plot depicting average and individual betamethasone plasma concentrations was created.

[0054] Figure 14A An exemplary curved applicator device of this disclosure is described.

[0055] Figure 14BAn exemplary curved applicator device of this disclosure is described. Detailed Implementation

[0056] This disclosure provides compositions, devices, and methods for treating diseases and symptoms of the nose, sinuses, nasopharynx, ear, and other tissues. More generally, this disclosure provides compositions, devices, and methods for delivering therapeutically active ingredients to mucous membranes or other tissues via isotonic and, in some cases, sterilizable creams (e.g., by autoclaving without phase separation).

[0057] definition

[0058] As used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” may contain plural references.

[0059] The term "or" in the claims and this disclosure is used to mean "and / or" unless it is explicitly stated that it refers only to alternatives or that the alternatives are mutually exclusive.

[0060] When used with numerical values, the term “about” is intended to include + / - 10%. As an example, but not limited to, if an amount is identified as about 1 mg, this would include 0.9 to 1.1 mg (plus or minus 10%).

[0061] As used herein, “antimicrobial agent” should be understood to include antimicrobial agents such as antibacterial agents and antifungal agents. As used herein, “agent with antimicrobial activity” and “antimicrobial agent” are synonyms.

[0062] As used herein, “effective amount” means an amount sufficient to produce the desired pharmacological and / or pharmacodynamic results.

[0063] For example, an effective dose for treatment is an amount that can alleviate or eliminate the symptoms and / or pathology of an infection or disease. Another example is an effective dose that destroys or eradicates the biofilm protecting the pathogen to effectively eliminate it.

[0064] The terms “patient,” “individual,” and “subject” are used interchangeably herein and refer to a mammalian subject to treatment, with human patients being preferred. In some cases, the methods of the present invention can be used in laboratory animals, veterinary applications, and the development of animal models of disease and safety, including but not limited to rodents such as mice, rats, guinea pigs, and hamsters, as well as other animals including but not limited to canines, sheep, felines, horses, and primates.

[0065] "Treatment" refers to interventions aimed at preventing the progression of a disease or altering its pathology or symptoms. Therefore, "treatment" can refer to both therapeutic treatments and preventative or preventative measures. Patients requiring treatment include those already suffering from the disease and those needing to prevent its development.

[0066] As used herein, the term "cream" means a formulation containing one or more pharmaceutical agents dissolved and / or dispersed in an oil-in-water emulsion or a water-in-oil emulsion. For the avoidance of doubt, "cream" does not include "gel," a semi-solid system composed of dispersions of small or large molecules that, through the addition of a gelling agent, presents a jelly-like aqueous liquid medium. Therefore, the term "cream" does not include thermally reversible gels, thermally reversible polymers, or copolymers of polyethylene oxide and polypropylene oxide. As used herein, "cream" should be understood to have a viscosity of at least 25,000 cP, as measured using Brookfield RVDVII+ at 1 rpm (shear rate) with a spindle 28.

[0067] It should also be understood that, unless otherwise stated, the tension or osmotic pressure mentioned is in mOsm / kg.

[0068] Composition

[0069] In some embodiments, a composition comprising a tensiating agent and an emulsifier is provided, wherein the composition is a cream and has an osmotic pressure of about 270 mOsm / kg to about 360 mOsm / kg. In some embodiments, a composition is provided that is an autoclaved cream composition, wherein the composition is a cream having an osmotic pressure of about 270 mOsm / kg to about 360 mOsm / kg and does not separate under autoclaving conditions, such as at 110°C for 10-30 minutes or at 130°C for 1-5 minutes. In a later embodiment, the autoclaved cream composition may further comprise a tensiating agent and an emulsifier. As examples, but not limited to, the osmotic pressure of the composition according to any one of the foregoing embodiments may be between: about 270 mOsm / kg and about 360 mOsm / kg, between about 270 mOsm / kg and about 350 mOsm / kg, between about 270 mOsm / kg and about 340 mOsm / kg, between about 270 mOsm / kg and about 330 mOsm / kg, between about 270 mOsm / kg and about 320 mOsm / kg, and between about 270 mOsm / kg and about 310 mOsm / kg. Between approximately 270 mOsm / kg and approximately 300 mOsm / kg, between approximately 270 mOsm / kg and approximately 290 mOsm / kg, between approximately 270 mOsm / kg and approximately 280 mOsm / kg, between approximately 280 mOsm / kg and approximately 360 mOsm / kg, between approximately 280 mOsm / kg and approximately 350 mOsm / kg, between approximately 280 mOsm / kg and approximately 340 mOsm / kg, between approximately 280 mOsm / kg and approximately 330 mOsm / kg, approximately 280 mOsm / kg Between approximately 320 mOsm / kg, approximately 280 mOsm / kg and approximately 310 mOsm / kg, approximately 280 mOsm / kg and approximately 300 mOsm / kg, approximately 280 mOsm / kg and approximately 290 mOsm / kg, approximately 290 mOsm / kg and approximately 360 mOsm / kg, approximately 290 mOsm / kg and approximately 350 mOsm / kg, approximately 290 mOsm / kg and approximately 340 mOsm / kg, approximately 290 mOsm / kg and approximately 330 mOsm / kg Between 290 mOsm / kg and approximately 320 mOsm / kg, between approximately 290 mOsm / kg and approximately 310 mOsm / kg, between approximately 290 mOsm / kg and approximately 300 mOsm / kg, between approximately 300 mOsm / kg and approximately 360 mOsm / kg, between approximately 300 mOsm / kg and approximately 350 mOsm / kg, between approximately 300 mOsm / kg and approximately 340 mOsm / kg, between approximately 300 mOsm / kg and approximately 330 mOsm / kg.Between approximately 300 mOsm / kg and approximately 320 mOsm / kg, between approximately 300 mOsm / kg and approximately 310 mOsm / kg, between approximately 310 mOsm / kg and approximately 360 mOsm / kg, between approximately 310 mOsm / kg and approximately 350 mOsm / kg, between approximately 310 mOsm / kg and approximately 340 mOsm / kg, between approximately 310 mOsm / kg and approximately 330 mOsm / kg, approximately 310 Between mOsm / kg and approximately 320 mOsm / kg, between approximately 320 mOsm / kg and approximately 360 mOsm / kg, between approximately 320 mOsm / kg and approximately 350 mOsm / kg, between approximately 320 mOsm / kg and approximately 340 mOsm / kg, between approximately 320 mOsm / kg and approximately 330 mOsm / kg, between approximately 330 mOsm / kg and approximately 360 mOsm / kg, approximately 330 mOsm / kg Between approximately 350 mOsm / kg, between approximately 330 mOsm / kg and approximately 340 mOsm / kg, between approximately 340 mOsm / kg and approximately 360 mOsm / kg, between approximately 340 mOsm / kg and approximately 350 mOsm / kg, between approximately 350 mOsm / kg and approximately 360 mOsm / kg, between approximately 270 mOsm / kg and approximately 310 mOsm / kg, between approximately 280 mOsm / kg and approximately The osmotic pressures are between 320 mOsm / kg, between about 290 mOsm / kg and about 310 mOsm / kg, between about 310 mOsm / kg and about 360 mOsm / kg, about 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, or 360 mOsm / kg, and any range or value between these values. It should be understood that these osmotic pressures apply to any composition within the scope of this disclosure.

[0070] In some embodiments, the tonic agent can be any agent suitable for producing a composition isotonic with blood. Examples, but not limited to, include glycerol, propylene glycol, polyethylene glycol, butylene glycol, cyclodimethylsiloxane, polydextrose, sodium hyaluronate, sodium lactate, sorbitol, trehalose, triacetin, xylitol, sodium chloride, potassium chloride, or combinations thereof.

[0071] In any of the foregoing embodiments, the amount of the tensioning agent present, based on the total weight of the composition, may be from about 0.1% (w / w) to about 15% (w / w). As examples, but not limited to, the amount of the tensioning agent present, based on the total weight of the composition, may be from about 1% (w / w) to about 10% (w / w), from about 1% (w / w) to about 5% (w / w), from about 5% (w / w) to about 10% (w / w), from about 5% (w / w) to about 15% (w / w), or from about 10% (w / w) to about 15% (w / w). As another example, but not limited to, the amount of the tension agent present, based on the total weight of the composition, may be about 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.45% (w / w), or 1.5% (w / w). ), 1.65% (w / w), 1.75% (w / w), 2% (w / w), 2.5% (w / w), 3% (w / w), 4% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), 11% (w / w), 12% (w / w), 13% (w / w), 14% (w / w), or about 15% (w / w), or any range or value therebetween.

[0072] In any of the foregoing embodiments, the composition must not contain propylene glycol.

[0073] In any of the foregoing embodiments, the emulsifier may be any emulsifier suitable for producing cream compositions. Examples, but not limitations, of the emulsifier may include polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, calcium carboxymethyl cellulose, sodium docusate, ethylene glycol stearate, glyceryl behenate, hydroxypropyl starch, lanolin, lanolin alcohol, lauric acid, sodium laurate, lecithin, linoleic acid, medium-chain triglycerides, myristic acid, octyl dodecyl alcohol, oleyl alcohol, palmitic acid, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyglycerol esters, sodium lauryl sulfate, sorbitan fatty acid esters, and polyethylene glycol vitamin E. Succinate, cetyl alcohol, nonionic emulsified wax, hydrogenated castor oil, ceresin, cetearyl alcohol, dextrin, paraffin, stearyl alcohol, anionic emulsified wax, cetyl ester wax, microcrystalline wax, white wax, glyceryl monostearate, glyceryl monooleate, oleic acid, rapeseed oil, castor oil, cholesterol, ethylene glycol stearate, isopropyl myristate, isopropyl palmitate, mineral oil, myristol, safflower oil, trioleate, xylitol, oleyl alcohol polyether-2, polysorbate 80, polyethylene glycol 15-hydroxystearate, or combinations thereof, and those emulsifiers known to those skilled in the art. As another example, in the embodiments, the emulsifier may comprise a combination of polysorbate 80, polyethylene glycol 40 stearate, cetyl alcohol, glyceryl monostearate, and oleyl alcohol polyether-2. As another example, the emulsifier may comprise a combination of polysorbate 80, polyethylene glycol 40 stearate, cetyl alcohol, glyceryl monostearate, and Span 20 (sorbitan monolaurate). In some embodiments, the emulsifier may comprise a combination of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, cetyl alcohol, glyceryl monostearate, and sorbitan fatty acid ester. As an example, but not limited to, based on the total weight of the composition, the polyoxyethylene sorbitan fatty acid ester may be present in an amount of about 0.1% (w / w) to about 15% (w / w), the polyoxyethylene stearate may be present in an amount of about 0.25% (w / w) to about 10% (w / w), the cetyl alcohol may be present in an amount of about 0.25% (w / w) to about 10% (w / w), the glyceryl monostearate may be present in an amount of about 0.1% (w / w) to about 10% (w / w), and the sorbitan monolaurate may be present in an amount of about 0.1% (w / w) to about 10% (w / w), and the sorbitan monolaurate may be present in an amount of about 0.1% (w / w) to about 10% (w / w). The amount of sorbitol fatty acid ester may be from about 0.5% (w / w) to about 5% (w / w), and based on the total weight of the composition, the amount of polyoxyethylene dehydrated sorbitol fatty acid ester may be about 5% (w / w), the amount of polyoxyethylene stearate may be about 1% (w / w), the amount of cetyl alcohol may be about 1% (w / w), the amount of glyceryl monostearate may be about 0.5% (w / w), and the amount of dehydrated sorbitol fatty acid ester may be about 3% (w / w).As examples, but not limited to, the polyoxyethylene sorbitol fatty acid ester may be polysorbate 90, the polyoxyethylene stearate may be polyethylene glycol 40 stearate, and the sorbitol fatty acid ester may be oleyl alcohol polyether-2 or sorbitol monolaurate. In some embodiments, the emulsifier may comprise sorbitol fatty acid esters such as sorbitol monolaurate.

[0074] In any of the foregoing embodiments, the amount of the emulsifier present may be sufficient to produce the cream composition. In any of the foregoing embodiments, the amount of the emulsifier present may be sufficient to allow the resulting cream composition to withstand autoclaving without separating into its component phases. As examples, but not limited to, such autoclaving conditions may include 110°C for 10 minutes, 110°C for 19 minutes, 110°C for 30 minutes, 130°C for 1 minute, 130°C for 3 minutes, or 130°C for 5 minutes. As examples, but not limited to, the amount of the emulsifier in the composition may be from about 0.1% (w / w) to about 20% (w / w) based on the total weight of the composition. As examples, but not limited to, the amount of the emulsifier present, based on the total weight of the composition, may be from about 0.1% (w / w) to about 20% (w / w), from about 1% (w / w) to about 20% (w / w), from about 5% (w / w) to about 20% (w / w), from about 10% (w / w) to about 20% (w / w), from about 15% (w / w) to about 20% (w / w), from about 1% (w / w) to about 10% (w / w), from about 1% (w / w) to about 5% (w / w), from about 5% (w / w) to about 10% (w / w), from about 5% (w / w) to about 15% (w / w), or from about 10% (w / w) to about 15% (w / w). As another example, but not limited to, the amount of the emulsifier present, based on the total weight of the composition, may be about 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.5% (w / w), etc. / w), 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 10.5%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%, or any range or value between them.As, and even as other examples, but not limited to, in some embodiments, the emulsifier may comprise polysorbate 80, the amount of which is from about 0.1% (w / w) to about 15% (w / w) based on the total weight of the composition; the amount of which is polyethylene glycol 40 stearate in the composition may be from about 0.25% (w / w) to about 10% (w / w) based on the total weight of the composition; the amount of which is cetyl alcohol in the composition may be from about 0.25% (w / w) to about 10% (w / w) based on the total weight of the composition; the amount of which is glyceryl monostearate in the composition may be from about 0.1% (w / w) to about 5% (w / w) based on the total weight of the composition; and the amount of which is oleyl alcohol polyether-2 in the composition may be from about 0.5% (w / w) to about 10% (w / w) based on the total weight of the composition. For example, the compositions disclosed herein may comprise: about 5% (w / w) of polysorbate 80 based on the total weight of the compositions; about 1% (w / w) of polyethylene glycol 40 stearate based on the total weight of the compositions; about 1% (w / w) of cetyl alcohol based on the total weight of the compositions; about 0.5% (w / w) of glyceryl monostearate based on the total weight of the compositions; and about 3% (w / w) of oleyl alcohol polyether-2 based on the total weight of the compositions. As further examples, but not limited to, in some embodiments, the emulsifier may comprise polysorbate 80, the amount of which is from about 0.1% (w / w) to about 15% (w / w) based on the total weight of the composition; the amount of which is polyethylene glycol 40 stearate in the composition may be from about 0.25% (w / w) to about 10% (w / w) based on the total weight of the composition; the amount of which is cetyl alcohol in the composition may be from about 0.25% (w / w) to about 10% (w / w) based on the total weight of the composition; the amount of which is glyceryl monostearate in the composition may be from about 0.1% (w / w) to about 5% (w / w) based on the total weight of the composition; and the amount of which is oleyl alcohol polyether-2 in the composition may be from about 0.5% (w / w) to about 10% (w / w) based on the total weight of the composition. For example, the compositions disclosed herein may comprise: about 5% (w / w) of polysorbate 80 based on the total weight of the compositions; about 1% (w / w) of polyethylene glycol 40 stearate based on the total weight of the compositions; about 1% (w / w) of cetyl alcohol based on the total weight of the compositions; about 0.5% (w / w) of glyceryl monostearate based on the total weight of the compositions; and about 3% (w / w) of Span 20 based on the total weight of the compositions.

[0075] In any of the foregoing embodiments, the composition may further comprise a viscosity modifier. In any of the foregoing embodiments, the viscosity modifier may be any pharmaceutically acceptable viscosity modifier. As examples, but not limited to, the viscosity modifier may be carbomer, such as Carbomer 940 or Carbomer 980, gum arabic, calcium alginate, sodium alginate, carrageenan, chitosan, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polycarbophen, poly(methyl vinyl ether / maleic anhydride), xanthan gum, or combinations thereof, as well as those viscosity modifiers known to those skilled in the art.

[0076] In any of the foregoing embodiments, the amount of the viscosity modifier present in the composition may be sufficient to maintain the composition as a cream. In any of the foregoing embodiments, the amount of the viscosity modifier present may be sufficient to allow the resulting cream composition to withstand autoclaving without separating into its component phases. As examples, but not limited to, such autoclaving conditions may include 110°C for 10 minutes, 110°C for 30 minutes, 130°C for 1 minute, 130°C for 3 minutes, or 130°C for 5 minutes. As examples, but not limited to, the amount of the viscosity modifier present in the composition may be from about 0.1% (w / w) to about 10% (w / w) based on the total weight of the composition. As another example, but not limited to, the viscosity modifier may be present in the composition in amounts of about 0.1% to about 10% (w / w), about 0.1% (w / w) to about 5% (w / w), about 0.1% (w / w) to about 3% (w / w), about 0.1% (w / w) to about 2% (w / w), about 0.1% to about 1% (w / w), about 1% (w / w) to about 10% (w / w), or about 1% (w / w). (w / w) to about 5% (w / w), about 1% (w / w) to about 4% (w / w), about 1% (w / w) to about 3% (w / w), about 1% (w / w) to about 2% (w / w), about 2% (w / w) to about 10% (w / w), about 2% (w / w) to about 5% (w / w), about 2% (w / w) to about 4% (w / w), about 2% (w / w) to about 3% (w / w), about 3% (w / w) to about 10% (w / w) Approximately 3% (w / w) to approximately 5% (w / w), approximately 3% (w / w) to approximately 4% (w / w), approximately 4% (w / w) to approximately 10% (w / w), approximately 4% (w / w) to approximately 5% (w / w), approximately 5% (w / w) to approximately 10% (w / w), approximately 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.5% (w / w), 2% (w / w), 2.5% (w / w), 3% (w / w), 3.5% (w / w), 4% (w / w), 4.5% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), or 10% (w / w), or any range or value between them. As another example, but not limited to, in the case where the viscosity modifier is hydroxypropyl methylcellulose, the amount of hydroxypropyl methylcellulose present in the composition may be from about 2% (w / w) to about 5% (w / w) based on the total weight of the composition.As another example, but not limited to, the viscosity modifier may be carbomer, such as carbomer 980, and may be present in the composition in an amount of about 0.6% (w / w).

[0077] In any of the foregoing embodiments, the composition may further comprise a pH adjuster. In any of the foregoing embodiments, the amount of the pH adjuster added is sufficient to cause the pH of the composition to be between about 3.5 and about 8, preferably between about 4 and about 7, more preferably between about 5 and about 6. As examples, but not limited to, the presence of the pH adjuster is sufficient to adjust the pH of the composition to about 3.5 to about 8, about 4 to about 7, about 5 to about 7, about 5 to about 6, about 6 to about 7, about 4 to about 6, about 4 to about 5, or about 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8, and any range or value between them. As examples, but not limited to, the pH adjuster may be sodium hydroxide, potassium hydroxide, boric acid, sodium borate, triethanolamine or combinations thereof, as well as those adjusters known to those skilled in the art.

[0078] In any of the foregoing embodiments, the amount of the pH adjuster present in the composition may be sufficient to minimize the chemical degradation of the pharmaceutically active compound (such as a steroid or antimicrobial agent) in the formulation. As an example, but not limited to, the amount of the pH adjuster present in the composition may be from about 0.005% (w / w) to about 0.15% (w / w) based on the total weight of the composition. As another example, but not limited to, the amount of the pH adjuster present in the composition may be from about 0.005% (w / w) to about 0.1% (w / w), from about 0.005% (w / w) to about 0.05% (w / w), from about 0.05% (w / w) to about 0.1% (w / w), from about 0.05% (w / w) to about 0.15% (w / w), or from about 0.1% (w / w) to about 0.15% (w / w) based on the total weight of the composition. As another example, but not limited to, the amount of the pH adjuster present, based on the total weight of the composition, may be about 0.005% (w / w), 0.006% (w / w), 0.007% (w / w), 0.008% (w / w), 0.009% (w / w), 0.01% (w / w), 0.0125% (w / w), 0.015% (w / w), 0.0175% (w / w), 0.02% (w / w), or 0.02%. The pH adjuster may be 5% (w / w), 0.03% (w / w), 0.04% (w / w), 0.05% (w / w), 0.06% (w / w), 0.07% (w / w), 0.08% (w / w), 0.09% (w / w), 0.1% (w / w), 0.11% (w / w), 0.12% (w / w), 0.13% (w / w), 0.14% (w / w), or about 0.15% (w / w), or any range or value between these values. It should be understood that the pH adjuster may be added to the pure formulation or as a diluent to the composition, as included in the methods of this disclosure. Therefore, when using a diluent (such as a 1% NaOH solution), the amount of solution added needs to be sufficient to add an appropriate amount of pH adjuster.

[0079] In any of the foregoing embodiments, the composition may further comprise a tension modifier. In any of the foregoing embodiments, the amount of the tension modifier present may be sufficient to generate the desired tension, i.e., the osmotic pressure of the composition. In any of the foregoing embodiments, the tension modifier may be benzyl alcohol, benzalkonium chloride, chlorhexidine, phenethyl alcohol, sodium metabisulfite, methylparaben, propylparaben, or combinations thereof. In any of the foregoing embodiments, the amount of the tension modifier present in the composition, based on the total weight of the composition, may be from about 0.5% (w / w) to about 15% (w / w). By way of example, but not limited to, the amount of the tension modifier present, based on the total weight of the composition, may be from about 0.5% (w / w) to about 10% (w / w), from about 0.5% (w / w) to about 5% (w / w), from about 5% (w / w) to about 10% (w / w), from about 5% (w / w) to about 15% (w / w), or from about 10% (w / w) to about 15% (w / w). As another example, but not limited to, the amount of the tension modifier present, based on the total weight of the composition, may be about 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), 2% (w / w), 2.5% (w / w), 3% (w / w), 4% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), 11% (w / w), 12% (w / w), 13% (w / w), 14% (w / w), or about 15% (w / w), or any range or value between these values.

[0080] In any of the foregoing embodiments, the composition may further comprise an emollient. In any of the foregoing embodiments, the emollient may be petrolatum, mineral oil, light mineral oil, paraffin, petrolatum or paraffin alcohol, white petrolatum, or combinations thereof, and any emollient known to those skilled in the art. In any of the foregoing embodiments, the amount of the emollient present in the composition, based on the total weight of the composition, may be from about 4% (w / w) to about 30% (w / w). As examples, but not limited to, the amount of the emollient present in the composition, based on the total weight of the composition, may be from about 4% (w / w) to about 10% (w / w), from about 4% (w / w) to about 20% (w / w), from about 10% (w / w) to about 20% (w / w), from about 10% (w / w) to about 30% (w / w), or from about 20% (w / w) to about 30% (w / w). As another example, but not limited to, the amount of the emollient present, based on the total weight of the composition, may be about 4% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), 11% (w / w), 12% (w / w), 13% (w / w), 14% (w / w), 15% (w / w), 16% (w / w), 17% (w / w), 18% (w / w), 19% (w / w), 20% (w / w), 21% (w / w), 22% (w / w), 23% (w / w), 24% (w / w), 25% (w / w), 26% (w / w), 27% (w / w), 28% (w / w), 29% (w / w), or 30% (w / w).

[0081] In any of the foregoing embodiments, the composition may further include a mediator. Any pharmaceutically acceptable aqueous mediator may be used. As an example, but not limited to, the mediator may be water.

[0082] In any of the foregoing embodiments, the composition may further comprise a steroid. Various corticosteroids, glucocorticoids, or combinations thereof can be used in the compositions and methods of this disclosure. As examples, but not limited to, corticosteroids that can be used in the compositions and methods of this disclosure include cortisone, cortisol, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, betamethasone, ciclesonide, dexamethasone, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, budesonide, and chlorprednisolone. clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortivazol, deflazacort, desonide, deoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl ester, fluocortolone, fluorometholone, fluperolone acetate, fluprednideneAcetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, methylprednisone, methylprednisolone, mometasone furoate Prednisolone, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisolone valerate, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, etc. Esters, derivatives, and salts of corticosteroids, including hydrates and hydrogen chloride salts, may also be used in the compositions and methods disclosed herein. For example, betamethasone is often marketed as betamethasone dipropionate (its chemical name is 9-fluoro-11β,17,21-trihydroxy-16β-methylpregn-1,4-diene-3,20-dione 17,21-dipropionate, its empirical formula is C...). 28 H 37 The betamethasone is administered in the form of FO7 (with a molecular weight of 504.59 g / mol), and the betamethasone dosages given in Table 1 below are based on this specific salt. It should be understood that any pharmaceutically acceptable steroid may be used in the compositions and methods of this disclosure.

[0083] In any of the foregoing embodiments, the steroid may be present in the composition in an "effective amount". The amount of steroid in the compositions disclosed herein may vary based on patient condition, patient sensitivity, route of administration, biological half-life of the steroid, patient age, systemic factors, and other factors, depending on the desired dose to be delivered. Furthermore, the state of infection or disease and susceptibility to steroids may be considered. Those skilled in the art can determine an appropriate dose, including determining an "effective amount" of the composition to be applied.

[0084] In any of the foregoing embodiments, the amount of the steroid in the composition may be from about 0.01% (w / w) to about 15% (w / w) based on the total weight of the composition. As examples, but not limited to, the amount of the steroid in the composition may be from about 0.01% (w / w) to about 15% (w / w), from about 0.01% (w / w) to about 10.5% (w / w), from about 0.01% (w / w) to about 8.5% (w / w), from about 0.01% (w / w) to about 3.5% (w / w), from about 0.01% (w / w) to about 2% (w / w), from about 0.01% (w / w) to about 1.7% (w / w), from about 0.01% (w / w) to about 0.03% (w / w), from about 1% (w / w) to about 10.5% (w / w), or from about 0.8% (w / w). (w) to about 8% (w / w), about 1.7% (w / w) to about 17% (w / w), about 0.2% (w / w) to about 2% (w / w), about 0.025% (w / w) to about 0.25% (w / w), about 0.03% (w / w) to about 0.3% (w / w), about 0.01% (w / w), about 0.02% (w / w), about 0.03% (w / w), 0.0322% (w / w), 0.05% (w / w), 0.0644% (w / w), 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5 % (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.1% (w / w), 1.2% (w / w), 1.3% (w / w), 1.4% (w / w), 1.5% (w / w), 1.6 % (w / w), 1.7% (w / w), 1.8% (w / w), 1.9% (w / w), 2% (w / w), 2.25% (w / w), 2.5% (w / w), 2.75% (w / w), 3% (w / w), 3.25% (w / w), 3.5% (w / w), 3. 75% (w / w), 4% (w / w), 4.25% (w / w), 4.5%% (w / w), 4.75% (w / w), 5% (w / w), 5.5% (w / w), 6% (w / w), 6.5% (w / w), 7% (w / w), 7.5% (w / w), 8% (w / w), 8.5% (w / w), 9% (w / w), 9.5% (w / w), 10% (w / w), 10.5% (w / w), 11% (w / w), 12% (w / w), 13% (w / w), 14% (w / w) or 15% (w / w), and any range or value therebetween.

[0085] In any of the foregoing embodiments, when the steroid is betamethasone dipropionate, the amount of the steroid present in the composition, based on the total weight of the composition, may, for example but not limited to, be from about 0.01% (w / w) to about 1.0% (w / w), more preferably, from 0.03% (w / w) to about 0.6% (w / w). For example but not limited to, the amount of the steroid present in the composition, based on the total weight of the composition, may be from about 0.01% (w / w) to about 1.0% (w / w), from about 0.01% (w / w) to about 0.5% (w / w), from 0.02% (w / w) to about 0.8% (w / w), from 0.03% (w / w) to about 0.7% (w / w), from 0.0322% (w / w) to about 0.0644% (w / w), from 0.04% (w / w) to... Approximately 0.6% (w / w), 0.05% to approximately 0.5% (w / w), approximately 0.01% (w / w) to approximately 0.1% (w / w), approximately 0.01% (w / w) to approximately 0.09% (w / w), approximately 0.01% (w / w) to approximately 0.08% (w / w), approximately 0.01% (w / w) to approximately 0.07% (w / w), approximately 0.1% (w / w) to approximately 0.06% (w / w), approximately 0.01% (wow) to approximately 0.05% (w / w) Approximately 0.01% (w / w) to approximately 0.04% (w / w), approximately 0.01% (w / w) to approximately 0.03% (w / w), approximately 0.01% (w / w) to approximately 0.02% (w / w), approximately 0.1% (w / w) to approximately 1.0% (w / w), approximately 0.1% (w / w) to approximately 0.2% (w / w), approximately 0.2% (w / w) to approximately 1.0% (w / w), approximately 0.3% (w / w) to approximately 1.0% (w / w), approximately 0.4% (w / w) / w) to about 1.0% (w / w), about 0.5% (w / w) to about 1.0% (w / w), about 0.1% (w / w) to about 0.5% (w / w), about 0.5% (w / w) to about 1.0% (w / w), about 0.6% (w / w) to about 1.0% (w / w), about 0.7% (w / w) to about 1.0% (w / w), about 0.8% (w / w) to about 1.0% (w / w), or about 0.9% (w / w) to about 1.0% (w / w).As another example, but not limited to, the steroid may be present in the composition in amounts of about 0.015% (w / w), 0.02% (w / w), 0.025% (w / w), 0.03% (w / w), 0.0322% (w / w), 0.035% (w / w), 0.04% (w / w), 0.045% (w / w), 0.05% (w / w), 0.055% (w / w), 0.06% (w / w), 0.0644% (w / w), or 0.065% (w / w). The amounts may be 0.07% (w / w), 0.075% (w / w), 0.08% (w / w), 0.085% (w / w), 0.09% (w / w), 0.095% (w / w), 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), or 1.0% (w / w), or any range or value between these values. As an example, but not limited to, the amount of the steroid in the composition may be about 0.0322% (w / w) based on the total weight of the composition. It should be understood that the amount of steroid (or an antimicrobial agent, if present) may refer to the active amount of the compound. As an example, but not limited to, when 0.0644% (w / w) of betamethasone dipropionate is added, the active amount can be 0.05% (w / w) of betamethasone. Therefore, in the examples, when a 0.05% betamethasone dipropionate cream is indicated, wherein the steroid is betamethasone dipropionate, the amount added to achieve 0.05% active betamethasone is 0.0644% (w / w).

[0086] Additional exemplary, non-limiting dose ranges for specific steroids in the cream compositions used in this method are shown in Table 1 below.

[0087] Table 1: Exemplary, non-limiting dosage ranges for corticosteroids (in mg / g of composition)

[0088]

[0089] In any of the foregoing embodiments, the composition may comprise a total of about 0.01 mg to about 3 g of steroids. By way of example, but not limitation, the amounts in Table 1 may be multiplied by 0.17 g, 0.34 g, 0.7 g, 1 g, 1.4 g, 2 g, 2.1 g, 4 g, 4.2 g, 5 g, 6 g, 8 g, 10 g, or 20 g. As another example, but not limited to, the composition may include a total of about 0.01 mg to about 3 g, about 0.1 mg to about 3 g, about 0.5 mg to about 3 g, about 1 mg to about 3 mg, about 1.5 mg to about 3 mg, 0.01 mg to about 1.5 g, about 0.01 mg to about 1 g, about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 1 mg, about 0.01 mg to about 0.1 mg, about 0.02 mg to about 1.5 g, about 0.0 2 mg to about 1 g, about 0.02 mg to about 500 mg, about 0.02 mg to about 250 mg, about 0.02 mg to about 100 mg, about 0.02 mg to about 10 mg, about 0.02 mg to about 5 mg, about 0.02 mg to about 1 mg, 0.02 mg to about 0.2 mg, about 0.03 mg to about 1.5 g, about 0.03 mg to about 1 g, about 0.03 mg to about 500 mg, about 0.03 mg to about 250 mg, about 0.03 mg to about 100 mg, about 0.03 mg to about 10 mg, about 0.03 mg to about 5 mg, about 0.03 mg to about 1 mg, about 0. 0.3 mg to about 0.3 mg, about 1 mg to about 1.5 g, about 1 mg to about 1 g, about 1 mg to about 500 mg, about 1 mg to about 250 mg, about 1 mg to about 100 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 2 mg to about 1.5 g, about 2 mg to about 1 g, about 2 mg to about 500 mg, about 2 mg to about 250 mg, about 2 mg to about 100 mg, about 2 mg to about 10 mg, about 2 mg to about 5 mg, about 8 mg to about 1.5 g, about 8 mg to about 1 g, about 8 mg to about 500 mg, about 8 mg to about 250 mg, about 8 mg to about 100 mg Approximately 8 mg to approximately 10 mg, approximately 10 mg to approximately 1.5 g, approximately 10 mg to approximately 1 g, approximately 10 mg to approximately 500 mg, approximately 10 mg to approximately 250 mg, approximately 10 mg to approximately 100 mg, approximately 100 mg to approximately 1.5 g, approximately 100 mg to approximately 1 g, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 250 mg, approximately 250 mg to approximately 1.5 g, approximately 250 mg to approximately 1 g, approximately 250 mg to approximately 500 mg, approximately 500 mg to approximately 1.5 g, approximately 500 mg to approximately 1 g, approximately 1 g to approximately 1.5 g, approximately 0.01 mg, 0.02 mg, 0.05 mg, 0.1mg, 0.125mg, 0.15mg, 0.2mg, 0.25mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2mg, 2.25mg, 2.5mg, 2.75mg, 3mg, 3.25mg, 3.5mg, 3.75mg, 4mg, 4.25mg, 4.5mg, 4.75mg, 5mg, 7.5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80 mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 220mg, 240mg, 250mg, 260mg, 280mg, 300mg, 330mg, or 1.5g, 1.6g, 1.7g, 1.8g, 1.9g, 2g, 2.1g, 2.2g, 2.3g, 2.4g, 2.5g, 2.6g, 2.7g, 2.8g, 2.9g, or 3g, or any range or value between these values.

[0090] In some embodiments, the steroid is betamethasone or betamethasone dipropionate and is present in the compositions disclosed herein in amounts of about 0.322 mg to about 3.215 mg per gram of cream composition, or about 0.322 mg to about 0.644 mg per gram of cream composition, or about 0.322 mg to about 0.644 mg per gram of cream composition. In other embodiments, the total dose of betamethasone dipropionate administered in a single application (i.e., bilateral intranasal application) is about 0.322 mg to about 3.215 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.

[0091] In any of the foregoing embodiments, the composition may further comprise an antimicrobial agent. In any of the foregoing embodiments, the antimicrobial agent may be present in the composition in an "effective amount". The amount of the antimicrobial agent in the compositions disclosed herein may vary based on patient condition, patient susceptibility, route of administration, biological half-life of the steroid, patient age, systemic factors, and other factors, depending on the desired dose to be delivered. Furthermore, the state of infection or disease and susceptibility to steroids may be considered. Those skilled in the art can determine an appropriate dose, including determining an "effective amount" of the composition to be applied.

[0092] Various antifungal agents can be used in the compositions and methods disclosed herein. By way of example, but not limited to, such antifungal agents may include natamycin, ciclopirox, fluconazole, terbinafine, clotrimazole, itraconazole, ketoconazole, econazole, miconazole, nystatin, oxiconazole, terconazole, tolnaftate, efinaconazole, abafungin, terbinafine, butenafine, metronidazole, etc., combinations thereof, and those antifungal agents known to those skilled in the art. In some embodiments, the antifungal agent is clotrimazole.

[0093] The antifungal agent may be present in an effective amount in the compositions disclosed herein. In some embodiments, the effective amount or total amount of the antifungal agent per application (i.e., bilateral intranasal application) is from about 20 mg to about 50 mg, and more preferably, from about 25 mg to about 40 mg. In some embodiments, the amount of the antifungal agent is 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 at about 0.1 to about 5% by weight of the composition. As examples, but not limited to, the antifungal agent may be present in 0.1 to 5 weight percent, 0.5 to 4 weight percent, 0.5 to 3 weight percent, 0.5 to 2 weight percent, 0.5 to 1 weight percent, 1 to 5 weight percent, 2 to 5 weight percent, 3 to 5 weight percent, 4 to 5 weight percent, 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, or 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.

[0094] In some embodiments, the compositions disclosed herein may further comprise antibiotics as agents with antimicrobial activity. Examples, but not limited to, such antimicrobial agents may include flucloxacillin, triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether), alcohols (including ethanol and isopropanol), peroxides (including benzoyl peroxide), iodine, benzyl chloride, chloroxylenol, and aminoglycoside antibiotics (such as ciprofloxacin), as well as their salts or derivatives. As examples, but not limited to, other antibiotics may include amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromycin, geldanamycin, herbimycin, loracarbef, ertapenem, doripenem, imipenem, meropenem, cefaclor, cefmandole, cefotoxin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, and cefpodox. The following are listed as examples of antibiotics: ceftazidime, cefbutan, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, vancomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, aztreonam, amoxicillin, amoxicillin, ampicillin, azocillin, carbenicillin, cloxacillin, and dicloxacillin.Flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, peperacillin, ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, clavulanic acid (acid), enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nonfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, AL-15469A, AL-38905, OP-145, mafenide, prontosil, sulfacetamide ide), sulfamethizole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, cotrimoxazole, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, linezolid, asogebanubem chloramphenicol Chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platinummycin, pyrazinamideQuinupristin, dalfopristin, rifampicin, thiamphenicol, tinidazole, amoxicillin / clavulanic acid, Maximin H5, Dermcidin, Cecropins, andropin, moricin, ceratotoxin, melittin, Magainin, dermaseptin, bombinin, brevinin-1, esculentins, and buforin II. CAP18, LL37, abaecin, apidaecins, prophenin, indolicidin, brevinins, protegrin, tachyplesins, defensins, drosomycin, alamethicin, pexiganan, or MSI-78, MSI-843, MSI-594, polyphemusin, colicin, pyocin, klebicin, subtilin, epidermin, herbicolacin, brevicornuate. (cin), halocin, agrocin, alveicin, carnocin, curvaticin, divercin, enterocin, enterolysin, erwiniocin, glycinecin, lactococin, leucoccin, mesentericin, pediocin, plantaricin, sakacin, sulfolobicin, vibriocin, warnerin andNisin and other lactic acid nisin, as well as their salts or derivatives.

[0095] In some embodiments, the agent with antimicrobial activity may be EDTA, such as, but not limited to, disodium EDTA.

[0096] In any of the foregoing embodiments, the amount of the antimicrobial agent present in the composition may be from about 0.25% (w / w) to about 2% (w / w) based on the total weight of the composition. As examples, but not limited to, the amount of the antimicrobial agent in the composition may be from about 0.25% (w / w) to about 1% (w / w), 0.5% (w / w) to about 1% (w / w), 0.5% (w / w) to about 2% (w / w), about 1% (w / w) to about 2% (w / w), or 1.5% (w / w) to about 2% (w / w) based on the total weight of the composition. As another example, but not limited to, the amount of the antimicrobial agent in the composition, based on the total weight of the composition, may be about 0.25% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.75% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.25% (w / w), 1.5% (w / w), 1.75% (w / w), or 2% (w / w), or any range or value between these values.

[0097] In any of the foregoing embodiments, the composition may include a total of about 0.01 mg to about 500 mg of an antimicrobial agent.As examples, but not limited to, the composition may include, in total amounts of about 0.01 mg to about 500 mg, about 0.1 mg to about 500 mg, about 1 mg to about 500 mg, about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 300 mg to about 500 mg, about 400 mg to about 500 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 1 mg, about 0.01 mg to about 0.1 mg, about 0.02 mg to about 100 mg, about 0.02 mg to about 10 mg, and about 0.02 mg. About 5 mg, about 0.02 mg to about 1 mg, 0.02 mg to about 0.2 mg, about 0.03 mg to about 100 mg, about 0.03 mg to about 10 mg, about 0.03 mg to about 5 mg, about 0.03 mg to about 1 mg, about 0.03 mg to about 0.3 mg, about 1 mg to about 100 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 2 mg to about 100 mg, about 2 mg to about 10 mg, about 2 mg to about 5 mg, about 8 mg to about 100 mg, about 8 mg to about 10 mg, about 10 mg to about 100 mg, about 50 mg to about 200 mg, about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 0. 01mg, 0.02mg, 0.03mg, 0.04mg, 0.05mg, 0.06mg, 0.07mg, 0.08mg, 0.09mg, 0.1mg, 0.15mg, 0.2mg, 0.25mg, 0.3mg, 0.35mg, 0.4mg, 0.45mg, 0.5mg, 0.6mg , 0.7mg, 0.75mg, 0.8mg, 0.9mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2mg, 2.25mg, 2.5mg, 2.75mg, 3mg, 3.25mg, 3.5mg, 3.75mg, 4mg, 4.25mg, 4.5mg, 4.75mg, 5m 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg, or any range or value between them.

[0098] In any of the foregoing embodiments, the cream compositions of this disclosure may contain any suitable therapeutic active agent. Therapeutic active agents contemplated within the scope of this invention (including, but not limited to, steroids and / or antimicrobial agents) should be understood to include hydrophobic, hydrophilic, and amphiphilic compounds. They may be in the form of free acids, free bases, or pharmaceutically acceptable salts, and may include derivatives, esters, or prodrugs. It should be understood that the cream compositions of this disclosure may include only steroids, only antimicrobial agents (antifungal, antibacterial, or a combination thereof), or a combination of steroids and antimicrobial agents. The type of therapeutic active ingredient in the cream composition may be determined based on the condition being treated, and in some cases, only steroids may be required, in others only antimicrobial agents, in still others both steroids and antimicrobial agents, or in other cases different therapeutic active agents may be used. Therefore, in some embodiments, the cream composition does not contain an antimicrobial agent. In other embodiments, the cream composition does not contain steroids. In such cases, by example but not limitation, the cream composition may contain only steroids as the therapeutic active agent, i.e., the cream composition does not contain an antimicrobial agent. In other instances, by way of example but not limited to, the cream composition may contain only an antimicrobial agent as a therapeutic active agent, i.e., the cream composition does not contain steroids. In some embodiments, the cream composition does not contain steroids or agents with antimicrobial activity.

[0099] In any of the foregoing embodiments, the composition may further comprise a stabilizer. In any of the foregoing embodiments, the amount of stabilizer present may be sufficient to reduce the amount of degradation products in the active pharmaceutical ingredient after autoclaving, particularly during autoclaving, relative to a composition without a stabilizer. Examples, but not limited to, such autoclaving conditions may include 110°C for 10 minutes, 110°C for 30 minutes, 130°C for 1 minute, 130°C for 3 minutes, or 130°C for 5 minutes. In any of the foregoing embodiments, the stabilizer may be edetic acid, a pharmaceutically acceptable salt of edetic acid, citric acid, sodium citrate, fumaric acid, malic acid, maltose, pentetic acid, or combinations thereof, and those stabilizers known to those skilled in the art. A pharmaceutically acceptable salt of edetic acid may comprise any suitable salt, for example, disodium edeticate. In any of the foregoing embodiments, the amount of the stabilizer present in the composition may be from about 0.005% (w / w) to about 0.25% (w / w), or any amount sufficient to reduce the degradation of the pharmaceutically active compound (or therapeutically active agent) in the composition relative to a composition without the stabilizer during autoclaving. As examples, but not limited to, the amount of the stabilizer present in the composition may be from about 0.005% (w / w), 0.01% (w / w), 0.015% (w / w), 0.025% (w / w), 0.05% (w / w), 0.075% (w / w), 0.1% (w / w), or 0.25% (w / w), or any range or value between these values, based on the total weight of the composition.

[0100] In any of the foregoing embodiments, the composition may be sterile. As an example, but not limited to, sterility can be determined by a USP 71 test.

[0101] The compositions disclosed herein can be sterilized by any suitable means, preferably by autoclaving. By way of example, but not limited to, the compositions can be sterilized by gamma irradiation or, in some cases, by filtration. As another example, but not limited to, autoclaving at 6-12 times the D value of the composition is sufficient to sterilize it, such as by measuring the survival curve of Bacillus subtilis S230 using standard methods to achieve a given autoclaving temperature.

[0102] In any of the foregoing embodiments, as measured by a Brookfield RVDVII+ with spindle 28 at room temperature, the viscosity of the composition can be (1) about 200,000 centipoise (cP) to about 2,000,000 cP at a shear rate of about 0.3 RPM; (2) about 100,000 cP to about 1,500,000 cP at a shear rate of about 0.5 RPM; (3) about 100,000 cP to about 1,000,000 cP at a shear rate of about 0.6 RPM; (4) about 100,000 cP to about 1,000,000 cP at a shear rate of about 0.8 RPM. (5) At a shear rate of about 1 RPM, about 50,000 cP to about 750,000 cP; (6) At a shear rate of about 1.5 RPM, about 40,000 cP to about 500,000 cP; (7) At a shear rate of about 2.0 RPM, about 30,000 cP to about 250,000 cP; (8) At a shear rate of about 2.5 RPM, about 20,000 cP to about 200,000 cP; (9) At a shear rate of about 3.0 RPM, about 20,000 cP. (10) At a shear rate of about 4.0 RPM, about 15,000 cP to about 150,000 cP; (11) At a shear rate of about 5.0 RPM, about 15,000 cP to about 150,000 cP; (12) At a shear rate of about 6.0 RPM, about 10,000 cP to about 100,000 cP; (13) At a shear rate of about 10.0 RPM, about 8,000 cP to about 70,000 cP; (14) At a shear rate of about 12.0 RPM, about 10,000 cP (15) at a shear rate of about 20.0 RPM, about 1,000 cP to about 40,000 cP; (16) at a shear rate of about 30.0 RPM, about 1,000 cP to about 20,000 cP; (17) at a shear rate of about 50.0 RPM, about 500 cP to about 15,000 cP; (18) at a shear rate of about 60.0 RPM, about 500 cP to about 10,000 cP; or (19) at a shear rate of about 100.0 RPM, about 250 cP to about 7,000 cP.In some embodiments, when the composition is sterile, the viscosity of the composition, as measured by a Brookfield RVDVII+ with spindle 28 at room temperature, can be (1) about 200,000 centipoise (cP) to about 2,000,000 cP at a shear rate of about 0.3 RPM; (2) about 100,000 cP to about 1,500,000 cP at a shear rate of about 0.5 RPM; (3) about 100,000 cP to about 1,000,000 cP at a shear rate of about 0.6 RPM; (4) at about 0.8 RPM. (5) At a shear rate of about 1 RPM, about 100,000 cP to about 750,000 cP; (6) At a shear rate of about 1.5 RPM, about 50,000 cP to about 500,000 cP; (7) At a shear rate of about 2.0 RPM, about 50,000 cP to about 250,000 cP; (8) At a shear rate of about 2.5 RPM, about 30,000 cP to about 200,000 cP; (9) At a shear rate of about 3.0 RPM, about 3 (10) At a shear rate of about 4.0 RPM, about 20,000 cP to about 150,000 cP; (11) At a shear rate of about 5.0 RPM, about 20,000 cP to about 150,000 cP; (12) At a shear rate of about 6.0 RPM, about 15,000 cP to about 100,000 cP; (13) At a shear rate of about 10.0 RPM, about 10,000 cP to about 70,000 cP; (14) At a shear rate of about 12.0 RPM, about 10,000 cP to about 200,000 cP; (15) At a shear rate of about 4.0 RPM, about 20,000 cP to about 150,000 cP; (16) At a shear rate of about 12.0 RPM, about 10,000 cP to about 200,000 cP; (17) At a shear rate of about 4.0 RPM, about 20,000 cP to about 150,000 cP; (18) At a shear rate of about 4.0 RPM, about 20,000 cP to about 150,000 cP; (19) At a shear rate of about 4.0 RPM, about 20,000 cP to about 150,000 cP; (10 ... (15) at a shear rate of about 20.0 RPM, about 1,000 cP to about 40,000 cP; (16) at a shear rate of about 30.0 RPM, about 1,000 cP to about 20,000 cP; (17) at a shear rate of about 50.0 RPM, about 500 cP to about 15,000 cP; (18) at a shear rate of about 60.0 RPM, about 500 cP to about 10,000 cP; or (19) at a shear rate of about 100.0 RPM, about 250 cP to about 7,000 cP.Alternatively, in any of the foregoing embodiments, the viscosity of the composition, as measured by a Brookfield DV3T CP rheometer with a CP52 spindle at 25.0 ± 0.1 °C, may be: (1) about 30,000 cP to about 500,000 cP at a shear rate of about 0.3 RPM; (2) about 30,000 cP to about 300,000 cP at a shear rate of about 0.6 RPM; (3) about 10,000 cP to about 200,000 cP at a shear rate of about 1.5 RPM. P; (4) at a shear rate of about 3.0 RPM, about 7,000 cP to about 70,000 cP; (5) at a shear rate of about 12.0 RPM, about 3,000 cP to about 20,000 cP; (6) at a shear rate of about 30.0 RPM, about 300 cP to about 7,000 cP; or (7) at a shear rate of about 60.0 RPM, about 150 cP to about 3,500 cP. In some embodiments, when the composition is sterile, such as by a Brookfield rheometer DV3T with a CP52 spindle. The viscosity of the composition, as measured by a CP rheometer at 25.0 ± 0.1 °C, can be: (1) about 70,000 cP to about 700,000 cP at a shear rate of about 0.3 RPM; (2) about 30,000 cP to about 300,000 cP at a shear rate of about 0.6 RPM; (3) about 10,000 cP to about 200 cP at a shear rate of about 1.5 RPM and a torque of 10-100%. (4) at a shear rate of about 3.0 RPM, about 10,000 cP to about 70,000 cP; (5) at a shear rate of about 12.0 RPM, about 3,000 cP to about 20,000 cP; (6) at a shear rate of about 30.0 RPM, about 300 cP to about 7,000 cP; or (7) at a shear rate of about 60.0 RPM, about 150 cP to about 3,500 cP. It should be understood that, as used in this disclosure, room temperature can be a temperature of 20°C to 25°C.

[0103] In any of the foregoing embodiments, the composition may be a water-in-oil emulsion or an oil-in-water emulsion. In such embodiments, the composition may have microsphere sizes or particle sizes of less than 50 μm, 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 20 μm, 15 μm, 10 μm, 9 μm, 8 μm, 7 μm, 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm, whether by number average or by volume average. As examples, but not limited to, the microsphere size or particle size of the composition can be from about 1 μm to about 50 μm, from 1 μm to about 45 μm, from 1 μm to about 40 μm, from 1 μm to about 35 μm, from 1 μm to about 30 μm, from 1 μm to about 25 μm, from 1 μm to about 20 μm, from 1 μm to about 15 μm, from 1 μm to about 10 μm, from about 1.5 μm to about 50 μm, from about 1.5 μm to about 45 μm, from about 1.5 μm to about 40 μm, from about 1.5 μm to about 35 μm, from about 1.5 μm to about 30 μm, from about 1.5 μm to about 25 μm, from about 1.5 μm to about 20 μm, from about 1 0.5μm to about 15μm, about 1.5μm to about 10μm, about 2.0μm to about 50μm, about 2.0μm to about 45μm, about 2.0μm to about 40μm, about 2.0μm to about 35μm, about 2.0μm to about 30μm, about 2.0μm to about 25μm, about 2.0μm to about 20μm, about 2.0μm to about 15μm, about 2.0μm to about 10μm, about 3.0μm to about 50μm, about 3.0μm to about 45μm, about 3.0μm to about 40μm, about 3.0μm to about 35μm, about 3.0μm to about 30μm, about 3 0μm to about 25μm, about 3.0μm to about 20μm, about 3.0μm to about 15μm, about 3.0μm to about 10μm, about 5.0μm to about 50μm, about 5.0μm to about 45μm, about 5.0μm to about 40μm, about 5.0μm to about 35μm, about 5.0μm to about 30μm, about 5.0μm to about 25μm, about 5.0μm to about 20μm, about 5.0μm to about 15μm, about 5.0μm to about 10μm, about 1μm to about 5μm, about 1.5μm to about 5μm, about 2μm to about 5μm, about 3μm to about 5μm Approximately 5 μm to approximately 10 μm, approximately 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 μm or any range or value between them, whether by quantity mean or by volume mean.In some embodiments, the composition is sterile and has a measurable microsphere size. It should be understood that, for oil-in-water emulsions, microsphere size refers to oil globule size. It should be further understood that microsphere size or particle size can be measured according to USP 729.

[0104] In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% relative humidity (RH) for one month, varies by no more than 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, as measured by quantity mean. In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% RH for 3 months, varies by no more than 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, as measured by the quantity mean. In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% RH for 6 months, varies by no more than 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, as measured by quantity mean. In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% relative humidity (RH) for 12 months, varies by no more than 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, as measured by quantity mean. In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% relative humidity (RH) for 18 months, varies by no more than 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, as measured by quantity mean. In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% relative humidity (RH) for 24 months, varies by no more than 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, as measured by quantity mean.In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% relative humidity (RH) for one month, varies by no more than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% as measured by volume average. In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% RH for 3 months, varies by no more than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% as measured by volume average. In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% RH for 6 months, varies by no more than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% as measured by volume average. In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% RH for 12 months, varies by no more than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% RH for 18 months, varies by no more than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.In any of the foregoing embodiments, the composition may have a spherical size or particle size that, when stored at 25°C / 60% RH for 24 months, varies by no more than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, as measured by volume average. By way of example, but not limitation, the spherical size or particle size can be measured according to USP 729. It should be understood that for oil-in-water emulsions, spherical size refers to oil spherical size.

[0105] In any of the foregoing embodiments, the composition does not exhibit agglomeration, emulsification, sedimentation, flocculation, phase inversion, or coalescence after storage at 25°C / 60% relative humidity for 1 month, 3 months, 6 months, 12 months, 18 months, or 24 months. In any of the foregoing embodiments, the composition does not exhibit agglomeration, emulsification, sedimentation, flocculation, phase inversion, or coalescence after storage at 40°C / 70% relative humidity for 1 month, 3 months, 12 months, 18 months, or 24 months. Agglomeration can be understood as the aggregation of small spheres into larger spheres. Emulsification and sedimentation can be understood as the aggregation of small spheres into larger spheres, where these spheres are no longer separately dispersed at the top or bottom of the composition. Flocculation can be understood as the aggregation of droplets, where the size of the initial droplets does not increase to larger units. Phase inversion can be understood as an exchange between the dispersed phase and the medium, such as an o / w emulsion becoming a w / o emulsion or vice versa. Coalescence can be understood as the fusion of droplets into larger droplets due to the thinning and disruption of the liquid film between the droplets, resulting in phase separation.

[0106] In any of the foregoing embodiments, the composition did not penetrate the cadaver's skin or nasal mucosa after 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, or 48 hours. In any of the foregoing embodiments, the composition did not penetrate the cadaver's skin or nasal mucosa at a concentration >45 ng / mL after 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, or 48 hours.

[0107] In any of the foregoing embodiments, the composition may contain less than 10% total degradation products from steroids or agents with antimicrobial activity (if present). As examples, but not limited to, the composition may include less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% total degradation products from steroids or agents with antimicrobial activity. As another example, but not limited to, the total degradation products may be measured by HPLC. As another example, but not limited to, the total degradation products may include betamethasone (EP impurity A, CAS number 378-44-9), betamethasone 17-propionate (EP impurity B, CAS number 5534-13-4), betamethasone 21-propionate (EP impurity C, CAS number 75883-70-7), betamethasone 21-acetic acid 17-propionate (EP impurity D, CAS number 5514-81-8), beclomethasone dipropionate (EP impurity E, CAS number 5534-09-8), betamethasone 9,11-epoxide 17,21-dipropionate (EP impurity F, CAS number 66917-44-0), beclomethasone tripropionate (… EP impurity G, CAS No. 1186048-33-8), 6-bromo-betamethasone-17,21-dipropionate (EP impurity H, CAS No. 1186048-34-9), (8S,9R,10S,11S,13S,14S,16S,17R)-9-fluoro-1-hydroxy-10,13,16-trimethyl-3-oxo-17-(2-(propionyloxy)acetyl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentene-cyclopentadieno[a]phenanthrene-17-ylpropionate (EP impurity I, CAS No. 80163-83-3), and combinations thereof. In some respects, total degradation products may contain betamethasone EP impurities A, B, C, D, E, F, G, H and I.

[0108] In any of the foregoing embodiments, after storage at 25°C / 60% RH for 1 month or 3 months, the composition may contain less than 10% total degradation products from steroids or agents with antimicrobial activity (if present). As examples, but not limited to, after storage at 25°C / 60% RH for 1 month or 3 months, the composition may contain less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% total degradation products from steroids or agents with antimicrobial activity. As further examples, but not limited to, the total degradation products may be measured by HPLC.

[0109] In any of the foregoing embodiments, as measured after storage at 25°C / 60% RH for 1 month or 3 months, the composition may contain a steroid or an antimicrobial agent, if present, within 10% of the initial content. As examples, but not limited to, as measured after storage at 25°C / 60% RH for 1 month or 3 months, the composition may contain a steroid or an antimicrobial agent, if present, within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the initial content. As further examples, but not limited to, the content of the steroid or antimicrobial agent can be measured by liquid chromatography (LC) such as HPLC. As examples, but not limited to, the steroid may be betamethasone dipropionate or betamethasone.

[0110] In any of the foregoing embodiments, the pH of the composition may be about 3.5 and about 8, preferably about 4 and about 7, more preferably about 5 and about 6. As examples, but not limited to, the presence of the pH adjuster is sufficient to adjust the pH of the composition to about 3.5 to about 8, about 4 to about 7, about 5 to about 7, about 5 to about 6, about 6 to about 7, about 4 to about 6, about 4 to about 5, or about 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8, and any range or value between them.

[0111] In any of the foregoing embodiments, the pH of the composition, as measured after storage at 25°C / 60% RH for 1 month or 3 months, may be within 0.5 of the initial pH of the composition. As examples, but not limited to, the pH of the composition, as measured after storage at 25°C / 60% RH for 1 month or 3 months, may be within 0.5, 0.4, 0.3, 0.2, or 0.1 of the initial pH. As further examples, but not limited to, the pH may be measured using standard methods.

[0112] In any of the foregoing embodiments, the osmotic pressure of the composition, as measured after storage at 25°C / 60% RH for 1 month or 3 months, may be within 10 mOsm / kg of the initial osmotic pressure of the composition. As examples, but not limited to, the osmotic pressure of the composition, as measured after storage at 25°C / 60% RH for 1 month or 3 months, may be within 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mOsm / kg of the initial osmotic pressure. As further examples, but not limited to, the osmotic pressure may be measured using USP 785.

[0113] In any of the foregoing embodiments, as measured after storage at 25°C / 60% RH for 1 month or 3 months, the viscosity of the composition may be within 10% of the initial viscosity of the composition. By way of example, but not limitation, as measured after storage at 25°C / 60% RH for 1 month or 3 months, the viscosity of the composition may be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the initial viscosity. By way of example, but not limitation, the viscosity may be measured using the viscosity measurement methods described in this disclosure.

[0114] It should be understood that for any initial property, such as initial viscosity, these properties can be measured either at the start of storage or from the start of formulation, and the two can overlap.

[0115] In any of the foregoing embodiments, the composition must not contain an inhibitor of pro-inflammatory cytokines.

[0116] In any of the foregoing embodiments, the sole pharmaceutically active compound in the composition may be a steroid or an agent with antimicrobial activity. In any of the foregoing embodiments, the composition must not contain any pharmaceutically active compound that is not a steroid or an agent with antimicrobial activity.

[0117] In any of the foregoing embodiments, the composition may be packaged in a syringe or other container.

[0118] Various local analgesics may also be included in the compositions described herein. These include, but are not limited to, nonsteroidal anti-inflammatory drugs, lidocaine, capsaicin, amitriptyline, nitroglycerin, opioids, menthol, pimecrolimus, phenytoin, etc.

[0119] In any of the foregoing embodiments, the composition may be a cream, and in some respects an isotonic cream, capable of withstanding autoclaving without separating into its component phases. By example, but not limited to, such autoclaving conditions may include 110°C for 10 minutes, 110°C for 19 minutes, 110°C for 30 minutes, 130°C for 1 minute, 130°C for 3 minutes, or 130°C for 5 minutes. In some embodiments, the lack of separation can be assessed by measuring the microsphere size. In some embodiments, the composition does not undergo clumping, emulsification, sedimentation, flocculation, phase inversion, aggregation, or combinations thereof after autoclaving, as exemplified but not limited to, under the conditions described. As long as the composition maintains the microsphere size, it has not separated and remains an emulsion. By example, but not limited to, the lack of separation can also be assessed by measuring the change in microsphere size before and after sterilization. As an example, the size of the spheres, whether by number or volume, can be within approximately 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 75%, 100%, or 200% of their original size after sterilization. This isotonic cream can be sterile and can be used as a composition for delivering a therapeutic agent to tissues including tissues of the nose and ears, and any mucosal tissues, such as, but not limited to, ophthalmic, vaginal, rectal, or urethral tissues, as well as nasal, sinus, nasopharyngeal, and ear tissues, or any other mucosal tissues.

[0120] It should be understood that in any of the foregoing embodiments, tension modifiers and emulsifiers can be used as tension agents as long as they alter the tension, and the quantity and type of tension agent, tension modifier, and emulsifier used may be sufficient to produce a composition with the desired tension. Therefore, it should be understood that tension modifiers and emulsifiers can replace tension agents. For example, in some compositions, a tension agent is not required if the tension modifier and / or emulsifier is sufficient to produce the desired tension.

[0121] It should be understood that those skilled in the art can design and / or produce compositions of this disclosure with the desired tension based on any suitable method. As an example, but not limited to, the sodium chloride equivalent method can be used to calculate the expected osmotic pressure of the composition based on its compositional composition.

[0122] It should be understood that, without departing from the scope of this disclosure, the features and aspects of the compositions of this disclosure can be combined in various combinations by those skilled in the art. As examples, but not limited to, autoclaved cream compositions or sterile cream compositions may contain the properties described in the foregoing embodiments and may have the osmotic pressures described or different from them. As examples, but not limited to, the osmotic pressure may be isotonic with the mucosal tissue to which the composition is to be applied.

[0123] Exemplary compositions of this disclosure are provided in Table 2 below.

[0124] Table 2: Exemplary Cream Compositions of this Disclosure

[0125]

[0126]

[0127] Table 3 below provides exemplary ranges for each component in Table 2 above. It should be understood that the exemplary cream compositions in Tables 2 and 3 can also be prepared without clotrimazole.

[0128] Table 3: Exemplary range of components in the exemplary cream compositions of Table 2

[0129] Element %w / w scope Clotrimazole 1.00 0.25–2％ Betamethasone dipropionate 0.0322 0.015–0.322％ Polysorbate 80 5.00 0.1–15％ glycerin 1.75 0.1–15％ Disodium EDTA (Disodium edetate) 0.05 0.005-0.25％ Capop 980 0.60 0.1–1％ Polyethylene glycol 40 stearate 1.00 0.25–10％ cetyl alcohol 1.00 0.25–10％ Glyceryl monostearate 0.50 0.1–5％ Vaseline 8.00 4–30％ Oleol polyether-2 or Span 20 3.00 0.5–10％ benzyl alcohol 0.90 0.5–15％ 1% NaOH Adjust pH to 5-7 Purified water QS 1–99％

[0130] Manufacturing method

[0131] This disclosure also provides methods for manufacturing the compositions of this disclosure. It should be understood that the methods described herein do not preclude other methods for producing the compositions of this disclosure.

[0132] In some embodiments, a method for manufacturing a cream includes the steps of preparing an aqueous dispersion, preparing an oil dispersion, and combining the aqueous and oil dispersions to form an emulsion mixture. In some embodiments, the pH is adjusted during the step of forming the aqueous dispersion. In other embodiments, the pH is adjusted after combining the aqueous and oil dispersions to form the emulsion mixture. By way of example, but not limited to, the pH of the aqueous dispersion or emulsion mixture may be adjusted to about 3.5 and about 8, preferably about 4 and about 7, more preferably about 5 and about 6. As examples, but not limited to, the pH of the aqueous dispersion can be adjusted to about 3.5 to about 8, about 4 to about 7, about 5 to about 7, about 5 to about 6, about 6 to about 7, about 4 to about 6, about 4 to about 5, or about 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8, and any range or value between them. In some embodiments, the pH of the aqueous dispersion can be adjusted by adding the pH adjuster described herein.

[0133] In some embodiments, the aqueous dispersion is prepared by forming an aqueous dispersion, adjusting the pH of the dispersion, adding at least one emulsifier to the aqueous dispersion, heating the aqueous dispersion containing at least one emulsifier, and adding a first portion of at least one pharmaceutically active compound to the aqueous dispersion. As an example, but not limited to, heating may be maintained at about 25-80°C for a sufficient time to form the dispersion. In other embodiments, the aqueous dispersion is prepared by forming an aqueous dispersion and adding a first portion of at least one pharmaceutically active compound to the aqueous dispersion, wherein the pH is not adjusted prior to the addition of the first portion of the at least one pharmaceutically active compound. In some embodiments, the step of forming the aqueous dispersion may further include adding a tensioning agent to the aqueous dispersion. In some embodiments, the step of forming the aqueous dispersion may further include adding a mediator as described herein. In some embodiments, the step of forming the aqueous dispersion may further include adding a stabilizer as described herein. In some embodiments, the step of forming the aqueous dispersion may further include adding a viscosity modifier as described herein.

[0134] Simultaneously, an oil phase dispersion can be prepared to prepare an aqueous dispersion. In some embodiments, the oil phase is prepared by heating the oil phase and adding a second portion of at least one pharmaceutically active compound to the oil phase. As an example, but not limited to, heating can be maintained at about 25-80°C for a sufficient time to form a dispersion. In some embodiments, the oil phase includes an emulsifier as described herein, which may be the same as or different from the emulsifier in the aqueous dispersion, if an emulsifier is added. In some embodiments, at least one emulsifier may be added during the preparation of the oil phase dispersion. In some embodiments, the preparation of the oil phase dispersion may further include adding a moisturizing agent to the oil phase dispersion.

[0135] After generating the aqueous dispersion and the oil phase, the aqueous dispersion and the oil phase are combined to produce an emulsion mixture. Preferably, the oil phase is still hot, for example, above 30°C, when the two phases are combined. After combining the two phases, the emulsion mixture can be cooled. In some embodiments, once the emulsion mixture has been cooled, for example, below 30°C, a tension modifier and / or preservative, as described herein, can be added to the emulsion mixture.

[0136] In some embodiments, if the pH of the aqueous dispersion is not adjusted, the pH of the emulsion mixture may be adjusted. In such embodiments, after the addition of a tension modifier and / or preservative, an emulsifier as described herein may be added to the emulsion mixture and the mixture may be heated. By way of example, but not limited to, heating may be carried out at about 25-80°C for a sufficient time to form a dispersion.

[0137] After the emulsion mixture has been prepared, the composition can be filled into a container and sterilized, for example, but not limited to, by autoclaving. For example, but not limited to, sterilization can be performed by autoclaving at 110°C for 10-30 minutes or at 130°C for 1-5 minutes. For example, but not limited to, the container can be a syringe. For other examples, but not limited to, sterilization can be performed by gamma irradiation, such as 15-25 mGy, or by filtration without separating the cream phase.

[0138] It should be understood that in the foregoing manufacturing embodiments, the amount of components added can yield the composition of this disclosure, and certain components or steps may be omitted or rearranged based on the composition and the knowledge of those skilled in the art.

[0139] It should also be understood that the components of the aqueous and oil dispersions, as well as the final emulsion mixture, may be as described throughout this disclosure. As examples, but not limited to, emulsifiers, emollients, tension agents, tension modifiers, viscosity modifiers, stabilizers, mediators, and pH adjusters may be as described in other parts of this disclosure.

[0140] Exemplary methods for producing compositions of the present disclosure are provided in Figure 1A and 1B It should be understood that these methods can be modified to replace oleyl alcohol polyether-2 with Span 20.

[0141] It should be understood that in any of the foregoing embodiments of the manufacturing method, the heating step may be heating the dispersion or mixture to about 25–80°C. As examples, but not limited to, the heating may be about 25 to about 80°C, about 30 to about 80°C, about 35 to about 80°C, about 40 to about 80°C, about 50 to about 80°C, about 60 to about 80°C, about 70 to about 80°C, about 30 to about 70°C, about 40 to about 70°C, about 50 to about 70°C, about 60 to about 70°C, about 30 to about 60°C, about 40 to about 60°C, about 50 to about 60°C, about 30 to about 50°C, about 40 to about 50°C, about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80°C, or any range or value between these values.

[0142] Device

[0143] This disclosure provides devices for applying compositions to nasal and ear tissues. Such devices can be used to apply compositions, such as the cream compositions of this disclosure, to any tissue of the nose or ear. As examples, but not limited to, the devices can be used to deliver compositions to sinus or nasopharyngeal tissues, such as the frontal lobe, ethmoid bone, maxilla, and sphenoid bone. As further examples, but not limited to, the devices can be used to deliver compositions to ear tissues, such as the auricle, cochlea, ear canal, eustachian tube, external auditory canal, inner ear, middle ear, outer ear, round window, semicircular canals, tympanic membrane, tympanic cavity, external auditory canal tissue, or hair cells.

[0144] In some embodiments, the apparatus of this disclosure may include a conduit having a first end and a second end disposed at opposite ends of the conduit, wherein the conduit has an outer diameter at the first end; a structural support element extending through the conduit from the first end toward the second end for a length at least a portion of the length of the conduit; and an arcuate tip disposed at the second end, the tip tapering towards the end of the second end of the conduit and having a maximum outer diameter near the end of the second end of the conduit, the maximum outer diameter being greater than the outer diameter at the first end of the conduit, and the structural support element having sufficient rigidity to maintain the shape of the conduit but also sufficient flexibility to allow the shape of the conduit to be altered. The arcuate tip, which may be referred to as a "mushroom" tip, may be used to spread the cream composition of this disclosure onto mucosal tissue and navigate the tissue to deliver the cream composition to the appropriate tissue. In some embodiments, the apparatus of this disclosure may include a conduit having a first end and a second end disposed at opposite ends of the conduit, wherein the conduit has an outer diameter at the first end; and an arc-shaped tip disposed at the second end, the tip tapering gradually toward the end of the second end of the conduit and having a maximum outer diameter near the end of the second end of the conduit, the maximum outer diameter being greater than the outer diameter at the first end of the conduit. In such a latter embodiment, the conduit may be rigid and / or incorporate bends.

[0145] In some embodiments, the length of the conduit segment can be from about 0.5 to about 10 inches. As examples, but not limited to, the length of the conduit segment can be about 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 inches, and any range or value between these. In some embodiments, the structural support element can be a wire or other flexible structure. As examples, but not limited to, the structural support element can be a plastic or metal wire. In some embodiments, the structural support element extends through the entire length of the conduit segment. In some embodiments, the structural support element extends through about half the length of the conduit segment. In some embodiments, the device does not include the structural support element and the conduit segment is rigid. In some embodiments, the device does not include the curved tip or structural support element and the conduit segment is rigid. In some embodiments, the rigid design may include bends in the first pipe section. In some embodiments, the rigid design may include a second pipe section attached to the first pipe section, having a smaller diameter than the first pipe section. In this case, the diameter may be as described herein.

[0146] In some embodiments, the device may further include a connector at a first end configured to attach to a syringe. In some embodiments, the device further includes a syringe connected to the device at the first end via the connector. As an example, but not limited to, the connector is a Leur lock connector. In some embodiments, the tubing is made of a flexible material, such as, but not limited to, polyether block amides, such as Pebax 45D, Pebax 55D, or Pebax 63D. In some embodiments, the polyether block amide or other tubing material may be modified with additives to reduce the coefficient of friction of the polyether block amide. As an example, but not limited to, the dry static coefficient of friction of the tubing material against stainless steel, as measured by ASTM D1894, may be less than 0.2. For example, the dry static coefficient of friction of the tubing material against stainless steel, as measured by ASTM D1894, may be less than 0.2, 0.15, 0.1, 0.05, or 0.025, or any value in between. As another example, but not limited to, the dry static coefficient of friction of pipe material against stainless steel, as measured by ASTM D1894, can be between about 0.025 and about 0.2, between about 0.025 and about 0.15, between about 0.025 and about 0.1, between about 0.025 and about 0.05, and any value range therein. In some embodiments, the material may have a flexural modulus between about 100 and about 400 MPa, as measured by ASTM D790 testing. As an example, but not limited to, the flexural modulus of the material, as measured by ASTM D790 testing, can be between about 100 and about 400 MPa, between about 150 and about 300 MPa, between about 150 and about 200 MPa, between about 200 and 300 MPa, about 100, 125, 150, 164, 175, 200, 225, 250, 275, 278, or 300 MPa, and any range or value therein. In some embodiments, the material may have a Shore hardness (Shore D) of about 35 to about 80, as measured by ASTM D2240, under conditions of instantaneous or 15 seconds later. By example, but not limited to, the Shore hardness (Shore D) of the material, as measured by ASTM D2240, may be about 35 to about 80, about 40 to about 80, about 45 to about 75, about 50 to about 70, about 50 to about 60, about 40, 41, 45, 46, 50, 54, 55, 58, 60, 64, 65, 70, 75, or 80, and any range or value between these values, under conditions of instantaneous or 15 seconds later. In some embodiments, the conduit may be made of a rigid material, such as, by example, but not limited to, high-density polyethylene (HDPE). In some embodiments, the tip and the conduit may be made of the same material. In some embodiments, the maximum outer diameter of the tip may be about 4 mm.As examples, but not limited to, the maximum outer diameter of the tip can be about 1.5 mm to about 6 mm, about 2 mm to about 6 mm, about 2 mm to about 4 mm, about 4 mm to about 6 mm, about 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6 mm, and any value or range between them. In some embodiments, the tip has a length of about 1 mm. As examples, but not limited to, the length of the tip can be from about 0.5 mm to about 10 mm, from about 0.5 mm to about 2 mm, from about 0.5 mm to about 1 mm, from about 1 mm to about 2 mm, from about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 mm, and any range or value between them. In some embodiments, the outer diameter of the first end of the pipe segment can be about 2 mm. As examples, but not limited to, the outer diameter of the first end can be approximately 1 mm to approximately 4 mm, approximately 1 mm to approximately 2 mm, approximately 1 mm to approximately 3 mm, approximately 2 mm to approximately 4 mm, approximately 3 mm to approximately 4 mm, approximately 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4 mm, and any value or range therebetween. In some embodiments, the conduit has an inner diameter of approximately 1.4 mm. As examples, but not limited to, the inner diameter of the pipe can be about 1 mm to about 2 mm, about 1 mm to about 1.5 mm, about 1.5 mm to about 2 mm, about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mm, or any value or range therebetween. In some embodiments, the structural support element has a diameter of about 0.5 mm. As examples, but not limited to, the diameter of the structural support element can be about 0.1 mm to about 1 mm, about 0.5 mm to about 1 mm, about 0.1 mm to about 0.5 mm, about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mm, or any value or range therebetween. In some embodiments, the device is sterile.

[0147] It should be understood that in the foregoing embodiments of the device, the section of pipe can have any suitable shape, and if the pipe is non-circular, the diameter can refer to the length or width of the pipe. As an example, but not limited to, the device can have a bend between a first end and a second end, wherein the bend has a curvature of approximately 60° relative to the axis from the first end to the bend. As examples, but not limited to, the bend can be approximately 0° to approximately 90°, approximately 0° to approximately 80°, approximately 0° to approximately 70°, approximately 0° to approximately 60°, approximately 0° to approximately 50°, approximately 0° to approximately 45°, approximately 0° to approximately 40°, approximately 0° to approximately 30°, approximately 0° to approximately 20°, approximately 0° to approximately 10°, approximately 10° to approximately 90°, approximately 10° to approximately 80°, approximately 10° to approximately 70°, approximately 10° to approximately 60°, approximately 10° to approximately 50°, etc. 0°, approximately 10° to approximately 45°, approximately 10° to approximately 40°, approximately 10° to approximately 30°, approximately 10° to approximately 20°, approximately 20° to approximately 90°, approximately 20° to approximately 80°, approximately 20° to approximately 70°, approximately 20° to approximately 60°, approximately 20° to approximately 50°, approximately 20° to approximately 45°, approximately 20° to approximately 40°, approximately 20° to approximately 30°, approximately 30° to approximately 90°, approximately 30° to approximately 80°, approximately 30° to approximately 70° Approximately 30° to approximately 60°, approximately 30° to approximately 50°, approximately 30° to approximately 45°, approximately 30° to approximately 40°, approximately 40° to approximately 90°, approximately 40° to approximately 80°, approximately 40° to approximately 70°, approximately 40° to approximately 60°, approximately 40° to approximately 50°, approximately 40° to approximately 45°, approximately 45° to approximately 90°, approximately 45° to approximately 80°, approximately 45° to approximately 70°, approximately 45° to approximately 60°, approximately 45° to approximately 50°, approximately 50° The range or value is approximately 0° to 90°, approximately 50° to 80°, approximately 50° to 70°, approximately 50° to 60°, approximately 60° to 90°, approximately 60° to 80°, approximately 60° to 70°, approximately 70° to 90°, approximately 70° to 80°, approximately 80° to 90°, approximately 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, or 90°, and any range or value between these values. An exemplary curved applicator is shown below. Figures 14A-14B As shown.

[0148] Exemplary devices and portions thereof are shown in this disclosure. Figure 2-3E In the middle. For example Figure 2 As shown, various embodiments of the device are illustrated, comprising a section of tubing 1 and a connector 2 for attaching a syringe to a first end 3 of the tubing, the connector having an arc-shaped tip not in... Figure 2 As shown in the image. Figures 3A-3CAs shown, the pipe segment 1 may include a pointed tip 5, which has an arcuate shape, disposed at the second end 4 of the pipe segment. The structural support element 6 provides flexibility to the device by supporting the bending shape of the flexible device. It should be understood that the structural support element may be in the form of a wire or other shape, or may run through the entire circumference of the pipe or be in any configuration sufficient to give the device the necessary rigidity while still allowing for flexibility. Figure 3D As shown, the device may also have a connector 2 attached to the first end 3 of the device. The connector allows the syringe 8 or other containers to be connected to the device, such as... Figure 3E As shown.

[0149] like Figures 4A-4D As shown, the device can also form a rigid structure. Figures 4A-4B A rigid applicator device is shown, comprising the aforementioned section of tubing 1, and optionally including a structural support element 6 to provide rigidity if the tubing itself is insufficiently rigid, and may include a tapered tip; however, any opening to the tip may also be used. The device may also include a first end 3 and a second end 4, and a connector 2 for connecting a syringe or other container to the connector (not shown). Figure 4C A hand-drawn diagram of a curved rigid applicator is shown, such as... Figure 4D As shown, it includes a connector 2, which is attached to the section of pipe 1 containing a bend, and is attached to a second section of pipe 7 with a diameter smaller than that of the section of pipe 1 by means of fittings or solder 9.

[0150] Reagent test kit

[0151] This disclosure provides a kit comprising an apparatus for applying a composition of this disclosure and a cream composition of this disclosure. In some embodiments, the apparatus is the apparatus of any of the foregoing embodiments. In some embodiments, the cream composition is the composition of any of the foregoing embodiments. If the apparatus does not already include a syringe or other container for containing the composition, the kit may include a syringe containing the composition in addition to the apparatus.

[0152] In any of the foregoing kit examples, the syringe or other container holding the composition may contain about 0.1 g to about 20 g of the composition. As examples, but not limited to, syringes or other containers containing the composition may contain about 0.1g to about 20g, about 0.5g to about 20g, about 1g to about 20g, about 2g to about 20g, about 5g to about 20g, about 10g to about 20g, about 0.1g to about 5g, about 0.1g to about 2.5g, about 0.1g to about 1g, about 0.1g to about 0.5g, about 0.5g to about 12g, about 0.5g to about 10g, about 0.5g to about 5g, about 0.5g to about 2.5g, about 0.5g to about 1g, about 1g to about 12g, about 1g to about 10g, about 1g to about 5g, about 1g to about 2g, about 2g to about 12g, about 2g to about 10g, about 2g to about 5g, about 2g to about 4g, about 4g to about 12g, about 4g to about 10g, about 4g to about 8g, about 4g to about 5g. Approximately 5g to approximately 12g, approximately 5g to approximately 10g, approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 13, 14, 15, 16, 17, 18, 19, or 20 g, or any range or value between them. As another example, but not limited to, syringes or other containers may contain a total of about 0.01 mg to about 3 g of steroids, in amounts such as 0.17 g, 0.34 g, 0.7 g, 1 g, 1.4 g, 2 g, 2.1 g, 3 g, 4 g, 4.2 g, 5 g, 6 g, 8 g, 10 g, or 20 g as shown in Table 1. As another example, but not limited to, syringes or other containers may contain the following total amounts of steroids: about 0.01 mg to about 3 g, about 0.1 mg to about 3 g, about 0.5 mg to about 3 g, about 1 mg to about 3 mg, about 1.5 mg to about 3 mg, 0.01 mg to about 1.5 g, about 0.01 mg to about 1 g, about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 1 mg, about 0.01 mg to about 0.1 mg, about 0.02 mg to about 1.5 g, about 0.02 mg to about 1 g, about 0.02 mg to about 500 mg, about 0.02 mg to about 250 mg, about 0.0.02 mg to about 100 mg, about 0.02 mg to about 10 mg, about 0.02 mg to about 5 mg, about 0.02 mg to about 1 mg, 0.02 mg to about 0.2 mg, about 0.03 mg to about 1.5 g, about 0.03 mg to about 1 g, about 0.03 mg to about 500 mg, about 0.03 mg to about 250 mg, about 0.03 mg to about 100 mg, about 0.03 mg to about 10 mg, about 0.03 mg to about 5 mg, about 0.03 mg to about 1 mg, about 0.03 mg to about 0.3 mg, about 1 mg to about 1 0.5g, about 1mg to about 1g, about 1mg to about 500mg, about 1mg to about 250mg, about 1mg to about 100mg, about 1mg to about 10mg, about 1mg to about 5mg, about 2mg to about 1.5g, about 2mg to about 1g, about 2mg to about 500mg, about 2mg to about 250mg, about 2mg to about 100mg, about 2mg to about 10mg, about 2mg to about 5mg, about 8mg to about 1.5g, about 8mg to about 1g, about 8mg to about 500mg, about 8mg to about 250mg, about 8mg to about 100mg mg, about 8 mg to about 10 mg, about 10 mg to about 1.5 g, about 10 mg to about 1 g, about 10 mg to about 500 mg, about 10 mg to about 250 mg, about 10 mg to about 100 mg, about 100 mg to about 1.5 g, about 100 mg to about 1 g, about 100 mg to about 500 mg, about 100 mg to about 250 mg, about 250 mg to about 1.5 g, about 250 mg to about 1 g, about 250 mg to about 500 mg, about 500 mg to about 1.5 g, about 500 mg to about 1 g, about 1 g to about 1.5 g, Approximately 0.01mg, 0.02mg, 0.05mg, 0.1mg, 0.125mg, 0.15mg, 0.2mg, 0.25mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2mg, 2.25mg, 2.5mg, 2.75mg, 3mg, 3.25mg, 3.5mg, 3.75mg, 4mg, 4.25mg, 4.5mg, 4.75mg, 5mg, 7.5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85m g, 90mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 220m 240mg, 250mg, 260mg, 280mg, 300mg, 330mg, 350mg, 360mg, 390mg, 400mg, 440mg, 450mg, 480mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1g, 1.1g, 1.2g, 1.3g, 1.4g, °r 1.5g, 1.6g, 1.7g, 1.8g, 1.9g, 2g, 2.1g, 2.2g, 2.3g, 2.4g, 2.5g, 2.6g, 2.7g, 2.8g, 2.9g, or 3g, or any range or value between them. As another example, but not limited to, the syringe or container may contain an antimicrobial agent in the range of about 0.01 mg to about 500 mg. As examples, but not limited to, the syringe or other container may contain a total of about 0.01 mg to about 500 mg, about 0.1 mg to about 500 mg, about 1 mg to about 500 mg, about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 300 mg to about 500 mg, about 400 mg to about 500 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 1 mg, about 0.01 mg to about 0.1 mg, about 0.02 mg to about 100 mg, about 0.02 mg to about 10 mg, about 0.02 mg to about 5 mg, about 0.02 mg... g to about 1 mg, 0.02 mg to about 0.2 mg, about 0.03 mg to about 100 mg, about 0.03 mg to about 10 mg, about 0.03 mg to about 5 mg, about 0.03 mg to about 1 mg, about 0.03 mg to about 0.3 mg, about 1 mg to about 100 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 2 mg to about 100 mg, about 2 mg to about 10 mg, about 2 mg to about 5 mg, about 8 mg to about 100 mg, about 8 mg to about 10 mg, about 10 mg to about 100 mg, about 50 mg to about 200 mg, about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05mg, 0.06mg, 0.07mg, 0.08mg, 0.09mg, 0.1mg, 0.15mg, 0.2mg, 0.25mg, 0.3mg, 0.35mg, 0.4mg, 0.45mg, 0.5mg, 0.6mg, 0.7mg, 0.75mg, 0.8mg, 0 .9mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2mg, 2.25mg, 2.5mg, 2.75mg, 3mg, 3.25mg, 3.5mg, 3.75mg, 4mg, 4.25mg, 4.5mg, 4.75mg, 5mg, 7.5mg, 10mg, 1 5mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, or 500mg, or any range or value between these values.

[0153] Methods of processing or using the apparatus of this disclosure

[0154] In some embodiments, a method for treating diseases or conditions of the nose, sinuses, or nasopharynx may include the step of topically applying the composition of this disclosure to the nose, sinuses, or nasopharynx of a subject. In other embodiments, a method for treating diseases or conditions of the ear may include the step of topically applying the composition of this disclosure to the ear of a subject. In yet another embodiment, a method for treating diseases or conditions of mucosal tissue may include the step of topically applying the composition of this disclosure to the mucosal tissue.

[0155] In any of the foregoing embodiments of the treatment method, the step of applying the composition may be performed as a single application, which in some cases is sufficient to provide effective treatment for diseases or symptoms of the nose, sinuses, or nasopharynx. In some other embodiments, by example but not limited to, the step of applying the cream composition may be performed only once every 10-21 days, every 21-30 days, every 30 to 60 days, every 60 to 90 days, every 90 to 180 days, or every 180 to 365 days. It should be understood that, in most cases, "single application" means sequential bilateral application via intranasal application, external auditory canal, middle ear, eye, or other tissue. In some embodiments, by example but not limited to, the step of applying the cream composition may be performed no more than twice every 21, 30, 60, 90, 180, or 365 days. In some embodiments, the composition may be applied daily or weekly.

[0156] In any of the foregoing embodiments of the treatment methods, the amount of the composition administered may be an effective amount. In methods for treating mucosal tissue, the composition may contain a therapeutically active ingredient suitable for treating diseases or conditions of the mucosal tissue. By way of example, but not limited to, glaucoma medications may be administered to the eye using the compositions of this disclosure. In some embodiments, the mucosal tissue may be the nose, sinuses, nasopharynx, ear, eye, vagina, rectum, or urethra. It should be understood that, by way of example, but not limited to, inflammation may be treated in these tissues using the compositions of this disclosure.

[0157] When the tissue to be treated is the eye, as examples, but not limited to, the tissues of the eye may include the anterior margin of the eyelid, medullary conjunctiva, lacrimal sarcoma, ciliary body and muscle, conjunctiva, cornea, eyebrow, eyelid, iris, posterior canthus, lateral palpebral commissure, lens, lower eyelid, macula, medial canthus, optic nerve, posterior margin of the eyelid, pupil, retina, sclera, upper palpebral sulcus, retinal vessels, upper eyelid, or vitreous body. When the disease or symptom is a disease or symptom of the eye, as examples, but not limited to, it includes glaucoma, diabetic retinopathy, macular degeneration, uveitis, retinopathy, retinoblastoma, dry eye syndrome, eye diseases, lacrimal system, orbit, conjunctiva, sclera, cornea, iris, ciliary body, lens, choroid, retina, choroidoretinitis, retinal detachment and rupture, retinal vascular occlusion, and general retinal diseases.

[0158] In any of the foregoing embodiments of the treatment method, the amount of cream composition applied will vary based on the size of the affected tissue area and the extent of the patient's size. In some embodiments, the amount of composition applied may be from about 0.5 cubic centimeters (cc) to about 15 cc per intranasal application, or from about 1 cc to about 10 cc of the total amount applied to the affected tissue of the sinus mucosa, but more commonly it is from about 2 cc to about 4 cc per intranasal application, or from about 4 cc to about 8 cc of the total amount applied to the affected tissue of the sinus mucosa. As examples, but not limited to, the amount of composition applied intranasally or intraocularly each time may 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, 5 cc, 6 cc, 7 cc, 8 cc, 9 cc, 10 cc, 11 cc, 12 cc, 13 cc, 14 cc, or 15 cc. It should be understood that for total bilateral application to diseased sinus mucosa, these amounts are doubled unless otherwise specified.

[0159] In other embodiments, when the composition is applied to the nasal, sinus, or nasopharyngeal tissue, the amount of composition applied may be from about 0.5 g to about 10 g per intranasal application, or from about 1 g to about 20 g of total application to the diseased tissue (bilaterally), but more commonly from about 2 g to about 4 g per intranasal application, or from about 4 g to about 8 g of total application to the diseased tissue. As examples, but not limited to, the amount of composition applied may 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, 5 g, 6 g, 7 g, 8 g, 9 g, or 10 g per intranasal application. It should be understood that, unless otherwise stated, these amounts are doubled for total bilateral application to the diseased sinus mucosa.

[0160] Therefore, in some embodiments, the amount of steroids administered to each nasal, sinus, or nasopharyngeal tissue may be from about 0.01 mg to about 1.5 g of steroids in total. As examples, but not limited to, the amounts in Table 1 may be multiplied by 0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, or 10 g. As another example, but not limited to, the amount of steroids administered to each tissue may be approximately 0.01 mg to approximately 1.5 g, approximately 0.01 mg to approximately 750 mg, approximately 0.01 mg to approximately 500 mg, approximately 0.01 mg to approximately 250 mg, approximately 0.01 mg to approximately 100 mg, approximately 0.01 mg to approximately 10 mg, approximately 0.01 mg to approximately 5 mg, approximately 0.01 mg to approximately 1 mg, approximately 0.01 mg to approximately 0.1 mg, approximately 0.02 mg to approximately 1.5 g, approximately 0.02 mg to approximately 750 mg, approximately 0.02 mg to approximately 1 g, approximately 0.02 mg to approximately 500 mg, approximately 0.02 mg to approximately 250mg, about 0.02mg to about 100mg, about 0.02mg to about 10mg, about 0.02mg to about 5mg, about 0.02mg to about 1mg, 0.02mg to about 0.2mg, about 0.03mg to about 1.5g, about 0.03mg to about 750mg, about 0.03mg to about 500mg, about 0.03mg to about 250mg, about 0.03mg to about 100mg, about 0.03mg to about 10mg, about 0.03mg to about 5mg, about 0.03mg to about 1mg, about 0.03mg to about 0.3mg, about 1mg to about 1.5g, about 1mg to about 750mg. 0 mg, about 1 mg to about 500 mg, about 1 mg to about 250 mg, about 1 mg to about 100 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 2 mg to about 1.5 g, about 2 mg to about 750 mg, about 2 mg to about 500 mg, about 2 mg to about 250 mg, about 2 mg to about 100 mg, about 2 mg to about 10 mg, about 2 mg to about 5 mg, about 8 mg to about 1.5 g, about 8 mg to about 750 mg, about 8 mg to about 500 mg, about 8 mg to about 250 mg, about 8 mg to about 100 mg, about 8 mg to about 10 mg, about 10 mg to about 1.5 g, About 10 mg to about 750 mg, about 10 mg to about 500 mg, about 10 mg to about 250 mg, about 10 mg to about 100 mg, about 100 mg to about 1.5 g, about 100 mg to about 750 mg, about 100 mg to about 500 mg, about 100 mg to about 250 mg, about 250 mg to about 1.5 g, about 250 mg to about 750 mg, about 250 mg to about 500 mg, about 500 mg to about 750 mg, about 500 mg to about 1.5 g, about 1 g to about 1.5 g, about 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5mg, 2.75mg, 3mg, 3.25mg, 3.5mg, 3.75mg, 4mg, 4.25mg, 4.5mg, 4.75mg, 5mg, 7.5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40m g, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170 The dosage may be 1 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 330 mg, 350 mg, 360 mg, 390 mg, 400 mg, 440 mg, 450 mg, 480 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, or 1.5 g, or any range or value between these values. It should be understood that in such embodiments, these amounts will be doubled when applying a bilateral application.

[0161] Therefore, in some embodiments, the total amount of antimicrobial active agent applied to each nasal, sinus, or nasopharyngeal tissue may be from about 0.01 mg to about 200 mg of antimicrobial active agent. As examples, but not limited to, the amount of antimicrobial active agent delivered may be from about 0.01 mg to about 200 mg, from about 0.01 mg to about 100 mg, from about 0.01 mg to about 10 mg, from about 0.01 mg to about 5 mg, from about 0.01 mg to about 1 mg, from about 0.01 mg to about 0.1 mg, from about 0.02 mg to about 200 mg, from about 0.02 mg to about 100 mg, from about 0.02 mg to about 10 mg, from about 0.02 mg to about 5 mg, from about 0.02 mg to about 1 mg, from about 0.02 mg to about 0.2 mg, from about 0.03 mg to about 200 mg, from about 0.03 mg to about 10 mg. 0 mg, about 0.03 mg to about 10 mg, about 0.03 mg to about 5 mg, about 0.03 mg to about 1 mg, about 0.03 mg to about 0.3 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 2 mg to about 200 mg, about 2 mg to about 100 mg, about 2 mg to about 10 mg, about 2 mg to about 5 mg, about 8 mg to about 200 mg, about 8 mg to about 100 mg, about 8 mg to about 10 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 50 mg to about 2 ... mg to about 100 mg, about 100 mg to about 200 mg, about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg, or any range or value between these values. It should be understood that in such embodiments, when using bilateral application, these amounts will be doubled.

[0162] In other embodiments, when the composition is applied to ear tissue, the amount of composition applied may be from about 0.1 g to about 3 g per ear. By way of example, but not limited to, the amount of the composition applied may be from about 0.1g to about 2.1g, from about 0.17g to about 2.1g, from about 0.1g to about 1g, from about 1g to about 2.5g, from about 1g to about 2g, from about 0.1g, 0.17g, 0.2g, 0.3g, 0.4g, 0.5g, 0.6g, 0.7g, 0.8g, 0.9g, 1g, 1.1g, 1.2g, 1.3g, 1.4g, 1.5g, 1.6g, 1.7g, 1.8g, 1.9g, 2g, 2.1g, 2.2g, 2.3g, 2.4g, 2.5g, 2.6g, 2.7g, 2.8g, 2.9g, or 3g, or any range or value between thereof, preferably about 0.7g. It should be understood that, unless otherwise stated, the total bilateral application to diseased ear tissue is in double the amount described. In some embodiments, the total amount of steroid delivered to the ear tissue is between about 0.01 mg and about 500 mg. As examples, but not limited to, the total amount of steroids delivered to the ear tissue may be from about 0.01 mg to about 500 mg, from about 0.01 mg to about 250 mg, from about 0.01 mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 0.01 mg to about 10 mg, from about 0.01 mg to about 5 mg, from about 0.01 mg to about 1 mg, from about 0.1 mg to about 500 mg, from about 0.1 mg to about 250 mg, from about 0.1 mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 0.1 mg to about 10 mg, from about 0.1 mg to about 5 mg, from about 0.1 mg to about 1 mg, from about 0.5 mg to about 500 mg, from about 0.5 mg to about 250 mg, from about 0.5 mg to about 100 mg, from about 0.5 mg to about 50 mg, from about 0.5 mg to about 10 mg, from about 0.5 mg to about 5 mg, from about 0.5 mg to 1 mg, from about 1 mg to about 500 mg About 1 mg to 250 mg, about 1 mg to 100 mg, about 1 mg to about 50 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 5 mg to about 500 mg, about 5 mg to about 250 mg, about 5 mg to about 100 mg, about 5 mg to about 50 mg, about 5 mg to about 10 mg, about 10 mg to about 500 mg, about 10 mg to about 250 mg, about 10 mg to about 100 mg, about 10 mg to Approximately 50 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 250 mg, approximately 50 mg to approximately 100 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 250 mg, approximately 250 mg to approximately 500 mg, approximately 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15mg, 0.2mg, 0.25mg, 0.3mg, 0.35mg, 0.4mg, 0.45mg, 0.5mg, 0.6mg, 0.7mg, 0.75mg, 0.8mg, 0.9mg, 1mg, 1.25mg, 1 .5mg, 1.75mg, 2mg, 2.25mg, 2.5mg, 2.75mg, 3mg, 3.25mg, 3.5mg, 3.75mg, 4mg, 4.25mg, 4.5mg, 4.75mg, 5mg, 5.5mg Dosage amounts are 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg, or any value or range in between. It should be understood that these amounts are for each ear, and for bilateral administration, the dosage will be doubled.

[0163] In some embodiments, the total amount of the antimicrobial agent delivered to the ear tissue is between about 0.01 mg and about 100 mg. As examples, but not limited to, the total amount of the antimicrobial agent delivered to the ear tissue may be about 0.01 mg to about 100 mg, 0.01 mg to about 50 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 1 mg, about 0.1 mg to about 100 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5 mg, about 0.1 mg to about 1 mg, about 0.5 mg to about 100 mg, about 0... 0.5 mg to about 50 mg, about 0.5 mg to about 10 mg, about 0.5 mg to about 5 mg, about 0.5 mg to 1 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 5 mg to about 100 mg, about 5 mg to about 50 mg, about 5 mg to about 10 mg, about 10 mg to about 100 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 0.01 mg, 0.02 mg, 0.03 mg mg, 0.04mg, 0.05mg, 0.06mg, 0.07mg, 0.08mg, 0.09mg, 0.1mg, 0.15mg, 0.2mg, 0.25mg, 0.3mg, 0.35mg, 0.4mg, 0.45mg, 0.5mg, 0.6mg, 0.7mg, 0.75mg, 0.8mg, 0.9mg, 1mg, 1.25mg, 1.5mg, 1.75mg, 2mg, 2.25mg, 2.5mg, 2.75mg Dosage amounts of 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg, or any value or range in between. It should be understood that these amounts are for each ear and, for bilateral administration, will be doubled.

[0164] It should also be understood that these amounts can be adjusted according to the mucosal tissue to be treated. As examples, but not limited to, in the case of tissue to be treated, the total amount of composition applied can be from about 0.01 g to about 10 g. As examples, but not limited to, the amount applied to the tissue can be from about 0.01 g to about 0.1 g, from about 0.02 g to about 0.1 g, from about 0.03 g to about 0.1 g, from about 0.04 g to about 0.1 g, from about 0.05 g to about 0.1 g, from about 0.1 g to about 1 g, from about 0.1 g to about 2 g, from about 1 g to about 5 g, from about 1 g to about 10 g, from about 2 g to about 5 g, from about 2 g to about 10 g, from about 5 g to about 10 g, from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0. 0.7, 0.08, 0.09, 0.1, 0.015, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10g, or any range or value between them.

[0165] In any of the foregoing embodiments of the treatment method, the disease or symptom may be the result of Gram-negative bacteria, Gram-positive bacteria, fungi, yeasts, or a combination of multiple microorganisms including bacteria, fungi, and / or yeasts. In other embodiments, the disease or symptom may be the result of inflammation without a defined microbial infection.

[0166] In any of the foregoing embodiments of the treatment methods, where the disease or symptom is a disease or symptom of the nose, sinuses, or nasopharyngeal tissue, the compositions disclosed herein can be used to treat various conditions of the nose, sinuses, and nasopharyngeal tissue. In any of the foregoing embodiments, the disease or symptom can be inflammation of the nose, sinuses, or nasopharyngeal tissue. By way of example, but not limited to, such conditions of the nose, sinuses, and nasopharyngeal tissue can include diseases, infections, symptoms, and combinations thereof. By way of example, but not limited to, such diseases or infections can include sinusitis, edema, chronic sinusitis, acute sinusitis, mucormycosis, multimicrobial sinusitis, nasal polyps, bacterial sinusitis, allergic fungal sinusitis, chronic bacterial sinusitis, chronic allergic fungal sinusitis, rhinosinusitis, etc. As other examples, but not limited to, such diseases or infections may include sinus edema, acute sinusitis, acute sinus infection, acute bacterial sinus infection, acute viral sinus infection, acute rhinosinusitis, allergic fungal sinusitis, anosmia, bacterial sinusitis, barotrauma, chronic polyposis, chronic bacterial sinusitis, chronic allergic fungal sinusitis, chronic sinusitis, chronic recurrent sinusitis, chronic recurrent sinus infection, chronic recurrent bacterial sinus infection, chronic recurrent viral sinus infection, chronic rhinosinusitis, and chronic rhinosinusitis. With polyps, chronic rhinosinusitis without polyps, chronic recurrent rhinosinusitis, central osteomuscular atopic disease, cystic fibrosis, diffuse sinusitis, diffuse type 2 sinusitis, eosinophilic rhinosinusitis, fungal sinusitis, granulomatous polyangiitis, maxillary sinus infection, mucormycosis, nasal polyps, non-eosinophilic rhinosinusitis, non-eosinophilic chronic rhinosinusitis, paranasal sinus retention cysts, multimicrobial sinusitis, recurrent rhinosinusitis, recurrent acute rhinosinusitis, rhinosinusitis, sinusitis, sinus polyps, and sphenoid sinus infection. As another example, but not limited to, the methods disclosed herein can be used to treat the following sinus symptoms: need to blow the nose, nasal congestion, sneezing, runny nose, cough, postnasal discharge, thick nasal discharge, ear fullness, dizziness, ear pain, facial pain or pressure, decreased sense of smell or taste, difficulty falling asleep, waking up at night, insufficient sleep, waking up tired, fatigue, decreased productivity, poor concentration, depression, irritability or restlessness, sadness, embarrassment, or combinations thereof. In some embodiments, the symptoms further include need to blow the nose, nasal congestion, sneezing, runny nose, cough, postnasal discharge, thick nasal discharge, ear fullness, dizziness, ear pain, facial pain or pressure, decreased sense of smell or taste, difficulty falling asleep, waking up at night, insufficient sleep, waking up tired, fatigue, decreased productivity, poor concentration, depression, irritability or restlessness, sadness, embarrassment, or combinations thereof. Therefore, these sinus symptoms can occur alongside diseases, infections, or other conditions, or they can be conditions that require self-treatment. In some embodiments, the subject has previously undergone functional endoscopic sinus surgery (FESS).In some embodiments, the subject developed a chronic inflammatory response after experiencing FESS. In some embodiments, the subject experienced FESS and developed chronic allergic fungal sinusitis. In some embodiments, the subject to whom this composition and method are useful has chronic allergic fungal sinusitis following FESS. In some embodiments, with or without the use of nasal steroid sprays, oral antibiotics, and / or nasal irrigation, the patient's symptoms worsened after a period of mild or asymptomatic symptoms following FESS. In some embodiments, the subject has undergone FESS resulting in abnormal nasal tissue, described as hypertrophic, inflammatory, and granulomatous tissue. In other aspects of these embodiments, the subject's post-FESS sinusitis was treated for one year with nasal steroid sprays, oral antibiotics, and / or nasal irrigation, with little change in disease status prior to the implementation of this method. In some embodiments, the subject has chronic sinusitis due to bacterial infection. In some embodiments, the method of this disclosure can be performed during FESS. In some embodiments, the patient has not previously received FESS. In some embodiments, the method of this disclosure can be performed during balloon sinus dilation. In some embodiments, the composition of this disclosure can be administered during FESS. In some embodiments, the composition of this disclosure can be administered during balloon sinus dilation. Even in cases where chronic inflammation results from a bacterial infection, cream compositions including clotrimazole may be useful because this active agent has been shown to have antibacterial activity in addition to its antifungal activity against Gram-positive and Gram-negative microorganisms. Specifically, clotrimazole has been shown to reduce *Pseudomonas aeruginosa* and has antibacterial activity against *Streptococcus*, *Staphylococcus*, *Gardnerella vaginalis*, and *Corynebacteria*. However, other antibiotic active agents may replace the cream compositions of this disclosure, as discussed in further 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. Therefore, the compositions and methods of this disclosure may be useful in cases where a detectable microbial infection is absent or present. In some embodiments, the symptoms may comprise a bacterial infection. In some embodiments, the symptoms are at least partially a result of a bacterial infection and a biofilm has formed on the surface of the sinus or nasopharyngeal tissue. In some embodiments, the symptoms may include a fungal infection. In some embodiments, the symptoms may include a yeast infection. In some embodiments, the symptoms may include a combination of microbial infections.In any of the foregoing embodiments of the treatment method, where the disease or symptom is a disease or symptom of the nose, sinuses, or nasopharyngeal tissue, the composition may be applied to the maxillary sinus, frontal sinus, ethmoid sinus, sphenoid sinus, maxillary mucosa, frontal mucosa, ethmoid mucosa, sphenoid mucosa, turbinate, nasal passage, nasolacrimal duct, nasal cavity, and nasal tissue.

[0167] In any of the foregoing embodiments of the treatment method, where the disease or symptom is a disease or symptom of the ear tissue, the compositions of this disclosure can be used to treat a variety of ear tissue symptom. By example, but not limited to, such ear tissue symptom can include diseases, infections, symptoms, and combinations thereof. By example, but not limited to, such diseases or infections can include otitis externa, such as, by example, but not limited to, acute diffuse bacterial otitis externa (swimmer's ear), acute localized otitis externa (furuncle), otitis externa pustulosis, erysipelas, chondritis, chronic otitis externa, otomycosis, malignant otitis externa, herpes, tubular otorrhea, bile duct disease, and perforated otitis media. As further examples, but not limited to, such diseases or infections may include acute otitis media, acute localized otitis externa (furuncle), acute mastoiditis, acoustic neuroma, auditory processing disorder, autoimmune inner ear disease, benign paroxysmal positional vertigo, barotrauma, cholesteatoma, chronic otitis externa, chronic otitis media, chronic otitis media with effusion, dizziness, erysipelas, herpes zoster otitis media, hearing loss, infectious tympanitis, inner ear infection, inner ear-related vertigo, labyrinthitis, malignant otitis externa, Meniere's disease, middle ear infection, otitis media, effusion otitis media, perforated otitis media, otitis externa, otomycosis, external ear infection, tympanic membrane perforation, perchocartilaginitis, recurrent vestibular disease, serous otitis media, superior semicircular canal dehiscence syndrome, tinnitus, tubular otorrhea, vertigo, vestibular disease, vestibular neuritis, and viral labyrinthitis. It should be understood that other ear conditions can be treated with the compositions of the present invention. In any of the foregoing embodiments, the ear tissue may be the auricle, cochlea, ear canal, eustachian tube, external auditory canal, inner ear, middle ear, outer ear, round window, semicircular canals, tympanic membrane, tympanic cavity, metallic tissue, or hair cells.

[0168] In any of the foregoing embodiments of the treatment method, the composition may be administered in an effective amount. In any of the foregoing embodiments of the treatment method, the composition of this disclosure may be applied to tissue using the apparatus of this disclosure. By way of example, but not limitation, a syringe containing the composition of this disclosure may be attached to the apparatus of this disclosure via a connector, and the tip of the apparatus may be inserted into the nose or ear to apply the composition to the target tissue. It should be understood that the step of applying the cream composition may be performed using other suitable apparatus that allows the composition to be applied to the target tissue. In some embodiments, the apparatus may be endoscopically guided.

[0169] In some embodiments, a method of treating a disease or symptom of the nose, sinuses, nasopharynx, or ear may include administering a composition to the tissue using the apparatus of this disclosure, wherein the composition is suitable for treating the disease or symptom. In such embodiments, the composition is not necessarily limited to the compositions of this disclosure. In such embodiments, the composition may be administered in an effective amount. It should be understood that such compositions can be administered using the apparatus of this disclosure as long as they are suitable for treating diseases and symptom of these tissues.

[0170] Pharmaceutical compositions and methods of application thereof will now be described with reference to the following non-limiting examples.

[0171] Example

[0172] The following examples are provided for illustrative and exemplary purposes and are not intended to otherwise limit the scope of this disclosure.

[0173] Example 1: Manufacturing and Physical Stability Testing of Cream Formulations

[0174] The cream formulations provided in Table 4 below are all prepared in accordance with... Figure 1A The method outlined in the text is used for preparation.

[0175] Table 4: Cream Ingredients (Amounts provided as a percentage by weight)

[0176]

[0177] In short, for a 250g batch size, to generate an aqueous phase, place approximately 125-150g of water in a 400mL beaker with a 4-bladed propeller, filling it to about half its capacity. In the case of 2019-10-8, add glycerol and mix at 200-300 rpm to dissolve it. Lower the mixing propeller and increase the speed to approximately 800 rpm for 1 minute. Then turn off the mixer and add Carboplatin by sprinkling a layer on top of the solution and then pulse 2-5 times to wet and disperse the Carboplatin. Repeat this process until all Carboplatin has been added. Then mix the mixture at 800-1000 rpm for 30 minutes, rotating the beaker every 5-10 minutes. If pH adjustment is required, add a dilute sodium hydroxide solution (approximately 1%) while mixing at 1000 rpm (pH 4, ~0g; pH 5, ~20-25g; pH 6, ~35-40g; pH 7, ~45-55g). Then mix the QS mixture with water for about 30 minutes. At 200-300 rpm, add polysorbate 80 and mix for about 45 minutes, raising and lowering the beaker every 5-10 minutes to avoid foaming.

[0178] To prepare the oil phase, all remaining components not used for preparing the aqueous phase, except for clotrimazole, betamethasone dipropionate, and benzyl alcohol, were added to a 250 mL beaker equipped with a stir bar in order from liquid to most solid. The mixture was heated on a hot plate to 65 ± 5 °C and mixed for approximately 15 minutes, until most of the solids had melted (settings: 80 °C; 100–350 rpm). At a setting of 75 °C, the stirring speed was reduced to 50–100 rpm for approximately 10 minutes, until the mixture was homogeneous.

[0179] Add the disc impeller blades to the aqueous phase container and mix at the lowest possible rate for approximately 5 minutes. Then heat the aqueous phase to 62 ± 3°C, mixing at the highest possible rate (approximately 1200 ml / min) without causing foaming. + Heat at rpm for approximately 30 minutes. Add the antibacterial agent – ​​clotrimazole – and the steroid – betamethasone dipropionate to the aqueous and oil phases, respectively. Add approximately half of the clotrimazole and betamethasone dipropionate to the aqueous phase (with mixing turned off) and the oil phase, respectively. Then mix each phase for another 10-15 minutes.

[0180] Adjust the blade in the 400 mL beaker to halfway above the liquid level and increase the mixing speed to approximately 1800 rpm to apply high shear force. Add the oil phase to the aqueous phase while the oil phase is still hot. Continue stirring for approximately 45 minutes, raising and lowering the mixing blade every 5–10 minutes. Add benzyl alcohol under high shear force at approximately 1800 rpm. Mix the mixture at approximately 1200 rpm for approximately 30 minutes, raising and lowering the mixing blade every 5–10 minutes. Add water to account for evaporation and mix the mixture for approximately 10 minutes.

[0181] The resulting cream was packaged into a syringe and then capped.

[0182] After packaging the obtained cream, autoclave it at 110°C for 10 minutes or at 130°C for 3 minutes.

[0183] The physical stability of the autoclaved cream was assessed by visual inspection. A photograph of the autoclaved cream is shown below. Figures 5A-5E As shown in the figure, composition 2019-10-8 failed to maintain physical stability and separated into two phases under both autoclaving conditions. Composition 2019-10-3 indeed maintained physical stability and did not separate into two phases under either autoclaving condition. As described in Example 3, the absence of two distinct phases was confirmed by the sphere size measurement results. Composition 2019-10-4 also maintained physical stability and did not separate into two phases under either autoclaving condition. As described in Example 3, the absence of two distinct phases was also confirmed by the sphere size measurement results. 2020-01-C partially separated ( Figures 5A-5E (Not shown in the image).

[0184] Example 2: Evaluating the tension in compositions containing glycerol

[0185] Compositions 2019-11-1, 2019-11-2, 2019-11-3 and 2019-11-4 were prepared as described above. Formulations of these compositions are shown in Table 5 below.

[0186] Table 5: Cream Ingredients (Amounts provided as a percentage by weight)

[0187]

[0188]

[0189] The osmotic pressure of each composition was measured using a Precision Systems Microosmette Model 5004 or equivalent. The microosmometer was calibrated according to the manufacturer's instructions. Cream composition samples were prepared by weighing approximately 1 g of cream into 3 or 15 mL conical tubes, followed by 3 g, 5 g, or 10 g of Milli-Q water into each tube. The samples were vortexed at 2000 rpm for at least 30 seconds and centrifuged at 1800 G for 45 minutes. The osmotic pressure of the samples was measured according to the manufacturer's instructions. To calculate the osmotic pressure, the average osmotic pressure measurements (y-axis) were plotted against the weight fraction of cream (amount of cream per sample per total weight) (x-axis), and the resulting slope (if linear) was determined as the osmotic pressure of the undiluted cream. Figure 6 As shown, the osmotic pressure of the composition changes linearly with the glycerol content. Therefore, the glycerol content can be used to adjust the tension of the formulation.

[0190] Example 3: Determination of microsphere size and particle size of the composition

[0191] In cream formulations, such as when the cream is an oil-in-water emulsion, the active ingredients – clotrimazole and betamethasone dipropionate – may not be completely dissolved, and some particles of these ingredients are “suspended” within the cream matrix. Furthermore, oil droplets dispersed in the aqueous phase are referred to as “spheres.”

[0192] The size and distribution of suspended particles and microspheres can be measured using a static microscopic image analyzer (Malvernmorphologi G3S). The size distribution is determined, and "Dn10, Dn50, and Dn90" represent the sizes of 10%, 50%, and 90% of the particles within the distribution that are smaller than the numerical value. Therefore, Dn50 = 2 μm means that 50% of the particles are smaller than 2 μm on a numerical basis.

[0193] Similarly, "Dv10, Dv50, and Dv90" represent the sizes of 10%, 50%, and 90% of the particles within the distribution that are smaller than their volumetric dimensions. Therefore, Dv50 = 2 μm means that 50% of the particles are smaller than 2 μm on a volumetric basis.

[0194] The quantity mean and volume mean dimensions are also reported. Particle shape is determined, and aspect ratio and roundness are reported.

[0195] Creams are thermodynamically unstable due to a significant increase in surface energy resulting from a combination of interfacial tension, the large surface area of ​​the dispersed phase, and the density difference between the two phases. Internal phase droplets can coalesce, and surface free energy decreases significantly. Therefore, creams tend to separate – the less dense phase rises, and the more dense phase sinks. When exposed to heat, uniformly distributed droplets begin to coalesce and eventually aggregate into large spheres, and the cream becomes unstable, often undergoing phase separation. Therefore, measurements of sphere size are indicators of stability. Maintaining the sphere size after exposure to heat and other stress conditions (such as autoclaving) indicates that the cream is stable.

[0196] Table 6 provides compositions (2020-01C refers to the “control” formulation) prepared by the method described in Example 1 for evaluating particle size distribution and particle size distribution.

[0197] Table 6: Cream Ingredients (Amounts provided as a percentage by weight)

[0198]

[0199] Table 7 below provides the microsphere size distribution (reported in micrometers, μm) of the formulations in Table 6 before (“as is”) and after autoclaving. Surprisingly, the compositions of the present invention did not separate and maintained the microsphere size.

[0200] Table 7: Size distribution of microspheres (reported in micrometers, μm)

[0201]

[0202]

[0203] The growth of suspended particles, or "Ostwald ripening," is also an unstable process caused by temperature fluctuations during storage. If the drug's solubility is temperature-dependent, temperature fluctuations can alter the particle size distribution. For example, if the temperature rises, undissolved drug crystals may dissolve and form a supersaturated solution, which favors crystal growth upon cooling. When the dissolved drug crystallizes from the solution, it will preferentially occur on the crystal surface in the suspension.

[0204] Table 8 provides the particle size distribution (reported in micrometers, μm) of the formulations in Table 6 before (“as is”) and after autoclaving. Surprisingly, the compositions of the present invention retain their particle size and no particle size increase was observed.

[0205] Table 8: Particle size distribution (reported in micrometers, μm)

[0206]

[0207]

[0208] For comparative purposes, Tables 9 and 10 provide the sphere size and particle size distributions (in micrometers and μm, respectively) for two unautoclaved commercial products.

[0209] Table 9: Size distribution of microspheres (reported in micrometers, μm)

[0210]

[0211] Table 10: Particle size distribution (reported in micrometers, μm)

[0212]

[0213]

[0214] Example 4: Chemical stability during sterilization

[0215] Representative batches, as described in the previous example, were packaged in four different configurations and sterilized by autoclaving or gamma irradiation (15 kGy dose). Sample specifications and autoclaving conditions are shown in the table below. The cream was packaged in Becton Dickenson syringes (rubber plungers), NormJect syringes (polyethylene plungers), or scintillation vials (glass) for investigation. A series of samples were packaged in scintillation vials with five rubber stoppers to ensure close contact between the cream and the rubber. These different packaging configurations were selected to investigate the effect of the rubber plunger and syringe materials on the chemical stability of the cream.

[0216] Chemical degradation products of clotrimazole and betamethasone in the samples will be analyzed using HPLC before and after the sterilization process. A prednisone internal standard (IS) stock solution will be prepared by adding approximately 25 mg of prednisone to a 25 mL volumetric flask containing approximately 2 / 3 ethanol, followed by sonication, and then thoroughly filling the flask with ethanol to produce a 1000 μg / mL stock solution. The stock solution will be diluted by transferring 4 mL of the stock solution to a 100 mL volumetric flask and diluting to the volume with ethanol to produce an internal standard solution. A betamethasone dipropionate stock solution will be prepared similarly, using approximately 33.4 mg of betamethasone dipropionate in a 25 mL volumetric flask.

[0217] A working standard solution was prepared by combining 1 mL of internal standard solution and 4 mL of betamethasone dipropionate stock solution in a 50 mL volumetric flask. Approximately 167 mg of clotrimazole and approximately 150 mg of benzyl alcohol were added to the flask, which was then filled to approximately 2 / 3 capacity with ethanol. The flask was then filled to the final volume with ethanol and thoroughly mixed.

[0218] The test standard was prepared by mixing approximately 33.4 mg of clotrimazole into a 10 mL volumetric flask filled with about 2 / 3 methanol, then adding enough methanol to fill the flask, and then mixing thoroughly.

[0219] To prepare an RCA stock solution, approximately 21 g of clotrimazole-related compound A (RCA) was weighed and placed in a 25 mL volumetric flask filled about 2 / 3 full with methanol. The mixture was then stirred and the flask was filled to the desired volume. Curve solutions were prepared by adding 8 mL, 5 mL, 4 mL, 5 mL, and 1 mL of RCA stock solution to 25 mL, 25 mL, 25 mL, 50 mL, and 25 mL volumetric flasks, respectively, and then adding methanol to the desired volume. Before adding methanol, 1 mL of IS stock solution was added to 5 mL of the stock solution and placed in a 50 mL flask. The dilution scheme is shown in Table 11 below.

[0220] Table 11: RCA solution preparation

[0221]

[0222] The standard curves for RCA and other standards will be created using an HPLC program and used to correlate peak area with concentration.

[0223] The cream composition for HPLC was prepared by weighing 2 g (+ / - 0.2 g) of the cream into a 50 mL centrifuge tube. 3 mL of ethanol and 3 mL of internal standard solution were added to each tube. The tube was then vortexed for approximately 30 seconds to disperse the contents. The sample was then placed in a 70°C oven for 15 minutes to dissolve the cream. The sample was then immediately vortexed for at least 30 seconds. The tube was then placed on a room temperature shaker at 400 rpm for 20 minutes. After shaking, the tube was centrifuged at 3000 G and 4°C for 30 minutes. The supernatant was then collected and transferred to a 3 mL syringe, and filtered if necessary for HPLC analysis. This process was also performed for corresponding batches of cream without active ingredients to exclude degradation peaks from inactive ingredients.

[0224] HPLC will be performed with a run time of 45 minutes, using a flow rate of 0.5 mL / min and the mobile phases being: A. ammonium phosphate buffer, pH 7.0 ± 0.1; B. methanol; and C. acetonitrile, using the gradients shown in Table 12.

[0225] Table 12: HPLC gradient

[0226] Time (minutes) ％A B％ C％ 0.0 63 25 12 1.8 43 45 12 10.8 28 60 12 22 28 60 12 23.3 30 5 65 38.5 30 5 65 38.6 63 25 12 45.0 63 25 12

[0227] The injection volume will be 3 μL, the sample temperature will be ambient temperature, the detector wavelength will be 254 nm (data will be collected only at 270 nm for information), the column temperature will be 35 °C, the chromatographic column will be a Thermo Hypersil ODS column (150 x 3 mm, 3 μm), and the guard column will be a Thermo ODS guard column (30 x 3 mm, 3 μm) or equivalent.

[0228] The percentage area is calculated by subtracting the area of ​​the analyte peak from the chromatogram, subtracting the total area of ​​the analyte from the chromatogram, and subtracting the relevant degradation peaks from the chromatogram.

[0229] Example 5: pH, viscosity and osmotic pressure tests

[0230] The pH of several commercial formulations was measured using standard methods, and the results are provided in Table 13 below.

[0231] Table 13: pH of Commercial Formulations

[0232]

[0233] The pH of the cream composition disclosed herein was determined on a virgin cream sample after centrifugation at 1000g (about 2g of cream) for 2 minutes, or on a 1:5 diluted cream prepared in a 15mL conical tube from about 1g of cream / 5g of water, and then the conical tube was vortexed at 2000rpm for at least 30 seconds until no separation of cream and water was observed.

[0234] The viscosity of three batches of cream prepared as described in the preceding example was measured using a Brookfield RVDVII+ spindle 28 and a sample chamber and water jacket 13R with a small sample adapter at 0.3–1 rpm (shear rate). Viscosity was measured by setting the speed and torque between 10% and 100%. Viscosity was then read at different speeds. Viscosities are reported in cP (centipoises) in Table 14.

[0235] Table 14: Viscosity Measurement Results (in cP)

[0236]

[0237]

[0238] Figure 7A and 7B The effects of shear rate and autoclaving temperature on the viscosity of the tested formulations are shown. Figure 7B The data was obtained at 0.3 rpm.

[0239] The viscosity of several commercial formulations was measured using standard methods, and the results are provided in Table 15 below.

[0240] Table 15: Viscosity Measurement Results of Commercial Products (in cP)

[0241]

[0242]

[0243] The osmotic pressure of several commercial formulations was measured using standard methods, and the results are provided in Table 16 below.

[0244] Table 16: Osmolarity of Commercial Products (in mOsmol / kg)

[0245]

[0246] Additional compositions as described in the examples are prepared based on the following formulations:

[0247] Table 17: Additional Cream Formulations

[0248]

[0249]

[0250] For batch 2020-07-06, the pH was adjusted at the end of manufacturing as described in this disclosure. The viscosity of each formulation was measured using a Brookfield RVDVII+ as previously described. The viscosity of batch 2020-07-05 was also measured using the cone-plate method with a Brookfield DV3T CP rheometer with a CP52 spindle at 25.0 + / - 0.1 °C and 10-100% torque. Briefly, 0.5 mL of formulation was added to a sample cup, and the program was run at 0.3 RPM, 0.6 RPM, 1.5 RPM, 3 RPM, 6 RPM, 12 RPM, 30 RPM, or 60 RPM. The formulation samples were also autoclaved at 110 °C for 10 minutes, and the viscosity of the sterile formulation was measured using a Brookfield RVDVII+ as previously described.

[0251] The results of the viscosity measurements are provided in Tables 18 and 19 below.

[0252] Table 18: Viscosity of Cream Formulations (in cP)

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] *AC = Autoclaving; Δ = Torque within the range; δ = Torque outside the range

[0260] Table 19: Viscosity of cream formulations obtained by two methods (in cP)

[0261]

[0262] The following table summarizes the properties of the tested composition:

[0263] Table 20: Summary of the properties of the composition

[0264]

[0265]

[0266] Example 6: Ototoxicity Study in Guinea Pigs

[0267] Guinea pigs were given an otoscope-guided intratympanic (IT) injection, and the clearance rate of the test sample (prepared on January 1, 2020, as described in the previous example, pH 5, containing EDTA) from the middle ear was analyzed.

[0268] Hearing was assessed at baseline using auditory brainstem response (ABR) thresholds (4, 10, 20 kHz). Sixteen animals (eight males and eight females) were administered 50 μL of the test substance bilaterally, and eight animals (four males and four females) were administered 50 μL of saline bilaterally. The sixteen animals receiving the test substance were randomly assigned to eight post-injection survival time points (days 1, 3, 5, 7, 10, 14, 21, and 28), at which time hearing in the left ear was reassessed using ABR thresholds (4, 10, 20 kHz). Control animals were allowed to survive for 1 or 28 days, and were assessed using the same ABR thresholds. After each time point, the animals were euthanized and bilateral bullous stomas were performed to examine each middle ear and record the presence of any creams, edema, or erythema.

[0269] IT injection was performed using a 1.9mm endoscope placed in the ear canal near the tympanic membrane (TM), allowing visualization and image capture of the TM before, during, and after the injection. The injection was performed using a Becton Dickinson Exespine 0.5mm x 90mm spinal needle, beveled to allow penetration of the TM, but with a shortened stem to reduce the possibility of damage to underlying structures. Non-beveled versus beveled tip... Figure 8 As shown, the injection setup is as follows Figures 9A-9B As shown (6 = a three-dimensionally positioned microinjector; 7 = a microinjector; and 8 = a microinjection control system).

[0270] Using the World Precision Instruments micro-injection system, a precise volume of 50 μL of test sample cream or saline is delivered within 10 seconds.

[0271] Bilateral otoscopy was performed immediately before and after the injection, continued for up to 7 days, and was repeated during the autopsy.

[0272] The table below provides the ABR test results, including those with the ABR offset as the threshold. Figure 10 The study shows the shift of the average threshold from baseline as a function of survival time and indicates that the threshold recovers to near-normal levels, similar to that of an ear treated with saline solution.

[0273] Table 21: ABR Test Results

[0274]

[0275] Cytocochleography was performed on eight cochleas (treated with TA and saline) at days 1, 7, 21, and 28. Qualitative assessment of damage to the most extreme basal portion of the cochlea was performed, and quantitative assessment of the number of internal (IHC) and external hair cells (OHC) was performed. Table 4 provides the raw IHC and OHC counts for each subject. The IHC counts in saline-treated animals were 61–65 across all three frequency regions, and those in TA-treated animals were 61–62. In the saline-treated control group, the total OHC count across the three frequency regions ranged from 211–224, and in the TA-treated samples, the count ranged from 220–227. No evidence of frequency-specific hair cell loss was found in the quantitative hair cell count assessment. In addition to quantitative assessment at specific sound frequency locations, qualitative assessment of the most extreme basal portion of the cochlea was performed using images at lower magnification. Qualitative evidence of hair cell loss was found in this extreme base region in no samples except for #18F treated with TA. However, significant anatomical damage was also present at the most extreme base of the sample, severing all outer hair cells and leaving only the inner hair cells for evaluation. Among the remaining inner hair cells, moderate hair cell loss appeared. However, given the small sample size and the anatomical damage to this portion of the cochlea, this qualitative observation may be subjective.

[0276] Table 22 below provides the hair cell count results from the cochlear imaging. These results indicate that the test sample did not cause hair cell loss.

[0277] Table 22: Hair cell count results

[0278]

[0279] Figure 11 The mean auditory hair cell counts (per 200 μm) for each frequency range were depicted for all animals across the test sample group (gray bars) and the saline group (black bars).

[0280] Figure 12Still images of the middle ear of animals surviving for 28 days were depicted – one with saline (top row); and two with test material (middle and bottom rows). As shown, the ears of the animals treated with saline appeared normal, with no visible fluid. On day 28, one ear appeared normal (middle row, left column) with only a small amount of cream on the ossicles. The other three ears had a gel-like mass filling most of the space in the middle ear (~20-30% air space). This is similar to the findings in the 21-day animals, where the gel-like mass contained adhesions (to the TM, ossicles, cochlea, and surrounding walls), making dissection from the surrounding tissue difficult, although there appeared to be more air space in the gel-like mass on day 28 compared to day 21. The consistency of the gel-like quality was similar between the two time points. Mild erythema and canal inflammation were observed post-treatment, which typically subsided around day 21 post-treatment, except that the right ear of animal #032-07 was swollen and did not allow visualization of the TM.

[0281] Example 7: Microbiological testing of creams containing and without clotrimazole / betamethasone

[0282] The antimicrobial efficacy of the cream composition 2020-01-01 and the placebo composition 2020-01-04 described in the foregoing examples was evaluated using USP 51. Results for each composition against five microorganisms tested at full strength using USP 51 are shown in Tables 23-28 below.

[0283] Table 23: Effects of the composition on microbial growth

[0284]

[0285] Table 24: Effects of the composition on microbial growth

[0286]

[0287] Table 25: Effects of the composition on microbial growth

[0288]

[0289]

[0290] Table 26: Effects of the composition on microbial growth

[0291]

[0292] Table 27: Effects of the composition on microbial growth

[0293]

[0294] Example 8: A human clinical study of patients with sinusitis

[0295] Human clinical trials will be conducted to evaluate the safety and efficacy of the cream disclosed herein for the treatment of sinusitis. The investigational pharmaceutical product will be betamethasone dipropionate cream (0.05%, 0.5 mg / g) containing 0.9% benzyl alcohol, polysorbate 80, glycerin, disodium EDTA, carboplatin 980, polyethylene glycol 40 stearate, cetyl alcohol, glyceryl monostearate, petrolatum, Span 20, sodium hydroxide, and water (the same formulation as in Table 28, except that the amount of glycerin used is 1.65% (w / w)). The cream will be applied using a 4-inch flexible-tip applicator attached to a syringe pre-filled with the cream to be applied endoscopically.

[0296] The cream will be stored at a controlled room temperature.

[0297] We will recruit a limited number (planned to be 50) of post-FESS patients aged 18 to 80 years who have been diagnosed with sinusitis and have had uncontrolled symptoms for at least 30 days. All patients have a history of bilateral ethmoid osteotomy and maxillary sinusostomy. A single 5cc dose of cream will be applied to the inflamed sinus mucosa on both sides (10cc total). This is equivalent to 1.288 mg betamethasone dipropionate per side or a total of 2.576 mg betamethasone dipropionate. Follow-up will be conducted on days 5 and 21 following application and safety assessments. Patients will undergo a 7-day adjustment period between screening and measuring disease status with the cream prior to treatment.

[0298] Inclusion criteria include:

[0299] 1. Male or non-pregnant, non-lactating female, aged between 18 and 80.

[0300] 2. Bilateral ethmoid bone resection and maxillary sinusostomy within the past 20 years (but at least 6 months prior).

[0301] 3. Clinical diagnosis of worsening sinusitis, with uncontrolled flare-ups of current symptoms lasting at least 30 days. Both the ethmoid bone and maxilla will be treated.

[0302] 4. Within the 0 to 3 range, at least two “basic” symptom scores are ≥2.

[0303] 5. Within the 0 to 3 range, the "basic" symptom obstruction and congestion score is ≥2.

[0304] 6. It must manifest as mucosal edema.

[0305] 7. Not exceeding a mild polyp load, which will not interfere with the application of the cream as assessed by each physician.

[0306] 8. Try a topical corticosteroid spray or rinse at least once a month before screening.

[0307] 9. Able to understand and provide a signed informed consent form.

[0308] 10. Women of childbearing potential must have a negative urine pregnancy test at screening and agree to use an acceptable method of contraception.

[0309] 11. Agreed to avoid immersing the sinuses in water during the study.

[0310] 12. Agree to avoid prolonged use of ocular steroids or nonsteroidal anti-inflammatory drugs (NSAIDs) and biologics for asthma or sinusitis during the period of withdrawal from treatment. Antihistamines may only be used if the patient continues to take them at a consistent dose from screening to withdrawal from treatment.

[0311] 13. Patients taking analgesics or other non-steroidal maintenance medications (e.g. for arthritis) will be allowed to participate in the study, provided that the dose has been stable for at least 8 weeks before enrollment and must remain stable during the study.

[0312] 14. Normal activity, and based on medical history and physical examination, the researcher believes that the overall health condition is good.

[0313] 15. Patients and / or caregivers who are able to adhere to the appointment schedule and protocol requirements and complete the entire study.

[0314] Exclusion criteria include:

[0315] 1. Women who are pregnant, breastfeeding, or wish to become pregnant during the study period.

[0316] 2. The current signs and symptoms of sinusitis have lasted for less than 30 days.

[0317] 3. Uncontrolled asthma.

[0318] 4. History of diabetes, immunodeficiency, allergy or intolerance to corticosteroids, oral steroid dependence, clinical evidence of acute bacterial sinusitis or invasive fungal sinusitis.

[0319] 5. History or diagnosis of glaucoma or ocular hypertension, presence of grade +3 or higher cataracts, or presence of posterior subscapular cataracts.

[0320] 6. Clinically diagnosed sinus diseases other than aggravated sinusitis (such as congenital abnormalities in the sinus and nasal region, obstructive exostosis or tumors, upper respiratory tract infections, including chickenpox and herpes simplex infection, cellulitis).

[0321] 7. Known or suspected hypersensitivity to betamethasone dipropionate or local anesthetic.

[0322] 8. Local sinus abnormalities, such as abscesses, nasal septum perforations, or nasal polyps, can cause severe nasal obstruction, preventing access to or visualization of the affected sinuses.

[0323] 9. Unwilling to discontinue use of nasal medications, rinsing agents, or sprays within 5 days after treatment.

[0324] 10. The affected sinuses underwent sinus surgery within 3 months of entering the study.

[0325] 11. The patient uses any type of device in the nose or sinuses (e.g., PROPEL).

[0326] 12. Surgical procedures performed in the nose or sinuses after the use of the cream during the study, unless prescribed by the investigator after the patient withdraws from the study.

[0327] 13. Previously participated in this study.

[0328] 14. Systemic or local immunosuppressive drugs or immunomodulators (e.g., azathioprine, infliximab, calcineurin inhibitors).

[0329] 15. Any significant psychological or mental / psychological condition that the researcher believes would interfere with the ability to provide informed consent or comply with research instructions, or could mislead the interpretation of research results or expose patients to undue risk. This should include: a recent (within the past 12 months) history of alcohol or drug abuse, or a high probability of alcohol or drug abuse.

[0330] 16. Non-investigational drugs, such as acetaminophen or ibuprofen, may be used for pain relief. All such uses should be reported to researchers.

[0331] Safety assessments will include recording adverse events (AEs) that will be collected during the study (via each patient's withdrawal visit). The reporting group will include all participants who received the study drug. AEs will be obtained through consultation with patients and / or caregivers in the study, or through observations by the study's investigators. This will also include reporting of serious adverse events (SAEs).

[0332] An ENT (head and neck) examination will be performed during screening and at each clinic visit.

[0333] Six patients will be included in the PK study. Plasma drug concentrations will be measured during pretreatment, then 24 hours after administration, or sometimes to be determined.

[0334] Patients will need to begin the study between 8 and 9 a.m. to test morning serum cortisol and / or ACTH levels. Cortisol levels will be measured: before administration at the treatment visit, then on day 5, and at the exit visit (day 21 after administration).

[0335] Intraocular pressure (IOP) will be measured during screening and at the time of discharge. IOP must be normal, between 12 and 22 mm Hg, to be eligible to participate in the study.

[0336] The presence of cream in PK patients will be measured daily until it is no longer visible, and for all patients on days 5 and 21. The presence of cream in the sinuses will be assessed by endoscopy.

[0337] 4. A daily diary of basic symptom scores will be completed by the patient daily during a 7-day adjustment period until discharge. "Basic" symptoms are congestion and congestion, facial pain and pressure, runny nose, and loss of smell. Patients will report these symptoms daily as 0-none, 1-mild, 2-moderate, and 3-severe. The change in the total mean over the first 7 days of treatment and the total mean over the first 7 days of discharge will be the primary measure of efficacy. An exploratory measure of efficacy will be the change in the visual analoguescale (VAS) of common sinus symptoms completed by the patient before treatment and at discharge ("Basic" symptoms or the visual analoguescale for sino-nasal symptoms severity correlates with sino-nasal outcometest 22: paving the way for a simple outcome tool of CRS burden." *Clin Transl Allergy*, 2018; 8:32). Another exploratory measure of efficacy was the change in the modified Lund-Mackay postoperative endoscopy score based on video assessments by three independent, blinded physicians (pre-treatment vs. day 21) (Snidvongs et al. Modified Lund-Mackay Postoperative Endoscopy Score for defining inflammatory burden in chronic rhinosinusitis. Rhinology, 52:53-59, 2013).

[0338] Using a nasal endoscope, the amount of cream present in the sinuses will be graded as follows: visible (any amount) and invisible. This will be measured daily for the first six patients and again on day 5 of the study visit and when all patients withdraw from the study.

[0339] Example 9: Phase 2 clinical trial in patients with confirmed or suspected otofungal disease

[0340] A multicenter, sham-controlled, double-blind, prospective, randomized phase 2 clinical trial of a single-dose combination cream of clotrimazole (1%) / betamethasone (0.025%), clotrimazole (1%) cream, betamethasone (0.025%) cream, or sham (air injection) will be conducted to treat patients with confirmed or suspected otomycosis.

[0341] Patients will be divided into four treatment groups: Group 1 will receive clotrimazole / betamethasone cream at or below the established maximum potential dose of 15 mg clotrimazole and 0.375 mg betamethasone per treated ear; Group 2 will receive clotrimazole cream at or below the established maximum potential dose of 15 mg clotrimazole per treated ear; Group 3 will receive betamethasone cream at or below the established maximum potential dose of 0.375 mg betamethasone per treated ear; and Group 4 will receive sham (air) treatment. Each cream will be formulated as described in the presented disclosure.

[0342] If necessary, groups 1-3 will have their external auditory canals (EACs) cleaned and receive a single application of cream to fill the EAC. If necessary, group 4 will have their EACs cleaned and receive an air application within the EAC. Study participants will return for evaluation on day 10+ / -1 post-treatment. Primary efficacy will be assessed based on the resolution of signs and symptoms on day 10+ / -1 post-treatment, judged by a blinded assessor as complete resolution of erythema, edema, otorrhea, and tenderness, to compare clotrimazole / betamethasone cream with sham (air) treatment. Secondary objectives to be evaluated include:

[0343] 1. Signs and symptoms subsided on day 10+ / -2 post-treatment, and the blinded evaluator determined that erythema, edema, otorrhea, and tenderness had completely subsided, in order to compare clotrimazole / betamethasone cream with clotrimazole cream.

[0344] 2. Signs and symptoms subsided on day 10+ / -2 after treatment, and the blinded assessor judged that the erythema, edema, otorrhea and tenderness had completely subsided, in order to compare clotrimazole / betamethasone cream with betamethasone cream.

[0345] 3. Patients reported the time itching subsided in their daily diaries to compare clotrimazole / betamethasone cream with sham (air) treatment.

[0346] 4. Patients reported the time itching subsided in their daily diaries to compare clotrimazole / betamethasone cream with clotrimazole cream.

[0347] 5. Patients reported the time itching subsided in their daily diaries to compare clotrimazole / betamethasone cream with betamethasone cream.

[0348] 6. Patients reported pain relief time in their daily diaries to compare clotrimazole / betamethasone cream with sham (air) treatment.

[0349] 7. Patients reported pain relief time in their daily diaries to compare clotrimazole / betamethasone cream with clotrimazole cream.

[0350] 8. Patients reported pain relief time in their daily diaries to compare clotrimazole / betamethasone cream with betamethasone cream.

[0351] 9. Clinical cure is defined as the patient’s condition at the time of the cure trial (TOC) presentation where a blinded assessor determines that no further treatment is needed for erythema, edema, otorrhea, and tenderness, and reviews the symptoms with the patient to compare clotrimazole / betamethasone cream with sham (air) treatment.

[0352] 10. Clinical cure is defined as the patient’s condition at the time of the cure trial (TOC) presentation where a blinded assessor determines that no further treatment is needed for erythema, edema, otorrhea, and tenderness, and reviews the symptoms with the patient to compare clotrimazole / betamethasone cream with clotrimazole cream.

[0353] 11. Clinical cure is defined as the patient’s condition at the time of the cure trial (TOC) presentation where a blinded assessor determines that no further treatment is needed for erythema, edema, otorrhea, and tenderness, and reviews the symptoms with the patient to compare clotrimazole / betamethasone cream with betamethasone cream.

[0354] 12. Fungal eradication, comparing clotrimazole / betamethasone cream with sham (air) treatment.

[0355] 13. Fungal eradication, comparing clotrimazole / betamethasone cream with clotrimazole cream.

[0356] 14. Fungal eradication, comparing clotrimazole / betamethasone cream with betamethasone cream.

[0357] 15. Bacterial eradication, comparing clotrimazole / betamethasone cream with sham (air) treatment.

[0358] 16. Bacterial eradication, comparing clotrimazole / betamethasone cream with clotrimazole cream.

[0359] 17. Bacterial eradication, comparing clotrimazole / betamethasone cream with betamethasone cream.

[0360] 18. Safety based on reported adverse events.

[0361] 260 patients will be included in the study, aged 8 years or older, diagnosed with otomycosis (suspected or confirmed), and meeting all inclusion / exclusion criteria. Patients will return on day 10+ / -2 (Time to Cure (TOC)) to assess the effectiveness of their treatment. Patients or caregivers will record treatment for ear pain and itching in a daily diary at home, according to a pain scale from: no pain, mild pain, moderate pain, severe pain, extreme pain to the most severe pain possible; and according to an itching scale from: no itching, mild itching, moderate itching to severe itching. The time when pain and itching cease will be defined as the first time point (morning or evening) when pain and itching are absent and do not recur in any subsequent diary entries.

[0362] The inclusion criteria for this study will include:

[0363] 1. Male or non-pregnant, non-lactating female, aged at least 8 years.

[0364] 2. Clinical diagnosis of unilateral or bilateral otomycosis (suspected or confirmed, and may also involve multiple microorganisms, including fungi / yeasts).

[0365] 3. At the time of screening, at least one affected ear should have a combined numerical severity score for tenderness, discharge, erythema, and edema. > 4. Each measure was scored as follows: 0 = None [absolutely no signs or symptoms], 1 = Mild [mild / detectable], 2 = Moderate [definitely present], 3 = Severe [marked, intense]. In patients with bilateral otomycosis, only one ear had to meet the criteria, and both ears were assessed, cultured, and treated according to group randomization.

[0366] 4. Women of fertility at the time of screening consent to the use of acceptable methods of contraception.

[0367] 5. Agree to avoid immersing ears in water during the study.

[0368] 6. Patients taking analgesics or other non-steroidal maintenance medications (e.g., for arthritis) will be allowed to participate in the study, provided that their dosage has been stable for at least 8 weeks prior to enrollment and must remain stable during the study.

[0369] 7. Able to understand and provide a signed informed consent form. Parents or legal guardians of patients under the age of 18 must also read and sign a written informed consent form before participating in the study.

[0370] 8. Normal activity; based on medical history and physical examination, the researchers consider the patient to be in good health.

[0371] 9. Patients and / or caregivers who are able to adhere to the appointment schedule and protocol requirements and complete the entire study.

[0372] The exclusion criteria will include:

[0373] 1. Current diagnosis of malignant otitis externa.

[0374] 2. Known or suspected hypersensitivity or allergy to clotrimazole, betamethasone dipropionate, or any other component of the investigational drug.

[0375] 3. Ear canal abscess.

[0376] 4. Diagnosis of any type of diabetes.

[0377] 5. Patients who use earplugs, headphones, or other ear tips and do not wish to discontinue use during the study.

[0378] 6. The affected ear underwent ear surgery within one year of entering the study.

[0379] 7. It is not possible to discontinue systemic antibiotics before the study of treatment.

[0380] 8. Currently or previously (within 3 days) used topical vinegar, alcohol or other astringents in the external auditory canal of the affected ear.

[0381] 9. Use of any systemic glucocorticoids.

[0382] 10. During the study period (from screening to TOC visit), the use of a hearing aid or earpiece in the treated ear could not be stopped.

[0383] 11. Previously participated in this study.

[0384] 12. Any significant medical or psychological / psychiatric condition that the PI believes would interfere with the ability to provide informed consent or comply with research instructions, or could potentially obscure the interpretation of research results or expose the patient to undue risk.

[0385] 13. Currently participating in investigational drug or device research or participating in such research within 30 days of entering this study.

[0386] 14. Any reason why the principal investigator believes the patient should not participate.

[0387] During each study visit, scores for each of the following markers and systems will be recorded using the scoring system described above. Signs: Tenderness, edema, discharge, and erythema of the tragus and auricle. Symptoms: Itching and pain, as reported by the patient.

[0388] At the initial study visit, the patient's medical history will be obtained, including past medical history (e.g., tinnitus, mastoidectomy, hearing loss, recurrent otitis externa, previous tympanostomy). The onset dates of signs and symptoms associated with otomycosis, as well as any accompanying medications, will be recorded. A head and neck examination will also be performed. The affected ear will also be clinically evaluated according to the aforementioned signs and symptoms. Culture samples will be collected from the EAC wall. Mechanical cleaning of the EAC will be performed if necessary. Treatment will be administered according to the patient's group.

[0389] The patient or caregiver will record the severity of itching and pain twice daily, as well as any analgesics used for each episode of pain. Any adverse events will also be recorded.

[0390] Patients will be clinically evaluated on day 10+ / -2 post-treatment (TOC). Any residual study drug will be removed. Blinded medical professionals will examine the patient and record vital signs according to the above 4-point scale. Itching and pain will be assessed based on patient reports. Culture samples will be collected from the EAC wall.

[0391] Example 10: Local absorption and tolerance study

[0392] The compositions of this disclosure containing 0.05% (w / w) betamethasone dipropionate were tested in sheep models to evaluate local absorption and tolerability.

[0393] Six Merino sheep will undergo bilateral frontal trephineing under general anesthesia (insertion of small metal cannulas through burrs into two frontal sinuses). The sheep will be randomly assigned to receive the test formulation in one sinus and a saline control in the contralateral sinus, with further randomization of the treated sinuses. The test formulation will be administered to fill the entire frontal sinus until the cream appears in the nasal cavity. The volume administered will be measured. The trephine will be removed, and the skin over the burr holes will be closed.

[0394] The sheep will be reinstated in an enclosure and their general health will be monitored. Nasal discharge will be recorded twice daily.

[0395] Blood samples will be collected from sheep at various times, including before administration, 1 hour, 2 hours, 6 hours, 24 hours, 48 ​​hours, and 72 hours after administration, for pharmacodynamic and pharmacokinetic analysis. Some of these blood samples, as well as optional blood samples at other time points, will be collected to measure ACTH and / or cortisol levels.

[0396] The sheep will be euthanized 10 days after administration. Sinus tissue will be evaluated by a blinded veterinary pathologist for macroscopic assessment and histopathology. For macroscopic assessment, a rough qualitative assessment of mucosal integrity and irritation will be performed using a scale, and photographs will be taken. Any cream residue will be qualitatively observed and evaluated, and photographs will be taken. For histopathology, scanning electron microscopy will be performed to assess the ciliary and tight junction morphology of the sinus mucosa. Paraffin-embedded histopathology will also be performed using hematoxylin and eosin staining. The integrity of the epithelial layer and signs of metaplasia will be assessed. Inflammation and fibrosis of the mucosa will be evaluated.

[0397] Example 11: Membrane diffusion and permeability test

[0398] The diffusion and retention properties of the disclosed compositions will be tested on cadaver skin and mucous membranes. The composition will vary the amount of betamethasone dipropionate. Drug penetration through cadaver skin and excised nasal mucosa will be measured by HPLC. Compositions with and without active agents will be tested.

[0399] Transdermal permeability was measured using surgically excised fresh human skin in Franz diffusing cells. The effects of the applied doses were also evaluated (control group doses = 0.2 g, 0.5 g, and 1 g, n = 6 and n = 3). Samples were drawn from recipient body fluids at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, and 48 h. HPLC analysis was performed to measure the drug as described in Example 4. Statistical analysis of non-normally distributed data was performed using the Wilcoxon rank-sum test (α = 0.05).

[0400] Transnasal permeability was measured in fresh bovine nasal mucosa excised from Franz diffusing cells. Doses up to 1 g were tested. Samples were drawn from recipient body fluids at 0.5 h, 1 h, 2 h, 4 h, and 6 h (and optionally, 8 h, 12 h, 24 h, and 48 h). HPLC analysis was performed to measure the drug as described in Example 4. Non-normally distributed data were statistically analyzed using the Wilcoxon rank-sum test (α = 0.05).

[0401] The percentage of penetration into bovine nasal mucosa was found to be below the limit of quantitation (<45 ng / mL) at all time points (0 h, 0.5 h, 1 h, 2 h, 4 h, and 6 h, excluding 8 h, 12 h, 24 h, and 48 h), and the percentage of penetration into human skin was also found to be below the limit of quantitation at all time points (0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, and 48 h). This indicates a local effect of the cream composition.

[0402] Example 12: Production of Blended Materials

[0403] Alternative formulations for betamethasone dipropionate cream are prepared having the following compositions as shown in Table 28.

[0404] Table 28: Formulation of Betamethasone Dipropionate Cream

[0405]

[0406] The above-mentioned formulation has been expanded from formulation development to production scale (2000g).

[0407] Preparation of aqueous phase

[0408] The laboratory-scale process reportedly begins by dispensing approximately 125-150g of water into a 400mL beaker. Using a top-mounted mixer with a 4-bladed propeller, mixing of the water begins at 200-300rpm. EDTA and glycerin are added for dissolution, and the mixer speed is increased to ~800rpm for ~1 minute. The mixer is then turned off, and carboplatin is slowly added by sprinkling it on the surface and pulsating the mixer 2-5 times between small additions to wet the material. After all the carboplatin has been added, mixing is resumed at 800-1000rpm for 30 minutes, rotating the beaker every 5-10 minutes. After complete mixing, the pH is tested and adjusted as needed using a 1% NaOH solution to achieve the target pH of 6. The mixture is then QS-tested with water and mixed for ~30 minutes. The mixer is then set to 200-300rpm, and polysorbate 80 is carefully added to avoid foaming. Mix for up to 45 minutes, moving the container up and down every 5-10 minutes ("shake" mix) to ensure a thorough mixing.

[0409] To avoid the need to add excessive amounts of 1% sodium hydroxide solution for pH adjustment (which could risk over-diluting the product), a 2% sodium hydroxide solution is recommended. Mixing time and speed can be adjusted as needed using visual observation to determine dispersion while minimizing air trapping. Recommended scaling parameters are provided in Table 29 below.

[0410] Table 29: Comparison of Aqueous Phase (Phase A) Parameters

[0411]

[0412] Preparation of oil phase

[0413] Laboratory-scale processes for oil-phase activities can be performed concurrently with aqueous-phase activities. Add Span 20, petrolatum, polyethylene glycol 40 stearate, cetyl alcohol, and glyceryl monostearate (GMS) to a 250 mL beaker equipped with a stir bar (ordered from liquid to most solid). Heat the beaker on a hot plate until the composition reaches a temperature of 65 ± 5 °C. During heating, mix the materials with the stir bar at 100–350 rpm for approximately 15 minutes, until most solids have melted. Reduce the mixing speed to 50–100 rpm and mix the composition for approximately 10 minutes until homogeneous.

[0414] To achieve a more robust and repeatable process at a larger 2000g scale, it is recommended that this batch utilize a hot water bath and overhead mixing for the oil phase. This should better simulate a large-scale jacketed tank for future scalability. Furthermore, a propeller-type impeller is recommended for mixing, rather than a simple stirring bar. Temperature, mixing speed, and mixing time will be adjusted and recorded as needed based on visual observation. Recommended scaling parameters are provided in Table 30 below.

[0415] Table 30: Comparison of Oil Phase (B Phase) Parameters

[0416]

[0417] API Add

[0418] The laboratory-scale process report describes changing the mixing blades in the aqueous phase to higher shear disc impeller blades and mixing for ~5 minutes at the lowest available rpm setting. The aqueous phase is heated to a target temperature of 62 ± 3 °C, and the mixing speed is set to the highest rpm (~1200+ rpm) that will not cause foaming. It has been reported that heating to the target temperature takes ~30 minutes on a small laboratory scale. Betamethasone dipropionate is properly distributed, with half of the total amount allocated to the aqueous phase and half to the oil phase. The aqueous phase mixer is turned off, and betamethasone dipropionate is added to both phases. Mixing is resumed, and the two phases are mixed for 10–15 minutes while still being heated.

[0419] The following calculations are used to determine the approximate tip velocity for an average laboratory-scale batch of production:

[0420]

[0421] Based on average tip velocities calculated during laboratory-scale batches (300g and 600g batch sizes), and considering mixer sizes proposed for engineered and cGMP scales, the approximate mixing rate at this larger scale is ~760 RPM. However, the primary indicator for determining the appropriate mixing rate will be visual cues to minimize the possibility of excessive air incorporation into the mixture.

[0422] Because APIs are highly effective compounds for inhalation and must be contained in powder form, for engineered and cGMP batches, a closed system will be used for the dispensing process and around the heated container, while simultaneously adding the activity to both phases. Recommended scaling parameters are provided in Table 31 below.

[0423] Table 31: Comparison of Active Addition (C Phase) Parameters

[0424]

[0425] Phase combination

[0426] For laboratory-scale batches, the mixing of the aqueous phase is increased to ~1800 rpm. Since the aqueous phase is being mixed and still heated, the hot oil phase is added to the aqueous phase in 2-3 portions. The now-combined emulsion is then removed from the heat source and mixed for ~45 minutes, moving the container up and down in the mixture every 5-10 minutes to ensure a homogeneous mixture. After cooling to <30°C, benzyl alcohol (D phase) is added to the mixture and mixed at high shear at ~1800 rpm, then at ~1200 rpm for ~30 minutes, moving the container up and down every 5-10 minutes. The laboratory-scale emulsion with water is then reportedly QS-tested based on beaker tare weight, theoretical mass, and oil phase loss, and then mixed for ~10 minutes.

[0427] To achieve a more robust and repeatable process at larger 2000g scales, it is recommended that each batch utilize a mixing shaft consisting of one or two disc blades at various points along the shaft. While using high-flow, high-shear disperser blades may require only one blade for thorough mixing, this will be evaluated during the process. This should alleviate the need for up-and-down container movement during so-called "shake" mixing at the customer formulation development site, which could pose safety risks at larger scales.

[0428] Based on the average tip speed calculated during laboratory-scale batches, and based on the mixer size proposed for larger scales, the approximate mixing speed for that scale would be ~1120 rpm. However, the primary indicator for determining the appropriate mixing speed will be a visual cue to minimize the possibility of excessive air incorporation into the mixture.

[0429] It is unclear what adjustment formula to use to adjust the final water volume. QCL recommends adjusting the final water volume based on the amount of API loss in the oil phase; however, if excessive loss occurs, there is a risk of batch-specific effectiveness, and the oil-to-water ratio will be inconsistent when using this method. As an alternative, an excess of oil phase can be prepared and carefully partitioned into the aqueous phase to prevent adjustments that must be calculated based on the loss. It is currently unclear how much excess is needed at this scale.

[0430] No additional pH measurements or adjustments were recorded during the lab-scale process prior to QS of the final product. pH checks are recommended, and adjustments should be made as needed using the same 2% sodium hydroxide solution as the aqueous phase. Mixing time and rate will be adjusted as needed using visual observation to determine dispersion while minimizing air trapping. Recommended scaling-up parameters are provided in Table 32 below.

[0431] Table 32: Comparison of active additive (C phase) parameters

[0432]

[0433] Below is an example manufacturing process:

[0434] Aqueous phase

[0435] 1. Obtain two (2) soup pots, one of which can be placed inside the other, so as to be able to create a heated water bath.

[0436] 2. Add approximately 1 / 2 of the USP purified water, glycerol, and disodium EDTA in sequence.

[0437] 3. Use a top mixer to mix NLT for 5 minutes, until EDTA is dissolved.

[0438] 4. Stop the mixer and slowly add the carbomer, while periodically "pulsing" the mixer during the addition process. Mix the NLT for 5 minutes until fully dispersed.

[0439] 5. Measure the pH and adjust it to the target of 6.0 using a 2% sodium hydroxide solution if necessary, mixing for at least 5 minutes between measurements.

[0440] 6. Slowly add polysorbate 80 and mix to disperse while preventing foaming.

[0441] 7. Start heating the water bath to bring the product temperature to 62+ / -3℃.

[0442] oil phase

[0443] 1. Obtain two (2) soup pots, one of which can be placed inside the other, so as to be able to create a heated water bath.

[0444] 2. Add Span 20, petrolatum, cetyl alcohol, polyethylene glycol 40 stearate and GMS in sequence.

[0445] 3. Begin heating the water bath to melt the mixture and bring the product temperature to 65 + / - 3°C.

[0446] 4. Use the top mixer to begin mixing until completely melted and combined.

[0447] API additions and combinations

[0448] 1. Add an appropriate amount of betamethasone dipropionate to the aqueous and oil phase mixture and mix while heating to perform NLT for 15 minutes.

[0449] 2. Stop mixing the oil phase and carefully remove the pot from the heat source to add it to the hot water phase.

[0450] 3. Allow the oil phase to fully dissolve into the water phase, and then remove the combined phase from the heat source while continuing to mix.

[0451] 4. To cool the combined phases to <30℃.

[0452] 5. Measure the pH and adjust it to the target pH as needed.

[0453] 6. Add benzyl alcohol while mixing. Mix for 5 minutes for NLT.

[0454] 7. Stop mixing, weigh the container, and perform a QS test using USP purified water to adjust for the target weight (adjust according to the oil phase loss).

[0455] Package

[0456] 1. Calculate the density of the finished product and fill a 10cc syringe to the target weight, which is equivalent to 5mL.

[0457] 2. Label the syringes and pack two (2) syringes in each bag.

[0458] 3. Label each bag and pack it in a (1) bag. Label the bag.

[0459] Example 13: Sheep Research

[0460] Sheep were accepted as a model for frontal sinus treatment. Aside from monkeys, apes, and pigs, sheep sinuses are most similar to humans in anatomy, physiology, and pathology. Sheep were chosen for sinus studies using betamethasone dipropionate cream because they possess nasal cavities, maxillary sinuses, ethmoid sinuses, and frontal sinuses, as well as respiratory sinus epithelium very similar to that in humans. Furthermore, sheep sinuses have a complex immune system, sharing many similarities with humans.

[0461] In humans, after topical or intramuscular administration, betamethasone dipropionate is metabolized to betamethasone-17-propionate, and betamethasone with low levels of betamethasone-21-propionate has also been reported in some studies.

[0462] In humans, plasma concentrations of betamethasone dipropionate, betamethasone-17-dipropionate, and betamethasone were measured at baseline following topical application of Servino spray (FDA PharmReview, NDA208079) and in 75 psoriasis subjects who received a 0.05% topical betamethasone dipropionate spray or lotion BID for 15 consecutive days before and after the last dose. Most subjects did not have measurable plasma concentrations of betamethasone dipropionate (<5 pg / mL). Both betamethasone and betamethasone-17-propionate were present at plasma concentrations of up to 120 pg / mL.

[0463] A non-GLP study of BMDP CREAM (0.05% betamethasone) was conducted in sheep. Sheep were chosen for this study because they have nasal cavities, maxillae, ethmoid sinuses, and frontal sinuses similar to human sinuses, as well as respiratory sinus nasal epithelium, and they possess a complex immune system with many similarities to humans (Ha 2007; Le 2008; Rajiv 2013; Drilling 2014; Ooi 2018). Although this was a novel route of administration, the study design was consistent with the principles described in typical toxicology study design and ICH M3(R2). The study was conducted in accordance with the ISO 9001 (2015) Quality Management System Guidelines and the Standard Operating Procedures (SOPs) for research planning and testing facilities. Appropriate animal ethics approvals were obtained. The results are described below.

[0464] The aim of this study was to evaluate the potential local tolerability and systemic absorption of BMDP CREAM after a single intrasinusal administration and a 10-day recovery period. Intrasinusal administration was the intended clinical route of administration. During the study, clinical signs of toxicity, local tissue responses, clinicopathological findings, pharmacodynamic responses (serum cortisol and glucose), and histopathological evaluation of selected tissues were examined in animals (n = 6 castrated males; 15–16 months old) to determine systemic exposure to betamethasone and betamethasone-17-propionate. 0.9% saline was used as a control.

[0465] On day 0, under general anesthesia, small metal cannulas were inserted into both frontal sinuses via bilateral frontal trephine burrs to establish sinus access for the injection of test and control items. Successful access was checked using fluorescein flushing through the trephine burrs and verified endoscopically. During the procedure, either BMDP cream or saline was administered directly into one frontal sinus, with animals randomly assigned to receive both BMDP cream and saline simultaneously in the contralateral sinus. The entire frontal sinus was filled (between 7 and 15 mL / side) until BMDP cream or saline was present in the nasal cavity (verified endoscopically). After administration of the test items, the trephine burrs were removed, and the skin over the burr holes was sutured.

[0466] Weight was recorded before the test sample was administered, and then weekly throughout the study. Nasal discharge was specifically observed twice daily, at least 6 hours apart, throughout the study. The color and texture of the fluid, as well as its estimated volume, were recorded.

[0467] Blood samples were collected at 10 days post-dose (via a jugular cannula inserted during surgery) for pharmacokinetic, hematological, clinical chemistry, glucose, and morning cortisol analyses. Pharmacokinetic bioanalysis of stable plasma was performed using qualified LC / MS / MS methods, with limits of quantification for betamethasone 17-propionate and betamethasone at 0.02 ng / mL.

[0468] On day 10, the animals were euthanized for gross pathological examination and selected tissues were examined under a microscope. The collected tissues included the frontal sinus, nasopharynx, esophagus, rumen, duodenum, brain, heart, lungs, liver, kidneys, and spleen.

[0469] The volume of BMDP CREAM (0.05% betamethasone) instilled into the sinus cavity reflects the variability in sheep sinus volume. Individual doses of BMDP CREAM and betamethasone were determined based on a cream density of 0.8 g / mL and body weight.

[0470] All sheep recovered well from surgery, with no adverse clinical signs of toxicity observed throughout the 10-day recovery period. One animal exhibited significant postoperative discharge and sneezing on day 2 after administration, but no other signs were observed in this animal. At the end of the study, both animals had lost approximately 2% or 6% of their body weight. All other sheep maintained or gained weight during the study period.

[0471] Plasma levels of betamethasone and betamethasone 17-propionate were measured 3 days after administration, and the plasma concentration versus time curves reflected the metabolism of betamethasone dipropionate to betamethasone. Maximum plasma levels of betamethasone were observed approximately 24 hours after administration.

[0472] In summary, the betamethasone dipropionate cream (0.05% betamethasone, density 0.78) of Example 8 was administered to sheep via the intrasinus route, and the levels of the active metabolite in the plasma were measured. The betamethasone dipropionate cream was delivered in doses to fill one sheep sinus. Due to the variability in sheep sinus volume, the total volume ranged from 5 to 15 mL. Table 33 provides the corresponding doses of betamethasone dipropionate (and the calculated betamethasone doses). Doses calculated based on body weight and body surface area (BSA) are also shown.

[0473] Table 33: Dosage administered to the frontal sinus of sheep during surgery

[0474]

[0475] *Based on the following determination (FDA 2005) [https: / / www.fda.gov / media / 72309 / download] ； Industry Guideline: "Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Treatment in Healthy Adult Volunteers" U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2005, Pharmacology and Toxicology.

[0476] It should be noted that, compared to the thinner and more vascularized mucosal surface, the systemic absorption from the mucosal surface will be greater than the absorption from dermal application due to the skin's epithelial barrier layer.

[0477] The concentrations of betamethasone and betamethasone-17-propionate in plasma were determined, and the resulting average concentration-time curves and pharmacokinetic parameters are as follows: Figure 13A -C is shown. Tables 34-36 below provide overall and individual data.

[0478] Table 34: Pharmacokinetic parameters of betamethasone and betamethasone dipropionate in sheep treated with intrasinus 0.05% betamethasone dipropionate cream (mean (SD, n=6))

[0479]

[0480]

[0481] The median (range) of Tmax.

[0482] Table 35: Individual Betamethasone-17-propionate Plasma Concentrations (pg / mL) (Mean ± SD (n = 6)) (BLQ = Below Limit of Quantification)

[0483] Individual betamethasone-17-propionate plasma concentrations (pg / mL)

[0484]

[0485] BLQ = below the limit of quantitation

[0486] Table 36: Individual Betamethasone Plasma Concentrations (pg / mL) (Mean ± SD (n = 6)) (BLQ = Below Limit of Quantification)

[0487]

[0488] BLQ = below the limit of quantitation

[0489] The variability in pharmacokinetic data (e.g., coefficient of variation of Cmax = 40%) was not correlated with the administered dose (it varied 3-fold), indicating that the absorption of this product at this site will be variable. AUC was more consistent, with a CV of 25%.

[0490] Following dose administration, plasma glucose levels increased by approximately 30% on day 1, but subsequently returned to pre-dose levels on day 2. Serum cortisol decreased to baseline levels (below 10 nmol / L) on day 1 and remained below pre-dose levels throughout the 10-day study. The lower cortisol and day 1 glucose levels are consistent with the pharmacological activity of the glucocorticoids. The prolonged cortisol suppression time is likely due to prolonged plasma levels of betamethasone and betamethasone 17-propionate.

[0491] Compared with the pre-drug values, there were no significant steroid-related changes in other clinical chemistry or hematology parameters.

[0492] At autopsy, one animal presented with thickened sinuses and marked bacterial infection. No other preliminary findings were observed in the other sheep. Furthermore, no sinus irritation was observed. Histopathological evaluation of the sinuses treated with BMDP cream and saline revealed infection leading to inflammatory cell infiltration in one sheep, as well as evidence of ciliary abruption in some mucosal samples. Local toxicity was not correlated with either the test or control treatment. No histopathological changes were observed in the heart, lungs, liver, kidneys, or spleen.

[0493] Overall, there appears to be no evidence that intrasinus of BMDP CREAM into the frontal sinus mucosa induced local toxicity, inflammation, or adverse pathology.

[0494] Due to the variability of sheep sinuses, the dose of betamethasone used to calculate the human equivalent dose is expressed as total surface area (BSA) as described in FDA guidance (FDA 2005). The mean dose in sheep studies was 0.072 mg / kg, and can be calculated based on the sheep's K... m (37) Converted to the dose per BSA. It is worth noting that sheep and humans have different doses of K. mThe same. Therefore, the average dose calculated in the sheep study was 2.6 mg / m². 2 (range 1.3 to 3.7 mg / m²) 2 In the planned clinical trial, patients will receive a total maximum dose of 10 mL, equivalent to 4.0 mg of betamethasone, or 0.067 mg / kg for a 60 kg individual. Based on BSA, this dose is equivalent to approximately 2.5 mg / mL. 2 .

[0495] Sheep have been used as a preclinical model for steroids containing betamethasone compounds, and the metabolism and pharmacokinetics of these drugs are similar in both species (9, 11, 12). Current data suggest that the metabolism of betamethasone dipropionate during intrasinus administration may predict human metabolism via this route of administration.

[0496] The sheep's weight was relatively consistent, varying between 52 and 60 kg, with an average of 56.3 kg. This is similar to the FDA's definition of a nominal human weight of 60 kg for standardized human dosage calculations.

[0497] The average volume of cream delivered to sheep was 10 mL. The resulting betamethasone dose in sheep was 0.072 mg / kg or 2.6 mg / mL. 2 .

[0498] It has been reported that the volume of the human frontal sinus is variable, ranging from 2 mL to 10 mL.

[0499] A human dose of 10 mL of the same formulation is equivalent to 4.0 mg of betamethasone, which is equivalent to 0.067 mg / kg for a 60 kg individual. Based on BSA, this dose is equivalent to approximately 2.5 mg / mL. 2 .

[0500] Therefore, the recommended dosage for clinical use is almost identical to that used in sheep studies.

[0501] Because the metabolism and pharmacokinetics of betamethasone products are similar between sheep and humans, and the sinus mucosa, body weight, and surface area are also similar, the resulting absorption curves in humans treated with intrasinus BMDP are likely to be similar.

[0502] Example 14: Phase 1 Human Study

[0503] Twenty-five patients aged 18 to 80 years who have undergone FESS and have been diagnosed with chronic rhinosinusitis (CRS) with symptoms lasting at least 30 days will be recruited. All patients must have undergone FESS surgery at least 6 months prior to enrollment. The first six patients will return daily for observation of cream retention until the cream is no longer visible endoscopically.

[0504] Apply up to 5 mL of 0.05% betamethasone dipropionate cream to the mucosa of each left and right sinus as described in Example 12 (total 10 mL). The cream will be applied topically to the inflamed sinus mucosa using a custom-designed applicator attached to a syringe with the aid of a nasal endoscope.

[0505] During the study, all patients will return 5 days after treatment for a safety assessment and 21 days after treatment for a withdrawal appointment.

[0506] During the study, morning cortisol levels, intraocular pressure, and adverse events will be measured before treatment, on day 5 after treatment, and at the time of discharge.

[0507] During the study, the 7-day average daily total symptom score during the screening adjustment period was compared with the 7-day average daily total score 7 days prior to the withdrawal visit using a daily diary of the 4-basic symptom score (4CSS). The 4CSS is a composite score of the basic symptoms of CRS in patients with a CRS score of 0.3-, with a total score of 12. The four “basic” symptoms are: (1) congestion and congestion; (2) facial pain and pressure; (3) nasal discharge; and (4) loss of smell (anosmia).

[0508] During the study, changes in total SNOT-22 scores will be measured between before treatment and 21 days after treatment.

[0509] During the study, changes in 4CSS VAS scores will be assessed before treatment and on day 21 after treatment.

[0510] During the study, changes in the modified Lund-Mackay endoscopic score based on video assessments by three independent blinded ENTs will be evaluated (pre-treatment vs. day 21).

[0511] During the study, the retention time of the cream in the sinuses of the initial six patients will also be measured. Patients will return until the cream is no longer visible via endoscopy.

[0512] This is a prospective, open-label, single-site clinical study investigating the safety, tolerability, and preliminary efficacy of BMDP CREAM application to the sinus mucosa of patients aged 18 to 80 years diagnosed with uncontrolled chronic rhinosinusitis symptoms following febrile endoscopic sinusitis (FESS). To be considered a patient with uncontrolled FESS-related chronic rhinosinusitis, patients must have a prior diagnosis of chronic rhinosinusitis and have been actively treating their symptoms, which must have persisted for the past 30 days. FESS surgery must have been performed at least 6 months prior to screening. Please refer to the activity schedule for detailed information on the learning activities.

[0513] ● Patients will need to complete the 4CSS questionnaire and must have at least two “basic” symptoms (one of which must be obstruction and congestion) with a score of ≥2 at the time of screening to be eligible to participate.

[0514] ● Following screening and assessment, enrolled patients will undergo a 7-day adjustment period during which they will continue with their current treatment regimen.

[0515] ● At the time of screening, enrolled patients will receive a 4CSS daily diary, which will be completed during the 7-day integration screening period.

[0516] ●On the day of their treatment visit, patients will report their four basic symptoms. Patients with a score of ≥2 for at least two of the “basic” symptoms (one of which must be obstruction and congestion) will be excluded from the study and will not be considered uncontrollable by available treatments.

[0517] ● Video recordings of the patient's sinus mucosa will be made on the day of treatment (before treatment) and upon discharge to independently assess the inflammatory burden.

[0518] ● Patients will complete a VAS assessment of symptom burden according to the study plan.

[0519] ●The patient will complete the SNOT-22 assessment according to the study plan.

[0520] ● Intraocular pressure (IOPs) will be measured at all medical visits.

[0521] ● Up to 10 mL of BMDP CREAM is instilled onto the inflamed sinus mucosa using an endoscope. Patients receive this medication in a single dose at their office. If 10 mL cannot be inserted due to sinus structure, the actual dose is recorded by measuring the weight of the syringe before and after instillation.

[0522] ● Patients will receive a 4-basic symptom score daily diary, which must be completed daily until discharge. The overall score for the 7 days prior to discharge will be the primary measure of improvement in CRS symptoms.

[0523] ● The patient will discontinue the standard CRS treatment regimen the night before their scheduled treatment appointment and will return 5 days after treatment for a safety assessment before resuming standard treatment.

[0524] ●Patients returned to the clinic 21 days after treatment for evaluation, safety assessment, and withdrawal from the study.

[0525] ●The first six of the 25 patients planned to be recruited will participate in the cream retention group of this study. These six patients will return daily until no more cream is visible in the sinus cavity.

[0526] ●Assessment:

[0527] Morning cortisol levels will be measured in all patients before treatment, on day 5, and on day 21 (after withdrawal from treatment).

[0528] ○ Fasting blood glucose levels will be measured in the first six patients before treatment, on day 5, and on day 21 (after withdrawal from treatment).

[0529] ○ The cream residue from the first six patients each day was retained until it was no longer visible (and for all patients, on days 5 and 21).

[0530] Inclusion criteria:

[0531] 1. Healthy adults, 18-80 years old

[0532] 2. Patients who have undergone functional endoscopic sinus surgery within at least 6 months prior to enrollment.

[0533] 3. Clinically diagnosed chronic rhinosinusitis

[0534] 4. Try a topical corticosteroid spray or rinse at least once a month before screening, with no adverse reactions.

[0535] 5. Able to provide informed consent and comply with research conditions.

[0536] 6. Women of childbearing age must use appropriate methods of contraception and must not intend to become pregnant during the study.

[0537] 7. Patients whose condition is stable after taking other nonsteroidal anti-inflammatory drugs.

[0538] 8. Patients must have at least two “basic” symptoms (one of which must be obstruction and congestion) with a score of ≥2 at the time of screening to be eligible to participate in the study and treatment.

[0539] Exclusion criteria:

[0540] 1. Pregnant or breastfeeding women

[0541] 2. Patients who have undergone any sinus surgery within 6 months prior to enrollment.

[0542] 3. Acute sinusitis

[0543] 4. Uncontrolled asthma

[0544] 5. Medical history or current glaucoma or cataracts

[0545] 6. Hypersensitivity or contraindications to betamethasone dipropionate, corticosteroids, or local anesthetics.

[0546] 7. Application of treatment for sinus abnormalities, diseases, or implanted devices.

[0547] 8. Those who have previously participated in this study

[0548] 9. Unable to provide informed consent or comply with the research protocol

[0549] 10. If they had abnormal IOP (abnormal IOP defined as greater than 21 mm Hg) before screening or treatment.

[0550] 11. Diabetes

[0551] For the 4-CSS diary, the ratings for “congestion and congestion,” “facial pain and pressure,” “nasal discharge,” and “loss of smell” will be “none,” “mild,” “moderate,” or “severe.” The VAS will have the patient assess total sinus symptoms, nasal congestion, headache / facial pressure, loss of smell, postnasal drip (secretions from the nose to the throat), runny nose, itchy eyes, itchy nose, sneezing, tearing, coughing, chest tightness / pressure, shortness of breath / difficulty breathing, and wheezing ranging from “none” to “more than I expected.” For symptoms such as needing to blow one's nose, nasal congestion, sneezing, runny nose, cough, postnasal discharge, thick nasal discharge, ear fullness, dizziness, earache, facial pain / pressure, decreased sense of smell / taste, difficulty falling asleep, waking up at night, lack of sleep, feeling tired upon waking, fatigue, decreased productivity, poor concentration, depression / irritability / anger, sadness, and embarrassment, SNOT-22 rates them as "No problem (0)", "Very minor problem (1)", "Mild or minor problem (2)", "Moderate problem (3)", "Severe problem (4)" or "Problem as severe as possible (5)", with another symptom being the most important (maximum 5).

[0552] Example 15: Phase II Human Study

[0553] A phase 2 randomized, double-blind, multicenter, placebo-controlled, single-dose safety, pharmacokinetics, and efficacy study will be conducted on betamethasone dipropionate (equivalent to 0.05% w / w betamethasone) cream for the treatment of chronic rhinosinusitis in patients who have previously received FESS.

[0554] Sixty randomized patients (1:1 positive: placebo) aged 18 to 80 years will be recruited who have been diagnosed with chronic rhinosinusitis with uncontrolled symptoms for at least 30 days and have previously undergone FESS surgery at least 6 months prior to enrollment.

[0555] This is a prospective, randomized, double-blind, multicenter, placebo-controlled clinical study investigating the efficacy and safety of BMDP CREAM application to the sinus mucosa of patients aged 18 to 80 years diagnosed with uncontrolled CRS after FESS. To be considered a patient with uncontrolled CRS after FESS, they must have a prior diagnosis of CRS and have been actively treating their rhinosinusitis symptoms, which must have persisted for the past 30 days. FESS surgery must have been performed at least 6 months prior to screening.

[0556] Patients will complete the 4CSS questionnaire and must have at least two “basic” symptoms (one of which must be obstruction and congestion) with a score of ≥2 at the time of screening to be eligible to participate.

[0557] Following screening and assessment, enrolled patients will undergo a 7-day adjustment period during which they will continue to use their current treatment regimen.

[0558] During screening, enrolled patients will receive a 4CSS daily diary, which must be completed at home every day during the 7-day adjustment screening period.

[0559] During treatment visits, patients will report their four basic symptoms, and patients with a score of ≥2 for at least two of the “basic” symptoms (one of which must be obstruction and congestion) are considered to have failed the screening.

[0560] Before treatment and upon discharge, videos of the patient's sinus mucosa will be recorded to independently assess the inflammatory burden.

[0561] The patient will complete a VAS assessment of symptom burden.

[0562] Enrolled patients will receive a single dose at their office (or at the clinical research unit, CRU). Patients will receive a 4-basic symptom score daily diary, which will be completed daily until discharge. Up to 5 mL of betamethasone dipropionate cream will be placed on the inflamed sinus mucosa of both sinuses (total 10 mL). The cream will be pre-filled into a syringe during manufacturing and applied topically to the inflamed sinus mucosa via an applicator attached to the syringe. Placement will be performed with the aid of a nasal endoscope.

[0563] Patients will discontinue their regular sinusitis treatment regimen after applying BETACREAM and resume regular treatment 5 days after treatment.

[0564] Patients returned to the clinic 21 days after treatment for evaluation, safety assessment, and withdrawal from the study.

[0565] Inclusion criteria:

[0566] 12. Healthy adults, 18-80 years old

[0567] 13. Patients who have undergone functional endoscopic sinus surgery within at least 6 months prior to enrollment.

[0568] 14. Clinically diagnosed chronic rhinosinusitis

[0569] 15. Try a topical corticosteroid spray or rinse at least once a month before screening, with no adverse reactions.

[0570] 16. Able to provide informed consent and comply with research conditions.

[0571] 17. Women of childbearing age must use appropriate methods of contraception and must not intend to become pregnant during the study.

[0572] 18. Patients whose condition is stable after taking other nonsteroidal anti-inflammatory drugs.

[0573] 19. Patients must have at least two “basic” symptoms (one of which must be obstruction and congestion) with a score of ≥2 at the time of screening to be eligible to participate in the study and treatment.

[0574] Exclusion criteria:

[0575] 20. Pregnant or breastfeeding women

[0576] 21. Patients who have undergone any sinus surgery within 6 months prior to enrollment.

[0577] 22. Acute sinusitis

[0578] 23. Uncontrolled asthma

[0579] 24. Medical history or current glaucoma or cataracts

[0580] 25. Hypersensitivity or contraindication to betamethasone dipropionate, corticosteroids, or local anesthetics.

[0581] 26. Application of treatment for sinus abnormalities, diseases, or implanted devices that hinder treatment.

[0582] 27. Those who have previously participated in this study

[0583] 28. Unable to provide informed consent or comply with the research protocol

[0584] 29. If they had abnormal IOP (abnormal IOP defined as greater than 21 mm Hg) before screening or treatment.

[0585] 30. Diabetes

[0586] Main objectives:

[0587] Security:

[0588] Comparison of adverse events in the active treatment group and the placebo group.

[0589] Pharmacokinetics:

[0590] PK analysis will be performed on the subgroups of patients participating in this study.

[0591] Therapeutic effects:

[0592] Based on the clinical results and regulatory discussions of the OT-007 study, one of the following potential endpoints may be used as the primary efficacy endpoint, while other potential endpoints will be used as secondary or exploratory endpoints:

[0593] ● The change in the 7-day average daily total symptom score during the screening adjustment period was compared with the 7-day average daily total score 7 days before the patient's withdrawal from the consultation using the 4-basic symptom score (4CSS) daily diary. The 4CSS is a comprehensive score of the basic symptoms of CRS in patients with a CRS score of 0-3, with a total score of 12 points. The four "basic" symptoms are: (1) obstruction and congestion; (2) facial pain and pressure; (3) nasal discharge; and (4) loss of smell (anosmia).

[0594] ● Changes in total SNOT-22 score between before treatment and day 21 after treatment.

[0595] ● Changes in 4CSS VAS scores between before treatment and 21 days after treatment.

[0596] ● Changes in modified Lund-Mackay endoscopic scores based on video assessments by three independent, blinded ENTs (pre-treatment vs. day 21).

[0597] Exploratory endpoint:

[0598] ●Adverse events related to BMDP CREAM

[0599] Adverse events related to BMDP CREAM application

[0600] Example 16: Stability Testing

[0601] Betamethasone dipropionate (0.05%) cream was prepared as described in Table 28, but using 1.75% glycerin and stored for one or three months at 25°C / 60% RH (sample #1), 30°C / 65% RH (sample #2), or 40°C / 75% RH (sample #3). The contents of betamethasone dipropionate (BMDP) and betamethasone (BA) were measured at the beginning of storage and at one- or three-month intervals. The pH of the pure formulation and the 1:5 dilution were also measured at the beginning of storage and at one- or three-month intervals. Particle size and sphere size were measured at the beginning of storage and at one- or three-month intervals, according to USP 729. Impurities were also measured at the beginning of storage and at one- or three-month intervals. Viscosity was also measured at the beginning of storage and at one- or three-month intervals. Osmolarity was also measured at the beginning of storage and at one- or three-month intervals, according to USP 785.

[0602] The results of the stability study are shown in Tables 40-46.

[0603] In short, HPLC was used to measure the content of betamethasone dipropionate and betamethasone, as well as impurities / degradation products. Two samples were prepared. 2 g of cream was weighed into a 50 mL centrifuge tube, 3.0 mL of diluent (ethanol) was added, and 3.0 mL of IS working stock solution was added to the tube. To prepare the IS working stock solution, approximately 16.7 mg of prednisone reference standard was weighed into a 50 mL volumetric flask and dissolved to volume using diluent (ethanol) via sonication as needed, followed by mixing to obtain the IS stock solution. Then, 12.0 mL of the IS stock solution was transferred to a 100 mL volumetric flask and diluted to volume with diluent (ethanol) to obtain the IS working stock solution. The 50 mL tube was then vortexed for approximately 30 seconds and placed in a 70°C water bath for 15 minutes to dissolve the cream via intermittent cortisolization after approximately 7 minutes. The 50 mL tube was then removed from the heat source and vortexed again for 30 seconds. If necessary, return the tube to the water bath to prevent cooling. Then shake the tube for 20 minutes and place it in the refrigerator for 15 minutes to allow the petroleum jelly in the cream to solidify in the tube. Then centrifuge the tube at 12,000 RPM for 30 minutes and transfer the supernatant to an HPLC vial for analysis.

[0604] After each run, the HPLC system was rinsed with a 50:50 acetonitrile:water solution to remove buffer salts. In some cases, a syringe wash with 100% ethanol was used. HPLC was run using a Hypersil ODS 10 x 30 mm, 3 μm column as a guard column and a Hypersil ODS 3 x 150 mm, 3 μm column as the analytical column. The column temperature was maintained at 35 °C, the run time was 45 min, the flow rate was 0.5 mL / min, the injection volume was 3 μL, the autosampler temperature was 30 °C, and identification tests were performed using a 254 nm (UV absorbance) detector and a PDA collecting samples from 200 nm to 400 nm.

[0605] Mobile phase A was prepared as an 88:12 buffer:acetonitrile solution, wherein the buffer was prepared from 6.6 g of diammonium phosphate in 1 L of water, and the pH was adjusted to 7.00 + / - 0.05 using phosphoric acid. Mobile phase B was prepared as an 88:12 methanol:acetonitrile solution. Mobile phase C was prepared as a 30:5:65 buffer:methanol:acetonitrile solution. All mobile phase solutions were thoroughly mixed and degassed before use. Additionally, approximately 33.4 mg of betamethasone dipropionate reference standard was weighed into a 25 mL volumetric flask, dissolved to volume in diluent, and sonicated to dissolve and mix thoroughly to prepare a betamethasone dipropionate stock standard solution (BD stock solution). A working standard solution was prepared in a 50 mL volumetric flask from 3.0 mL of IS stock solution and 8.0 mL of BD stock solution. 150 mg of benzyl alcohol reference standard was added to the flask, and diluent was added to volume, followed by thorough mixing. Prepare a sensitivity solution from 5.0 mL of working standard solution in a 100 mL volumetric flask, dilute to volume with diluent, mix thoroughly, then transfer 1.0 mL of the resulting solution to a 100 mL volumetric flask, dilute to volume with diluent, and mix thoroughly.

[0606] To prepare Peak ID standards, weigh 5 mg of each impurity standard into a separate 100 mL volumetric flask, dissolve completely to volume with diluent, and then dilute 1.0 mL of each stock impurity solution together to 100 mL in a new volumetric flask, and dilute to volume with diluent. The impurities include betamethasone and betamethasone dipropionate from Sigma-Aldrich, as well as reference standards for betamethasone 21-acetic acid-17-propionate, betamethasone 21-propionate, betamethasone dipropionate EP impurity B, betamethasone dipropionate EP impurity F, betamethasone dipropionate EP impurity G, betamethasone dipropionate EP impurity I, and 6-bromo-betamethasone-17,21-dipropionate.

[0607] The gradient procedure and injection sequence used are provided in Table 37 below. System suitability requirements are outlined in Table 38. Peak identification parameters are provided in Table 39 below.

[0608] The RT (RRT) ratio in Table 39 can be calculated as the ratio of the sample retention time to the average retention time of the bracketed standard. The %LC is calculated as follows: peak area response ratio in the sample multiplied by the weight of the reference standard (mg), the purity of the reference standard (decimal), the dilution of the standard solution, the volume of the sample solution (mL), multiplied by 100, then divided by the average peak area response ratio of the bracketed standard divided by the volume of the standard solution (mL), divided by the weight of the sample (mg), and divided by the sample's label statement (% w / w / 100%). The % of related substances can be calculated as: peak area of ​​the related substance in the sample injection multiplied by 100, divided by the peak area of ​​betamethasone dipropionate in the sample injection, divided by the relative response factor of the related substance (assumed to be 1.0).

[0609] Table 37: Gradient Procedure and Injection Sequence

[0610]

[0611] Table 39: Peak Identification

[0612] Label Compound Name ~RT (minutes) ~RRT(BMDP) RRF - placebo related 2.154 0.14 - - placebo related 2.872 0.18 - - benzyl alcohol 3.848 0.24 - - BA-2 4.986 0.31 - - placebo related 5.411 0.34 - - Prednisone (internal standard) 6.185 0.39 - 1 Betamethasone 8.093 0.50 1.00 5 Betamethasone 17-propionate (Impurity B) 11.465 0.71 1.00 4 Betamethasone 21-propionate 11.890 0.74 1.00 3 Betamethasone 21-acetic acid 17-propionate 13.982 0.87 1.00 - Betamethasone dipropionate 16.050 1.00 - 6 Betamethasone dipropionate (Impurity F) 16.348 1.02 1.00 8 Betamethasone dipropionate (Impurity I) 17.165 1.07 1.00 2 Betamethasone dipropionate 17.658 1.10 1.00 7 Betamethasone dipropionate (Impurity G) 19.577 1.22 1.00 9 6-Bromo-betamethasone-17-21-dipropionate 20.394 1.27 1.00

[0613] Table 40: Content of Betamethasone Dipropionate (BMDP) and Betamethasone (BA)

[0614]

[0615]

[0616] *Not up to standard

[0617] Table 41: pH stability of betamethasone dipropionate cream formulations

[0618]

[0619] Table 42: Particle size (μm) of betamethasone dipropionate cream formulation

[0620]

[0621] Table 43: Microsphere size (μm) of betamethasone dipropionate cream formulation

[0622]

[0623]

[0624] Table 44A: Impurities in betamethasone dipropionate cream formulations (stored at 25°C / 60% RH)

[0625]

[0626] Table 44B: Impurities in betamethasone dipropionate cream formulations (stored at 30°C / 65% RH)

[0627]

[0628]

[0629] Table 44C: Impurities in betamethasone dipropionate cream formulations (stored at 40°C / 75% RH)

[0630]

[0631]

[0632] Table 45: Viscosity (cP) of Betamethasone Dipropionate Cream Formulation

[0633]

[0634]

[0635] Table 46: Osmolarity (mOsm / kg) of betamethasone dipropionate cream formulation

[0636]

[0637] Example 17: Cream formulations containing other active agents

[0638] Aqueous phase of mometasone furoate monohydrate (batch number 2021-06-03) cream formulation was prepared by distributing 144.82 g of water into a mixer with a 4-bladed propeller to approximately half-full height and then mixing at 200-300 rpm to dissolve 0.125 g of disodium EDTA and 4.37 g of glycerin in water. 1.502 g of Carbopol 980 was added by sprinkling a layer on the surface and pulsating the mixer 2-5 times after each addition. The mixture was then mixed at 800-1000 RPM for 30 minutes, rotating the beaker every 5-10 minutes. 43.08 g of 1% NaOH was added while mixing at approximately 1000 RPM, and the mixture was QS-reduced to 250 g with water. When mixing at 200-300 RPM, add 12.51 g of polysorbate 80 and mix at about half height for about 45 minutes, mixing "shake" every 5-10 minutes.

[0639] The oil phase of the mometasone furoate monohydrate cream formulation was prepared as follows: 2.5 g of polyethylene glycol 40 stearate, 2.5 g of cetyl alcohol, 1.25 g of glyceryl monostearate, 20.00 g of petrolatum, and 7.51 g of Span 20 were added to a beaker equipped with a stir bar. The mixture was heated to 65 + / - 5 °C and mixed for about 15 minutes until most of the solids melted (setting: 80 °C; 100-350 RPM). Then, the mixture was slowly stirred for about 10 minutes until homogeneous (setting: 75 °C; 50-100 RPM).

[0640] The aqueous phase is then mixed with the disc impeller blades for about 5 minutes and heated to 62 + / - 3°C at the highest RPM (about 1200+ RPM) that does not cause foaming, and allowed to stand for about 30 minutes for heating. 0.125 g of mometasone furoate monohydrate is added to each aqueous and oil phase, and they are then mixed for about 10-15 minutes.

[0641] Adjust the blades in the aqueous phase to half-height and mix at a high shear rate of approximately 1800 RPM. Add the oil phase to the hot water phase and remove the mixture from the heat source. Stir the mixture for approximately 45 minutes, "shaking the milkshake" every 5–10 minutes. Then add 2.24 g of benzyl alcohol to the combined mixture and mix at a high shear rate of approximately 1800 RPM, followed by stirring at approximately 1200 RPM for approximately 30 minutes, "shaking the milkshake" every 5–10 minutes. Measure the pH (pH 5.958), perform a QS test on the mixture with additional water for water loss, and mix for approximately 10 minutes, "shaking the milkshake" every 3–5 minutes.

[0642] In the absence of mometasone furoate monohydrate, a placebo cream (batch number 2020-11-01) was prepared similarly using 0.125 g disodium EDTA, 4.389 g glycerin, 1.501 g carbopol 980, 43.10 g 1% NaOH, 12.46 g polysorbate 80, 2.5 g polyethylene glycol 40 stearate, 2.5 g cetyl alcohol, 1.25 g glyceryl monostearate, 20.00 g petrolatum, 7.51 g Span 20, and 2.26 g benzyl alcohol. The pH of the cream was 5.953.

[0643] Fluticasone propionate cream was prepared similarly using 0.1253 g disodium EDTA, 4.39 g glycerin, 1.5009 g Carbopol 980, 43.06 g 1% NaOH, 12.51 g polysorbate 80, 2.5 g polyethylene glycol 40 stearate, 2.5 g cetyl alcohol, 1.25 g glyceryl monostearate, 20.00 g petrolatum, 7.5 g Span 20, 2.24 g benzyl alcohol, and 12.517 g fluticasone propionate. This cream was assigned batch number 2021-07-01. Another batch, totaling 200g, was prepared using 0.100g disodium EDTA, 3.5g glycerin, 1.201g Carbopol 980, 34.38g 1% NaOH, 10.01g polysorbate 80, 2g polyethylene glycol 40 stearate, 2g cetyl alcohol, 1g glyceryl monostearate, 16.00g petrolatum, 6g Span 20, 1.81g benzyl alcohol, and 100.1g fluticasone propionate. This cream was assigned batch number 2021-07-02. The final pH values ​​for the two creams were 5.961 and 5.964, respectively.

[0644] The cream was degraded and impurities were analyzed using HPLC. The following parameters were used for the analysis of mometasone furoate monohydrate.

[0645] Table 47: HPLC parameters

[0646]

[0647] Degradation of pure mometasone furoate monohydrate (MFM) material and analysis of potential chromatographic interferences were performed. Briefly, pure MFM was exposed to various conditions to induce degradation, including heat (60°C / 5 days), light (6 inches from a white desk lamp for 5 days), acid (0.1N HCl for 1 hour, followed by neutralization with 0.1N NaOH), alkali (0.1N NaOH for 1 hour, followed by neutralization with 0.1N HCl), and oxidation (3% H₂O₂ for 1 hour). All samples, including degraded samples, control samples (dissolved in HPLC-grade methanol), and reference solutions, were analyzed.

[0648] For each condition, the recovery percentage is provided in Table 48 below.

[0649] Table 48: Percentage recovery of MFM under each degradation condition

[0650] Degradation methods acid alkali peroxide hot Light Comparison Actual amount (μg mL) 240.289 6.091 262.576 249.211 249.916 254.279 Theoretical quantity (μg mL) 251.550 252.10 266.950 253.450 252.70 255.60 Recovery rate percentage 95.52 2.42 98.36 98.33 98.90 99.48

[0651] Table 49 below provides the relative retention time (RRT) of the samples and the detection rate of ≥0.05%.

[0652] Table 49: Peak Table of MFM Degradation Products (Degraded Pure Material)

[0653]

[0654] Pure MFM material and degraded material were spiked into placebo cream (batch number 2020-11-01) to investigate potential partitioning effects and peak interference. Spiked and active cream samples were compared using the procedure in Table 50, with the difference being that the amounts of HCl, NaOH, and peroxide added were calculated accordingly for acid, alkali, and peroxide degradation.

[0655] Table 50: Extraction Procedure

[0656]

[0657]

[0658] The recoveries of the forced degradation material spiked into the placebo are provided in Table 51 below, while the recoveries of the active cream formulation (0.1% MFM) are provided in Table 52 below. The total MFM-related peak areas are provided in Table 53 below.

[0659] Table 51: Recovery rates of forced degradation materials spiked into placebo

[0660]

[0661] Table 52: Recovery rate of active cream formulation (0.1% MFM)

[0662] Material Storage conditions MFM recovery rate placebo difference Active cream (0.1% MFM) Keep at room temperature in the dark 84.02％ 0％ 84.02％

[0663] Table 53: Area of ​​total MFM-related peaks

[0664]

[0665] These results indicate that MFM was not properly degraded due to the cream-making process, as a common peak at RRT = 0.96 (relative to MFM) was identified in the forced degradation analysis.

[0666] A similar analysis was performed on 0.005% fluticasone propionate cream (batch number 2021-07-01). HPLC parameters are provided in Table 54.

[0667] Table 54: HPLC parameters

[0668]

[0669] Table 55 below provides the percentage recovery of fluticasone propionate under each forced degradation condition.

[0670] Table 55: Percentage recovery of fluticasone propionate under each forced degradation condition

[0671] Degradation methods acid alkali peroxide hot Light Comparison Actual amount (μg / mL) 12.1791 11.7484 16.4961 12.0739 11.6609 12.5695 Theoretical amount (μg / mL) 12.4997 12.5000 17.8514 12.4998 12.4999 12.4999 Recovery rate percentage 97.44 93.99 92.41 96.59 93.29 100.6

[0672] The extraction procedure is provided in Table 56 below.

[0673] Table 56: Extraction Procedure

[0674]

[0675]

[0676] The percentage recovery of the forced degradation material spiked into the placebo is provided in Table 57 below. The percentage recovery of the fluticasone propionate active cream formulation is provided in Table 58 below. The peak areas of total fluticasone propionate are provided in Table 59 below.

[0677] Table 57: Percentage of recovery rate of forced degradation materials spiked into placebo

[0678]

[0679] Table 58: Percentage recovery of active cream formulations containing fluticasone propionate

[0680]

[0681] Table 59: Peak Areas Related to Total Fluticasone Propionate

[0682]

[0683]

[0684] Except for fluticasone propionate treated with peroxide, all spiked and active cream extracts produced a common peak at RRT = 1.17 (relative to fluticasone propionate). This peak was not identified in the forced degradation chromatogram or pure chromatogram and was not a relevant substance or a true degradation product. This suggests that the extraction method of the active cream, the addition of alkali, heating of the cream, or light exposure may cause degradation, supported by the peak present at RRT = 0.32, which is also present in the forced degradation samples treated with spiked acid, alkali, and light.

[0685] For all the aforementioned HPLC in this example, prednisolone was used as an internal standard.

[0686] Example 18: D value of betamethasone dipropionate cream formulation

[0687] The D value of the 0.05% betamethasone dipropionate cream prepared in Example 8 was determined by measuring the autoclaving time required to kill 90% of the bacterial reference (in this case, Bacillus substilis "S230") at a specific temperature. The autoclaving temperatures used included 110°C, 115°C, and 121°C, with time ranges of 0 to 8 minutes (110°C), 0 to 4 minutes (115°C), and 0 to 3 minutes (121°C).

[0688] The exposure data is provided in Table 60 below.

[0689] Table 60: Exposure Data

[0690]

[0691] In a 3.0 mL syringe, based on the best-fit line of the survival curve, D was found... 110 The value was 1.6 minutes, and D was also found. 115 The value was 0.8 minutes and D was found. 121 The value is 0.6 minutes.

[0692] All references cited in this article (including publications, patent applications and patents) are hereby incorporated by reference to the same extent that each reference is individually and specifically indicated by reference and incorporated by reference and is presented in its entirety in this article.

[0693] Unless otherwise stated, the terms “comprising,” “having,” “including,” and “containing” should be interpreted as open-ended terms (i.e., meaning “including but not limited to”). Unless otherwise stated herein, descriptions of value ranges herein are intended only as a shorthand for individually referring to each individual value falling within that range, and each individual value is incorporated into this specification as if it were described separately herein. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein can be performed in any suitable order. The use of any and all instances or exemplary language (e.g., “such”) provided herein is intended only to better illustrate the invention and does not constitute a limitation on the scope of the invention, unless otherwise indicated. No language in this specification should be construed as indicating that any unclaimed element is necessary for practicing the invention.

[0694] This document describes preferred embodiments of the invention, including the best modes known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those skilled in the art after reading the foregoing description. The inventors intend that those skilled in the art will adopt these variations where appropriate, and the inventors intend that the invention be practiced in ways different from those specifically described herein. Therefore, the invention includes all modifications and equivalents to the subject matter set forth in the appended claims, where permitted by applicable law. Furthermore, unless otherwise stated or otherwise clearly contradicted herein, the invention covers any combination of the foregoing elements with all possible variations.

Claims

1. A composition comprising: The tension agent, wherein the tension agent is glycerin, and wherein the amount of the tension agent present in the composition is from 1% w / w to 2.5% w / w based on the total weight of the composition; Therapeutic active agent, wherein the therapeutic active agent is betamethasone dipropionate, wherein the amount of betamethasone dipropionate present in the composition is from 0.01% w / w to 0.3% w / w based on the total weight of the composition; A viscosity modifier, wherein the viscosity modifier is carbomer, and wherein the amount of the viscosity modifier present in the composition is from 0.1% w / w to 2% w / w based on the total weight of the composition; A stabilizer, wherein the stabilizer is edetic acid or a pharmaceutically acceptable salt thereof, wherein the stabilizer is present in the composition in an amount of 0.005% w / w to 0.25% w / w based on the total weight of the composition; Emollients comprising petrolatum, wherein the petrolatum is present in the composition at an amount of 4% w / w to 10% w / w based on the total weight of the composition; and Emulsifier, wherein the emulsifier is a combination of polyoxyethylene sorbitan fatty acid ester, glyceryl monostearate, polyoxyethylene stearate, sorbitan monolaurate and cetyl alcohol, wherein the emulsifier is present in the composition at an amount of 5% w / w to 15% w / w based on the total weight of the composition; The composition thereon is a cream. The pH of the composition is 5 to 7; and The osmotic pressure of the composition is from 270 mOsm / kg to 360 mOsm / kg.

2. The composition according to claim 1, wherein the composition does not contain propylene glycol.

3. The composition according to claim 1 or 2, wherein the pH of the composition is selected from the group consisting of: 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4 and 6.

5.

4. The composition according to claim 1, wherein the stabilizer is disodium edetate.

5. The composition according to claim 1 or 2, wherein the viscosity of the composition, as measured by a Brookfield RVDVII+ with spindle 28 at room temperature, is (1) 200,000 centipoise (cP) to 2,000,000 cP at a shear rate of 0.3 RPM; (2) 100,000 cP to 1,500,000 cP at a shear rate of 0.5 RPM; (3) 100,000 cP to 1,000,000 cP at a shear rate of 0.6 RPM; (4) 50,000 cP to 800,000 cP at a shear rate of 0.8 RPM; (5) 50,000 cP to 750,000 cP at a shear rate of 1 RPM; (6) 40,000 cP to 500,000 cP at a shear rate of 1.5 RPM. (7) 30,000 cP to 250,000 cP at a shear rate of 2.0 RPM; (8) 20,000 cP to 200,000 cP at a shear rate of 2.5 RPM; (9) 20,000 cP to 200,000 cP at a shear rate of 3.0 RPM; (10) 15,000 cP to 150,000 cP at a shear rate of 4.0 RPM; (11) 15,000 cP to 150,000 cP at a shear rate of 5.0 RPM; (12) 10,000 cP to 100,000 cP at a shear rate of 6.0 RPM; (13) 8,000 cP to 70,000 cP at a shear rate of 10.0 RPM; (14) at 12.0 RPM. (15) 1,000 cP to 40,000 cP at a shear rate of 20.0 RPM; (16) 1,000 cP to 20,000 cP at a shear rate of 30.0 RPM; (17) 500 cP to 15,000 cP at a shear rate of 50.0 RPM; (18) 500 cP to 10,000 cP at a shear rate of 60.0 RPM; or (19) 250 cP to 7,000 cP at a shear rate of 100.0 RPM.

6. The composition according to claim 1, wherein the composition is an oil-in-water emulsion.

7. The composition according to claim 6, wherein the oil globules of the composition are less than 5 µm, 4 µm, 3 µm, 2 µm or 1 µm in number or volume average.

8. The composition according to claim 1, wherein the composition is sterile.

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