Corticosteroid nano-suspension and its use

Abstract

A suspension formulation of clobetasol propionate nanoparticles is described. This suspension can be used therapeutically to treat burns of the skin and eyes, to promote wound healing, to prevent or reduce hypertrophic scarring / keloids, and to treat allergic rhinitis / sinusitis, asthma, inner ear disorders (including hearing loss, tinnitus, or dizziness), tenosynovitis, tendinitis, enthesitis, or arthritis.

Description

[Technical Field]

[0001] The inventions described herein relate to suspension formulations of corticosteroid nanoparticles such as clobetasol propionate, and methods for treating thermal injuries of the skin or eyes, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, and arthritis. [Background technology]

[0002] Treatment of thermal damage

[0003] Burns are injuries to the skin or other tissues, including the tissues of the eyes, and are caused by a number of factors that damage cellular structure. The severity of thermal burns can vary depending on the extent of tissue damage and can lead to widespread tissue inflammation, cell death, and necrosis. Treatment of dermal burns depends on the type and severity of the burn. In more severe cases, intensive care is required to improve the healing process and reduce complications such as hypertrophic scarring, skin contractures, keloids, and deformities.

[0004] Burns of the eye can be particularly problematic because the damage can cause irreversible damage to the cornea and other structures within the eye, potentially significantly impacting vision. The cornea is the primary refractive tissue at the front of the eye. Normally, the cornea is avascular and consists of a thin anterior epithelial layer, a thin posterior endothelial layer, and a highly complex stromal layer that makes up about 90% of the corneal thickness. Corneal transparency is essential for allowing light to enter the eye and reach the photosensitive cells of the retina at the back of the eyeball. Corneal transparency is achieved by having a cellular stromal layer in which several types of collagen fibers and other extracellular matrix molecules are highly ordered and structured. When this complex stromal organization is disrupted by mechanical damage, inflammation, edema, or neovascularization, the cornea becomes increasingly cloudy, and vision can be severely impaired. Therefore, to avoid vision loss, it is necessary to reduce and / or prevent inflammation, edema, neovascularization, and the breakdown of stromal matrix proteins after thermal damage. Current treatments are not entirely effective in restoring these structures to normal.

[0005] Because inflammation and abnormal healing processes can lead to long-term complications, the healing process should be carefully monitored regardless of the type of burn. For example, in cases of skin thermal injuries, hypertrophic scarring, skin contractures, and abnormal pigmentation can significantly impact the patient's quality of life. Thermal injuries to the eye can affect the conjunctiva, sclera, cornea, and even extraocular tissues such as the eyelids, and can become an ophthalmic emergency requiring rapid evaluation and therapeutic intervention to preserve vision by minimizing inflammation and the accumulation of substances that block light from entering the eye. Treatment and management methods for thermal injuries are continuously needed, including those focused on reducing the extent of scarring, accelerating the healing process, and restoring and preserving vision.

[0006] Treatment of abnormal wound healing

[0007] Skin wounds typically heal in four stages: hemostasis, followed by inflammation, cell proliferation, and subsequent remodeling. Scar tissue is formed during the remodeling stage. Usually, small, shallow wounds heal by forming new skin that fuses with the surrounding tissue. Wounds deeper than the dermis require more extensive connective tissue remodeling and collagen deposition to repair the wound, which can result in permanent scarring. Some skin injuries result in prolonged, excessive inflammation and are associated with abnormal wound healing. There is also a genetic predisposition to excessive scarring and keloid formation. Current treatments for hypertrophic and keloid scars, including laser therapy, antiproliferative drug injections such as bleomycin and 5-fluorouracil, and cryotherapy, offer only limited effectiveness. Conventional steroid injections are limited because they do not prevent the progression of scarring, cosmetic problems, and motor impairment, and require repeated painful injections to achieve suboptimal effectiveness. Therefore, more effective treatments are needed to prevent scarring that impairs appearance.

[0008] Treatment for allergic rhinitis / sinusitis

[0009] Allergic rhinitis and sinusitis (rhinitis / sinusitis) are common types of allergies that can be caused by seasonal or non-seasonal allergens. Acute hypersensitivity reactions to allergens are characterized by sneezing, runny nose, itching of the eyes, nose, and palate, congestion of the nose and sinuses, postnasal drip, cough, airway obstruction, and other debilitating symptoms. While mild symptoms of allergic rhinitis / sinusitis can be managed with conventional treatments, in some cases these treatments are insufficient, and therapeutic intervention is necessary to prevent severe complications such as airway obstruction. Therapeutics and management methods for allergic rhinitis / sinusitis are continuously needed.

[0010] Treatment for asthma

[0011] Asthma is a chronic disease affecting the lungs, characterized by the presence of inflammation, narrowing of the airways, and bronchoconstriction, causing wheezing, chest tightness, shortness of breath, and cough. While the exact cause of asthma is not fully understood, there may be a genetic predisposition to environmental stimuli such as allergens, cigarette smoke, other harmful gases, and suspended particulate matter. The release of inflammatory mediators after exposure to these factors contributes to bronchospasm, airway edema, and abnormal mucus production, resulting in characteristic asthma symptoms. In some cases, conventional steroid preparations can be used, but generally, they need to be administered concurrently with beta-adrenergic receptor agonists to alleviate airway inflammation and asthma symptoms. However, in many cases, current drug therapy is insufficient to prevent asthma attacks, and therefore, excessively high doses and concurrent administration of long-acting beta-agonists are required. Thus, continuous research and development of asthma treatment and management methods are necessary.

[0012] Inner ear disorders

[0013] Disorders of the inner ear can manifest as hearing loss, dizziness, and tinnitus, affecting many adults, especially the elderly. When tinnitus, hearing loss, and dizziness occur simultaneously, they are called Meniere's disease. Such inner ear disorders are often accompanied by endolymphatic hydrops, which is a dilation of the endolymphatic compartment of the inner ear. No pharmacological treatments to prevent or treat hearing loss, dizziness, or tinnitus have yet been approved by the U.S. Food and Drug Administration. Because the etiology of these symptoms is unknown, many of the proposed treatments are ineffective, limited, or have severe side effects. Therefore, there is a continuing need for treatment and management methods for hearing loss, tinnitus, and dizziness.

[0014] Treatment of tenosynovitis, tendinitis, enthesitis, and arthritis

[0015] Tenosynovitis is inflammation of the tendon within the synovial sheath, while enthesitis is inflammation of the site where a tendon or ligament attaches to a bone. Tendons moving within the sheath or at their attachment to the bone can be irritated by trauma or repetitive or excessive movement, causing painful inflammation and significantly limiting function. Chronic inflammation can lead to swelling and / or fibrosis of the tendon sheath, reducing the space for the tendon and causing conditions such as "trigger finger" or nerve compression, as in the case of carpal tunnel syndrome. Repetitive joint movements or impact from vibrating tools can trigger an inflammatory process in the tendon sheath or attachment point, which can occur in the hands or feet and affect individuals in many occupations.

[0016] Medical treatment for tenosynovitis, tendinitis, and enthesitis includes the use of splints to reduce tendon movement and corticosteroid injections. In some cases, if tendon pain and dysfunction do not respond favorably to rest and anti-inflammatory treatment, surgery may be necessary, but this can be very painful and may lead to further fibrosis and long-term complications.

[0017] Arthritis is the most common cause of physical disability in the United States, causing pain and inflammation in the joints and affecting more than 50 million people of all ages, including children. Osteoarthritis and rheumatoid arthritis are the two most common types of arthritis, but there are other types as well, such as ankylosing spondylitis, gout, and psoriatic arthritis. Osteoarthritis is the most common type of arthritis and often develops in middle-aged and older adults, but can develop at any age after joint damage. Osteoarthritis initially affects the smooth cartilage surface of the joint, restricting movement and causing pain and stiffness. If the damage to the cartilage surface continues, the joint may swell, bone spurs may form, and joint function may be destroyed. Rheumatoid arthritis is less common than osteoarthritis and is an immune-mediated injury of the joint tissue that begins in the synovial surface of the joint, resulting in pain, swelling, and joint deformation.

[0018] Symptoms of arthritis include joint pain, tenderness and stiffness, inflammation within and around the joint, limited joint movement, redness of the skin with warmth over the affected joint, weakness, and muscle wasting. There is no cure for arthritis, but current treatments, including lifestyle changes, medication, physiotherapy, and surgery, may be useful in slowing joint damage. Treatment options depend on the severity of the arthritis, the symptoms, and the patient's overall health, but in many cases, symptoms and signs do not improve. Surgical interventions, including bone fusion to immobilize the joint and reduce pain caused by movement, or artificial joint replacement to maintain joint function and movement, remain the only option in certain severe cases of arthritis. Therefore, treatments and methods for osteoarthritis, rheumatoid arthritis, and other less common types of arthritis are still needed. [Overview of the Initiative]

[0019] In an exemplary embodiment of the present invention, a composition comprising a nanoparticle suspension of corticosteroids and / or glucocorticoids, and the use of the composition for manufacturing pharmaceuticals and compositions for treating diseases are described herein. Exemplary diseases include thermal injuries of the skin or eyes, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, and arthritis.

[0020] This specification has shown that thermal injuries of the skin or eyes, abnormal wound healing, allergic rhinitis / sinusitis, inner ear disorders (including asthma, hearing loss, tinnitus and dizziness), tenosynovitis, tendinitis, enthesitis, and arthritis (including osteoarthritis and rheumatoid arthritis) can be more effectively treated with nano-suspension formulations of glucocorticoids, such as but not limited to clobetasol propionate. Such glucocorticoids are formulated as nanoparticle suspensions that can be applied topically, administered orally, administered parenterally by injection, injected intratympanically; injected around joints, synovial spaces, or tendon attachments; or administered as sprays, aerosols, or drops into the nasal cavity, respiratory system, or external auditory canal.

[0021] In another embodiment, compositions comprising nanosuspensions of glucocorticoids for use in the treatment of thermal injuries of the skin or eyes, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders (including hearing loss, dizziness and tinnitus), tenosynovitis, tendinitis, enthesitis and arthritis are described herein.

[0022] In another embodiment, methods for treating thermal injuries of the skin or eyes, abnormal wound healing, allergic rhinitis / sinusitis, asthma, and inner ear disorders are described herein. The method comprises administering an effective amount of a nanosuspension of glucocorticoid to the subject of interest.

[0023] In another embodiment, the use of a composition comprising a nanosuspension of a glucocorticoid in the manufacture of a medicament for treating thermal injury of the skin or eye, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, insertional tendinitis and arthritis is described herein.

[0024] In another embodiment, packaged articles and kits comprising a composition comprising a nanosuspension of a glucocorticoid are described herein. The packaged products and kits include instructions for using the nanosuspension in the treatment of thermal injury of the skin or eye, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, insertional tendinitis and arthritis.

[0025] Corticosteroids are clinically used to treat hearing loss, tinnitus, and dizziness, but the success rate is limited. Glucocorticoid receptors are expressed in the inner ear, including hair cells and spiral ganglion neurons. Glucocorticoids are thought to maintain hearing and treat inner ear diseases through multiple mechanisms of action, including reduction of inner ear inflammation and reactive oxygen species, activation of cell survival pathways, and reduction of apoptosis of hair cells and spiral ganglion neurons. However, the current corticosteroid treatment paradigm is not optimal due to limited efficacy related to a combination of factors including insufficient potency of corticosteroids and insufficient concentration of corticosteroids in the inner ear due to poor delivery or limited permeability. As described herein, embodiments of the present invention include the use of nanoparticle formulations containing clobetasol propionate, the most potent glucocorticoid used in clinical practice, to increase the permeation and concentration of glucocorticoids in inner ear tissue and inner ear lymph fluid.

[0026] Embodiments of the present invention include drops, sprays, mists, or aerosols for treating various types of tissue burns, such as burns due to heat, chemical exposure, sunlight exposure, or mechanical damage. The drops, sprays, mists, and aerosols are optionally attached to or included in an applicator, a burn dressing, etc. In other embodiments, the drops, sprays, mists, and aerosols minimize or relieve pain, improve healing, reduce scarring, and / or improve vision.

[0027] Embodiments of the present invention include injections into hypertrophic scars or keloids that reduce the accumulation of connective tissue, skin deformation, contracture, and improve the cosmetic appearance. Embodiments of the present invention include nasal sprays, mists, aerosols, or drops for treating allergic rhinitis / sinusitis, or inhalations into the lungs for treating asthma. In other embodiments, the sprays, mists, aerosols, or drops relieve the symptoms of allergic rhinitis / sinusitis or prevent, relieve, or stop asthma attacks.

[0028] Embodiments of the present invention include sprays or drops applied onto the tympanic membrane via the external auditory canal to treat disorders of the inner ear, specifically hearing loss, tinnitus, and dizziness. Embodiments of the present invention include intratympanic injection or intranasal administration with sprays, aerosols, or drops to treat disorders of the inner ear, specifically hearing loss, tinnitus, and dizziness. Without being bound by theory, it is believed herein that the failure of current drug therapy treatments occurs due to insufficient efficacy and limited penetration into inner ear tissue and inner ear lymph fluid, and that nanoparticle suspensions of very potent glucocorticoids such as clobetasol propionate described herein achieve higher penetration into the inner ear.

[0029] Embodiments of the present invention include aseptic injections into the synovial cavity for treating tenosynovitis, tendinitis, or aseptic injections into or around the tendon / ligament attachment point for treating insertional tendinitis. Embodiments of the present invention include aseptic injections into joints for treating arthritis.

[0030] In another exemplary embodiment, suspension formulations in the form of sprays, mists, aerosols, injections, and drops containing about 0.025% to about 0.15% w / v clobetasol propionate nanoparticles are described herein. The suspension formulations may include, but are not limited to, preservatives, disinfectants, and / or bactericides.

[0031] In another embodiment, a process for producing a nanoparticle suspension of corticosteroids and / or glucocorticoids, such as clobetasol propionate, is described herein.

[0032] It should be understood that the compositions, kits, and methods described herein may include, but are not limited to, clobetasol propionate, or one or more alternative and / or additional corticosteroids and / or glucocorticoids, including but not limited to dexamethasone, difluprednate, triamcinolone, betamethasone dipropionate, and prednisolone.

[0033] Other features and advantages of the present invention described herein will become apparent from the detailed description, together with the accompanying drawings which further illustrate the invention as non-limiting examples. [Brief explanation of the drawing]

[0034] [Figure 1] A flowchart of the steps used to produce an exemplary suspension formulation of clobetasol propionate nanoparticles is shown. [Figure 2A] This study demonstrates the efficacy of CPN 0.1% after alkaline burns to the eye in New Zealand white rabbits. Statistical differences compared to excipients are indicated by * (p<0.05). [Figure 2B] This study demonstrates the efficacy of CPN 0.1% after alkaline burns to the eye in New Zealand white rabbits. [Figure 2C] This study demonstrates the efficacy of CPN 0.1% after alkaline burns to the eye in New Zealand white rabbits. [Figure 2D]This study demonstrates the efficacy of CPN 0.1% after alkaline burns to the eye in New Zealand white rabbits. [Figure 3A] This study demonstrates the effectiveness of CPN 0.1% in treating skin burns in Yorkshire crossbred pigs. Statistical differences compared to the untreated control group are indicated by * (p<0.05). [Figure 3B] This study demonstrates the effectiveness of CPN 0.1% in treating skin burns in Yorkshire crossbred pigs. Statistical differences compared to the untreated control group are indicated by * (p<0.05). [Figure 3C] This study demonstrates the effectiveness of CPN 0.1% in treating skin burns in Yorkshire crossbred pigs. Statistical differences compared to the untreated control group are indicated by * (p<0.05). [Figure 4A] This study demonstrates the efficacy of CPN 0.1% in a hypertrophic scar model of rabbit ears. Statistical differences compared to the untreated control group are indicated by * (p<0.05). [Figure 4B] This study demonstrates the efficacy of CPN 0.1% in a hypertrophic scar model of rabbit ears. Statistical differences compared to the untreated control group are indicated by * (p<0.05). [Figure 4C] This study demonstrates the efficacy of CPN 0.1% in a hypertrophic scar model of rabbit ears. Statistical differences compared to the untreated control group are indicated by * (p<0.05). [Figure 4D] This study demonstrates the efficacy of CPN 0.1% in a hypertrophic scar model of rabbit ears. [Figure 5] Figures A and B show the efficacy of CPN 0.1% in a collagen-induced arthritis (CIA) model in male Lewis rats. Statistical differences compared to excipients are indicated by * (p<0.05). [Modes for carrying out the invention]

[0035] The following exemplary clauses illustrate additional embodiments of the invention as described herein. 1. A method for treating a subject having burns of the skin or eyes, abnormal wound healing, allergic rhinitis / sinusitis, asthma, or inner ear disorders (including but not limited to hearing loss, tinnitus, or dizziness), comprising applying a suspension formulation of clobetasol propionate nanoparticles to burns of the skin or eyes, skin wounds, mucous membranes of the nose or sinuses (in the case of allergic rhinitis / sinusitis or inner ear disorders), airways and tissues of the lungs, or the eardrum of the ear.

[0036] 2. The method according to Clause 1, wherein the formulation is applied using a dropper bottle, spray bottle or device, aerosol delivery device, or inhaler.

[0037] 3. The method according to Clause 1 or 2, wherein the burns to the skin or eyes are caused by sunburn, radiation burns, radioactive burns, electrical burns, boiling liquid burns, friction burns, chemical burns, burns caused by fire, flames, explosives, ignition of fuel or lubricant, weapons of war, or a combination thereof, and optionally, the treatment of the burns to the eyes includes long-term improvement of vision and / or visual acuity after thermal damage to the eyes.

[0038] 4. The method according to Clause 1 or 2, wherein the abnormal wound healing is caused by burns, inflammation, infection, or trauma (including surgical incision), and the treatment optionally includes reducing and / or preventing hypertrophic scarring.

[0039] 5. The allergic rhinitis / sinusitis or asthma is caused by exposure to chemicals, particulate matter, or seasonal allergens. The method according to Clause 1 or 2, wherein the inner ear disorder is caused by noise, trauma, or ototoxic chemicals, and optionally, the treatment of said allergic rhinitis / sinusitis or asthma includes the treatment or prevention of bronchospasm with reversible obstructive airway disease, the management of nasal symptoms of perennial non-allergic rhinitis, the relief of symptoms of seasonal and perennial allergic rhinitis, or any combination thereof.

[0040] 6. The method according to any one of the preceding clauses, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, or inner ear disorders, including but not limited to inflammation, pain, discomfort, swelling, corneal opacity, abnormal granulation and / or scarring, contracture, hypertrophic scarring, keloids, rhinorrhea, nasal obstruction and sinus obstruction, airway obstruction and dyspnea, hearing loss, tinnitus and dizziness.

[0041] 7. The method according to any one of the preceding clauses, wherein the suspension formulation of clobetasol propionate nanoparticles improves wound healing, relieves allergic rhinitis / sinusitis or asthma, or reduces hearing loss, tinnitus or dizziness.

[0042] 8. A method for treating a subject having a tendon / synovial disorder, including but not limited to tendinitis, synovitis, or enthesitis, or arthritis, comprising introducing a sterile suspension formulation of clobetasol propionate nanoparticles into the tympanic cavity, synovial cavity, tendon enthes, or joint of the subject, wherein the treatment optionally includes reducing inflammation around the joint, tendon, and / or ligament of the subject.

[0043] 9. A method for treating a subject having an inner ear disorder, including but not limited to hearing loss, tinnitus, or dizziness, comprising introducing a sterile suspension formulation of clobetasol propionate nanoparticles into the tympanic cavity, synovial cavity, tendon attachment, or joint of the subject, wherein the treatment optionally includes reducing cochlear hair cell loss, preserving hearing, or a combination thereof.

[0044] 10. The method according to Clause 8 or 9, wherein the preparation is introduced by injection, such as by using a syringe and needle.

[0045] 11. The method according to Clause 8 or 9, wherein inner ear damage is caused by noise, trauma, or ototoxic chemicals.

[0046] 12. The method according to Clause 8 or 9, wherein the tendon / synovial disorder is not caused by mechanical vibration, overuse, autoimmune disorder, or a combination thereof, and / or caused by an infection or infectious agent, or at least partially caused by an infection or infectious agent.

[0047] 13. The method according to Clause 8 or 9, wherein the arthritis is osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout, or psoriatic arthritis, or a combination thereof, and / or is not caused by an infection or disease, or at least not in part by an infection or disease.

[0048] 14. The method according to any one of the clauses 8 to 13, wherein the suspension formulation of clobetasol propionate nanoparticles alleviates inner ear disorders, or tendon / synovial fluid disorders, or complications of arthritis, including but not limited to hearing loss, tinnitus, dizziness, inflammation, swelling, pain, discomfort, or reduced mobility.

[0049] 15. The method according to any one of the claims 8 to 14, wherein the suspension formulation of clobetasol propionate nanoparticles reduces hearing, tinnitus, dizziness, or improves joint or tendon function.

[0050] 16. The method according to either of the preceding clauses, wherein the suspension formulation of clobetasol propionate nanoparticles is administered at least once daily for up to 52 weeks, or at least once daily for 1 to 4 weeks.

[0051] 17. A drop, spray, mist, aerosol, or injectable formulation comprising clobetasol propionate, wherein the clobetasol propionate is formulated as a suspension of nanoparticles.

[0052] 18. Drops, sprays, mists, or aerosols or injectable formulations described in Clause 17 for use in any of the methods described in Clauses 1 to 16.

[0053] 19. Drops, sprays, mists, aerosols, or injection formulations for use in any of the methods described in Clause 17 or 18 and / or Clauses 1 to 16, further comprising sodium chloride, hydrogenated soy lecithin, anhydrous citric acid, glycerin, poloxamer 407, polyvinyl alcohol (PVA), boric acid, disodium edetate dihydrate, benzalkonium chloride, methylcellulose, or sodium citrate such as trisodium citrate, or combinations thereof.

[0054] 20. Drops, sprays, mists, aerosols, or injectable formulations for use in any of the methods described in any of Clauses 17-19 and / or Clauses 1-16, further comprising antioxidants, antibacterial agents, anesthetics, analgesics, lubricants, flavoring agents, or combinations thereof.

[0055] 21. A unit dose configured for administration via transdermal, transmucosal, ocular, or injection route, comprising clobetasol propionate, wherein the clobetasol propionate is formulated as a sterile suspension of nanoparticles.

[0056] 22. The unit dose set out in Clause 21 for use in any of the methods described in Clauses 1 to 16.

[0057] 23. Unit doses for use in any of the methods described in Clause 21 or 22 and / or Clauses 1 to 15, further comprising sodium chloride, hydrogenated soy lecithin, anhydrous citric acid, glycerin, poloxamer 407, polyvinyl alcohol (PVA), boric acid, disodium edetate dihydrate, benzalkonium chloride, methylcellulose, or sodium citrate such as trisodium citrate, or combinations thereof.

[0058] definition The term "embodiment" generally refers to a descriptive example of the present invention. An embodiment may describe one or more distinguishable features, structures, and / or properties of the present invention, but not necessarily all features, structures, and / or properties. The term "aspect" generally refers to a specific feature, structure, or property of the invention as described herein. It should be understood that such aspects may appear individually or in combination. However, in any case, such aspects may be optional and are not necessarily included in the present invention.

[0059] Unless otherwise defined, all terms used herein, including technical and scientific terms, should be construed as having their common meaning in the art, including when interpreted within the context of this disclosure and in the specific context in which each term is used.

[0060] The use of examples anywhere in this Specification, including examples of any term discussed herein, is for illustrative purposes only and is not intended to further limit the scope and meaning of this Disclosure or any example of any term. Similarly, this Disclosure is not limited to the various embodiments given herein.

[0061] The terms “activator,” “active ingredient,” “active compound,” “active component,” “active pharmaceutical ingredient,” or “API” generally refer to a substance, compound, chemical, or molecule that is biologically active or otherwise induces a biological, physiological, or pharmacological effect on a target to which it is administered. In other words, an “activator” or “active ingredient” refers to one or more components of a composition to which all or part of the effects of that composition are due. Glucocorticoids may be the primary activator, or in other words, they may be the component of a composition to which all or part of the effects of that composition are due. An activator may be a secondary agent, or in other words, they may be the component of a composition to which additional parts and / or other effects of that composition are due.

[0062] The terms “effective dose” and “therapeutic effect dose” generally refer to the amount of a defined component sufficient to achieve the desired biological and / or therapeutic outcome. This may result in the alleviation or improvement of the signs, symptoms, or causes of a disease, or any other desired change in the biological system. If the desired outcome is a therapeutic response, it should be understood that the effective dose will vary depending on the specific disease or symptom to be treated or alleviated, the age, sex, weight, overall health and diet of the person being treated, the timing of administration, the rate of excretion, possible drug combinations, the dosage plan of the formulation, the size or location of the area to be treated and the form of administration, the severity of the disease condition (e.g., type, extent, and location of burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders (specifically hearing loss, tinnitus, or dizziness), tenosynovitis, tendinitis, enthesitis, or arthritis), the use of other drugs, and the method of administration. All of these can be readily determined by those skilled in the art.

[0063] The terms “to treat,” “treatment,” or “alleviate” generally refer to both therapeutic treatments and preventive or preventive measures aimed at preventing or suppressing (reducing) a pathological condition or disorder in question. If, after administration of a therapeutic dose of nanoparticle suspension according to the methods described herein, the subject exhibits an observable and / or measurable reduction or disappearance of one or more signs and symptoms of a particular disease or condition, the “treatment” is considered successful for the disease, disorder, or condition. For example, in the case of thermal injury, treatment or prevention may include reduction of the size or severity of the thermal injury, reduction of pain, acceleration of the healing process, and / or improvement of healing (e.g., reduction of scarring / granulation / pigmentation). Other examples include, in the case of abnormal wound healing, treatment or prevention may include reduction of scar tissue size, acceleration of the healing process, and / or improvement of healing. In the case of burns of the eye, treatment or prevention may include reduction of corneal opacity and improvement of vision, and in the case of allergic rhinitis / sinusitis, treatment or prevention may include reduction of symptoms such as runny nose, itching, and nasal congestion. In cases of asthma, treatment or prevention may include relief of bronchoconstriction, wheezing, shortness of breath, chest tightness, pain, or cough. In cases of inner ear disorders, treatment or prevention may include improvement of hearing, dizziness, and tinnitus. In cases of tenosynovitis, tendinitis, enthesitis, and arthritis, treatment or prevention may include relief of pain, swelling, and deformity, as well as improvement of mobility.

[0064] The term "administration" generally refers to introducing a given amount of a substance into or onto the body of a subject by a specific and appropriate method. The compositions disclosed herein may be administered via any of the common routes, including, for example, adding drops to the eyes, spraying, or applying drops to the surface of the eyes, skin or mucous membranes, or to the eardrum through the external auditory canal, or by local administration such as injection into the synovial cavity, attachment points of tendons or ligaments, or joints or scars, or intratympanic injection.

[0065] As used herein, the term “pharmaceutically acceptable” means that the composition is sufficient to achieve a therapeutic effect without adverse side effects, which can be readily determined depending on the type, severity and location of the burn, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders (specifically hearing loss, tinnitus or dizziness), tenosynovitis, tendinitis, enthesitis or arthritis, the age, weight, health status, sex, drug sensitivity, mode of administration, frequency of administration, duration of treatment, drugs used in combination with or concurrently with the compositions disclosed herein, and other factors known in medicine.

[0066] The terms "burn" and "burn condition" generally refer to a wide range of conditions, including those resulting from excessive exposure to radiation such as sunburn or solar radiation, thermal radiation, welding flashes, fires, electrical discharges, contact with chemicals, friction, contact with hot objects such as cookware parts, or hot fluids such as boiling water, steam, hot oil, or flames, and thermal injuries on the battlefield. While such burns and burn conditions can arise from various causes, they share common symptoms and disease progression.

[0067] The term "allergic rhinitis / sinusitis" generally refers to a range of conditions, including those resulting from seasonal exposure to allergens such as pollen, and those resulting from exposure to chemicals or particulate matter, which may not be seasonal.

[0068] The term asthma generally refers to a range of conditions resulting from exposure to allergens, irritating gases, pollutants, and chemicals, as well as symptoms arising from exposure to cold or dry air or exercise / physical activity.

[0069] The term "inner ear disorder" generally refers to a condition defined by hearing loss, tinnitus, or dizziness, which may have multiple causes, including but not limited to noise and endolymphatic hydrops.

[0070] The term "tenosynovitis" generally refers to a variety of conditions, including those caused by infectious and non-infectious factors. Non-infectious causes include autoimmune disorders, overuse of the affected tissue, and idiopathic cases where the cause of the condition is not established.

[0071] The term "entenditis" generally refers to a variety of conditions, including those caused by infectious and non-infectious factors. Non-infectious causes include trauma, overuse, diseases such as ankylosing spondylitis, and idiopathic conditions where the cause of the condition is not established.

[0072] The term "arthritis" generally refers to a variety of conditions, including those caused by infectious and non-infectious factors. Non-infectious causes include osteoarthritis, gout, and autoimmune disorders such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and systemic lupus erythematosus.

[0073] The term "subject" generally refers to host animals treated with the compositions and methods described herein, including, but not limited to, humans and companion animals and livestock, such as dogs, cats, rabbits, birds, cattle, horses, monkeys, sheep, goats, reptiles, hamsters, guinea pigs, and other animals (whether domesticated or not). Exemplary subjects include host animals having or diagnosed with skin or eye injuries, heat injuries, allergic rhinitis / sinusitis or asthma, inner ear disorders (including hearing loss, tinnitus or dizziness), tenosynovitis, tendinitis, enthesitis or arthritis.

[0074] The term "granular tissue" generally refers to the new connective tissue and microvessels that form in a wound during the healing process. Granular tissue typically grows from the sides and base of a wound and can fill wounds of almost any size. Examples of granular tissue can be seen in convalescent wounds resulting from surgical procedures. Its histological appearance is characterized by fibroblast proliferation, new thin-walled, delicate capillaries (angiogenesis), and inflammatory cells infiltrating the loose extracellular matrix of proteins such as collagen.

[0075] The term "corneal opacity" is generally used when corneal opacity or scarring causes a loss of transparency in the cornea, which can prevent light from reaching the retina at the back of the eye. As a result, images may become distorted or blurred, and vision may be reduced or completely lost. Corneal transparency depends on the correct arrangement of corneal collagen fibrils and the absence of edema. Changes in the spacing and type of collagen fibers, as well as edema, can be caused by burns or harmful chemicals coming into contact with the surface of the eye.

[0076] The terms "glucocorticoid" or "glucocorticosteroid" generally refer to a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to glucocorticoid receptors, which are present in almost all vertebrate cells. Glucocorticoids are part of the stress response and play a role in the immune system's feedback mechanism, thereby mitigating certain aspects of immune function, such as inflammation. For this reason, they are often used to treat diseases caused by an overactive immune system (e.g., allergies, asthma, steroid-sensitive skin diseases, and autoimmune diseases). Clobetasol propionate is a highly selective and potent agonist of glucocorticoid receptors.

[0077] The term "clobetasol propionate" generally refers to the following molecules: [ka]

[0078] The term "nanomilling" generally refers to the process of reducing the particle size of a drug to nanometer dimensions by grinding using a polymer medium, a ceramic medium, or other proprietary technology. By using nanomilling, APIs that are poorly soluble in water can be formulated into small particles with a large surface area that enhances the solubility of the API.

[0079] The term "nanoparticles" generally refers to small particles, typically with an average particle size in the range of 1 to 300 nanometers. Nanoparticles, which are undetectable as individual particles to the human eye, can exhibit significantly different physical and chemical properties compared to their larger material counterparts.

[0080] The term "nanoparticle suspension" generally refers to a suspension containing nanoparticle-sized particles of an active agent. For example, glucocorticoids are hydrophobic and can be provided in the form of an aqueous suspension. However, aqueous suspensions of glucocorticoid compounds with particles larger than nanoparticles can be problematic because the larger steroid particles precipitate or solidify over time, and therefore, patients must shake the container before use to uniformly disperse the active ingredient in the liquid phase. Even with shaking, larger particles in the suspension can easily aggregate or clump together to form clusters, resulting in an increase in the particle size of the drug over time and a loss of uniformity in the content of the suspension. Due to these problems, it is difficult to obtain a uniform dispersion of larger particles and to consistently administer the active ingredient. Furthermore, the reduced surface area of ​​larger particles leads to a decrease in the dissolution rate of the API, resulting in reduced penetration of the API into the tissue and a decrease in the therapeutic effect. However, the invention described herein does not have such aggregation or clumping problems.

[0081] When used herein, the particle size distribution of suspended nanoparticles in the formulation is determined using dynamic light scattering with a commercially available instrument such as an Otsuda ELSZ-2000ZS particle size analyzer. The analyzer generates a histogram of the particle size distribution, and from the histogram, D 10 , D 50 , D 90、 And the average particle size is determined.

[0082] The term "metered-dose spray" or "MDTS" generally refers to a device that delivers medication to the surface of the skin, mucous membranes, or airways, allowing the medication to be continuously absorbed into the tissue. The device functions similarly to a transdermal patch or topical gel. The medication is delivered by the device, which is placed near the skin or mucous membrane. When activated, the device releases a light spray containing its own drug molecule formulation, forming an invisible drug accumulation site. As with a patch, the medication is then absorbed steadily over a predetermined period of time.

[0083] The term "scar" generally refers to the connective tissue that leaves a mark where skin or other tissue has healed after being damaged, for example, by a burn or other trauma. Scars are the body's natural way of healing and replacing lost or damaged skin or other tissue. Scars are usually composed of fibrous tissue. Hypertrophic scars are an abnormal reaction to wound healing in which there is an excess of connective tissue and collagen deposition within the original wound area, causing the scar to be abnormally raised. The term "keloid" generally refers to a type of abnormal scarring that spreads beyond the initial wound area. In contrast to hypertrophic scars, keloid scars are large, abnormal scars that progress slowly, spread beyond the original wound area, and can become much larger than the original wound area. These types of scars can lead to significant and permanent disfigurement.

[0084] The term "contracture" generally refers to an abnormal event that occurs when a large area of ​​skin is damaged and lost, resulting in scarring. Scar formation causes the edges of the skin to pull against each other, resulting in tightness of the skin around the damaged area. Contractures can also occur when there is chronic inflammation in tendons, tendon sheaths, tendon / ligament attachments, or joints. Treatment options for contracture release include surgery to cut away the scar tissue or chronically inflamed tissue to release the tension. In some cases, skin replacement with donor tissue that matches in texture, color, and flexibility may be an option.

[0085] In all cases disclosed herein, any description of a range of a variable is understood to be a description of the range itself, all individual elements within the range, and all possible subranges of that variable. For example, the description that n is an integer between 0 and 8 describes its range, the individual and selectable values ​​0, 1, 2, 3, 4, 5, 6, 7, and 8, for example, n is 0, or n is 1, or n is 2, and so on. Furthermore, the description that n is an integer between 0 and 8 also describes any subrange, each of which may form the basis for further embodiments, for example, n is an integer in the range of 1 to 8, 1 to 7, 1 to 6, 2 to 8, 2 to 7, 1 to 3, 2 to 4, and so on.

[0086] Unless otherwise indicated, it should also be understood that the description of a number necessarily reflects its relative precision. For example, the description of a number with a specified precision based on significant figures necessarily includes the range of values ​​that, after appropriate rounding, will match that number. For instance, the description of the number 1 with a single significant figure is understood to appropriately represent the range of values ​​from 0.5 to 1.4. Similarly, the description of the number 1.0 with two significant figures is understood to appropriately represent the range of values ​​from 0.95 to 1.04. The relative precision of a number can be further indicated by modifying it with the term "approximately" to indicate that the precision of the modified number is low.

[0087] When used herein, the term “approximately” when used with a number or limit generally means that the number is an approximation and includes a range of values, as described. For example, a real number described with a single significant digit will, by definition, include a so-called rounding range. The number approximately 5 will include a range of at least 4.5 to 5.4, since each of these values ​​is rounded to 5. The same understanding applies to real numbers described with additional significant digits, where the corresponding rounding range applies to the last significant digit. Integers will be understood to include values ​​such as ±1 for single-digit numbers and ±10 for two-digit numbers. Depending on the context and the variable described, the term “approximately” may also be interpreted as intending a range based on a percentage of the described number. For example, approximately 5 will be interpreted as including 5 ± 10%, and in some cases, including 5 ± 5%. Notwithstanding the foregoing, a range of values ​​should not be interpreted as including a negative range for a number described positively, unless otherwise indicated, and vice versa. Furthermore, depending on the context, the stated numbers should not be interpreted as including zero values ​​when used in combination with added components, unless otherwise specified.

[0088] All numerical specifications, such as pH, temperature, time, concentration, and molecular weight, including ranges, should be understood as approximations according to common practice in the relevant art.

[0089] Unless otherwise indicated, the components and percentages (%) of the amounts of components of the formulations described herein, expressed in units of %w / v, refer to grams per deciliter (g / dL).

[0090] When used herein, the transitional phrase "consisting essentially of" is understood to mean that the corresponding composition, unit dose, method, or scope of use encompasses a particular compound or described step and does not substantially affect the fundamental and novel features of the invention as described herein. For example, a method described herein that consists essentially of a single compound or a genus of compounds is understood to represent monotherapy for the described disease. Monotherapy may include the co-administration of one or more carriers, media, diluents, adjuvants, excipients, etc., and combinations thereof, and / or the co-administration of one or more additional active pharmaceutical ingredients, the latter of which should be understood to be for the treatment of diseases and / or symptoms different from the treatment of the underlying diseases described herein, such as thermal injuries of the skin or eyes, ulcerative wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, or arthritis itself. Exemplary additional active ingredients may include, for example, active ingredients for treating pain, associated bacterial infections, coughs, congestion, etc.

[0091] In embodiments that include a list of alternatives, which may be included individually or in various combinations, it should be understood that the list also describes not only the individual alternatives but also all possible subsets of those alternatives.

[0092] Many known and useful compounds used in formulations and other applications can be found in Remington's Pharmaceutical Sciences (13th Ed), Mack Publishing Company, Easton, PA, which is a standard reference for various administrations. As used herein, the term “formulation” refers to a combination of at least one active ingredient and one or more other ingredients (which may be independently active or inactive), also commonly called excipients. It should be understood that formulations as described herein may or may not refer to pharmaceutically acceptable compositions for administration to humans or animals, and may include compositions that are intermediates, such as for storage or research purposes.

[0093] Conventional topical preparations of corticosteroids have been proposed for the treatment of burns (see Brown, et al., Journal of Burn Care & Research, Volume 39, Issue suppl_1, April 2018, pp. S239-S240). However, using such conventional preparations on damaged skin tissue can be painful and problematic. More severe tissue damage (e.g., third- and fourth-degree burns) typically involves significant loss of skin tissue and fluid exudation. In such cases, conventional preparations may not adequately cover the damaged tissue area and cannot ensure sufficient penetration of clobetasol propionate into the target area without causing significant pain and discomfort. Furthermore, such conventional preparations are intended for common skin conditions (e.g., allergic, inflammatory, or autoimmune disorders). Therefore, although these formulations may contain excipients such as ethanol to improve the solubility of corticosteroids, they may cause severe pain when exposed to burns, may interfere with drug exposure or burn healing, and / or may not be suitable for certain treatments, including the treatment of burns to the eyes.

[0094] While certain glucocorticoids are used to treat allergic rhinitis / sinusitis and asthma, this specification suggests that the use of the formulations described herein, and / or glucocorticoids such as clobetasol propionate, offers new treatment options. For example, the formulations described herein allow for the use of smaller amounts of spray or injection. Reducing the injection volume has the potential benefit of reducing post-injection pain, especially when the injection site is limited, such as in the synovial sheath. Furthermore, formulations using glucocorticoids such as clobetasol propionate having threshold activity levels, as described herein, may be applied directly to the eardrum through the external auditory canal as a spray or ear drops, or injected into the middle ear, or applied to the nasal mucosa, to treat hearing loss, tinnitus, or dizziness when conventional formulations are insufficient to improve symptoms.

[0095] Clobetasol propionate nanoparticle suspension A sterile suspension of clobetasol propionate nanoparticles can be delivered as drops, a uniform spray, mist, aerosol, or injection. As drops, sprays, or aerosols, it can be applied to wound areas, the nasal cavity, or inhaled into the lungs, or applied to the eardrum in the external auditory canal to achieve uniform coverage while avoiding direct contact. The sterile suspension of clobetasol propionate nanoparticles can also be administered as drops onto the eyes or into the nasal cavity or external auditory canal.

[0096] In other embodiments, a suspension formulation of clobetasol propionate nanoparticles is described. Certain suspensions described herein are optimized for treating burn complications and can be uniformly applied by spraying onto the injured area or by droplet application. Spray or aerosol application can cover a large surface area and can provide efficiency and comfort by avoiding the pain associated with the required mechanical application of rubbing conventional ointments / lotions onto the burn injury. The nanoparticle suspension allows for effective penetration of clobetasol propionate into burn tissue and therefore presents an improved clinical efficacy and safety profile compared to conventional formulations.

[0097] Certain suspension formulations described herein are optimized for treating abnormal wound healing and can be applied by spraying or dropping them onto the wound, or by injecting them into abnormally healing wounds. The nanoparticle suspensions allow for effective penetration of clobetasol propionate into the tissue, thus presenting a superior clinical efficacy and tolerability profile compared to conventional formulations.

[0098] Certain nanoparticle suspension formulations described herein are optimized for treating allergic rhinitis / sinusitis and asthma, inner ear disorders (specifically hearing loss, tinnitus, or dizziness), tenosynovitis, tendinitis, enthesitis, and arthritis, and can be applied to the nasal and sinus mucosa by spray, aerosol, or drops, inhaled into the lungs, applied to the tympanic membrane through the external auditory canal, injected into the tympanic cavity, or injected into the synovial space, enthes, or joints. The nanoparticle suspensions enable effective penetration of clobetasol propionate into tissues, and therefore present a superior clinical efficacy and tolerability profile compared to conventional formulations.

[0099] Nanoparticle suspension formulations can be manufactured by dispersing nano-milled clobetasol propionate in an aqueous formulation, optionally with a mixture of one or more excipients. The nanomilling process allows clobetasol propionate to be formulated as a suspension with an average particle size distribution of less than 250 nm, so that individual particles are invisible to the naked eye, the formulation appears as a milky liquid, and is smooth and comfortable when administered to the skin, eyes, or mucous membranes (e.g., nasal cavity or lungs) or applied to the tympanic cavity or synovial cavity, tendon attachments, joints, or scars. The clobetasol propionate nanoparticle suspensions described herein allow for effective penetration of clobetasol propionate from high-surface-area nanoparticles into tissues upon surface application or injection. The nanoparticle formulations described herein are designed to optimally deliver therapeutic doses of clobetasol propionate to target tissues. Furthermore, such aqueous spray formulations would be suitable for damaged tissues oozing bodily fluids when ointments, emulsions, and / or creams cannot be used. As an injectable preparation, the suspension of clobetasol propionate nanoparticles described herein may allow for the injection of a more concentrated amount of drug in a smaller volume, and may also extend the duration of action. Composition of a spray or injectable formulation of a nanoparticle suspension

[0100] In other embodiments, transdermal, transepithelial, transmembrane, transmucosal, and transcorneal sprays, drops, or aerosols are described herein. Sprays, drops, or aerosols can be applied to the skin, eyes, nasal and sinus mucosa, or respiratory tract to treat diseases or injuries without the adverse effects of conventional ointments / lotions.

[0101] In another embodiment, an injectable formulation is described herein. This injectable formulation can be injected into tendons / ligaments, synovial spaces, or joints to treat disease or injury without the adverse effects of conventional ointments / lotions.

[0102] In another embodiment, a nanoparticle suspension formulation of clobetasol propionate in the form of a spray, drop, mist, aerosol, or injection is prepared as a sterile liquid adapted for filling into sterile spray bottles, eye drop bottles, aerosol devices, or inhalers, or can be filled into injectable vials or ampoules, or into pre-filled syringes for ease of use.

[0103] In another embodiment, topical spray, drop, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains clobetasol propionate at concentrations ranging from about 0.01% to about 0.25% w / v (including both ends) or from about 0.025% to about 0.15% w / v (including both ends). In another embodiment, the concentrations are about 0.025%, about 0.05%, about 0.075%, about 0.1%, about 0.125%, or about 0.15% w / v.

[0104] In another embodiment, topical spray, drop, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains sodium chloride at a concentration ranging from about 0.05% to about 3.0% w / v, or from about 0.15% to about 1.5% w / v. In yet another embodiment, the concentration is about 0.6%, about 0.8%, or about 1.2% w / v.

[0105] In another embodiment, topical spray, drop, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains lecithin at a concentration of about 0.01% to about 0.5% w / v, or about 0.025% to about 0.25% w / v. In another embodiment, the concentration is about 0.025%, about 0.05%, about 0.075%, about 0.1%, about 0.15%, about 0.2%, or about 0.25% w / v.

[0106] In another embodiment, the lecithin is hydrogenated soy lecithin. In another embodiment, the lecithin is derived from egg yolk, marine sources (including algae and kelp), milk, nata seed, cottonseed, and sunflower oil. In yet another embodiment, the lecithin is hydrolyzed lecithin.

[0107] In another embodiment, topical spray, drop, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains citric acid at a concentration ranging from about 0.001% to about 0.4% w / v, or from about 0.001% to about 0.012% w / v. In another embodiment, the concentration is about 0.002%, about 0.004%, about 0.006%, about 0.008%, or about 0.01% w / v.

[0108] In another embodiment, topical spray, drop, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains glycerin at a concentration ranging from about 0.04% to about 0.6% w / v, or from about 0.08% to about 0.32% w / v. In another embodiment, the concentrations are about 0.08%, about 0.12%, about 0.16%, about 0.20%, about 0.24%, about 0.28%, or about 0.32% w / v.

[0109] In another embodiment, a topical spray, drop, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains a nonionic surfactant at a concentration ranging from about 0.002% to about 0.05% w / v, or from about 0.0025% to about 0.025% w / v. In another embodiment, the concentration is about 0.0025%, about 0.005%, about 0.01%, about 0.015%, about 0.02%, or about 0.025% w / v.

[0110] In another embodiment, the nonionic surfactant is poloxamer 407. In another embodiment, the nonionic surfactant is any combination thereof, including polysorbate, polysorbate 20, polysorbate 80, sorbitan, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, or combinations thereof with poloxamer 407.

[0111] In another embodiment, topical spray, drop, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains a thickener in a concentration ranging from about 0.01% to about 2% w / v, or from about 0.025% to about 0.25% w / v. In another embodiment, the concentration is about 0.025%, about 0.05%, about 0.075%, about 0.1%, about 0.15%, about 0.2%, or about 0.25% w / v.

[0112] In another embodiment, the thickeners are polyvinyl alcohol (PVA), agar, albumin, alginate, casein, cetyl alcohol, cholic acid, deoxycholic acid, diacetyl tartrate, egg yolk glycerol, gum, Irish mist (carrageenan), monoglycerides, diglycerides, monostearates, sucrose esters, stearoyl lactylate salts, propylene glycol (including their esters), and any combination thereof.

[0113] In another embodiment, topical spray, drop, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains boric acid at a concentration ranging from about 0.0% to about 0.5% w / v, more specifically from about 0% to about 0.25% w / v. In another embodiment, the concentration is about 0.0%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, or about 0.25% w / v.

[0114] In another embodiment, topical spray, drop, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains disodium edetate dihydrate (EDTA) at a concentration ranging from about 0.0% to about 0.3% w / v, or from about 0.0% to about 0.15% w / v. In another embodiment, the concentration is about 0.0%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, or about 0.05% w / v.

[0115] In this specification, it was unexpectedly discovered that the combination of boric acid and EDTA improves tissue penetration by the formulations described herein. In another embodiment, an aqueous suspension of the nanoparticles described herein, comprising boric acid and EDTA, allows for higher tissue concentrations (e.g., peak concentration C) of active drug molecules such as clobetasol propionate at an equivalent dose. max ) provides. In another embodiment, an aqueous suspension of the nanoparticles described herein, comprising boric acid and EDTA, does not show loss of long-term therapeutic exposure to active drug molecules such as clobetasol propionate and maintains a significant half-life in tissue.

[0116] The suspension formulations described herein may optionally contain a preservative. Benzalkonium chloride (BAC) is an antimicrobial agent with an established history of use in pharmaceutical preparations to maintain the sterility of products. In conventional formulations, a BAC level of approximately 0.1% w / v is generally required for the preservative to be effective. However, such high concentrations of BAC often cause irritation or inflammation. Surprisingly, it has been found that when combined with certain additional excipients such as boric acid and EDTA, BAC levels can be minimized, thus avoiding irritation and inflammation. The antimicrobial effect is maintained at low levels of BAC when combined with boric acid and EDTA. Unexpectedly, when combined with boric acid and EDTA, BAC levels reduced to less than 0.006% to approximately 0.004%, or less than approximately 0.003%, have been found to maintain antimicrobial effect and be an effective preservative in the formulations described herein.

[0117] In another embodiment, topical spray, drop, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains benzalkonium chloride at concentrations ranging from about 0.0% to about 0.03% w / v, or from about 0.0% to about 0.01% w / v. In another embodiment, the concentrations are about 0.0%, about 0.002%, about 0.003%, about 0.0036%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, or about 0.01% w / v.

[0118] Additional preservatives may be included in concentrations effective in inhibiting microbial growth, ultraviolet and / or oxygen-induced degradation of the composition's components, etc. If one or more preservatives are included, each preservative or combination thereof may be in a concentration range of about 0.01% w / v to about 2% w / v. In another embodiment, the preservatives may include phenol, benzyl alcohol, phenoxyethanol, propylparaben, methylparaben, benzoic acid, sorbic acid, bronidiol, or propylene glycol, or combinations thereof.

[0119] In another embodiment, topical spray, drop, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains methylcellulose in a concentration ranging from about 0.00% to about 3.0% w / v, or from about 0.0% to about 2.0% w / v. In another embodiment, the concentration is about 0.0%, about 0.1%, about 0.2%, about 0.5%, about 0.75%, about 1.0%, about 1.5%, or about 2.0% w / v.

[0120] In this specification, it was unexpectedly discovered that increasing the concentration of methylcellulose improves the retention of drug molecules at local target tissue sites by the formulations described herein. In another embodiment, an aqueous suspension of the nanoparticles described herein, containing a higher concentration of methylcellulose, allows for higher tissue concentrations (e.g., peak concentration C) of active drug molecules such as clobetasol propionate at an equivalent dose. max In another embodiment, an aqueous suspension of the nanoparticles described herein, containing a higher concentration of methylcellulose, provides a longer therapeutic exposure to an active drug molecule such as clobetasol propionate, as indicated by a longer half-life in the target tissue.

[0121] In another embodiment, topical spray, drop, aerosol or injection formulations of a suspension of clobetasol propionate nanoparticles include sodium citrate, such as trisodium citrate, at a concentration in the range of about 0.01% to about 0.8% w / v to adjust the pH of the nanosuspension to an appropriate range, for example, about 4.5 to about 6.5.

[0122] The formulations described herein may also include several additional therapeutic compounds as desired for the indication being treated (e.g., burns of the skin or eyes). These additional therapeutic compounds generally exhibit complementary activity that does not adversely affect the activity of the other components. Exemplary therapeutic compounds that can be used as part of a combination for treating burns, infectious tenosynovitis, or infectious arthritis are antimicrobial agents. Other therapeutic agents that can be used as adjunctive therapeutic compounds for treating burns include silver sulfadiazine, penicillin, or penicillin derivatives such as amoxicillin, as well as beta-lactamase inhibitors such as amoxicillin-clavulanate, cephalosporins such as cephalexin, fluoroquinolones such as ciprofloxacin, tetracyclines such as doxycycline, macrolides such as erythromycin, aminoglycosides such as gentamicin, oxazolidinones such as linezolid, glycopeptides such as vancomycin, daptomycin, fusidic acid, clindamycin, trimethoprim-sulfamethoxazole, metronidazole, daptomycin, linezolid, rifampicin, bacitracin, neomycin, polymyxin B or E, nystatin, amphotericin B, echinocandins such as caspofungin, triazoles such as fluconazole, or combinations thereof. Other medications that can be used to treat burns to the eye include nonsteroidal anti-inflammatory drugs (NSAIDs) or antibiotics, and combinations thereof.

[0123] In another embodiment, antimicrobial agents used to treat burns of the skin or eyes include, but are not limited to, silver sulfadiazine, penicillin, or penicillin derivatives such as amoxicillin, as well as beta-lactamase inhibitors such as amoxicillin-clavulanate, cephalosporins such as cephalexin, fluoroquinolones such as ciprofloxacin, tetracyclines such as doxycycline, macrolides such as erythromycin, aminoglycosides such as gentamicin, oxazolidinones such as linezolid, glycopeptides such as vancomycin, daptomycin, fusidic acid, clindamycin, trimethoprim-sulfamethoxazole, metronidazole, daptomycin, linezolid, rifampicin, bacitracin, neomycin, polymyxin B or E, nystatin, amphotericin B, echinocandins such as caspofungin, triazoles such as fluconazole, or combinations thereof.

[0124] In another embodiment, antimicrobial agents for use in the treatment of allergic rhinitis / sinusitis and asthma with secondary infections include, but are not limited to, penicillin or penicillin derivatives such as amoxicillin, as well as beta-lactamase inhibitors such as amoxicillin-clavulanate, cephalosporins such as cephalexin, fluoroquinolones such as levofloxacin, tetracyclines such as doxycycline, macrolides such as erythromycin, clindamycin, and trimethoprim-sulfamethoxazole, or combinations thereof, as well as combinations thereof with doxycycline, trimethoprim-sulfamethoxazole, ciprofloxacin, penicillin, or combinations thereof.

[0125] In another embodiment, antimicrobial agents used to treat infected tendons or joints include, but are not limited to, penicillin or penicillin derivatives such as dicloxacillin, and may also be used in combination with beta-lactamase inhibitors such as amoxicillin-clavulanate, cephalosporins such as cephalexin, fluoroquinolones such as ciprofloxacin, tetracyclines such as doxycycline, carbapenems such as meropenem, and may also be used in combination with beta-lactamase inhibitors such as meropenem-babolbactam, aminoglycosides such as gentamicin, oxazolidinones such as linezolid, glycopeptides such as vancomycin, daptomycin, fusidic acid, clindamycin, trimethoprim-sulfamethoxazole, rifampicin, or combinations thereof.

[0126] In another embodiment, the aqueous suspension described may optionally contain a local anesthetic such as lidocaine and / or incorporate a suitable antimicrobial agent to further reduce pain, provide comfort, and reduce the risk of infection. Anesthetics that may be used in combination with clobetasol propionate include, but are not limited to, lidocaine, pramoxin, phenol, prilocaine, benzocaine, dibucaine, menthol, methyl salicylate, zinc acetate, camphor, tetracaine, pentafluoropropane, tetrafluoroethane, or combinations thereof.

[0127] The suspensions containing clobetasol propionate nanoparticles disclosed herein may further comprise pharmaceutically acceptable carriers, excipients, or diluents. Exemplary excipients are those bearing the "Generally Recognized as Safe" (GRAS) designation. These may include, for example, antioxidants, preservatives such as ascorbic acid, sorbic acid, or alpha-lipoic acid, and antimicrobial agents. Other components may include those other than the therapeutic active ingredient and the component that is the primary effector of penetration into the skin, eye, inner ear, epithelium, or synovial membrane, or those provided for aesthetic purposes, such as menthol or other aromatic compounds, and components that affect the physical state of the composition, such as lubricants in the case of intra-articular or synovial cavity injection. These components may be present in very small or large proportions in the composition.

[0128] The disclosed suspension containing nanoparticles of clobetasol propionate can be formulated into various dosage forms in combination with the pharmaceutically acceptable carriers described above. For example, for topical administration by spray (including aerosol sprays for inhalation or nebulization) or droplet use, the pharmaceutical composition can be formulated into a liquid form that can be sprayed onto a thermal wound of the subject, or applied as droplets to the surface of the skin or eye, for example; or, for injection, the pharmaceutical composition can be formulated into a liquid form that can be injected into the tympanic cavity, keloid or hypertrophic scar, or inflamed synovial cavity, tendon / ligament attachment point or joint of the subject.

[0129] The formulations described herein may be sterilized. Sterilized formulations may be prepared, exemplary, by filtration through a sterile filtration membrane before or after the preparation of a spray, drop, liquid, or injectable formulation, or by other methods known in the art, including, but not limited to, pasteurization and gamma irradiation.

[0130] Formulations relating to the subject matter described herein may be in the form of topical administration packaged in multi-use or single-use packages, for example, including tubes, pumps, containers or bottles, vials, jars, cans, cassettes, or packets, or in the form of injection packaged in multi-use or single-use packages or pre-filled syringes. Single-dose kits and packages containing a once-daily dose or other appropriate dose of the topical delivery formulation or injection formulation may be prepared. Single doses, unit doses, and once-daily disposable containers of the formulation are also provided.

[0131] In certain embodiments, the kit may incorporate therapeutic agents such as a suspension containing nanoparticles of clobetasol propionate for treating burns of the skin or eyes, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders (particularly hearing loss, tinnitus or dizziness), tenosynovitis, tendinitis, enthesitis, or arthritis. In other embodiments, the kit may include, but is not limited to, a spray bottle having one or more chambers, any form of inhaler, dropper bottle, or injection vial / ampoule or pre-filled syringe for administering one or more therapeutic compounds (including clobetasol propionate) as described herein. In various embodiments, the kit may include pharmaceutical compositions for topical or injectable administration via application of drops, sprays, aerosols, mists, or injections, comprising one or more therapeutic compounds, at least one of which is clobetasol propionate for administration to the subject. In this regard, the therapeutic compound(s) may be placed there by application to the skin, eyes, nasal cavity and sinus mucosa by spray or drop, by inhalation into the lungs, by application to the tympanic membrane, by intratympanic injection, or by injection into hypertrophic scars, keloids, synovial spaces, tendon / ligament attachments or joints. In these embodiments and all other embodiments, the kit may include one or more spray bottles, inhalers of any form, dropper bottles, or injection vials / ampoules or pre-filled syringes, in accordance with any of the above-described instructions and / or packaging materials.

[0132] How to use In another embodiment, the duration of administration of a therapeutic compound, such as an aqueous suspension containing nanoparticles of clobetasol propionate, for treating thermal burns of the skin or eyes, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders (specifically hearing loss, tinnitus or dizziness), tenosynovitis, tendinitis, enthesitis or arthritis (including clobetasol propionate), is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In further embodiments, the period for which administration is suspended or discontinued may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0133] In another embodiment, the dose of the suspension containing nanoparticles of the therapeutic compound, namely clobetasol propionate, may be administered multiple times a day, daily, every two weeks, weekly, bi-weekly, or monthly. The initial dose(s) may be higher or lower than subsequent doses.

[0134] In another embodiment, a therapeutically effective amount of a suspension comprising clobetasol propionate nanoparticles for treating a subject suffering from a thermal injury, as disclosed herein, reduces the size or severity of the thermal injury site by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0135] In another embodiment, a therapeutically effective amount of a suspension comprising clobetasol propionate nanoparticles for treating a subject suffering from an eye burn disclosed herein improves vision by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0136] In another embodiment, a therapeutically effective amount of a suspension comprising clobetasol propionate nanoparticles for treating subjects suffering from abnormal wound healing as disclosed herein reduces the size or severity of hypertrophic scars or keloids by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0137] In another embodiment, a therapeutically effective dose of a suspension comprising nanoparticles of clobetasol propionate for treating a subject suffering from allergic rhinitis / sinusitis or asthma, as disclosed herein, reduces inflammation of the mucous membrane or airway by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0138] In another embodiment, a therapeutically effective dose of a suspension comprising clobetasol propionate nanoparticles for treating a subject suffering from an inner ear disorder as disclosed herein improves symptoms of hearing loss, tinnitus, or dizziness by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0139] In another embodiment, a therapeutically effective amount of a suspension comprising tendon nanoparticles for treating a subject suffering from tenosynovitis, tendinitis, enthesitis, or arthritis, as disclosed herein, reduces inflammation of a tendon, ligament, or joint by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0140] In another embodiment, symptoms or complications associated with thermal injuries of the skin or eyes, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis or arthritis (e.g., hypertrophic granulation and unstable scarring, keloid formation, visual impairment, nasal congestion and runny nose, airway inflammation, hearing loss, tinnitus, dizziness, arthralgia, tendon attachment pain or "trigger finger") described herein are reduced by at least 5%, at least 10%, and reduced by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% after administration of the formulation.

[0141] In another embodiment, the application of the formulations described herein shortens the healing and recovery time of thermal injuries, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders (specifically hearing loss, tinnitus or dizziness), tenosynovitis, tendinitis, enthesitis or arthritis by 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0142] In another embodiment, application of the formulations described herein reduces pain and / or discomfort caused by heat injury, tenosynovitis, tendinitis, enthesitis, or arthritis by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0143] In another embodiment, application of the formulations described herein improves mucosal edema and inflammation and reduces bronchoconstriction caused by allergic rhinitis / sinusitis or asthma by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0144] In another embodiment, a suspension containing nanoparticles of clobetasol propionate reduces the frequency of adverse events or complications associated with thermal injuries, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders (specifically hearing loss, tinnitus or dizziness), tenosynovitis, tendinitis, enthesitis, or arthritis over a predetermined period of time. In aspects of this embodiment, a suspension comprising nanoparticles of clobetasol propionate reduces the frequency of adverse events or complications related to thermal injuries, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders (specifically hearing loss, tinnitus or dizziness), tenosynovitis, tendinitis, enthesitis or arthritis, over a predetermined period of time, by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0145] In another embodiment, a spray or droplet of a suspension of clobetasol propionate nanoparticles is applied directly to the affected area of ​​the skin, eyes, mucous membranes of the nose and sinuses, airways of the lungs, or eardrum. When applying the formulations of the invention disclosed herein, the formulation itself is exemplary administered to the eye or nose by droplet, or sprayed onto the skin, eye, nose and sinus mucous membranes and inhaled into the lungs, or applied to the eardrum by using, for example, a spray bottle or dropper bottle or other suitable device. Spray bottles may include pump spray bottles, spray mist bottles, inhalers of any form, aerosol spray bottles, atomizer bottles, metered-dose spray devices, etc. Dropper bottles can drop a predetermined approximate amount, such as about 50 μL per dose. The amount of formulation used is usually sufficient to cover the desired surface area. In some embodiments, after applying the formulation, a protective cover is placed over it and left for an appropriate time (e.g., 5, 10, 20 minutes or more, and in some embodiments, 1 or 2 hours or more). The protective cover may be a simple bandage, including a bandage with a moisture-proof cover. In the case of eye burns, the protective cover can be used simply as a bandage to protect the external tissues of the eye and reduce the risk of mechanical damage and infection. When applied to the skin, this essentially fixes the contact between the formulation and the skin, preventing the formulation from being distorted by evaporation or distributed to other parts of the body or to other people. The formulation can also be applied to the skin using standard application procedures such as a brush, syringe, gauze pad, dropper, or any convenient applicator (e.g., for smaller areas). More complex application methods, including the use of delivery devices, may also be used, but are not mandatory. External reservoirs of the formulation may also be used for long-term administration.

[0146] In another embodiment, a suspension of clobetasol propionate nanoparticles is injected into the tympanic cavity, or into the synovial space, tendon / ligament attachment point or joint, or into a keloid or hypertrophic scar affected by disease and / or injury. When applying the formulations disclosed herein, the formulation itself is injected, for example, using a syringe and needle. The amount of formulation used is usually minimal and sufficient to treat the disease and / or injury. More complex application methods, including the use of delivery devices, may be used, but are not essential. External reservoirs of the formulation for long-term administration may also be used. Not bound by theory, it is believed herein that potent glucocorticoids such as clobetasol propionate reduce pathological scarring by decreasing fibroblast inflammation and activation, thereby reducing pathological scarring and ultimately leading to the resolution of hypertrophic scars or keloids by limiting the synthesis of proteins such as collagen that characterize scar tissue.

[0147] The formulations can be administered as a single dose, in one application, or more frequently as needed, for example, once daily to every hour as needed. The formulations disclosed herein can be administered topically once or more times daily over a period of 1 to 4 weeks, 1 to 2 weeks, 1 week, 2 weeks, 3 weeks, 4 weeks, or 4 weeks or longer. In some cases, it may be desirable to continue treatment indefinitely as long as symptoms persist. Appropriate dosages of the formulations are, for example, once, twice, three times, four times, six times, eight times daily, or every hour as needed. The formulations described herein can be injected once or more times daily over a period of 1 to 4 weeks, 1 to 2 weeks, 1 week, 2 weeks, 3 weeks, 4 weeks, or 4 weeks or longer.

[0148] The compositions according to the embodiments described herein have desirable properties such as desirable solubility, viscosity, sprayability, applicability, isotonicity, injectability, injectability, compatibility, homogeneity, resuspensionability, sterility, and stability.

[0149] In another embodiment, the pH of the described formulation is in the range of about 2 to about 8, or about 4.5 to about 6.5. [Examples]

[0150] The above description and the following examples are for illustrative and explanatory purposes only, and should be understood as intended to further enhance the understanding of the nature and scope of the invention as described herein. The following non-limiting examples should be understood as a representative subset of the actual embodiments of the invention and should not be construed as limiting any of the embodiments described herein, including those relating to the types and amounts of formulation components and / or the methods and uses thereof.

[0151] Example 1. Preparation of a suspension formulation of clobetasol propionate nanoparticles. A suspension formulation of clobetazole propionate nanoparticles is prepared by grinding clobetazole propionate drug particles with a grinding agent to form a clobetazole propionate nanomixture, as exemplified in U.S. Patents 8,226,983, 10,588,913, and 11,376,262, and U.S. Patent Application Publications US2018 / 0117064 and US2020 / 0129526. The nanomixture is then dispersed in an aqueous medium with various excipients exemplified in Tables 1A, 1B, and 2.

[0152] Figure 1 shows an overview flowchart of the steps used to produce an exemplary clobetasol propionate nanoparticle suspension. Step A involves compounding the active ingredient (API) with a milling agent. Exemplary milling agents include sodium chloride, hydrogenated soy lecithin, and anhydrous citric acid. Step B involves grinding the compounding mixture with glycerin to obtain a particle size distribution D 90 This includes producing a nano-mixture of pulverized clobetasol propionate with a particle size of less than 250 nm.

[0153] Step C involves using a high-shear homogenizer to disperse a nano-mixture of poloxamer 407 and clobetasol propionate containing polyvinyl alcohol into a suspension, thereby dispersing the particle size distribution D.90 Step D involves preparing nano-suspensions smaller than 250 nm. Step D involves compounding the mixture and mixing it with other excipients including methylcellulose and preservatives (boric acid, EDTA, and benzalkonium chloride), adjusting the pH with sodium citrate (e.g., trisodium citrate), isotonicizing with glycerin, and adding an appropriate amount of water for injection (WFI). Step E involves the formulated suspension undergoing final redispersion before sterile filtration to produce a final aqueous suspension of clobetasol propionate nanoparticles.

[0154] The nanomilling process produces a suspension of clobetasol propionate nanoparticles with an average particle size distribution in the range of approximately 120-200 nm. This suspension appears as a milky white liquid with no visible particles and provides a smooth, comfortable feel when applied to skin or mucous membranes. This suspension can be administered as a sterile spray over large areas of burn wounds or other mucous membranes, or as drops to more limited areas of skin, eyes, nose, mucous membranes, or eardrums, or as an injection into the tympanic cavity, keloid or scar tissue, synovial cavity, tendon / ligament attachment points, joints, or scars. The clobetasol propionate nanoparticles in the formulation effectively penetrate tissue via surface application or injection, delivering therapeutically effective concentrations of clobetasol propionate to target tissues in thermal wounds of the skin or eyes, nasal cavity, lungs, external auditory canal, inner ear, synovial cavity, tendon / ligament attachment points, joints, or scars. Water-based sprays and drops are suitable for use on tissues oozing bodily fluids, such as the mucous membranes of the nose and sinuses and the respiratory tract, in cases of burns or inflammation.

[0155] Exemplary formulation compositions are shown in Tables 1A, 1B, and 2. [Table 1A] [Table 1B] [Table 2]

[0156] Example 2. Treatment of eye burns The efficacy of clobetasol propionate nano-suspension 0.1% (CPN0.1%) was evaluated in an alkaline burn model of the eye in New Zealand white rabbits (n=5 CPN0.1% group, n=5 excipient group). Baseline slit-lamp ophthalmology, anterior segment optical coherence tomography (OCT), and corneal surface fluorescein staining were performed to confirm the absence of eye abnormalities or damage. Ophthalmology examinations were scored according to the modified McDonald-Shadduck scoring system, and inclusion in the study required a score of 0 for all parameters.

[0157] On day 1, the animals were anesthetized with ketamine and xylazine, and the local anesthetic was applied to the test eye. To induce an alkaline burn of the eye, a round filter paper (No. 1 Whatman, approximately 5 mm in diameter) was immersed in 1 M NaOH for approximately 10 seconds, and then placed on the center of the cornea of ​​the study eye for approximately 20 seconds. Immediately after removing the filter paper, the eye surface was washed with approximately 30 mL of equilibrium salt solution. Thirty minutes after eye injury, the study eye was treated with either CPN 0.1% or one drop (approximately 50 μL) of the excipient (CPN 0.1% group n=5, solvent group n=5). These treatments were continued four times a day (at 2-hour intervals) from day 1 to day 7 of the study. To prevent infection, antibiotic eye drops were administered to the study eye three times a day from day 1 to day 3. Eye examinations, slit-lamp imaging, OCT measurements, and surface fluorescein staining were performed on day 1 immediately after rinsing the alkaline burns, and on days 3 and 7 prior to administration. Slit-lamp imaging assessed corneal opacity, corneal damage area, corneal neovascularization, and conjunctival discharge, congestion, and swelling. Anterior OCT and fluorescein staining imaging were performed using the Spectralis® imaging platform and the Heidelberg Retina Angiograp-OCT device.

[0158] The results are shown in Figure 2. By day 3, the CPN 0.1% group showed a significant and rapid decrease in clinical scores for inflammation, including conjunctival hyperemia and swelling, as well as corneal neovascularization, compared to the control group (Student's unpaired t-test, p<0.05) (Panel A). CPN 0.1% also showed a rapid decrease in clinical scores for corneal opacity and interstitial opacity by day 3 compared to the control group, and this decrease was maintained until day 7 [Two-way ANOVA, F(1,8)=12.25, p=0.008] (Panel B). On day 7, surface fluorescein staining showed that CPN 0.1% treatment accelerated corneal epithelial healing compared to excipients (Panel C). Panel C shows representative fluorescein stained images of central corneal epithelial defects (a) and representative corresponding infrared images of the eye showing the position of the pupil (central cornea) and iris (b). The degree of fluorescein staining determines the extent of epithelial damage on the corneal surface. By day 7, the CPN 0.1% group showed little to no fluorescein staining, while the excipient-treated eyes still exhibited significant fluorescein staining, indicating continued damage to the corneal epithelium. On day 7, forward OCT images showed a significant reduction in corneal thickness (edema) and corneal stromal opacity compared to the excipient-treated group (Panel D). Panel D shows representative cross-sectional OCT images of damaged rabbit corneas on day 7 (the plane of the cross-section is indicated by the horizontal white line in the left image). The corneal OCT images of the CPN 0.1% group show a significant reduction in corneal thickness (lower image, arrow), indicating a substantial reduction in corneal edema. In the excipient-treated group, corneal thickness and opacity were significantly increased, indicated by the bright white area in the central part of the cornea (upper image, arrow).

[0159] Histological analysis confirmed that in eyes treated with CPN 0.1%, corneal stromatous findings (fibrosis, mononuclear cell infiltration, edema, and neovascularization), as well as the incidence and severity of corneal epithelial thickening / thickening, were reduced. CPN 0.1% rapidly and significantly reduces ocular inflammation, corneal opacity, and corneal matrix opacity, while simultaneously increasing the rate of corneal healing. The nanoparticle suspension formulation of clobetasol propionate described herein is useful for long-term improvement of vision and visual acuity after alkaline burns of the eye.

[0160] Example 3. Treatment of skin burns The efficacy of CPN 0.1% in reducing inflammation and granular tissue formation was evaluated in a porcine thermal wound model (n=3 female Yorkshire crossbreed pigs, 35±10kg). On day 0, the animals were sedated with tyletamine-zolazepam followed by isoflurane anesthesia. Ten thermal burns, each 2cm in diameter and full-thickness, were created on the backs of the animals by heating a 2cm diameter brass rod (4.8cm high, 100g mass) to 100°C. To induce the burns, the rod was rapidly dried and placed on the skin surface for 45 seconds without additional pressure. The wounds were excised with a 2cm trefin, covered with a clear film dressing (Tegaderm®), followed by a blue absorbent pad, and then the body was wrapped with an elastic bandage. Postoperative pain was managed with buprenorphine (0.02 mg / kg, IM), and fentanyl patches (50 μg / hour) were applied to shaved skin on days 0, 4, 7, and 11.

[0161] A wound from one animal served as an untreated control wound, while wounds from two animals were treated with CPN 0.1% (i.e., n=20 wounds in the CPN 0.1% group and n=10 wounds in the untreated control group). CPN 0.1% treatment was initiated on day 0 after wound induction, with additional treatments on days 2, 4, 7, and 9. On treatment days, CPN 0.1% was injected into the wound surface through a Tegaderm® dressing using a sterile syringe and needle, with doses of 1.5 mL on days 0–4 and 1 mL on days 7–9. On treatment days, wounds were evaluated using a modified Draize scoring system to assess erythema and edema. The degree of granular tissue was also assessed using the scoring system. A score of 1 indicates the absence of granular tissue. A score of 2 indicates that granular tissue partially covers the bottom of the wound, while a score of 3 indicates that granular tissue completely covers the bottom of the wound but does not fill the entire volume of the wound. A score of 4 indicates that granular tissue is present throughout the entire volume of the wound.

[0162] The results are shown in Figure 3. CPN 0.1% reduced inflammation scores (erythema and edema) with just two treatments and significantly reduced the amount of granular tissue from day 7 to day 11 (Bonferroni's post-hoc test performed after two-way ANOVA). Compared to control wounds, CPN 0.1% treatment resulted in a rapid reduction of erythema (Panel A) and edema (Panel B) by day 4, and a significant reduction of edema by day 9, indicating accelerated wound healing. CPN 0.1% also reduced granular tissue formation from days 7 to 11, supporting a reduction in hypertrophic scar formation (Panel C). Up to 90 percent of human thermal injuries result in hypertrophic scarring, and widespread and prolonged inflammation and excessive granular tissue formation are considered important factors in hypertrophic scar formation. The nanoparticle suspension formulation of clobetasol propionate described herein is useful in reducing hypertrophic scar formation in thermal injuries.

[0163] Example 4. Treatment and reduction of hypertrophic scars

[0164] The effect of CPN 0.1% on reducing hypertrophic scarring was evaluated in a hypertrophic scar model of rabbit ears (two New Zealand white rabbits, 2.5-3 kg). One rabbit was treated with CPN 0.1% (n=8 wounds), and the other rabbit served as an untreated control group (n=8 wounds). On day 0, the animals were anesthetized with ketamine / xylazine, and four 7 mm diameter full-thickness excision wounds were surgically created on the ventral side of both ears of each rabbit. Treatment with CPN 0.1% once daily was started within 60 minutes of wound induction and continued 5 days a week for 3 weeks. The treatment consisted of applying 50 μL of CPN 0.1% to the wound, followed by covering with an 8 × 8 mm sterile filter paper piece, and applying an additional 50 μL of CPN 0.1% to the filter paper. The wounds were bandaged with a circular adhesive bandage followed by a clear film bandage (Tegaderm®). Untreated control wounds were bandaged in exactly the same way, except that no treatment was applied. Wound inflammation was assessed twice a week using the Draize scoring system. In this system, an erythema score of 0 indicates no erythema, 1 indicates mild erythema, 2 indicates clear erythema, 3 indicates moderate to severe erythema, and 4 indicates severe erythema or crusting. An edema score of 0 indicates no edema, 1 indicates mild edema, 2 indicates mild edema with well-defined borders, 3 indicates edema (elevated more than 1 mm), and 4 indicates severe edema (elevated more than 1 mm and extending beyond the treatment site). On day 28 (7 days after the last treatment), the animals were euthanized, and the wounds were collected, fixed, and stained with Masson's trichrome for histological evaluation.

[0165] The results are shown in Figure 4. At one week after the start of treatment, CPN 0.1% rapidly and significantly reduced erythema [two-way ANOVA, F(8,112)=3.695, p=0.0007] and edema [two-way ANOVA, F(8,112)=4.680, p<0.0001] compared to the control group. Histological analysis at day 28 revealed hypertrophic scarring in all wounds in the untreated control group, as indicated by increased scar formation. CPN 0.1% treatment significantly reduced new collagen formation (Panel A), scar height (Panel B), and scar area (Panel C) compared to the control group (Student's unpaired t-test). Panel D shows representative images of untreated wounds and wounds treated with CPN 0.1% at day 28. The overall size of the scar was determined by measuring the pixel area of ​​the scar, and the scar height was determined by the pixel height of the scar from the bottom to the top of the epidermis. Scar height was measured at the position of the arrow. Untreated control wounds (top image, box in hatching) show clear evidence of hypertrophic scarring, while wounds treated with CPN 0.1% (bottom image) show no hypertrophic scarring. The nanoparticle suspension formulation of clobetasol propionate described herein significantly and substantially reduces and / or prevents abnormal hypertrophic scarring in wounds.

[0166] Example 5. Reduction or removal of abnormal hypertrophic scarring. The effect of intralesional injection of the nanoparticle suspension formulation of clobetasol propionate described herein on reducing hypertrophic scarring was evaluated in a hypertrophic scar model of rabbit ears. For example, on day 0, New Zealand white rabbits (CPN 0.1% group n=4, excipient group n=4) were anesthetized with ketamine / xylazine, and four 7 mm diameter full-thickness excision wounds were surgically created on the ventral side of both ears. The wounds were left untreated for 20 days, by which time they had closed and formed hypertrophic, raised scars. On days 21, 28, and 35, CPN 0.1% or the excipient was injected into the scars (10 μL) using a 32-gauge needle and microsyringe pump (Hamilton). On day 40, the animals were euthanized, the wounds were excised and fixed, and stained with Masson's trichrome for histological evaluation of the collagen and fibrous cell structure.

[0167] Histological analysis is used to compare hypertrophic scarring of wounds, indicated by increased scar formation and disruption of collagen and fibroblast structure. Intra-lesional injection of the clobetasol propionate nanoparticle suspension formulation described herein is expected to significantly reduce new collagen formation, scar height, abnormal fibroblast structure, and scar area compared to the control group, and to lead to the disappearance of hypertrophic scars, demonstrating that intra-lesional injection of the clobetasol propionate nanoparticle suspension formulation described herein can significantly reduce the size of abnormal hypertrophic scars from wounds.

[0168] Example 6: Treatment of tenosynovitis, tendinitis, enthesitis, and arthritis The efficacy of CPN 0.1% in reducing arthritis symptoms was evaluated in a rat model of collagen-induced arthritis (CIA). To induce the arthritis phenotype, 200 μL of 1 mg / mL bovine type II collagen / incomplete Freund's adjuvant solution was subcutaneously injected into the base of the tail of male Lewis rats (n=20, 200-250g) on ​​day 0, followed by an additional 100 μL injection on day 7. In the CIA model, the arthritis phenotype appeared in one or both hind limbs of the rats between days 28 and 42, with inflammation of the joints and tendons and swelling of the feet. Once the arthritis phenotype appeared, CPN 0.1% or an excipient was subcutaneously injected (50 μL) into the paw pads of both hind legs once daily for 14 days (randomized into CPN 0.1% group n=10 and excipient group n=10). Hind limb inflammation was assessed daily using a clinical score of 0–4. 0 was normal, 1 was mild redness and swelling of the ankle or toes, 2 was moderate redness and swelling of the ankle and foot, 3 was severe redness and swelling of the ankle and entire foot including the toes, and 4 indicated the hind limb with maximum inflammation involving multiple joints. A volume pulse wave meter was used to measure foot volume twice a week. On day 15, rats were evaluated for inflammation of the foot and joints, followed by euthanasia.

[0169] The results are shown in Figure 5. Compared to the excipient group, CPN 0.1% rapidly and significantly reduced the clinical score of hindlimb inflammation (Panel A) and hindlimb volume (Panel B) by day 3 of treatment (two-way ANOVA followed by Bonferroni's post-hoc test). These effects were maintained throughout the observation period. The feet of rats treated with CPN 0.1% appeared normal within 7 days of treatment, while animals treated with the excipient showed reduced mobility due to inflammation of the feet, joints, and tendons throughout the observation period. CPN 0.1% rapidly and significantly reduced foot swelling and inflammation of the joints and tendons. This indicates that the suspension formulation of clobetasol propionate nanoparticles described herein is effective in reducing inflammation around the joints, tendons, and ligaments in subjects suffering from arthritis, tenosynovitis, tendinitis, and enthesitis.

[0170] Example 7. Treatment of inner ear disorders (hearing loss)

[0171] The efficacy of the clobetasol propionate nanoparticle suspension formulations described herein is evaluated in a noise-induced hearing loss model. For example, C57BL / 6J mice (CPN 0.1% group, n=10; excipient group, n=10) are housed in a noise-controlled environment throughout the study period. Baseline hearing thresholds are measured by bilateral auditory brainstem response (ABR) and distortion component otoacoustic emissions (DPOAE) at 5–40 kHz. On day 0, animals are anesthetized with isoflurane and 5 μL of 0.1% CPN or excipient is injected intratympanically (IT). IT injection is performed with the animal immobilized in a stereotactic device equipped with a microsyringe / microinjection pump assembly. After IT injection, the animal is held with the injected ear facing upward for 30 minutes to allow the administered suspension to come into contact with the round window membrane and diffuse into the inner ear fluid.

[0172] One and a half hours after the IT injection, the animals are exposed to a single noise exposure in a soundproof room. Noise exposure is performed using mice in a wire cage surrounded by ceramic speakers, which generates noise that is filtered to 4.0–45.0 kHz. The mice are exposed to 110 dB of noise for 30 minutes at a time. Two weeks after exposure, hearing threshold assessment is performed using ABR, after which the mice are euthanized and the cochlea is collected for histological analysis of the auditory organs of the inner ear.

[0173] Using histological analysis of the cochlea, the number of inner and outer hair cells and the level of preservation of their neural connections will be compared in the treatment group and the excipient-treated group. It is expected that IT administration of the formulations described herein will significantly reduce ABR threshold shift, demonstrating that the formulations prevent noise-induced hearing loss compared to excipient injections, and that the suspension formulation of clobetasol propionate nanoparticles is effective in treating noise-induced hearing loss by reducing cochlear hair cell loss and preserving hearing.

[0174] Example 8. Treatment of inner ear disorders (tinnitus) This specification evaluates the tinnitus-reducing effect of IT-administered (IT) injections of a suspension formulation of clobetasol propionate nanoparticles described herein in a mouse model. For example, C57BL / 6J mice (n=10 CPN 0.1% group, n=10 excipient group) are tested using an acoustically based avoidance detection (SBAD) paradigm. Mice are trained to perform Go or No-Go operant responses in a shuttle box using a shock to the foot (0.1–0.4 mA) as negative reinforcement. The shuttle box has two chambers of the same size with a shutter door in the center, and a light beam is shone throughout the shuttle box to detect the animal's position. Motor function, motivation, and learning / memory function are monitored in the Go test, and tinnitus-like behavior is monitored in the No-Go test. Both types of trials are randomly assigned throughout each training and test session, with a 4-second interval between trials. Training sessions begin with a 2-minute adaptation period, followed by 100 trials per day for a total of 30–40 minutes. In a Go trial, the animal is trained to move from one compartment to another when presented with an auditory stimulus. A shutter closes when the animal moves to the other compartment. If the animal does not pass through the shutter, it receives a shock to the foot 5 seconds after the start of the auditory stimulus. In a No-Go trial, the animal is trained to remain in the compartment unless a sound is made. If the animal passes through the shutter within 10 seconds, it receives a shock, but the shutter remains open. The shock is turned off after the animal moves to another room, or at the end of both the Go and No-Go trials. The auditory stimuli are presented randomly, with both frequency and intensity varying.

[0175] During the Go test, the shock to the animal's foot continues even after an error occurs, and the shutter closes immediately when the animal moves to another compartment. However, in the No-Go test, no shock is administered once the animal enters another compartment, and the shutter closes immediately. Therefore, the No-Go test demonstrates that the animal experiences tinnitus when moving from one compartment to another without external auditory stimuli.

[0176] After successfully completing SBAD training (90-100% correct trial response), mice undergo unilateral noise-induced trauma, resulting in tinnitus. On day 0 prior to noise exposure, mice are anesthetized with isoflurane and administered 5 μL of CPN 0.1% or excipient IT injection into the right ear. The IT injection is performed with the animal fixed in a stereotactic device equipped with a microsyringe / microinjection pump assembly. After the IT injection, the animal is held with the injected ear facing upward for 30 minutes to allow the administered suspension to contact the round window membrane and diffuse clobetasol propionate into the inner ear fluid. The left ear is blocked with an improved earplug (Decidamp2®) and secured with Stomahesive® (ConvaTec). After 2 hours, the mice are placed in an acoustic attenuation chamber and exposed to 120 dB of broadband noise (4-25 kHz) for 2 hours.

[0177] To assess the presence of tinnitus, mice underwent SBAD tests 2 weeks, 1 month, and 2 months after noise exposure. At each time point, both the excipient group and the treatment group showed little error in the Go test, exhibiting normal motivation, motor skills, and memory / learning abilities. However, in the No-Go test, the excipient group showed a higher error rate compared to the treatment group, meaning they moved from one compartment to another more frequently in the absence of external auditory stimuli, indicating the presence of tinnitus. Efficacy is demonstrated when the accuracy rate in the No-Go test, i.e., the rate at which mice do not move from one compartment to another in the absence of external auditory stimuli, is 20% or higher. A low error rate in the No-Go test (90-100% accuracy rate) indicates a high effectiveness in reducing noise-induced tinnitus. It is expected that injecting the suspension formulation of clobetasol propionate nanoparticles described herein into intrathecal injection will result in high accuracy rates, demonstrating the formulation's effectiveness in treating tinnitus in subjects including humans. Example 9. Treatment of allergic rhinitis / sinusitis

[0178] The clobetasol propionate nanoparticle suspension formulation described herein is useful for treating patients with allergic rhinitis. For example, a 30-year-old woman visits a clinic complaining of excessive nasal discharge, nasal itchiness, and difficulty breathing through the nose, which have not improved with conventional allergy treatments. The clinician observes the following signs / symptoms characteristic of allergic rhinitis: nasal exudate, deep redness of the nasal mucosa, and marked swelling of the nasal and sinus mucosa. The clinician recognizes the problem that conventional allergy therapies may not be effective in treating the patient's symptoms and signs, especially when there is significant fluid exudation. In this example, the clinician applies an aqueous suspension of clobetasol propionate nanoparticles to the nasal cavity and sinus mucosa using a spray bottle. The liquid suspension is applied by spraying it as uniformly as possible over the entire surface of the nasal mucosa and left for 5-10 minutes. The liquid suspension is then reapplied at a frequency of at least once a day for a period of more than one week. After more than one week, the patient visits the clinic for evaluation. Participants recognized a significant improvement in the symptoms and signs of allergic rhinitis and reported to clinicians that the treatment reduced itching and nasal breathing difficulties. Further observation by clinicians confirmed that the suspension of clobetasol propionate nanoparticles led to more rapid resolution of rhinitis. The suspension of clobetasol propionate nanoparticles has been demonstrated to be effective, convenient, and comfortable for treating allergic rhinitis.

[0179] Example 10. Treatment of asthma The clobetasol propionate nanoparticle suspension formulation described herein is useful for treating subjects with asthma. For example, a 15-year-old female visits a clinic complaining of shortness of breath, chest tightness and pain, wheezing, and cough. The clinician recognizes these symptoms as consistent with asthma and applies conventional treatment to rapidly alleviate acute asthma symptoms. In this embodiment, the clinician describes a method of administering the aqueous suspension of clobetasol propionate nanoparticles described herein for the treatment of asthma using an inhaler. To treat asthma symptoms, the liquid suspension is inhaled into the lungs at least once daily using an inhaler. After more than one week, the subject visits the clinic for evaluation. The subject recognizes a significant improvement in asthma symptoms, is currently asthma-free, and is breathing freely. Further observation by the clinician confirms the effective treatment of asthma with clobetasol propionate. The clobetasol propionate nanoparticle suspension has been demonstrated to be effective, convenient, and comfortable for treating asthma.

[0180] Example 11. Effects of methylcellulose concentration on tissue penetration. The tissue penetration of a suspension formulation of clobetasol propionate nanoparticles into the conjunctiva was measured using a conventional protocol. [Table 3]

[0181] The suspension of clobetasol propionate nanoparticles described herein provides a longer half-life after topical administration to the ocular surface (i.e., retention of the active ingredient, clobetasol propionate, in target tissues of pharmacological activity, such as the conjunctiva). Furthermore, the suspension of clobetasol propionate nanoparticles described herein provides a higher concentration of clobetasol propionate in target tissues (C) at a dose equivalent to that of the active ingredient in the formulation. max ) and therapeutic exposure are provided.

[0182] Example 11. Effects of tissue penetration, boric acid, and EDTA The tissue penetration of a suspension formulation of clobetasol propionate nanoparticles into the cornea was measured using a conventional protocol. After topical administration of 1 drop (50 μL) of a 0.05% clobetasol propionate nanoparticle formulation shown in Table 2 to the ocular surface, a formulation described herein containing boric acid and disodium edetate (EDTA) (Table 4) was prepared, and the concentration of clobetasol propionate measured in the target tissue to examine the pharmacological activity. [Table 4]

[0183] The suspension of clobetasol propionate nanoparticles containing boric acid and EDTA described herein provides a higher concentration and therapeutic exposure of clobetasol propionate in target tissues such as the cornea at an equivalent dose of the active ingredient. C max When presenting C values, different doses, 0.05% and 0.1%, were normalized.

[0184] All patents, patent publications, and other publications referenced and identified herein are hereby incorporated by reference in their entirety for the purpose of further describing the present invention. However, the patents, patent publications, and other publications cited should not be construed as approved prior art.

Claims

1. A method for treating burns to the skin or eyes in a subject, comprising applying a sterile suspension formulation of clobetasol propionate nanoparticles to the burns.

2. A method for treating a subject having abnormal wound healing, hypertrophic scarring, or keloids, comprising contacting a wound, scar, or keloid on the patient's skin with a sterile suspension formulation of clobetasol propionate nanoparticles.

3. A method for treating a subject having allergic rhinitis / sinusitis or asthma, comprising contacting the mucous membranes of the nose and sinuses or airways of the patient with a suspension formulation of clobetasol propionate nanoparticles.

4. A method for treating a subject having an inner ear disorder, particularly hearing loss, tinnitus, or dizziness, comprising bringing a suspension formulation of clobetasol propionate nanoparticles into contact with the patient's eardrum or delivering it to the patient's inner ear or nasal mucosa.

5. A method for treating a subject having tenosynovitis, tendinitis, or enthesitis of a tendon, comprising injecting a sterile suspension formulation of clobetasol propionate nanoparticles into the synovial cavity or tendon / ligament attachment site of the patient.

6. A method for treating a subject having arthritis, comprising injecting a sterile suspension formulation of clobetasol propionate nanoparticles into the joint of the patient.

7. The method according to claims 1, 2, 3, and 4, wherein the suspension formulation of clobetasol propionate nanoparticles is applied using a spray bottle, a dropper bottle, or an aerosol device, or by injection using a syringe and needle.

8. The method according to claims 5 and 6, wherein the sterile suspension formulation of clobetasol propionate nanoparticles is injected using a syringe and needle.

9. The method according to claims 1 and 2, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of burn or abnormal wound healing, including inflammation, pain, abnormal granulation, scarring, contracture, deformation, pigmentation, or visual impairment.

10. The method according to claims 3 to 6, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, or arthritis.

11. The method according to claim 4, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of inner ear disorders, including tinnitus, dizziness, and hearing loss.

12. The method according to claims 5 and 6, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of tenosynovitis, tendinitis, enthesitis, or arthritis, including pain and / or discomfort or reduced mobility.

13. The method according to any one of claims 1 to 6, wherein the suspension formulation of clobetasol propionate nanoparticles reduces inflammation.

14. The method according to claims 5 and 6, wherein the suspension formulation of clobetasol propionate nanoparticles improves the function of a joint, tendon, or ligament.

15. The method according to any one of claims 1 to 14, wherein the suspension formulation of clobetasol propionate nanoparticles is administered once or more daily to burned skin or to the eyes, nose, airways, nasal mucosa, eardrum, inner ear, synovial cavity, ligaments, or joints for a maximum of 52 weeks.

16. A drop, spray, mist, aerosol, or injectable formulation comprising clobetasol propionate, wherein the clobetasol propionate is formulated as a suspension of nanoparticles.

17. A drop, spray, mist, aerosol, or injectable formulation according to claim 16, further comprising sodium chloride, hydrogenated soy lecithin, anhydrous citric acid, glycerin, poloxamer 407, polyvinyl alcohol (PVA), boric acid, disodium edetate dihydrate, benzalkonium chloride, methylcellulose, or trisodium citrate, or a combination thereof.

18. A sterile form of the droplet, spray, mist, aerosol, or injectable formulation according to claim 16.

19. A drop, mist, spray, aerosol, or injectable formulation according to claim 16, further comprising an antioxidant, antibacterial agent, anesthetic, analgesic, lubricant, flavoring agent, or a combination thereof.

20. A unit dose configured for administration by injection or ophthalmic instillation, comprising clobetasol propionate, wherein the clobetasol propionate is formulated as a sterile suspension of nanoparticles.

21. The unit dose according to claim 20, further comprising sodium chloride, hydrogenated soy lecithin, anhydrous citric acid, glycerin, poloxamer 407, polyvinyl alcohol (PVA), boric acid, disodium edetate dihydrate, benzalkonium chloride, methylcellulose, or trisodium citrate, or a combination thereof.

22. The unit dose according to claim 20, further comprising an antioxidant, an antibacterial agent, an anesthetic, an analgesic, or a combination thereof.

23. The method according to claim 2, wherein the spray or drops according to claim 16 are applied to the surface of the skin or eyes of the subject.

24. The method according to claim 2, wherein the injection according to claim 16 is injected into a hypertrophic scar or keloid of interest.

25. The method according to claim 3, wherein the spray or drops described in claim 16 are applied to the mucous membranes of the nose and sinuses of the subject.

26. The method according to claim 3, wherein the spray or drops described in claim 16 are inhaled into the lungs.

27. The method according to claim 4, wherein the spray or drops according to claim 16 are applied to the eardrum of the ear or the nasal mucosa.

28. The method according to claim 4, wherein the unit dose described in claim 20 is administered by intratympanic injection.

29. The method according to claim 5, wherein the unit dose described in claim 20 is injected into the synovial cavity or attachment site of the tendon / ligament of the subject.

30. The method according to claim 6, wherein the unit dose described in claim 20 is injected into the target joint.

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