WO2022094602A1 - Proton pump inhibitors for the treatment of diseases characterized by inflammation and/or collagen accumulation - Google Patents

Abstract

Embodiments of the disclosure include methods and compositions related to treatment, prevention, delay of onset, or reduction in severity of medical conditions involved in uncontrolled inflammation and/or collagen accumulation. Uncontrolled inflammation or collagen accumulation including, but not limited to, musculoskeletal disorders, ocular surface disorders, neoplastic lesions, non-neoplastic lesions, or combinations thereof. In particular embodiments, one or more proton pump inhibitors are provided to an individual in need thereof. In some embodiments one or more proton pump inhibitors are provided to an individual having one or more musculoskeletal disorders, ocular surface disorders, neoplastic lesions, non-neoplastic lesions, or combinations thereof. In some embodiments, the providing step treats, prevents, delays onset, or reduces the severity of one or more musculoskeletal disorders, ocular surface disorders, neoplastic lesions, non-neoplastic lesions, or combinations thereof.

Description

PROTON PUMP INHIBITORS FOR THE TREATMENT OF DISEASES CHARACTERIZED BY INFLAMMATION AND/OR COLLAGEN ACCUMULATION

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63/107,948, filed October 30, 2020, which is incorporated by reference herein in its entirety.

TECHNICAL FIELD

[0002] Embodiments of the disclosure include at least the fields of cell biology, molecular biology, biochemistry, pharmacology, immunology, and medicine.

BACKGROUND

[0003] Inflammation is involved in a number of pediatric and adult onset disorders. Many of these conditions involve overproduction of a number of pro-inflammatory biomarkers, including C-reactive protein (CRP) and/or pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFa), interleukin 1 beta (ILip), and/or interleukin 6 (IL6), and/or the suppression of a number of anti-inflammatory cytokines, including interleukin 4 (IL4), interleukin 10 (IL10), interleukin 11 (IL11), and/or interleukin 13 (IL13), to drive the inflammatory process. Uncontrolled inflammation could exacerbate the diseases and trigger accumulation of extracellular matrix (ECM) proteins including collagen. There are a number of human disorders that are characterized by accumulation of abnormal levels of collagen and overproduction of a number of collagen accumulation biomarkers, including transforming growth factor beta (TGFP), collagen (Col) types 1, 2, 3, 4, 5, laminin, and/or fibronectin (FN). A non-limiting example of these disorders includes osteoarthritis. There are a number of inflammation and/or collagen mediators used in the treatment of the aforementioned clinical disorders. However, many of these agents target single molecules and thus are unable to effectively control the inflammation and/or collagen accumulation. As a result, there are millions of patients with one or more of the aforementioned conditions who are not effectively treated by these therapeutic interventions.

BRIEF SUMMARY

[0004] The present disclosure satisfies a long-felt need in the art of providing effective therapies for medical conditions involving uncontrolled inflammation or collagen accumulation, among other medical conditions. Embodiments of the present disclosure are directed to methods and compositions for treating, preventing, delaying onset of, and/or reducing severity of at least one or more musculoskeletal (relating to the bones, muscles, cartilage, ligaments, tendons, joints, and connective tissue) conditions, ocular surface (related to the cornea, conjunctiva, eyelids, or lacrimal glands) conditions, neoplastic lesions, non-neoplastic lesions, or other medical conditions involving uncontrolled inflammation or collagen accumulation. A neoplastic lesion is an abnormal growth of cells which is generally monoclonal, atypical/dysplastic, autonomous, uncontrolled, and irreversible. A non-neoplastic lesion is an abnormal proliferation of otherwise normal cells which is generally polyclonal, normal in structure/function, under control, serves the body’s needs, and reversible.

[0005] The one or more musculoskeletal conditions include at least osteoarthritis; amyopathic dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, juvenile myositis, orbital myositis, and antisynthetase syndrome; cryopyrin associated periodic syndromes including familial cold autoinflammatory syndrome and Muckle-Wells syndrome; sarcoidosis; adult onset Still’s disease; polychondrosis; polymyalgia; fibromyalgia; osteomyelitis; bursitis; synovitis and synovial fibrosis; arthrofibrosis (including post-partial or post-total joint replacement); tendinitis; fasciitis; systemic inflammatory response syndrome (e.g., after infection, trauma, surgery, etc.); extraintestinal manifestations of inflammatory bowel disease, ulcerative colitis, or Crohn’s disease; thyroid orbitopathy; rhinosinusitis; sepsis; diabetic neuropathy; chronic obstructive pulmonary disease; and liver fibrosis.

[0006] The one or more ocular surface conditions include at least dry eye disease, including chemotherapy-induced; uveitis, blepharitis; conjunctivitis; corneal infections; Meibomian gland dysfunction); ocular surface squamous neoplasia; corneal scarring; corneal abrasion, puncture or laceration; pterygium; allergic eye diseases; ocular rosacea; thermal, chemical, cold induced ocular burn; ocular graft vs host disease; cataracts; glaucoma; Fuch’s endothelial dystrophy; age-related macular degeneration, glaucoma; steroid-induced increase in intra-ocular pressure; and diabetic retinopathy.

[0007] One or more neoplastic lesions include at least benign, pre-cancerous, and cancerous tumors. One or more neoplastic lesions may occur in all tissue types, including at least bone; connective tissue; endothelium; mesothelium; blood cells; lymphoid cells; muscle; neural tissue; and epithelial tissue. One or more neoplastic lesions may present in epithelial tissue, including at least benign skin moles; and skin tags. One or more non-neoplastic lesions include at least cysts, nodules, polyps, bumps, and patches. One or more non-neoplastic lesions may occur in all tissue types, including at least bone; connective tissue; endothelium; mesothelium; blood cells; lymphoid cells; muscle; neural; epithelial, and neural tissue. One or more non-neoplastic lesions may present in epithelial tissue, including actinic keratosis and herpetic lesions.

[0008] Certain embodiments of the disclosure include methods of regulating collagen (such as regulating collagen production, accumulation, processing, distribution, or degradation for example) in an individual. In some embodiments, collagen is regulated by administering one or more proton pump inhibitors to an individual. The proton pump inhibitor may be any proton pump inhibitor provided at any concentration useful for regulating collagen.

[0009] Certain embodiments of the disclosure include methods for treating or preventing scleroderma. In some embodiments, scleroderma is treated or prevented by administering one or more proton pump inhibitors to an individual. The proton pump inhibitor may be any proton pump inhibitor provided at any concentration useful for treating or preventing scleroderma.

[0010] Embodiments of the disclosure include methods and compositions for treatment or prevention of one or more indications where one or more pro-inflammatory biomarkers (as examples only, CRP, TNF-a, IL6, and/or ILip) are involved, such as biomarkers that are elevated with respect to that of the general population. Embodiments of the disclosure include methods and compositions for treatment or prevention of one or more indications where one or more antiinflammatory biomarkers (as examples only, IL4, IL10, IL11, and/or IL13) are involved, such as biomarkers that are depressed with respect to that of the general population. Embodiments of the disclosure include methods and compositions for treatment or prevention of one or more indications where one or more collagen accumulation biomarkers (as examples only, TGFp, collagen (Col) types 1, 2, 3, 4, 5, laminin, and/or fibronectin) are involved, such as biomarkers that are elevated with respect to that of the general population. Methods and compositions of the disclosure concern treatment and/or prevention of uncontrolled inflammation and/or collagen accumulation related to any medical condition.

[0011] The present disclosure is directed to methods of treating, preventing, delaying onset of, or reducing severity of one or more medical conditions involving uncontrolled inflammation and/or collagen accumulation in an individual in need thereof, including the step of administering to the individual an effective amount of one or more proton pump inhibitors, wherein the one or more conditions are treated, prevented, delayed in onset, and/or reduced in severity in the individual. [0012] In specific embodiments, the one or more medical conditions involving uncontrolled inflammation and/or collagen accumulation are selected from the group consisting of musculoskeletal disorders, ocular surface disorders, neoplastic lesions, non-neoplastic lesions, or combinations thereof.

[0013] In specific embodiments, the group consisting of musculoskeletal disorders, ocular surface disorders, neoplastic lesions, non-neoplastic lesions, or combinations thereof, are selected from the group consisting of osteoarthritis; amyopathic dermatomyositis; inclusion body myositis; immune-mediated necrotizing myopathy; juvenile myositis; orbital myositis; antisynthetase syndrome; cryopyrin associated periodic syndromes; familial cold autoinflammatory syndrome; Muckle-Wells syndrome; sarcoidosis; adult onset Still’s disease; polychondrosis; polymyalgia; fibromyalgia; osteomyelitis; bursitis; synovitis; synovial fibrosis; arthrofibrosis; post-partial joint replacement; post-total joint replacement; tendinitis; fasciitis; systemic inflammatory response syndrome; extraintestinal manifestations of inflammatory bowel disease, ulcerative colitis, or Crohn’s disease; thyroid orbitopathy; rhinosinusitis; sepsis; diabetic neuropathy; chronic obstructive pulmonary disease; liver fibrosis; dry eye disease; chemotherapy-induced dry eye disease; uveitis, blepharitis; conjunctivitis; corneal infections; Meibomian gland dysfunction; ocular surface squamous neoplasia; corneal scarring; corneal abrasion, puncture or laceration;; pterygium; allergic eye diseases; ocular rosacea; ocular bum; ocular graft vs host disease; cataracts; glaucoma; Fuch’s endothelial dystrophy; age-related macular degeneration, glaucoma; steroid-induced increase in intra-ocular pressure; diabetic retinopathy; benign, pre-cancerous, or cancerous tumors; benign skin moles; skin tags cysts; nodules; polyps; bumps; patches; actinic keratosis; herpetic lesions; or combinations thereof.

[0014] In specific embodiments, the administering step treats, prevents, delays onset of, or reduces the severity of uncontrolled inflammation and/or collagen accumulation in the individual. In specific embodiments, the administering step treats, prevents, delays onset of, or reduces the severity of redness, thickening and swelling of the fingers or joints, pale fingers, numbness, tingling, pain, fever, fatigue, rash, loss of appetite, dry eyes, blurry vision, skin lesions, shortness of breath, or combinations thereof.

[0015] In specific embodiments, the administering step occurs systemically or locally. In specific embodiments, the administering step occurs locally to an area of the musculoskeletal system, the ocular surface, a neoplastic lesion, and/or a non-neoplastic lesion. [0016] In specific embodiments, the one or more proton pump inhibitors are formulated alone or in combination with one or more other agents. In specific embodiments, the one or more proton pump inhibitors are administered prior to, during, and/or subsequent to administration of one or more other agents. In specific embodiments, the one or more other agents comprise one or more antifibrotic drugs, one or more appetite stimulants, one or more bronchodilators, one or more artificial tears, one or more corticosteroids, one or more antibiotics, one or more pain relievers, or combinations thereof.

[0017] In specific embodiments, the one or more proton pump inhibitors are formulated for local administration. In specific embodiments, the one or more proton pump inhibitors are formulated for topical administration. In specific embodiments, the one or more proton pump inhibitors are formulated for intraarticular and/or intratumoral injection. In specific embodiments, the one or more proton pump inhibitors are formulated for administration outside of the alimentary canal. In specific embodiments, the one or more proton pump inhibitors are formulated for administration other than for the stomach. In specific embodiments, the one or more proton pump inhibitors are formulated as a liquid, troche, suppository, cream, solid, tablet, pill, aerosol, gel, film, foam, ointment, paste, cream, syrup, powder, drops, suspension, or combinations thereof.

[0018] In specific embodiments, the one or more proton pump inhibitors is Omeprazole, Lansoprazole, Dexlansoprazole, Esomeprazole, Pantoprazole, Rabeprazole, Haprazole, or combinations thereof. In specific embodiments, the concentration of the one or more proton pump inhibitors is in a range of l%-100% w/w. In specific embodiments, the concentration of the one or more proton pump inhibitors is not greater than 20% w/w.

[0019] In specific embodiments, the individual is or is not at risk of a medical condition involving uncontrolled inflammation and/or collagen accumulation, has or has not been tested for a medical condition involving uncontrolled inflammation and/or collagen accumulation, has or has not been diagnosed with a medical condition involving uncontrolled inflammation and/or collagen accumulation, and/or is or is not symptomatic for a medical condition involving uncontrolled inflammation and/or collagen accumulation.

[0020] In specific embodiments, the individual has or has not been tested for plasma concentrations of pro-inflammatory biomarkers, anti-inflammatory biomarkers, and/or collagen accumulation biomarkers, and/or has or has not been diagnosed with elevated plasma concentrations of pro-inflammatory biomarkers, depressed plasma concentrations of anti- inflammatory biomarkers, and/or elevated plasma concentrations of collagen accumulation biomarkers.

[0021] In specific embodiments, the administering step treats, prevents, delays onset of, or reduces the severity of elevated plasma concentrations of pro-inflammatory biomarkers, depressed plasma concentrations of anti-inflammatory biomarkers, and/or elevated plasma concentrations of collagen accumulation biomarkers in the individual. In specific embodiments, said pro- inflammatory biomarkers are CRP, TNF-a, IL6, ILip, or combinations thereof, said antiinflammatory biomarkers are IL4, IL10, IL11, IL13, or combinations thereof, and said collagen accumulation biomarkers are TGFp, Col 1, Col 2, Col 3, Col 4, Col 5, laminin, fibronectin, or combinations thereof.

[0022] In specific embodiments, the individual has or is at risk for a medical condition involving uncontrolled inflammation and/or collagen accumulation selected from the group consisting of musculoskeletal disorders, ocular surface disorders, neoplastic lesions, non- neoplastic lesions, or combinations thereof.

[0023] In specific embodiments, the individual has or is at risk for osteoarthritis; amyopathic dermatomyositis; inclusion body myositis; immune-mediated necrotizing myopathy; juvenile myositis; orbital myositis; antisynthetase syndrome; cryopyrin associated periodic syndromes; familial cold autoinflammatory syndrome; Muckle-Wells syndrome; sarcoidosis; adult onset Still’s disease; polychondrosis; polymyalgia; fibromyalgia; osteomyelitis; bursitis; synovitis; synovial fibrosis; arthro fibrosis; post-partial joint replacement; post-total joint replacement; tendinitis; fasciitis; systemic inflammatory response syndrome; extraintestinal manifestations of inflammatory bowel disease, ulcerative colitis, or Crohn’s disease; thyroid orbitopathy; rhinosinusitis; sepsis; diabetic neuropathy; chronic obstructive pulmonary disease; liver fibrosis; dry eye disease; chemotherapy-induced dry eye disease; uveitis, blepharitis; conjunctivitis; corneal infections; Meibomian gland dysfunction; ocular surface squamous neoplasia; corneal scarring; corneal abrasion, puncture or laceration;; pterygium; allergic eye diseases; ocular rosacea; ocular bum; ocular graft vs host disease; cataracts; glaucoma; Fuch’s endothelial dystrophy; age-related macular degeneration, glaucoma; steroid-induced increase in intra-ocular pressure; diabetic retinopathy; benign, pre-cancerous, or cancerous tumors; benign skin moles; skin tagscysts; nodules; polyps; bumps; patches; actinic keratosis; herpetic lesions; or combinations thereof. [0024] In specific embodiments, the individual has redness, thickening and swelling of the fingers or joints, pale fingers, numbness, tingling, pain, fever, fatigue, rash, loss of appetite, dry eyes, blurry vision, skin lesions, shortness of breath, or combinations thereof.

[0025] In specific embodiments, the individual has or is at risk for a medical condition involving uncontrolled inflammation and/or collagen accumulation selected from the group consisting of musculoskeletal disorders, ocular surface disorders, neoplastic lesions, non- neoplastic lesions, or combinations thereof, and wherein the one or more proton pump inhibitors is Esomeprazole that is topically formulated.

[0026] The foregoing has outlined rather broadly the features and technical advantages of the present disclosure in order that the detailed description that follows may be better understood. Additional features and advantages will be described hereinafter which form the subject of the claims herein. It should be appreciated by those skilled in the art that the conception and specific embodiments disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present designs. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope as set forth in the appended claims. The novel features which are believed to be characteristic of the designs disclosed herein, both as to the organization and method of operation, together with further objects and advantages will be better understood from the following description when considered in connection with the accompanying figures. It is to be expressly understood, however, that each of the figures is provided for the purpose of illustration and description only and is not intended as a definition of the limits of the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIGS. 1A-1B show the effect of esomeprazole on the regulation of collagen. Patient derived fibroblasts from scleroderma patients with limited (FIG. 1A) or diffuse (FIG. IB) were untreated (control), stimulated with only TGFB (TGF-B), or stimulated and treated with various concentrations of esomeprazole (TGF-B + Eso).

[0028] FIGS. 2A-2B show the effect of esomeprazole on body weight in mice with scleroderma. Scleroderma mouse models were untreated (Bleo control) or administered esomeprazole (Bleo + Eso) either topically (FIG. 2A) or systemically (FIG. 2B). [0029] FIGS. 3A-3B show the effect of esomeprazole on organ weigh in mice with scleroderma. Untreated control mice (No bleo) or a mouse model of scleroderma were untreated (Bleo Control) or treated with esomeprazole (Bleo + Eso) either topically (FIG. 3A) or systemically (FIG. 3B).

DETAILED DESCRIPTION

I. Definitions

[0030] As used herein the specification, “a” or “an” may mean one or more. As used herein in the claim(s), when used in conjunction with the word "comprising", the words “a” or “an” may mean one or more than one. As used herein “another” may mean at least a second or more. Still further, the terms “having”, “including”, “containing” and “comprising” are interchangeable and one of skill in the art is cognizant that these terms are open ended terms. Some embodiments of the disclosure may consist of or consist essentially of one or more elements, method steps, and/or methods of the disclosure. It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein. Reference throughout this specification to “one embodiment,” “an embodiment,” “a particular embodiment,” “a related embodiment,” “a certain embodiment,” “an additional embodiment,” or “a further embodiment” or combinations thereof means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0031] The term "administered" or "administering", as used herein, refers to any method of providing a composition to an individual such that the composition has its intended effect on the individual. For example, one method of administering is by a direct mechanism such as, local tissue administration, transdermal patch, topical, etc.

[0032] The term "pharmaceutically" or "pharmacologically acceptable", as used herein, refer to molecular entities and compositions that do not produce unacceptable adverse, allergic, or other untoward reactions when administered to an animal or a human. [0033] The term, "pharmaceutically acceptable carrier", as used herein, includes any and all solvents, or a dispersion medium including, but not limited to, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils, coatings, isotonic and absorption delaying agents, liposome, commercially available cleansers, and the like. Supplementary bioactive ingredients also can be incorporated into such carriers. Pharmaceutically acceptable carriers may comprise surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated.

[0034] The term “preventing” as used herein refers to the methods that avert a medical condition from occurring in an individual, including averting the onset of at least one symptom of the medical condition.

[0035] The term “subject” or "individual", as used herein, refers to a human or animal that may or may not be housed in a medical facility and may be treated as an outpatient of a medical facility. The individual may be receiving one or more medical compositions via the internet. An individual may comprise any age of a human or non-human animal and therefore includes both adult and juveniles (z.e., children) and infants. It is not intended that the term "individual" connote a need for medical treatment, therefore, an individual may voluntarily or involuntarily be part of experimentation whether clinical or in support of basic science studies. The term “subject” or “individual” refers to any organism or animal subject that is an object of a method or material, including mammals, e.g., humans, laboratory animals (e.g., primates, rats, mice, rabbits), livestock (e.g., cows, sheep, goats, pigs, turkeys, and chickens), household pets (e.g., dogs, cats, and rodents), horses, and transgenic non-human animals.

[0036] As used herein, the term “therapeutically effective amount” is synonymous with “effective amount”, “therapeutically effective dose”, and/or “effective dose” and refers to the amount of compound that will elicit the biological, cosmetic or clinical response being sought by the practitioner in an individual in need thereof. As one non-limiting example, an effective amount is the amount sufficient to inhibit elevated pro-inflammatory or collagen accumulation biomarkers in an individual. As one non-limiting example, an effective amount is the amount sufficient to reduce elevated pro-inflammatory or collagen production biomarkers in an individual. As one non-limiting example, an effective amount is an amount sufficient to prevent uncontrolled inflammation and/or collagen accumulation in an individual. As another non-limiting example, an effective amount is an amount sufficient to reduce elevated inflammation and/or collagen accumulation in an individual. As another non-limiting example, an effective amount is an amount sufficient to prevent the symptoms of elevated inflammation and/or collagen accumulation in an individual. As another non-limiting example, an effective amount is an amount sufficient to ameliorate the symptoms of elevated inflammation and/or collagen accumulation in an individual.

[0037] The appropriate effective amount to be administered for a particular application of the disclosed methods can be determined by those skilled in the art, using the guidance provided herein. For example, an effective amount can be extrapolated from in vitro and in vivo assays as described in the present specification. One skilled in the art will recognize that the condition of the individual can be monitored throughout the course of therapy and that the effective amount of a compound or composition disclosed herein that is administered can be adjusted accordingly.

[0038] “Treatment,” “treat,” or “treating” means a method of reducing the effects of a disease or condition. Treatment can also refer to a method of reducing the disease or condition itself rather than just the symptoms. The treatment can be any reduction from pre-treatment levels and can be but is not limited to the complete ablation of the disease, condition, or the symptoms of the disease or condition. Therefore, in the disclosed methods, treatment” can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease or the disease progression, including reduction in the severity of at least one symptom of the disease. For example, a disclosed method for reducing inflammation in a subject is considered to be a treatment if there is a detectable reduction in the level of pro-inflammatory biomarkers in a subject when compared to pre-treatment levels in the same subject or control subjects. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels. It is understood and herein contemplated that “treatment” does not necessarily refer to a cure of the disease or condition, but an improvement in the outlook of a disease or condition. In specific embodiments, treatment refers to the lessening in severity or extent of at least one symptom and may alternatively or in addition refer to a delay in the onset of at least one symptom. II. Examples of Methods of Use

[0039] Proton pump inhibitors (PPIs) are FDA approved drugs for the treatment of gastric reflux. They are available in packages for systemic administration including in tablet and intravenous (IV) format. None of the PPIs have been approved for any indication outside of diseases characterized by abnormal secretion of gastric acidity. Embodiments of the disclosure concern the use of one or more proton pump inhibitors (PPIs) that are effective for a medical condition other than gastritis or gastritis-related purposes. In particular embodiments, the methods are for medical conditions directly or indirectly affected by uncontrolled inflammation and/or accumulated collagen, including but not limited to musculoskeletal conditions, ocular surface conditions, or non-neoplastic lesions.

[0040] The methods encompass medical conditions in which the ocular system or the skin, epidermis, dermis, and/or mucus membranes are affected because of exposure to one or more external conditions and/or in which the musculoskeletal system, the ocular surface, or the skin, epidermis, dermis, and/or mucus membranes are affected because of internal causes, such as a genetic or other cause including underlying conditions such as diabetes. In conditions in which the cause of the medical condition is external, the methods may be utilized prior to exposure to the external condition, during exposure to the external condition, and/or after exposure to the external condition. In conditions in which the cause is internal, such as genetic or other causes, the methods may be utilized prior to onset of a symptom of the condition and/or after onset of a symptom of the condition. In situations in which the individual is predisposed to have the medical condition, the individual may prophylactically be subject to methods of the disclosure. The methods include treatment or prevention for any inflammation-related and/or fibrosis-related medical condition. In specific embodiments, the methods provide therapy or prophylaxis to the musculoskeletal system, the ocular surface, skin, dermis, epidermis, and/or mucus membranes.

[0041] In specific embodiments, the external cause of the medical condition is environmental, such as exposure to chemical(s), radiation of any kind, and/or one or more allergens or pathogens. In specific embodiments, the internal cause of the medical condition is an infection, a trauma, an allergic reaction, an injury, and/or a genetic condition.

[0042] In certain embodiments, an individual is at risk of having a medical condition, such as a musculoskeletal disorder, ocular surface disorder, neoplastic lesion, non-neoplastic lesion, or combinations thereof. An individual may be at risk of a musculoskeletal disorder from poor posture, repetitive movements, forceful movements (including heavy lifting or excessive pressure), vibrations, overexertion, work-related activities, awkward postures, stress, obesity, smoking, aging, or a combination thereof. An individual may be at risk of an ocular surface disorder from having diabetes, having glaucoma, being over- medicated, advancing age, gender, a dry environment, smoking, smoke exposure, having connective tissue disorder, a vitamin A deficiency, a prior eye surgery, having rosacea, or a combination thereof. An individual may be at risk of a neoplastic lesion from advancing age, a personal or family history of cancer, using tobacco, obesity, using alcohol, certain viral infections (such as human papillomavirus), exposure to carcinogens, exposure to radiation, or a combination thereof. An individual may be at risk of a non-neoplastic lesion from congenital issues, degenerative issues, inflammation, adaptive changes, reparative changes, or a combination thereof.

[0043] In certain embodiments, the individual administered the compositions disclosed herein, including any PPI disclosed herein, has, or is suspected of having, one or more treatment related injuries. In some embodiments, the individual is administered any of the compositions disclosed herein to prevent or reduce a treatment related injury. The injury may be from any treatment, such as a cancer treatment. The treatment may comprise a tyrosine kinase inhibitor (TKI). The injury may comprise any lung injury, such as a treatment- induced lung injury. In some embodiments, the individual has, or is suspected of having, interstitial lung disease, pneumonitis, and/or TKI-induced lung disease. In some embodiments, the individual is administered any composition disclosed herein to prevent or reduce interstitial lung disease, pneumonitis, and/or TKI-induced lung disease. In some embodiments, the individual has, or is suspected of having, an inflammatory condition. In some embodiments, the individual is administered any composition disclosed herein to prevent or reduce an inflammatory condition.

[0044] In some embodiments, an individual is tested for a medical condition in order to determine whether the individual should be treated, including treated with any methods or compositions disclosed herein. The medical condition may involve uncontrolled inflammation, such as any autoimmune disease, cancer, heart disease, or degenerative disease. The medical condition may involve collagen accumulation. The individual may be tested for inflammation. In some embodiments, the individual is tested for one or more biomarkers of inflammation, such as C-reactive protein. The C-reactive protein in an individual to be treated may be more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 mg/L or more. In some embodiments, the erythrocyte sedimentation rate (ESR) or plasma viscosity (PV) are tested. The ESR in an individual to be treated may be more than 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, mm/hr or more. The PV in an individual to be treated may be outside a normal range, including outside 1.10-1.30 mPa or outside of 1.50-1.72 mPa. In some embodiments, collagen accumulation is tested by immunohistochemistry, such as by trichrome staining or using molecules reactive or capable of binding to any collagen molecule. The individual may be tested for plasma concentrations of pro-inflammatory biomarkers, anti-inflammatory biomarkers, and/or collagen accumulation biomarkers. One skilled in the art is able to determine an appropriate test and the appropriate resulting values for determining whether an individual should be treated. In specific embodiments, an additional treatment or preventative therapy may be provided in combination with the disclosed treatment. In specific embodiments, the additional treatment or preventative therapy is for pain, allergy, infection, inflammation, shortness of breath, and/or bleeding.

[0045] Alternatively, the disclosed treatment may precede, follow, or both, an additional treatment or preventative therapy by intervals ranging from minutes to weeks to months. In embodiments where the disclosed treatment and the additional agent are provided separately to an individual, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the disclosed treatment and the additional agent would still be able to exert an advantageously combined effect against the medical condition. In such instances, it is contemplated that one may deliver both modalities within about 12-24 h of each other and, in some embodiments, within about 6-12 h of each other. In some situations, it may be desirable to extend the time period for treatment significantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) to several months (from 1-12), any subrange therein, and so forth, lapse between the respective administrations.

[0046] Various combinations may be employed, for example, wherein the disclosed treatment is “A” and the secondary additional treatment or preventative is “B”:

A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B

B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A

B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A

[0047] Administration of the disclosed treatment to a patient will follow general protocols for the administration of drugs, taking into account the toxicity, if any, of the molecule. It is expected that the treatment cycles would be repeated as necessary. It also is contemplated that various standard therapies, as well as surgical intervention, may be applied in combination with the described therapy.

III. Examples of PPIs and Compositions Thereof

[0048] PPIs are normally utilized for gastric conditions, but this disclosure encompasses reformulation of their use for conditions other than gastric conditions to formulations useful for one or more medical conditions involving uncontrolled inflammation and/or collagen accumulation. This characteristic of PPIs is devoid of the indication (z.e., treatment of gastritis) for which they are FDA- approved. PPIs directly regulate many of the pro -inflammatory and/or collagen accumulation biomarkers generated in response to many medical conditions, as encompassed herein. Many of these PPI-regulated cytokines are reported to be upregulated in musculoskeletal conditions, ocular surface conditions, and/or non-neoplastic lesions, for example.

[0049] Embodiments of the disclosure include one or more PPIs for treatment of one or more medical conditions involving uncontrolled inflammation and/or collagen accumulation. The PPIs may be formulated into any kind of composition suitable for the treatment or prevention required. The PPIs may be formulated for local or systemic administration, although in particular embodiments the administration is not for a gastric application. When more than one PPI is provided to an individual, they may or may not be formulated in the same composition.

[0050] As a specific example, the present disclosure demonstrates the direct application of topical PPI (esomeprazole) cream to the skin to prevent and/or treat collagen accumulation and confirms control of collagen secretion and wound healing in vitro and in an animal model of scleroderma. In accordance, the PPIs can be reformulated in various preparations including cream, liquid, troche, and suppository to prevent and/or treat collagen accumulation and to promote wound healing, as examples.

[0051] In particular embodiments, the PPI is Esomeprazole, Omeprazole, Lansoprazole, Dexlansoprazole, Pantoprazole, Rabeprazole, Ilaprazole, or a combination thereof. When an individual is provided multiple PPIs, they may or may not be formulated in different types of formulations, regardless of the regimen provided to the individual.

[0052] In particular embodiments, the one or more PPIs are formulated in a composition with one or more other agents for a therapeutic or other purpose. Examples include one or more antifibrotic drugs, appetite stimulants, bronchodilators, artificial tears, one or more corticosteroids, one or more antibiotics, one or more pain relievers, or a combination thereof. One particular embodiment of a composition comprises one or more PPIs with lidocaine that for example may be used to simultaneously relieve pain and treat the inflammatory and/or fibrotic condition(s).

[0053] Pharmaceutical compositions of the present disclosure comprise an effective amount of one or more PPIs dissolved or dispersed in a pharmaceutically acceptable carrier. The preparation of a pharmaceutical composition that contains at least one PPI or additional active ingredient will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington: The Science and Practice of Pharmacy, 21^st Ed. Lippincott Williams and Wilkins, 2005, incorporated herein by reference. Moreover, for animal (e.g., human) administration, it will be understood that preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biological Standards.

[0054] The one or more PPIs may comprise different types of carriers depending on whether it is to be administered in solid, liquid or aerosol form, and whether it need to be sterile for such routes of administration as injection. The one or more PPIs can be administered topically, locally, intradermally, transdermally, subcutaneously, mucosally, in creams or gels, and so forth, although in certain cases the PPIs are administered intravenously, intrathecally, intraarterially, intratumorally, intraarticularly, intraperitoneally, sublingually, intranasally, intravaginally, intrarectally, intramuscularly, orally, by inhalation (e.g., aerosol inhalation), injection (intraarticular, subcutaneous, intratumoral, etc.), as eye drops, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, via a lavage, in lipid compositions (e.g., liposomes), or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, incorporated herein by reference).

[0055] The one or more PPIs may be formulated into a composition in a free base, neutral or salt form. Pharmaceutically acceptable salts, include the acid addition salts, e.g., those formed with the free amino groups of a proteinaceous composition, or which are formed with inorganic acids such as for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric or mandelic acid. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as for example, sodium, magnesium, potassium, ammonium, calcium or ferric hydroxides; or such organic bases as isopropylamine, trimethylamine, histidine or procaine. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms such as formulated for parenteral administrations such as injectable solutions, or aerosols for delivery to the lungs, or formulated for alimentary administrations such as drug release capsules and the like.

[0056] Further in accordance with the present disclosure, the composition of the present disclosure suitable for administration is provided in a pharmaceutically acceptable carrier with or without an inert diluent. The carrier should be assimilable and includes liquid, semi-solid, pastes, or solid carriers. Except insofar as any conventional media, agent, diluent or carrier is detrimental to the recipient or to the therapeutic effectiveness of the composition contained therein, its use in administrable composition for use in practicing the methods of the present disclosure is appropriate. Examples of carriers or diluents include fats, oils, water, saline solutions, lipids, liposomes, resins, binders, fillers and the like, or combinations thereof. The composition may also comprise various antioxidants, including but not limited to sodium metabisulfite, glutathione or N-acetyl cysteine, to retard oxidation of one or more component. Additionally, the prevention of the action of microorganisms can be brought about by preservatives such as various antibacterial and antifungal agents, including but not limited to parabens (e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof.

[0057] In accordance with the present disclosure, the composition may be combined with the carrier in any convenient and practical manner, i.e., by solution, suspension, emulsification, admixture, encapsulation, absorption and the like. Such procedures are routine for those skilled in the art.

[0058] In a specific embodiment of the present disclosure, the composition is combined or mixed thoroughly with a semi-solid or solid carrier. The mixing can be carried out in any convenient manner such as grinding. Stabilizing agents can be also added in the mixing process in order to protect the composition from loss of therapeutic activity, e.g., denaturation in the stomach. Examples of stabilizers for use in the composition include buffers, amino acids such as glycine and lysine, carbohydrates such as dextrose, mannose, galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol, etc.

[0059] In further embodiments, the present disclosure may encompass the use of a pharmaceutical lipid vehicle compositions that include one or more PPIs, one or more lipids, and an aqueous solvent. As used herein, the term “lipid” will be defined to include any of a broad range of substances that is characteristically insoluble in water and extractable with an organic solvent. This broad class of compounds are well known to those of skill in the art, and as the term “lipid” is used herein, it is not limited to any particular structure. Examples include compounds which contain long-chain aliphatic hydrocarbons and their derivatives. A lipid may be naturally occurring or synthetic (/'.<?. , designed or produced by man). However, a lipid is usually a biological substance. Biological lipids are well known in the art, and include for example, neutral fats, phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, glycosphingolipids, glycolipids, sulphatides, lipids with ether and ester-linked fatty acids and polymerizable lipids, and combinations thereof. Of course, compounds other than those specifically described herein that are understood by one of skill in the art as lipids are also encompassed by the compositions and methods of the present disclosure.

[0060] One of ordinary skill in the art would be familiar with the range of techniques that can be employed for dispersing a composition in a lipid vehicle. For example, the PPI(s) may be dispersed in a solution containing a lipid, dissolved with a lipid, emulsified with a lipid, mixed with a lipid, combined with a lipid, covalently bonded to a lipid, contained as a suspension in a lipid, contained or complexed with a micelle or liposome, or otherwise associated with a lipid or lipid structure by any means known to those of ordinary skill in the art. The dispersion may or may not result in the formation of liposomes.

[0061] The actual dosage amount of a composition of the present disclosure administered to an individual can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, and/or on the route of administration. Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and/or an effective amount may vary according to the response of the individual. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual.

[0062] In certain embodiments, pharmaceutical compositions may comprise, for example, at least about 0.1% of an active compound. In other embodiments, the active compound may comprise between about 1% to about 75% of the weight of the unit, or between about 25% to about 60%, for example, and any range derivable therein. Naturally, the amount of active compound(s) in each therapeutically useful composition may be prepared in such a way that a suitable dosage will be obtained in any given unit dose of the compound. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable.

[0063] In other non-limiting examples, a dose may also comprise from about 1 microgram/kg/body weight, about 5 microgram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram/kg/body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body weight, about 350 milligram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 milligram /kg/body weight or more per administration, and any range derivable therein. In non-limiting examples of a derivable range from the numbers listed herein, a range of about 5 milligram /kg/body weight to about 100 milligram /kg/body weight, about 5 microgram/kg/body weight to about 500 milligram/kg/body weight, etc., can be administered, based on the numbers described above.

[0064] In certain embodiments, the PPI is formulated in a particular concentration in a composition. In specific embodiments, the PPI is formulated in a range of l%-100% w/w, or any range derivable therein. In specific cases, the PPI is formulated in a range of l%-100%, 1 %-75%, l%-50%, l%-25%, 10%-100%, 10%-75%, 10%-50%, 25%-100%, 25%-75%, 25%-50%, 1%- 20%, 1%-18%, 1%-16%, 1%-15%, 1%-12%, l%-10%, l%-8%, l%-6%, l%-5%, l%-4%, 1%- 3%, l%-2%, 2%-5%, 2%-4%, 2%-3%, 3%-5%, 3%-4%, 4%-5%, 5%-20%, 5%-15%, 5%-10%, 10%-20%, 10%- 15%, 12%-15%, 12%-20% w/w. The PPI may be formulated in a concentration of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% w/w, in some cases.

[0065] In particular embodiments, the concentration of proton pump inhibitor is not greater than 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21 20%, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% w/w.

A. Parenteral Compositions and Formulations [0066] In further embodiments, one or more PPIs may be administered via a parenteral route. As used herein, the term “parenteral” includes routes that bypass the alimentary tract. Specifically, the pharmaceutical compositions disclosed herein may be administered for example, but not limited to intravenously, intradermally, intramuscularly, intraarterially, intratumorally, intraarticularly, intrathecally, subcutaneous, or intraperitoneally such as described in U.S. Pat. Nos. 6,7537,514, 6,613,308, 5,466,468, 5,543,158; 5,641,515; and 5,399,363 (each specifically incorporated herein by reference in its entirety).

[0067] Solutions of the active compounds as free base or pharmacologically acceptable salts may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (U.S. Patent 5,466,468, specifically incorporated herein by reference in its entirety). In certain embodiments, the form must be sterile and must be fluid to the extent that easy injectability exists. In certain embodiments, it must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (z.e., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils. Proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0068] For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In this connection, sterile aqueous media that can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage may be dissolved in isotonic NaCl solution and either added hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences" 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.

[0069] Sterile injectable solutions may be prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation include vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. A powdered composition may be combined with a liquid carrier such as, e.g., water or a saline solution, with or without a stabilizing agent.

B. Alimentary Compositions and Formulations

[0070] Although, in some embodiments, the PPI(s) are formulated for parenteral administration, in an alternative embodiment of the present disclosure, the one or more PPIs may be formulated to be administered via an alimentary route. Alimentary routes include all possible routes of administration in which the composition is in direct contact with the alimentary tract. Specifically, the pharmaceutical compositions disclosed herein may be administered orally, buccally, rectally, or sublingually. As such, these compositions may be formulated with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard- or soft- shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.

[0071] In certain embodiments, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like (Mathiowitz etal., 1997; Hwang etal., 1998; U.S. Pat. Nos. 5,641,515; 5,580,579 and 5,792, 451, each specifically incorporated herein by reference in its entirety). The tablets, troches, pills, capsules and the like may also contain the following: a binder, such as, for example, gum tragacanth, acacia, cornstarch, gelatin or combinations thereof; an excipient, such as, for example, dicalcium phosphate, mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate or combinations thereof; a disintegrating agent, such as, for example, corn starch, potato starch, alginic acid or combinations thereof; a lubricant, such as, for example, magnesium stearate; a sweetening agent, such as, for example, sucrose, lactose, saccharin or combinations thereof; a flavoring agent, such as, for example peppermint, oil of wintergreen, cherry flavoring, orange flavoring, etc. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar, or both. When the dosage form is a capsule, it may contain, in addition to materials of the above type, carriers such as a liquid carrier. Gelatin capsules, tablets, or pills may be enterically coated. Enteric coatings prevent denaturation of the composition in the stomach or upper bowel where the pH is acidic. See, e.g., U.S. Pat. No. 5,629,001. Upon reaching the small intestines, the basic pH therein dissolves the coating and permits the composition to be released and absorbed by specialized cells, e.g., epithelial enterocytes and Peyer's patch M cells. A syrup of elixir may contain the active compound sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. Any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compounds may be incorporated into sustained-release preparation and formulations.

[0072] For oral administration, the compositions of the present disclosure may alternatively be incorporated with one or more excipients in the form of a mouthwash, dentifrice, buccal tablet, mucoadhesive agent, oral spray, or sublingual orally-administered formulation. For example, a mouthwash may be prepared incorporating the active ingredient in the required amount in an appropriate solvent, such as a sodium borate solution (Dobell's Solution). Alternatively, the active ingredient may be incorporated into an oral solution such as one containing sodium borate, glycerin and potassium bicarbonate, or dispersed in a dentifrice, or added in a therapeutically- effective amount to a composition that may include water, binders, abrasives, flavoring agents, foaming agents, and humectants. Alternatively, the compositions may be fashioned into a tablet or solution form that may be placed under the tongue or otherwise dissolved in the mouth. [0073] Additional formulations that are suitable for other modes of alimentary administration include suppositories. Suppositories are solid dosage forms of various weights and shapes, usually medicated, for insertion into the rectum. After insertion, suppositories soften, melt or dissolve in the cavity fluids. In general, for suppositories, traditional carriers may include, for example, polyalkylene glycols, triglycerides or combinations thereof. In certain embodiments, suppositories may be formed from mixtures containing, for example, the active ingredient in the range of about 0.5% to about 10%, and preferably about 1% to about 2%.

C. Miscellaneous Pharmaceutical Compositions and Formulations

[0074] In other preferred embodiments of the disclosure, the active compound PPI(s) may be formulated for administration via various miscellaneous routes, for example, topical (/'.<?., transdermal with or without the aid of patches or bandages) administration, mucosal administration (intranasal, oral, vaginal, etc.) and/or inhalation.

[0075] Pharmaceutical compositions for topical administration may include the active compound formulated for a medicated application such as an ointment, paste, cream, gel, or powder. Ointments include all oleaginous, adsorption, emulsion and water-solubility based compositions for topical application, while creams and lotions are those compositions that include an emulsion base only. Topically administered medications may contain a penetration enhancer to facilitate adsorption of the active ingredients through the skin. Suitable penetration enhancers include glycerin, alcohols, alkyl methyl sulfoxides, pyrrolidones and luarocapram. Possible bases for compositions for topical application include polyethylene glycol, lanolin, cold cream and petrolatum as well as any other suitable absorption, emulsion or water-soluble ointment base. Topical preparations may also include emulsifiers, gelling agents, and antimicrobial preservatives as necessary to preserve the active ingredient and provide for a homogenous mixture. Transdermal administration of the present disclosure may also comprise the use of a "patch". For example, the patch may supply one or more active substances at a predetermined rate and in a continuous manner over a fixed period of time.

[0076] In certain embodiments, the pharmaceutical compositions may be delivered by eye drops, eye suspensions, eye gels, eye ointments, intranasal sprays, inhalation, and/or other aerosol delivery vehicles. Methods for delivering compositions directly to the lungs via nasal aerosol sprays has been described e.g., in U.S. Pat. Nos. 5,756,353 and 5,804,212 (each specifically incorporated herein by reference in its entirety). Likewise, the delivery of drugs using intranasal microparticle resins (Takenaga et al., 1998) and lysophosphatidyl-glycerol compounds (U.S. Pat. No. 5,725, 871, specifically incorporated herein by reference in its entirety) are also well-known in the pharmaceutical arts. Likewise, transmucosal drug delivery in the form of a polytetrafluoroetheylene support matrix is described in U.S. Pat. No. 5,780,045 (specifically incorporated herein by reference in its entirety).

[0077] The term aerosol refers to a colloidal system of finely divided solid of liquid particles dispersed in a liquefied or pressurized gas propellant. The typical aerosol of the present disclosure for inhalation will consist of a suspension of active ingredients in liquid propellant or a mixture of liquid propellant and a suitable solvent. Suitable propellants include hydrocarbons and hydrocarbon ethers. Suitable containers will vary according to the pressure requirements of the propellant. Administration of the aerosol will vary according to subject’s age, weight and the severity and response of the symptoms.

IV. Kits of the Disclosure

[0078] Any of the PPI compositions described herein may be comprised in a kit. In a nonlimiting example, one or more PPIs may be comprised in a kit. The kits will thus comprise, in suitable container means, a PPI(s) and a lipid, and/or an additional agent of the present disclosure. The one or more PPI compositions may be formulated as a liquid, troche, suppository, cream, solid, tablet, pill, aerosol, gel, film, foam, ointment, paste, cream, syrup, powder, or combination thereof, for example. In specific embodiments, one or more PPI compositions formulated for use as prevention or treatment of indications encompassed herein and also may be provided in a kit with one or more antifibrotic drugs, appetite stimulants, bronchodilators, artificial tears, one or more corticosteroids, one or more antibiotics, one or more pain relievers, or a combination thereof. In some cases, a first PPI is packaged with a first other therapeutic while a second packaging comprises a second PPI packaged with a second other therapeutic. In such cases when a PPI and a pain reliever(s) and optionally another therapeutic are packaged in the same package they may be housed within different containers within the package.

[0079] The kits may comprise a suitably aliquoted PPIs, lipid and/or additional agent compositions of the present disclosure. The components of the kits may be packaged either in aqueous media or in lyophilized form. The container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which a component may be placed, and preferably, suitably aliquoted. Where there are more than one component in the kit, the kit also will generally contain a second, third or other additional container or compartment into which the additional components may be separately placed. However, various combinations of components may be comprised in a vial. The kits of the present disclosure also will typically include a means for containing the one or more PPIs, lipid, additional agent, and any other reagent containers in close confinement for commercial sale. Such containers may include injection or blow-molded plastic containers into which the desired vials are retained.

[0080] However, the components of the kit may be provided as dried powder(s). When reagents and/or components are provided as a dry powder, the powder can be reconstituted by the addition of a suitable solvent. It is envisioned that the solvent may also be provided in another container means.

[0081] The container means will generally include at least one vial, test tube, flask, bottle, syringe and/or other container means or compartment in which the formulation(s) are placed, preferably, suitably allocated. The kits may also comprise a second container means for containing a sterile, pharmaceutically acceptable buffer and/or other diluent.

[0082] The kits of the present disclosure will also typically include a means for containing the vials in close confinement for commercial sale, such as, e.g., injection and/or blow-molded plastic containers into which the desired vials are retained.

EXAMPLES

[0083] The following examples are included to demonstrate particular embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques that function well in the practice of the disclosure, and thus can be considered to constitute particular modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. EXAMPLE 1

PPIs UPREGULATING ANTI-INFLAMMATORY CYTOKINES

[0084] In a gene expression study for pro-inflammatory cytokines, primary human endothelial cells are being exposed to either bleomycin (25 pg/ml) to induce inflammation or a vehicle control. Primary human endothelial cells are also being exposed to esomeprazole (1-100 pM) to test the PPI for anti-inflammatory effect or a vehicle control. The study is confirming that the PPI esomeprazole is significantly (p<0.05) upregulating expression of IL4, IL10, IL11 and IL13 in primary human endothelial cells versus the control.

EXAMPLE 2

PPIs REDUCING PLASMA LEVELS OF PRO-INFLAMMATORY BIOMARKERS

[0085] In certain aspects, in a randomized clinical trial, levels of pro-inflammatory biomarkers are being studied in subjects diagnosed with inflammation condition before and after proton pump inhibitor supplementation or placebo, for 14-21 days. A group of subjects without inflammation is serving as a control. Levels of pro-inflammatory biomarkers are being measured in all subjects as levels of CRP, TNFa, IL6, and/or ILip in blood. Results are showing that levels of pro-inflammatory biomarkers are improving only in patients with inflammation who receive proton pump inhibitor supplementation, and not in patients with inflammation who receive placebo. Further analyses are showing that the levels of pro-inflammatory biomarkers in subjects with inflammation are decreasing to approximate values in subjects without inflammation.

EXAMPLE 3

PPIs REDUCE PLASMA LEVELS OF COLLAGEN ACCUMULATION BIOMARKERS

[0086] In certain aspects, in a randomized clinical trial, levels of collagen accumulation biomarkers are being studied in subjects diagnosed with collagen accumulation before and after proton pump inhibitor supplementation or placebo, for 14-21 days. A group of subjects without collagen accumulation is serving as a control. Levels of collagen accumulation biomarkers are being measured in all subjects as levels of TGFp, Collagen (Col) types 1, 2, 3, 4, 5, fibronectin, and/or laminin in blood. Results are showing that levels of collagen accumulation biomarkers are decreasing only in patients with collagen accumulation who receive proton pump inhibitor supplementation, and not in patients with collagen accumulation who receive placebo. Further analyses are showing that the levels of collagen accumulation biomarkers in subjects with fibrosis are decreasing to approximate values in subjects without fibrosis.

EXAMPLE 4

PPIs INCREASE PLASMA LEVELS OF ANTI-INFLAMMATORY BIOMARKERS

[0087] In certain aspects, in a randomized clinical trial, levels of anti-inflammatory biomarkers are being studied in subjects diagnosed with inflammation before and after proton pump inhibitor supplementation or placebo, for 14-21 days. A group of subjects without inflammation is serving as a control. Levels of anti-inflammatory biomarkers are being measured in all subjects as levels of IL4, IL10, IL11, and IL13 in blood. Results are showing that levels of anti-inflammatory biomarkers are increasing only in patients with inflammation who receive proton pump inhibitor supplementation, and not in patients with inflammation who receive placebo. Further analyses are showing that the levels of anti-inflammatory biomarkers in subjects with inflammation are increasing to approximate values in subjects without inflammation.

EXAMPLE 5

ESOMEPRAZOLE REGULATION OF COLLAGEN PRODUCTION

[0088] FIGS. 1A and IB provide an example of a particular embodiment of the disclosure wherein the PPI esomeprazole favorably regulates collagen production in scleroderma patient- derived skin fibroblasts from limited (FIG. 1A) and diffuse (FIG. IB) disease compared to TGFP- stimulated cells that are not treated with the drug.

EXAMPLE 6

ESOMEPRAZOLE IMPROVES HEALTH IN A MOUSE MODEL OF SCLERODERMA

[0089] FIGS. 2A-2B provide an example of a particular embodiment of the disclosure wherein the PPI esomeprazole, applied topically at 2% (FIG. 2A) or systemically at 60 mg/kg (FIG. 2B), improves the overall health in a mouse model of scleroderma as shown by the return of body weight to baseline levels compared to control animals not treated with esomeprazole. EXAMPLE 7

ESOMEPRAZOLE DOES NOT AFFECT ORGAN WEIGHT

[0090] FIGS. 3A-3B provide an example of a particular embodiment of the disclosure wherein the PPI esomeprazole, applied topically at 2% (FIG. 3A) or systemically at 60 mg/kg (FIG. 3B), does not adversely affect organ weight in a mouse model of scleroderma as shown by the lack of difference in the weight of the lungs, heart, and kidneys compared to control animals not treated with esomeprazole.

EXAMPLE 8

ASSAYS OF ESOMEPRAZOLE

[0091] In the present disclosure, examples of molecular, cell biological, and animal testing show that PPIs regulate processes involved in tissue inflammation and/or collagen overproduction. In an in vitro assay, the present disclosure confirmed that the PPI esomeprazole inhibited pro- inflammatory cytokines in primary human endothelial cells and simultaneously controls several pro-inflammatory molecules including TNFa, ILip, and IL6. The present disclosure further confirmed that PPIs controlled the proliferation of primary human fibroblasts (cells that are primarily responsible for collagen production) and the deposition of collagen. In a bioinformatics study, the present disclosure confirmed that PPIs controlled a network of extracellular matrix proteins including several collagen types, and induced wound healing related proteins. In an in vivo study in an animal model of scleroderma, the present disclosure confirmed that PPIs controlled the degree of collagen deposition and accelerated wound healing.

[0092] In certain aspects, in an in vitro assay, the PPI esomeprazole is decreasing collagen accumulation biomarkers in primary human endothelial cells and simultaneously decreasing concentrations of several collagen accumulation molecules including TGFp, Collagen 1, 2, 3, 4, 5. In certain aspects, in an in vitro assay, the PPI esomeprazole is increasing anti-inflammatory cytokines in primary human endothelial cells and simultaneously increasing concentrations of several anti-inflammatory molecules including IL4, IL10, IL11, and/or IL13.

[0093] In certain aspects, in a randomized clinical trial, proton pump inhibitor supplementation is reducing levels of pro-inflammatory biomarkers versus a placebo in subjects diagnosed with inflammation. In certain aspects, in a randomized clinical trial, proton pump inhibitor supplementation is reducing levels of collagen accumulation biomarkers versus a placebo in subjects diagnosed with collagen accumulation. In certain aspects, in a randomized clinical trial, proton pump inhibitor supplementation is increasing levels of anti-inflammatory biomarkers versus a placebo in subjects diagnosed with inflammation.

[0094] Although the present disclosure and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the design as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, composition of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the present disclosure, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present disclosure. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps.

Claims

CLAIMS What is claimed is:

1. A method of treating, preventing, delaying onset of, or reducing severity of one or more medical conditions in an individual in need thereof, comprising the step of administering to the individual an effective amount of one or more proton pump inhibitors wherein the one or more medical conditions comprise musculoskeletal disorders, ocular surface disorders, neoplastic lesions, non-neoplastic lesions, or combinations thereof.

2. The method of claim 1, wherein the administering step treats, prevents, delays onset of, or reduces the severity of uncontrolled inflammation and/or collagen accumulation in the individual.

3. The method of claim 1 or 2, wherein the administering step treats, prevents, delays onset of, or reduces the severity of redness, thickening and swelling of the fingers or joints, pale fingers, numbness, tingling, pain, fever, fatigue, rash, loss of appetite, dry eyes, blurry vision, skin lesions, shortness of breath, or combinations thereof.

4. The method of any one of claims 1-3, wherein the administering step occurs systemically or locally.

5. The method of any one of claims 1-4, wherein the administering step occurs locally to an area of the musculoskeletal system, the ocular surface, a neoplastic lesion, and/or a non-neoplastic lesion.

6. The method of any one of claims 1-5, wherein the one or more proton pump inhibitors are formulated alone or in combination with one or more other agents.

7. The method of any one of claims 1-6, wherein the one or more proton pump inhibitors are administered prior to, during, and/or subsequent to administration of one or more other agents.

8. The method of claim 6 or 7, wherein said one or more other agents comprise one or more antifibrotic drugs, one or more appetite stimulants, one or more bronchodilators, one or more artificial tears, one or more corticosteroids, one or more antibiotics, one or more pain relievers, or combinations thereof.

- 29 -

9. The method of any one of claims 1-8, wherein the one or more proton pump inhibitors are formulated for local administration.

10. The method of any one of claims 1-9, wherein the one or more proton pump inhibitors are formulated for topical administration.

11. The method of any one of claims 1-10, wherein the one or more proton pump inhibitors are formulated for intraarticular and/or intratumoral injection.

12. The method of any one of claims 1-11, wherein the one or more proton pump inhibitors are formulated for administration outside of the alimentary canal.

13. The method of any one of claims 1-12, wherein the one or more proton pump inhibitors are formulated for administration other than for the stomach.

14. The method of any one of claims 1-13, wherein the one or more proton pump inhibitors are formulated as a liquid, troche, suppository, cream, solid, tablet, pill, aerosol, gel, film, foam, ointment, paste, cream, syrup, powder, drops, suspension, or combinations thereof.

15. The method of any one of claims 1-14, wherein the one or more proton pump inhibitors comprises Omeprazole, Lansoprazole, Dexlansoprazole, Esomeprazole, Pantoprazole, Rabeprazole, Ilaprazole, or combinations thereof.

16. The method of any one of claims 1-15, wherein the concentration of the one or more proton pump inhibitors is in a range of l%-100% w/w.

17. The method of any one of claims 1-16, wherein the concentration of the one or more proton pump inhibitors is not greater than 20% w/w.

18. The method of any one of claims 1-17, wherein the individual is at risk of a medical condition involving uncontrolled inflammation and/or collagen accumulation, has been tested for a medical condition involving uncontrolled inflammation and/or collagen accumulation, has been diagnosed with a medical condition involving uncontrolled inflammation and/or collagen accumulation, and/or is symptomatic for a medical condition involving uncontrolled inflammation and/or collagen accumulation.

- 30 -

19. The method of any one of claims 1-18, wherein the individual has been tested for plasma concentrations of pro-inflammatory biomarkers, anti-inflammatory biomarkers, and/or collagen accumulation biomarkers, and/or has been diagnosed with elevated plasma concentrations of pro- inflammatory biomarkers, depressed plasma concentrations of anti-inflammatory biomarkers, and/or elevated plasma concentrations of collagen accumulation biomarkers.

20. The method of any one of claims 1-19, wherein the administering step treats, prevents, delays onset of, or reduces the severity of elevated plasma concentrations of pro-inflammatory biomarkers, depressed plasma concentrations of anti-inflammatory biomarkers, and/or elevated plasma concentrations of collagen accumulation biomarkers in the individual.

21. The method of claim 20, wherein said pro-inflammatory biomarkers comprise CRP, TNF- a, IL6, ILip, or combinations thereof, wherein said anti-inflammatory biomarkers comprise IL4, IL10, IL11, IL13, or combinations thereof, and/or wherein said collagen accumulation biomarkers comprise TGFp, Col 1, Col 2, Col 3, Col 4, Col 5, laminin, fibronectin, or combinations thereof.

22. The method of any one of claims 1-21, wherein the individual has or is at risk for osteoarthritis; amyopathic dermatomyositis; inclusion body myositis; immune-mediated necrotizing myopathy; juvenile myositis; orbital myositis; antisynthetase syndrome; cryopyrin associated periodic syndromes; familial cold autoinflammatory syndrome; Muckle-Wells syndrome; sarcoidosis; adult onset Still’s disease; polychondrosis; polymyalgia; fibromyalgia; osteomyelitis; bursitis; synovitis; synovial fibrosis; arthrofibrosis; post-partial joint replacement; post-total joint replacement; tendinitis; fasciitis; systemic inflammatory response syndrome; extraintestinal manifestations of inflammatory bowel disease, ulcerative colitis, or Crohn’s disease; thyroid orbitopathy; rhinosinusitis; sepsis; diabetic neuropathy; chronic obstructive pulmonary disease; liver fibrosis; dry eye disease; chemotherapy-induced dry eye disease; uveitis, blepharitis; conjunctivitis; corneal infections; Meibomian gland dysfunction; ocular surface squamous neoplasia; corneal scarring; corneal abrasion, puncture or laceration; pterygium; allergic eye diseases; ocular rosacea; ocular bum; ocular graft vs host disease; cataracts; glaucoma; Fuch’s endothelial dystrophy; age-related macular degeneration, glaucoma; steroid-induced increase in intra-ocular pressure; diabetic retinopathy; benign, pre-cancerous, or cancerous tumors; benign skin moles; skin tags; melanoma and non-melanoma skin cancers; cysts; nodules; polyps; bumps; patches; actinic keratosis; herpetic lesions; or combinations thereof.

23. The method of any one of claims 1-22, wherein the individual has redness, thickening and swelling of the fingers or joints, pale fingers, numbness, tingling, pain, fever, fatigue, rash, loss of appetite, dry eyes, blurry vision, skin lesions, shortness of breath, or combinations thereof.

24. The method of any one of claims 1-23 wherein the one or more proton pump inhibitors is Esomeprazole that is topically formulated.

25. A method of regulating collagen in an individual comprising the step of administering to the individual an effective amount of one or more proton pump inhibitors.

26. The method of claim 25, wherein the administering step occurs systemically or locally.

27. The method of claim 25 or 26, wherein the administering step occurs locally to an area of the musculoskeletal system, the ocular surface, a neoplastic lesion, and/or a non-neoplastic lesion.

28. The method of any one of claims 25-27, wherein the one or more proton pump inhibitors are formulated alone or in combination with one or more other agents.

29. The method of any one of claims 25-28, wherein the one or more proton pump inhibitors are administered prior to, during, and/or subsequent to administration of one or more other agents.

30. The method of claim 28 or 29, wherein said one or more other agents comprise one or more antifibrotic drugs, one or more appetite stimulants, one or more bronchodilators, one or more artificial tears, one or more corticosteroids, one or more antibiotics, one or more pain relievers, or combinations thereof.

31. The method of any one of claims 25-30, wherein the one or more proton pump inhibitors are formulated for local administration.

32. The method of any one of claims 25-31, wherein the one or more proton pump inhibitors are formulated for topical administration.

33. The method of any one of claims 25-32, wherein the one or more proton pump inhibitors are formulated for intraarticular injection.

34. The method of any one of claims 25-33, wherein the one or more proton pump inhibitors are formulated for administration outside of the alimentary canal.

35. The method of any one of claims 25-34, wherein the one or more proton pump inhibitors are formulated for administration other than for the stomach.

36. The method of any one of claims 25-35, wherein the one or more proton pump inhibitors are formulated as a liquid, troche, suppository, cream, solid, tablet, pill, aerosol, gel, film, foam, ointment, paste, cream, syrup, powder, drops, suspension, or combinations thereof.

37. The method of any one of claims 25-36, wherein the one or more proton pump inhibitors comprises Omeprazole, Lansoprazole, Dexlansoprazole, Esomeprazole, Pantoprazole, Rabeprazole, Ilaprazole, or combinations thereof.

38. The method of any one of claims 25-37, wherein the concentration of the one or more proton pump inhibitors is in a range of l%-100% w/w.

39. The method of any one of claims 25-38, wherein the concentration of the one or more proton pump inhibitors is not greater than 20% w/w.

40. The method of any one of claims 25-39, wherein the individual is at risk of a medical condition involving uncontrolled inflammation and/or collagen accumulation, has been tested for a medical condition involving uncontrolled inflammation and/or collagen accumulation, has been diagnosed with a medical condition involving uncontrolled inflammation and/or collagen accumulation, and/or is symptomatic for a medical condition involving uncontrolled inflammation and/or collagen accumulation.

41. The method of any one of claims 25-40, wherein the individual has been tested for plasma concentrations of pro-inflammatory biomarkers, anti-inflammatory biomarkers, and/or collagen accumulation biomarkers, and/or has been diagnosed with elevated plasma concentrations of pro- inflammatory biomarkers, depressed plasma concentrations of anti-inflammatory biomarkers, and/or elevated plasma concentrations of collagen accumulation biomarkers.

42. The method of any one of claims 25-41, wherein the administering step treats, prevents, delays onset of, or reduces the severity of elevated plasma concentrations of pro-inflammatory biomarkers, depressed plasma concentrations of anti-inflammatory biomarkers, and/or elevated plasma concentrations of collagen accumulation biomarkers in the individual.

- 33 -

43. The method of claim 42, wherein said pro-inflammatory biomarkers comprise CRP, TNF- a, IL6, ILip, or combinations thereof, wherein said anti-inflammatory biomarkers comprise IL4, IL10, IL11, IL13, or combinations thereof, and/or wherein said collagen accumulation biomarkers comprise TGFp, Col 1, Col 2, Col 3, Col 4, Col 5, laminin, fibronectin, or combinations thereof.

44. The method of any one of claims 25-43, wherein the individual has or is at risk for osteoarthritis; amyopathic dermatomyositis; inclusion body myositis; immune-mediated necrotizing myopathy; juvenile myositis; orbital myositis; antisynthetase syndrome; cryopyrin associated periodic syndromes; familial cold autoinflammatory syndrome; Muckle-Wells syndrome; sarcoidosis; adult onset Still’s disease; polychondrosis; polymyalgia; fibromyalgia; osteomyelitis; bursitis; synovitis; synovial fibrosis; arthrofibrosis; post-partial joint replacement; post-total joint replacement; tendinitis; fasciitis; systemic inflammatory response syndrome; extraintestinal manifestations of inflammatory bowel disease, ulcerative colitis, or Crohn’s disease; thyroid orbitopathy; rhinosinusitis; sepsis; diabetic neuropathy; chronic obstructive pulmonary disease; liver fibrosis; dry eye disease; chemotherapy-induced dry eye disease; uveitis, blepharitis; conjunctivitis; corneal infections; Meibomian gland dysfunction; ocular surface squamous neoplasia; corneal scarring; corneal abrasion, puncture or laceration; pterygium; allergic eye diseases; ocular rosacea; ocular bum; ocular graft vs host disease; cataracts; glaucoma; Fuch’s endothelial dystrophy; age-related macular degeneration, glaucoma; steroid-induced increase in intra-ocular pressure; diabetic retinopathy; benign, pre-cancerous, or cancerous tumors; benign skin moles; skin tags; melanoma and non-melanoma skin cancers; cysts; nodules; polyps; bumps; patches; actinic keratosis; herpetic lesions; or combinations thereof.

45. The method of any one of claims 25-44, wherein the individual has redness, thickening and swelling of the fingers or joints, pale fingers, numbness, tingling, pain, fever, fatigue, rash, loss of appetite, dry eyes, blurry vision, skin lesions, shortness of breath, or combinations thereof.

46. The method of any one of claims 25-45 wherein the one or more proton pump inhibitors is Esomeprazole that is topically formulated.

- 34 -