Compositions and methods for treatment of obesity and metabolic disorders

Abstract

The present disclosure provides compositions, uses thereof, and methods for treating subjects with obesity and / or metabolic disorders. In aspects and embodiments, the method comprises administering an effective amount of one or more of a mast cell stabilizer and an H1-antihistamine, in combination with a non-steroidal anti-inflammatory drug (NSAID), either in the same or separate compositions.

Description

[0001] SJP-011PC / 119887-5011

[0002] COMPOSITIONS AND METHODS FOR TREATMENT OF OBESITY AND METABOLIC DISORDERS

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U. S. Provisional Patent Application No. 63 / 735,359, filed on December 18, 2024, the entire contents of which are hereby incorporated by reference in their entirety.

[0004] BACKGROUND

[0005] Chronic low-grade inflammation is a persistent, subtle level of inflammation that is associated with metabolic conditions such as diabetes and obesity. Chronic low-grade inflammation can result from aberrant metabolism, due to, for example, poor diet, alcohol consumption, smoking, lack of exercise, stress, and weight management, among other factors. This chronic inflammation fuels chronic disease, including progression of diabetes and cardiovascular diseases, and increases the risk of cancer, among other risks. Accordingly, treatments for chronic low-grade inflammation, including for patients with diabetes and metabolic diseases, are needed.

[0006] DETAILED DESCRIPTION

[0007] The present disclosure provides compositions, uses thereof, and methods for treating subjects with obesity and / or metabolic disorders. In aspects and embodiments, the method comprises administering an effective amount of one or more of a mast cell stabilizer and an H1-antihistamine, in combination with a non-steroidal anti-inflammatory drug (NSAID) (either in the same or separate compositions). In embodiments, the subject is further undergoing therapy with a GLP-1 receptor agonist (which may include dual or triple receptor agonists). In such embodiments, subjects may experience synergistic effects in one or more of weight loss, blood glucose control, reductions in insulin resistance, and reductions in systemic inflammatory markers.

[0008] Without intending to be bound by theory, it is believed that the compositions and methods of this disclosure reduce inflammation resulting from the immune system’s signaling cascades (e.g., including but not limited to inflammation produced via cells of the

[0009] DBl / 165003233.2 1 SJP-011PC / 119887-5011

[0010] innate immune system, such as mast cells, basophils, eosinophils, and neutrophils). In aspects and embodiments, the methods and compositions reduce low-grade inflammation driven by cellular metabolism. In embodiments, the compositions and methods are useful for reducing chronic low-grade inflammation. “Chronic low-grade inflammation” refers to a persistent, subtle level of inflammation in the body, which may not produce noticeable inflammatory symptoms. This condition can be characterized by chronic but low-grade production of inflammatory factors. Chronic low-grade inflammation can be associated with conditions such as heart disease, diabetes, obesity, depression, chronic pain, malaise, and certain cancers. Chronic low-grade inflammation can result from poor diet, alcohol consumption, smoking, lack of exercise, stress, and weight management, among other factors (including genetic factors).

[0011] In embodiments, aberrant metabolism results in a persistent metabolic inflammation, which may activate innate immune cells (e.g., neutrophils, macrophages, mast cells, dendritic cells), and fuel progression of chronic diseases such as diabetes. In embodiments, the compositions and methods described herein address the underlying subclinical metabolic inflammation in addition to achieving glucose control, which can provide substantial benefits for patients with inflammation-driven metabolic disorders, for example, diabetes mellitus, insulin resistance, obesity, and metabolic syndrome.

[0012] In embodiments, the subject is undergoing therapy with a GLP-1 receptor agonist. The active agents of this disclosure operate through mechanisms that are distinct from GLP- 1 receptor agonists, impacting the underlying drivers of metabolic dysfunction. For example, the compositions and methods of this disclosure can reduce lipotoxicity, decreasing ectopic lipid accumulation in non-adipose tissues (e.g., liver, muscle). In embodiments, the composition and methods alleviate metabolic stress that contributes to insulin resistance. In embodiments, the compositions and methods reduce levels of C-reactive protein (CRP), modulating proinflammatory cytokines that are elevated in metabolic disorders (e.g., TNF- a, IL-6). In embodiments, the compositions and methods reduce systemic inflammation, improving metabolic and cardiovascular outcomes. In embodiments, the compositions and methods mitigate insulin sensitivity and resistance, improving adipokine profiles (e g., leptin / adiponectin balance) to enhance glucose metabolism, and / or restore physiological

[0013] DBl / 165003233.2 2 SJP-011PC / 119887-5011

[0014] insulin action through direct effects on skeletal muscle and adipose tissue. In embodiments, the compositions and methods produce indirect cardiovascular and renal benefits. In embodiments, the therapy further reduces other inflammatory conditions that may be present such as pancreatitis and / or inflammatory liver disease.

[0015] GLP-1 receptor agonists enhance insulin secretion, suppress glucagon, and promote satiety. Accordingly, the compositions of the present disclosure, when administered in combination with GLP-1 receptor agonists, further produce systemic metabolic correction via lipotoxicity reduction, inflammation modulation, and insulin resistance improvement. This complementary action amplifies outcomes, particularly for patients with persistent inflammation or insulin resistance despite GLP-1 therapy. In embodiments, combination therapy (e.g., with GLP-1 receptor agonists) results in reductions in weight loss, blood glucose control, reductions in insulin resistance, and / or reductions in systemic inflammatory markers that are about additive, or more than additive (e.g., as determined in a population of patients as compared to appropriate controls).

[0016] In embodiments, the subject (e.g., a human subject) is overweight or obese. For example, in embodiments, the subject is an adult with a Body Mass Index (BMI) of at least 25, or at least 28, or at least 30, or at least 35. In embodiments, the subject is morbidly obese, e.g., has a BMI of at least 40.

[0017] In embodiments, the subject is pre-diabetic or diabetic. Prediabetes is a condition where fasting blood sugar levels are higher than normal (e.g., 110-126 mg / dL), but not high enough to be diagnosed as diabetes. In some embodiments, the subject has type 1 or type 2 diabetes mellitus (e.g., has fasting blood sugar levels above 126 mg / dL). In embodiments, the subject receives insulin therapy.

[0018] In embodiments, the subject exhibits insulin resistance (e.g., may have type 2 diabetes). Insulin resistance occurs when the body's cells do not respond properly to insulin. In embodiments, the subject exhibits a fasting glucose level of 110 mg / dL or higher, and / or a blood sugar level of 140 mg / dL or higher two hours after a glucose load test.

[0019] DBl / 165003233.2 3 SJP-011PC / 119887-5011

[0020] In embodiments, the subject has metabolic syndrome. Metabolic syndrome is a group of risk factors that increase the likelihood of developing conditions such as type 2 diabetes, heart disease, and stroke. In embodiments, the subject exhibits abdominal obesity, a primary component of metabolic syndrome. The subject with metabolic syndrome may further exhibit insulin resistance, hypertension, high triglycerides, low HDL cholesterol, and high fasting blood sugar, each as understood in the art.

[0021] In embodiments, the subject is undergoing therapy with an incretin drug (or incretin mimetic), such as a GLP-1 receptor agonist or GIP receptor agonist. Examples of GLP-1 receptor agonists include: Dulaglutide (TRULICITY), Exenatide (BYETTA, BYDUREON), Liraglutide (VICTOZA), Lixisenatide (ADLYXIN), and Semaglutide (OZEMPIC, WEGOVY, RYBELSUS). In embodiments, the GLP-1 receptor agonist is a dual agonist of GLP-1 and GIP receptors. For example, Tirzepatide (MOUNJARO, ZEPBOUND) are dual GIP / GLP-1 receptor agonists. In embodiments, the subject is undergoing therapy with a triple agonist (e.g., Retatrutide), which is an agonist for the GLP-1 receptor, GIP receptor, and glucagon receptor.

[0022] In embodiments, the subject is administered an effective amount of a mast cell stabilizer. Mast cell stabilizers prevent the release of histamine and chemical mediators from mast cells, as well as basophils, eosinophils, and neutrophils. Examples of mast cell stabilizers include ketotifen, cromolyn, lodoxamide tromethamine, nedocromil, pemirolast, azelastine, and cromoglycate. In embodiments, the subject is administered ketotifen.

[0023] In embodiments, the subject is administered an H1-antihistamine (i.e. Hi receptor antagonists), and in embodiments is a second generation Hi.antihistamine and is nonsedating. In embodiments, the H1-antihistamine is fexofenadine, loratadine, cetirizine, desloratadine, or combinations thereof, and including salts thereof. Ketotifen is also classified as an H1-antihistamine. In embodiments, the H1-antihistamine is ketotifen or fexofenadine.

[0024] In embodiments, the NSAID is selected from aspirin (i.e., acetylsalicylic acid); ibuprofen (i.e., isobutylphenylpropanoic acid); naproxen (i.e., 6-met oxy-α-methyl-2- naphthaleneacetic acid); diclofenac (2-[(2,6-dichlorophenyl)-amino]benzene acetic acid);

[0025] DBl / 165003233.2 4 SJP-011PC / 119887-5011

[0026] diflunisal (2', 4'- difluoro-4-hydroxybiphenyl-3-carboxylic acid); etodolac (( 1,8 -Di ethyl - l,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)acetic acid); indomethacin (2-{ l-[(4- Chlorophenyl)-carbonyl]- 5-methoxy-2-methyl- lH-indol-3-yl}acetic acid); ketoprofen (3- benzoyl-α-methyl- benzeneacetic acid); ketorolac (2-amino-2-(hydroxymethyl)- 1,3- propanediol); mel oxicam (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-l,2- benzothiazine-3-carboxamide- 1,1 -dioxide); nabumetone (4-(6-methoxy-2-naphthyl)-2- butanone); oxaprozin (3-(4,5-diphenyl-l,3-oxazol-2-yl)propanoic acid); piroxicam (4- hydroxy-2-methyl-N-2-pyridinyl-2H-l,2-benzothiazine-3 -carboxamide 1,1 -di oxide); salsalate (2-(2-Hydroxybenzoyl)-oxybenzoic acid); sulindac ({(lZ)-5-fluoro-2-methyl-l-[4- (methylsulfmyl)-benzylidene]-lH-indene-3-yl}acetic acid); and tolmetin ([l-methyl-5-(4- methylbenzoyl)-lH-pyrrol-2-yl] acetic acid). In particular embodiments, the NS AID comprises naproxen and / or indomethacin.

[0027] As used herein, the NSAID, mast cell stabilizer, and H1-antihistamine includes all pharmaceutically acceptable versions thereof, including, for example, all pharmaceutically acceptable salts thereof, stereoisomers and / or any mixtures thereof, all pharmaceutically acceptable zwitterions and / or any mixtures thereof, all pharmaceutically acceptable polymorphic forms and / or any mixtures thereof, and all pharmaceutically acceptable complexes (including solvates) and / or any mixtures thereof. Salts include their racemates, enantiomers, or any mixtures thereof. Particularly suitable salts comprise alkali-metal salts (e.g., sodium and / or potassium salts), alkaline earth metal salts (e.g., magnesium and / or calcium salts), aluminum salts, ammonium salts, salts of suitable organic bases, salts of amino acids (e.g., salts of arginine and / or lysine). Salts also include all enantiomeric salts formed with pharmaceutically acceptable chiral acids and / or bases and / or any mixtures of enantiomers of such salts (e.g., (+) tartrates, (-) tartrates and / or any mixtures thereof including racemic mixtures). Examples of typical salts include indomethacin sodium and ketotifen fumarate.

[0028] In embodiments, the H1-antihistamine and / or mast cell stabilizer may be administered in compositions separate from the NSAID, or may be co-formulated with the NSAID (i.e., administered via the same pharmaceutical composition, also referred to as a unit dose).

[0029] DBl / 165003233.2 5 SJP-011PC / 119887-5011

[0030] In aspects and embodiments, the present disclosure provides pharmaceutical compositions (e.g., unit dose) that consist of or consist essentially of the NSAID (e.g., indomethacin and / or naproxen) and the Hi -anti histamine and / or mast cell stabilizer (e.g., ketotifen or fexofenadine) as active pharmaceutical ingredients. In these embodiments, the composition may further comprise inactive ingredients, such as pharmaceutical excipients, sweetening agent(s), flavoring agent(s), taste masking ingredient(s), diluent(s), alum, stabilizer(s), buffer(s), coloring agent(s), breath neutralizer(s) (e.g., peppermint or menthol scents), emulsifying agent(s), suspending agent(s), and agents to control delivery, for example. The compositions in some embodiments may have additional ingredients (including active ingredients) that do not affect the basic and novel characteristics of the composition.

[0031] In embodiments, the pharmaceutical composition(s) can be administered orally (e.g., enteral or buccal), intravenously, intramuscularly, subcutaneously, transdermally, by inhalation, or intranasally. In embodiments, the composition is in the form of a tablet, a capsule, a lozenge, or chewing gum. In embodiments, the composition is in the form of a transdermal patch.

[0032] In embodiments, compositions according to the disclosure can be administered orally by any method known in the art. For example, the compositions can be administered in the form of tablets, including, e.g., orally-dissolvable tablets, chewable tablets, capsules, lozenges, pills (e.g., pastilles, dragees), troches, gummy, elixirs, suspensions, syrups, wafers, chewing gum, strips, films (e.g., orally-dissolving thin films), soluble powders, effervescent compositions, and the like. In some embodiments, the composition is a tablet or capsule for oral delivery (e.g., enteral or buccal delivery).

[0033] In the case of tablets for oral use, carriers commonly used include lactose and corn starch, and lubricating agents such as magnesium stearate are commonly added. Further examples of carriers and excipients include milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, calcium stearate, talc, vegetable fats or oils, gums and glycols. When aqueous suspensions are used for oral administration, emulsifying and / or suspending agents

[0034] DBl / 165003233.2 6 SJP-011PC / 119887-5011

[0035] are commonly added. In addition, sweetening and / or flavoring agents may be added to the oral compositions.

[0036] In embodiments, the pharmaceutical composition comprises naproxen sodium and fexofenadine, and the composition may optionally be administered at least once daily, such as before or after eating a meal. In embodiments, the daily amount of naproxen sodium is about 110 mg to about 900 mg, and the daily amount of fexofenadine is about 25 mg to about 200 mg. In an embodiment, the daily amount of naproxen sodium from about 200 mg to about 880 mg (e.g., about 220 mg), and the daily amount of fexofenadine from about 60 mg to about 120 mg (e.g., about 60 mg). In an embodiment, the composition is in the form of a tablet for enteral administration, an orally-dissolving tablet or lozenge, gummy, or chewing gum. In embodiments, the agents are delivered in a single unit dose about daily.

[0037] In embodiments, the pharmaceutical composition comprises ibuprofen in the amount of about 200 mg to about 800 mg, and the composition may be optionally administered at least once daily, such as before or after eating a meal. In embodiments, the pharmaceutical composition comprises aspirin in the amount of about 325 mg to about 1000 mg, and the composition may be optionally administered about daily. In an embodiment, the pharmaceutical composition comprises loratadine in the amount of about 10 mg to about 20 mg (e.g., for administration about daily). In embodiments, the pharmaceutical composition comprises cetirizine in the amount of about 5 mg to about 20 mg (e.g., for administration about daily). In embodiments, the pharmaceutical composition comprises desloratidine in the amount of about 5 mg to about 10 mg (e.g., for administration about daily).

[0038] In embodiments, the composition comprises an effective amount of indomethacin and ketotifen. In embodiments, indomethacin and ketotifen are administered at least once daily, such as before or after eating a meal, and the daily dose of indomethacin is about 20 mg to about 300 mg, about 40 mg to about 200 mg, or about 75 mg to about 150 mg. In various embodiments, a daily dose of ketotifen is about 1 mg to about 10 mg, or about 1 mg to about 6 mg, or about 2 mg to about 5 mg, or about 3 mg to about 4 mg. In embodiments, a unit dose of the disclosure comprises about 50 mg indomethacin and about 1 mg ketotifen, and the unit dose is administered 2 or 3 times per day.

[0039] DBl / 165003233.2 7 SJP-011PC / 119887-5011

[0040] In embodiments, a method of the disclosure comprises administering naproxen and ketotifen (e.g., in a single composition as described). In certain embodiments, naproxen and ketotifen are administered at least once daily, such as before or after eating a meal, and the daily dose of naproxen is about 100 mg to about 1600 mg, about 200 mg to about 1400 mg, about 400 mg to about 1200 mg, about 600 mg to about 1000 mg, or about 700 mg to about 900 mg. In various embodiments, a daily dose of ketotifen is about 1 mg to about 10 mg, or about 1 mg to about 6 mg, or about 2 mg to about 5 mg, or about 3 mg to about 4 mg.

[0041] In embodiments, the composition comprises or consists of the active agents of indomethacin and ketotifen. In embodiments, the composition comprises 2 mg ketotifen formulated for immediate release, with 75 mg indomethacin formulated for sustained release (referred to herein as SJP-002C). The composition in these embodiments can be effective for reducing CRP levels with administration at least daily (e.g., for at least two weeks).

[0042] In embodiments, the composition comprises coated particles as disclosed in US provisional application no. 63 / 571,600, which is hereby incorporated by reference in its entirety. Such compositions provide formulations that solubilize and / or suspend poorly soluble active ingredients, such as ketotifen and indomethacin, for use in coating processes to manufacture drug products. These include drug products (e.g, spray-coated drug products) with low impurities and high homogeneity and mass transfer efficiencies

[0043] In embodiments, the composition is a drug product for oral administration, comprising beads coated with ketotifen and / or indomethacin. In embodiments, the drug product comprises beads that have two active ingredients and inactive ingredients coated onto a carrier substrate (e.g., sugar sphere cores). In embodiments, the composition is a ketotifen immediate release / indomethacin extended release capsule drug product for oral administration. In embodiments, the active ingredients are applied to separate bead populations and filled to the proper ratio within the same capsule.

[0044] In embodiments, a solution or suspension (for coating the beads) comprises indomethacin, and co-solvents. In embodiments, the co-solvents comprise about 60% to about 90% isopropyl alcohol (IP A) by volume (e.g., about 70% to about 80% IPA by volume) and about 0% to about 10% water by volume. The solution or suspension further

[0045] DBl / 165003233.2 8 SJP-011PC / 119887-5011

[0046] comprises one or both of a binder polymer (e g., povidone) and a sugar alcohol (e.g., mannitol) at about 1% to about 5% by weight individually. In embodiments, the polymer is a pharmaceutically acceptable water soluble polymer or combination thereof, such as one or more selected from polyvinylpyrrolidone (povidone), polyvinyl alcohol (PVA), methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, and hydroxypropylmethylcellulose (HPMC). In embodiments, the polymer is povidone. In embodiments, the povidone has an average molecular weight in the range of 10 kDa to about 70 kDa, or in the range of 30 to 40 kDa (e.g., K30). In embodiments, a sugar alcohol is present, which is optionally selected from one or more of mannitol, sorbitol, erythritol, xylitol, and lactitol. In embodiments, the sugar alcohol is mannitol.

[0047] In embodiments, one or both of povidone and mannitol are present at about 2 to about 5% by weight, such as about 2 to about 4% by weight. In embodiments, indomethacin is present in the solution / suspension up to about 70% by weight, such as from about 20% to about 70% by weight, or from about 25% to about 70% by weight, or from about 30% to about 70% by weight, or from about 40% to about 70% by weight, or from about 40% to 60% by weight. In embodiments, the indomethacin is present in the formulation at about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 55%, or about 60% by weight. In embodiments, the concentration of indomethacin in the solution or suspension is in the range of 50% to 60% by weight (e.g., about 55% by weight).

[0048] In embodiments, the solution or suspension can be employed to produce pharmaceutical compositions comprising beads having an indomethacin coating, which can be an extended release coating. These beads can be coated with other active agents, such as ketotifen, and / or combined with other populations of beads coated with other actives. Other active agents that can be combined with indomethacin according to the disclosure include fexofenadine, desloratadine, and cetirizine.

[0049] In embodiments, povidone (as described) is present and is a low peroxide grade. For example, povidone may be present at about 4% or less by weight (e.g., about 1 to about 4% by weight, or from about 2 to about 4% by weight), optionally with mannitol at about 4% or less by weight (e.g., about 1 to about 4% by weight, or from about 2 to about 4% by weight). In embodiments, mannitol is present at about 2 to about 4% by weight (e.g., about 4% by

[0050] DBl / 165003233.2 9 SJP-011PC / 119887-5011

[0051] weight), with or without povidone. In embodiments, the solution or suspension comprises both povidone and mannitol, which are each optionally present at about 4% by weight. In embodiments, the solution or suspension consists of indomethacin, isopropyl alcohol (IP A) and optionally water as solvent, and povidone and / or mannitol, each at amounts described above. In embodiments, the solution or suspension has a pH in the range of 5.5 to 6.5, and in embodiments the pH is in the range of 5.9 to 6.3.

[0052] In embodiments, the composition is prepared using a stable ketotifen feed solution / suspension that does not generate impurities during extended storage. In embodiments, the solution or suspension comprises a co-solvent system and a pharmaceutically acceptable ketotifen salt, such as ketotifen fumarate. In embodiments, the co-solvents comprises about 70% to about 95% isopropyl alcohol (IP A) by volume, about 5% to about 30% water by volume, and one or more polymers, such as one or more selected from polyvinylpyrrolidone (povidone), polyvinyl alcohol (PVA), methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, and hydroxypropylmethylcellulose (HPMC). In embodiments, the polymer is povidone and / or HPMC at about 0.5% to about 10% by weight, such as from about 0.5% to about 8% by weight, or from about 0.5% to about 5% by weight, or from about 0.5% to about 2% by weight (e.g., about 1% by weight). In embodiments, the polymer is povidone, and the povidone has an average molecular weight in the range of 10 kDa to about 70 kDa, or in the range of 30 to 40 kDa (e.g., K30). In embodiments, the polymer is HPMC, which in embodiments is a low viscosity HPMC, such as HPMC E-3 to E-15 (e.g., E-5). In embodiments, the solution or suspension further comprises a sugar alcohol, which is optionally selected from one or more of mannitol, sorbitol, erythritol, xylitol, and lactitol. In embodiments, the sugar alcohol is mannitol. In embodiments, a sugar alcohol such as mannitol is present at about 0.5% to about 5% by weight, such as about 0.5% to about 2% by weight (e.g., about 1% by weight). In embodiments, the solution or suspension consists of ketotifen fumarate, IP A, water, and povidone or HPMC (and optionally mannitol) in amounts as described.

[0053] In embodiments, the solution or suspension can be employed to produce pharmaceutical compositions comprising beads having a ketotifen (e.g., ketotifen fumarate) coating, which can be an immediate release coating. These beads can be coated with other

[0054] DBl / 165003233.2 10 SJP-011PC / 119887-5011

[0055] active agents, such as an NSAID, or combined with other populations of beads coated with other actives. NSAIDs other than indomethacin that can be employed in embodiments are described herein.

[0056] In embodiments, the solution / suspension comprising ketotifen comprises povidone (as described), and which is a low peroxide grade. For example, povidone may be present at about 0.5% to about 6% by weight, or about 0.5% to about 5% by weight, such as about 1%, 3%, or about 4%, or about 5%, or about 6% by weight. In embodiments, HPMC is present, and may be present at about 0.5% to about 6% by weight, or about 0.5% to about 4% by weight, such as about 1%, or about 2%, or about 3%, or about 4% by weight.

[0057] In embodiments, the ketotifen (e.g., ketotifen fumarate) is present in the solution / suspension at a concentration of about 0.1 mg / mL to about 60 mg / mL. In embodiments, the ketotifen is present at a concentration of about 1 mg / mL to about 45 mg / mL, or about 10 mg / mL to about 50 mg / mL, or about 10 mg / mL to about 40 mg / mL, or about 10 mg / mL to about 30 mg / mL. In embodiments, the ketotifen is present at about 10 mg / mL, or about 15 mg / mL, or about 20 mg / mL, or about 25 mg / mL, or about 30 mg / mL, or about 35 mg / mL, or about 40 mg / mL, or about 45 mg / mL, or about 50 mg / mL, or about 55 mg / mL, or about 60 mg / mL.

[0058] In embodiments, the solution or suspension comprising ketotifen has a pH in the range of 6.0 to 6.5, or in the range of 6.1 to 6.4. In embodiments, the solution or suspension has a pH or about 6.2 or about 6.4. In such embodiments, the solution or suspension is made by a process of admixing the ketotifen with the co-solvents, and adjusting the pH by the addition of acid or base.

[0059] In the various aspects and embodiments, other binders that may be suitable for use in the solutions or suspensions described herein include, but are not limited to, any pharmaceutically acceptable water soluble polymers, such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and the like. Other fdlers that may be used include sugars such as lactose, dextrose, sucrose and maltose, microcrystalline cellulose and the like.

[0060] DBl / 165003233.2 11 SJP-011PC / 119887-5011

[0061] In embodiments, the carrier is a bead, which may have an average size of from about 5 to about 50 mesh, or from about 5 to about 40 mesh, or from about 10 to about 50 mesh, or from about 10 to about 40 mesh, or from about 15 to about 50 mesh, from about 15 to about 40 mesh, or from about 20 to about 50 mesh, or from about 25 to about 50 mesh, or from about 25 to about 40 mesh, or from about 25 to about 35 mesh. The core particles can be water insoluble particles comprising different oxides, celluloses (e.g., microcrystalline cellulose), organic polymers and other materials, and mixtures thereof, or water soluble particles comprising different inorganic salts, sugars, and other materials, and mixtures thereof. Common forms of such core beads are commercially available such as Celpheres™. In embodiments, the bead is a sugar bead having a 25 to 32 mesh bead.

[0062] In embodiments, the pharmaceutical composition comprises a first inner drug coating prepared from the indomethacin solution or suspension, and a second outer drug coating prepared from the ketotifen (e.g., ketotifen fumarate) solution or suspension. In embodiments, the ketotifen coating has an immediate release dissolution profile. For example, in embodiments, the composition releases at least 75% of the ketotifen within 1 hour, or within 30 minutes, in dissolution media (e.g., phosphate buffer pH 6.2). In embodiments, the indomethacin coating has an extended release profile. For example, in embodiments, the composition releases no more than 25% of the indomethacin within 1 hour. In embodiments, the composition releases no more than 50% of the indomethacin within 2 hours. In embodiments, the composition releases no more than 75% of the indomethacin within 4 hours.

[0063] In embodiments, the beads comprise a protective barrier between the indomethacin and ketotifen fumarate coatings. In embodiments, a seal feed solution does not generate impurities during extended storage. For example, the seal feed may comprise or consist of water at about 10% or less by volume, solvent (e.g., IP A) at about 90% or less by volume (e.g., about 80 to about 90% by volume), polymer (e.g., HPMC) at about 3 wt% or less by weight (e.g., about 1 to about 3% by weight), sugar alcohol (e.g., mannitol) at about 3 wt% or less by weight (e.g., about 1 to about 3% by weight).

[0064] In other embodiments, the beads do not comprise a protective barrier between the indomethacin and ketotifen fumarate coating.

[0065] DBl / 165003233.2 12 SJP-011PC / 119887-5011

[0066] In embodiments, the composition comprises at least two bead populations, a first bead population comprising a coating formed from an NSAID coating, such as the indomethacin solution or suspension, and a second bead population comprising a coating formed from the ketotifen solution or suspension. In embodiments, a first (indomethacin- coated) bead population has an extended release profile as described above. In embodiments, the second (ketotifen-coated) bead population has an immediate release dissolution profile as described above.

[0067] The coated particles can optionally comprise an overcoat layer. The overcoat materials are pharmaceutically acceptable compounds selected from sugars, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium and others, used alone or in mixtures. The overcoat materials can prevent potential agglomeration of particles, protect the coatings from cracking during the manufacturing process. In embodiments, the beads further comprise an enteric coating (e.g., a pH-dependent polymer coating comprising polymethacrylates) that is stable in simulated gastric fluid but unstable in simulated intestinal fluid, to deliver active agents past the stomach. Such enteric agents are known, such as EUDRAGIT polymers.

[0068] In embodiments, the pharmaceutical composition comprises ketotifen fumarate and indomethacin coatings. In embodiments, the ketotifen beads exhibit a dissolution profile in which at least 90% of the ketotifen (e.g., ketotifen fumarate) is released at about 15 minutes. In embodiments, the composition exhibits a dissolution profile in which about 12% to about 32% of the indomethacin is released at 1 hour. In embodiments, the composition exhibits a dissolution profile in which about 27% to about 52% of the indomethacin is released at 2 hours. In embodiments, the composition exhibits a dissolution profile in which about 50% to about 80% of the indomethacin is released at 4 hours. In embodiments, the composition exhibits a dissolution profile in which at least about 80% of the indomethacin is released at 12 hours.

[0069] In embodiments, at least 90% of the ketotifen fumarate and indomethacin in the composition remain after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC. In embodiments, at least 95% of the ketotifen fumarate and DBl / 165003233.2 13 SJP-011PC / 119887-5011

[0070] indomethacin remains after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC.

[0071] In embodiments, the pharmaceutical composition (e.g., a unit dose) comprises a dose of indomethacin (or salt thereof) of about 20 mg to about 300 mg, or about 40 mg to about 200 mg, or about 75 mg to about 150 mg, and comprises a dose of ketotifen (or salt thereof) of about 1 mg to about 6 mg, or about 2 mg to about 5 mg, or about 3 mg to about 4 mg. In some embodiments, the pharmaceutical composition comprises ketotifen and at least one NS AID combined in unit dose.

[0072] In embodiments, the effective amount of one or more of a mast cell stabilizer and an Hl -antihistamine, in combination with a non-steroidal anti-inflammatory drug (NSAID) (either in the same or separate compositions), are administered at least once daily. In embodiments, such active agents are administered prior to (e.g., up to 2 hours before), simultaneously with, or after eating (e.g., up to 2 hours after) a meal. In further embodiments, such active agents are administered from about once daily to about three times daily. In certain embodiments, such active agents are administered for at least one week. In embodiments, such active agents are administered for at least two weeks. In still further embodiments, such active agents are administered for at least about three weeks, or at least about one month. In embodiments, such active agents are administered for at least three months or at least six months.

[0073] As used herein, the term “about”, unless the context requires otherwise, means ±10% of an associated numerical value.

[0074] As used herein, the term “comprising” indicates the presence of the specified feature, but allows for the possibility of other features, unspecified. This term does not imply any particular proportion of the specified features. Variations of the word “comprising,” such as “comprise” and “comprises,” have correspondingly similar meanings.

[0075] The word “exemplary” is used herein to mean “serving as an example, instance, or illustration.” Any embodiment described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments.

[0076] DBl / 165003233.2 14 SJP-011PC / 119887-5011

[0077] A reference to an element in the singular is not intended to mean “one and only one” unless specifically stated, but rather “one or more.”

[0078] Other aspects and embodiments will be apparent to the skilled person in view of the following working examples.

[0079] EXAMPLES

[0080] Example 1: Combination of Hi-antihistamine or Mast Cell Stabilizer with a Non-steroidal Anti-inflammatory Drug (NSAID) Treats Metabolic Inflammation

[0081] The following case studies demonstrate that symptoms of overindulgence in (e.g., excessively eating) a western diet (e.g., meals high in calories, fat, and / or sugar) are reduced when using the methods of the present application.

[0082] Symptoms of eating a western diet can present in patients who have overindulged in a meal high in calories and fat. Illustrative symptoms include, but are not limited to, abdominal hypersensitivity, gastrointestinal discomfort, bloat, gas, gastroesophageal reflux disease (GERD), fullness, and sluggishness. In the case studies presented below, patient- reported outcomes were collected with respect to these symptoms, with the severity of each symptom reported on a scale of 0 to 10, with 0 = no symptoms, and 10 = relatively worst experience of symptoms.

[0083] Study #1:

[0084] A 67 year old female, without a Past Medical History (PMH), lactose intolerance, or food allergies, ate a meal high in calories and fat - a chicken entree with Greek salad and half a potato, along with 1 cup of milk chocolate and 6 scoops of ice cream. After consuming the meal high in calories and fat, the individual experienced the following symptoms 3 hours later: (1) Abdominal hypersensitivity = 0; (2) GI discomfort = 7; (3) Bloat = 6; (4) Gas = 5; (5) GERD = 4; (6) Fullness = 7; and (7) Sluggishness = 5.

[0085] The individual was administered 220 mg of naproxen sodium and 60 mg of fexofenadine. At 1.5 hours after drug administration and without any other intervention other than the passage of time, the individual noted their symptoms as follows: (1) DBl / 165003233.2 15 SJP-011PC / 119887-5011

[0086] Abdominal hypersensitivity = 0; (2) GI discomfort = 3; (3) Bloat = 2; (4) Gas = 3; (5) GERD = 1; (6) Fullness = 1; and (7) Sluggishness = 1.

[0087] Study #2

[0088] The same 67 year old female individual, without PMH, lactose intolerance, or food allergies, on a separate occasion ate a meal high in calories and fat - turkey, stuffing, vegetables, bread, and 3 servings of dessert high in sugar and fat. 2 hours later, the individual recorded the following symptoms: (1) Abdominal hypersensitivity = 5; (2) GI discomfort = 6; (3) Bloat = 8; (4) Gas = 2; (5) GERD = 2; (6) Fullness = 8; and (7) Sluggishness = 8.

[0089] About 2 hours after meal consumption, the individual was administered 75 mg indomethacin and 2 mg ketotifen. The individual recorded the following symptoms 2 hours after administration of the drugs: (1) Abdominal hypersensitivity = 2; (2) GI discomfort = 2; (3) Bloat = 3; (4) Gas = 1; (5) GERD = 0; (6) Fullness = 2; and (7) Sluggishness = 2.

[0090] Study #3

[0091] A 63 year old female, without any PMH, experienced GI discomfort following an overindulgent meal that was high in calories and fat. The individual recorded the following symptoms 2 hours after consuming the meal: (1) Abdominal hypersensitivity = 4; (2) GI discomfort = 5; (3) Bloat = 7; (4) Gas = 3; (5) GERD = 0; (6) Fullness = 5; and (7) Sluggishness = 5.

[0092] The individual was then administered 220 mg of naproxen sodium and 60 mg of fexofenadine. An hour after administration of the drugs, the individual recorded the following symptoms: (1) Abdominal hypersensitivity = 0; (2) GI discomfort = 1; (3) Bloat = 2; (4) Gas = 1; (5) GERD = 0; (6) Fullness = 1; and (7) Sluggishness = 1.

[0093] Example 2: Combination of Mast Cell Stabilizer or Hi-antihistamine with a NSAID Could Treat Inflammation in Diabetic Subjects

[0094] According to embodiments employing SJP-002C in diabetic subjects, and without intending to be bound, it is believed that one or more of the following end points could be achieved in combination with GLP-1 receptor agonists, or dual agonists.

[0095] DBl / 165003233.2 16 SJP-011PC / 119887-5011 Table 1: Projected Endpoints

[0096] GLP-1 Dual GIP / GLP-1 Combination Endpoint SJP-002C Receptor Receptor Agonist

[0097] Agonist Therapy Weight Loss (% ofBW) 3-5% 10-15% 15-22.5% 20-25% BMI Reduction 5% 10-15% 18% 20-25% HbAlc Reduction 0.5-1.0% 1.5% 2.0% 2.2%

[0098] CRP Reduction 30-40% 25% 37.5% 45%

[0099] 20% 30% 40% 45%

[0100]

[0101] HOMA-IR Improvement

[0102] DBl / 165003233.2 17

Claims

SJP-011PC / 119887-5011CLAIMS:

1. A method for treating obesity or metabolic disorder, comprising: administering an effective amount of one or more of a mast cell stabilizer and an H1-antihistamine, in combination with a non-steroidal anti-inflammatory drug (NSAID).

2. The method of claim 1, wherein the subject is overweight or obese.

3. The method of claim 1 or 2, wherein the subject is pre-diabetic or diabetic.

4. The method of claim 3, wherein the subject exhibits insulin resistance.

5. The method of any one of claims 1 to 4, wherein the subject has metabolic syndrome.

6. The method of any one of claims 1 to 5, wherein the subject is undergoing therapy with a GLP-1 receptor agonist.

7. The method of claim 6, wherein the GLP-1 receptor agonist is a dual agonist for GLP-1 receptor and GIP receptor.

8. The method of claim 6, wherein the GLP-1 receptor agonist is triple receptor agonist for GLP-1 receptor, GIP receptor, and glucagon receptor.

9. The method of any one of claims 1 to 8, wherein the one or more of a mast cell stabilizer and an Hl -antihistamine, and the non-steroidal anti-inflammatory drug (NSAID), are combined in a single unit dose.

10. The method of any one of claims 1 to 9, comprising administering an effective amount of a mast cell stabilizer.

11. The method of any one of claims 1 to 10, comprising administering an effective amount of an Hi-antihistamine.

12. The method of any one of claims 1 to 11, wherein the NSAID is selected from aspirin, ibuprofen, naproxen, diclofenac, diflunisal, etodolac, indomethacin, ketoprofen, ketorolac, meloxicam, nabumetone, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin.DBl / 165003233.2 18SJP-011PC / 119887-501113. The method of claim 12, wherein the NS AID comprises naproxen and / or indomethacin.

14. The method of claim 13, wherein the NSAID is naproxen and the Hi -antihistamine is fexofenadine.

15. The method of claim 14, wherein the naproxen and fexofenadine are administered in a single unit dose taken orally, optionally in the form of a tablet, orally-dissolvable tablet, chewable tablet, capsule, lozenge, pill, troche, gummy, elixir, suspension, syrup, wafer, chewing gum, orally-dissolving thin film, soluble powder, and effervescent composition.

16. The method of claim 15, wherein the composition is a tablet or capsule for enteral delivery.

17. The method of any one of claims 14 to 16, wherein a unit dose composition comprising naproxen sodium and fexofenadine are administered at least daily.

18. The method of claim 17, wherein the composition comprises an amount of naproxen sodium from about 110 mg to about 900 mg, and an amount of fexofenadine from about 25 mg to about 200 mg.

19. The method of claim 13, wherein the NSAID is indomethacin and the mast cell stabilizer is ketotifen.

20. The method of claim 19, wherein indomethacin and ketotifen are administered at least daily, and the daily dose of indomethacin is from about 20 mg to about 300 mg and the daily dose of ketotifen is a daily dose of ketotifen is from about 1 mg to about 10 mg.

21. The method of claim 20, wherein indomethacin and ketotifen are provided in a unit dose composition, and which comprises indomethacin and ketotifen spay-coated onto a substrate.

22. The method of claim 21, wherein the composition comprises about 2 mg immediate release ketotifen and about 75 mg sustained release indomethacin.DBl / 165003233.2 19SJP-011PC / 119887-501123. A pharmaceutical composition comprising an effective amount of one or more of a mast cell stabilizer and an Hl -antihistamine, in combination with a non-steroidal antiinflammatory drug (NSAID), for use in a method of any one of claims 1 to 22.DBl / 165003233.2 20

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