Pharmaceutical formulations and manufacturing processes

Abstract

The present disclosure in various aspects and embodiments provides formulations that solubilize and / or suspend poorly soluble active ingredients, such as but not limited to ketotifen and indomethacin, for use in coating processes to manufacture drug products. In other aspects, the disclosure provides spray-coated products with low impurities and high homogeneity and mass transfer efficiencies relative to products produced with conventional pan coating or spray-coating processes. In aspects, the disclosure provides pharmaceutical compositions and methods of treatment involving these spray-coated products.

Description

[0001]SJP-010PC 119887-5010 PHARMACEUTICAL FORMULATIONS AND MANUFACTURING PROCESSES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No.63 / 571,600, filed on March 29, 2024, the entire content of which is hereby incorporated herein by reference in its entirety. BACKGROUND Pharmaceuticals products can comprise impurities of the active agent, such as artifacts of the manufacturing process and degradation products. These impurities are potentially harmful and can impact the effectiveness of the medication. Antihistamines such as ketotifen have been used and / or proposed for treatment of allergies and asthma, as well as for inhibiting beta-coronavirus infection and symptoms thereof. See WO 2022 / 032069, which is hereby incorporated by reference in its entirety. Ketotifen has been proposed for use in combination with other active agents, such as non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, and others. However, ketotifen and NSAIDs can produce undesirable impurities. Pharmaceutical compositions of ketotifen, including in combination with NSAIDs, including but not limited to indomethacin, are needed, and particularly where such compositions are stable and lack potentially toxic impurities at significant levels. DESCRIPTION OF THE DRAWINGS FIG.1 depicts the structure of indomethacin. FIG.2 depicts the structure of ketotifen fumarate. FIG.3 shows a dissolution profile for an exemplary immediate release (IR) ketotifen / extended release (ER) indomethacin bead formulation according to the disclosure. FIG.4. depicts a film coating process. FIG.5 depicts a Wurster spray coating process. DB1 / 145295370.1 1 SJP-010PC 119887-5010 FIG.6 shows the Assay model Standardized Effects with a half-normal probability plot. FIG.7 shows the Interaction Effect of nozzle pressure and spray rate. FIG.8 shows the Assay Surface Response of nozzle pressure and spray rate. FIG.9 shows the content uniformity (CU) model Standardized Effects with a half- normal probability plot. FIG.10 shows the CU model Predicted Results vs. Actual Results. FIG.11 shows the CU Surface Response of nozzle pressure and spray rate. FIG. 12A shows a 23factorial experimental design for the spray coating process. FIG. 12B illustrates the optimized critical processing parameters according to the experimental design (bottom left quadrant representing optimal combination of factors). DETAILED DESCRIPTION OF EMBODIMENTS The present disclosure in various aspects and embodiments provides formulations that solubilize and / or suspend poorly soluble active ingredients, such as but not limited to ketotifen and indomethacin, for use in coating processes to manufacture drug products. In other aspects, the disclosure provides drug products (e.g. spray-coated drug products) with low impurities and high homogeneity and mass transfer efficiencies relative to products produced with conventional pan coating or spray-coating processes. In aspects, the disclosure provides pharmaceutical compositions and methods of treatment involving these drug products. In various aspects and embodiments, the disclosure provides a drug product for oral administration (and corresponding manufacturing processes), 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 present disclosure provides a ketotifen immediate release / indomethacin extended release capsule drug product for oral administration. In embodiments, the coating process for manufacturing the drug product comprises a manual coating process, a fixed spray coating process, or a fluid bed dryer (FBD) spray coating DB1 / 145295370.1 2 SJP-010PC 119887-5010 process, or a combination of these coating techniques for different layers of the beads. In embodiments, the active ingredients are applied to separate bead populations and filled to the proper ratio within the same capsule. In embodiments, one or more poorly soluble drug substances are suspended in a mixture of an aqueous and organic solvent with co-solvent polymers that act as the vehicle for the feed suspension / solution to be coated or sprayed onto the carrier (e.g., sugar spheres). This matrix contains a concentration of actives, pH and seal / binder polymers that do not degrade the active ingredients in situ and produce a minimum concentration of impurities during extended storage. If two different actives are coated onto the same bead population, then a seal coating matrix may be applied between these active coating layers to prevent comingling of active ingredients. As described herein, critical process parameters were determined for a coating process to determine an optimal time of coating and uniformity of mass transfer to the coated beads. In addition, suitable packaging materials and configurations with oxygen scavengers can minimize the aggregate impurity profile during shelf life of the drug product. The final outcome of these measures produces a final oral solid dose product with minimal related substances or impurity profile. There are many challenges to creating a successful spray-coating feed solution / suspension. The matrix of the feed solution / suspension must be able to solubilize or suspend the active ingredients homogenously so that they can flow through a spray nozzle (atomization) during the coating process and maintain blend uniformity of the final beads. The matrix must also have a solid content and binder(s) to apply the active ingredients to the carrier (sugar spheres) in a uniform manner and not create twining or sticking of the beads to each other. The matrix must provide a chemical environment to minimize the initiation of degradation pathways for the active ingredients while the active ingredients are in situ during the spray coating process. The poor solubility of drugs such as ketotifen (e.g., ketotifen fumarate) and indomethacin is a significant challenge to the formulation of the feed solution / suspension. Indomethacin is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The molecular weight of indomethacin is 357.79 and its molecular formula is C19H16ClNO4. DB1 / 145295370.1 3 SJP-010PC 119887-5010 The structure of indomethacin is shown in FIG. 1. The following Table 1 illustrates indomethacin-related impurities. Table 1. Indomethacin Related Substances Structures Chemical Name IUPAC Name Structure DB1 / 145295370.1 4 SJP-010PC 119887-5010 Ketotifen (e.g., ketotifen fumarate) has poor solubility in both polar and non-polar solvents. The EP solubility description is sparingly soluble in water, slightly soluble in methanol and very slightly soluble in acetonitrile and is listed in literature as 0.00787 mg / mL in water. It has a pKa of 8.43 ± 0.11. The structure of ketotifen fumarate is shown in FIG. 2. The following Table 2 shows the primary ketotifen-related impurities. Table 2. Ketotifen Related Substances Structures Chemical Name IUPAC Name Structure DB1 / 145295370.1 5 SJP-010PC 119887-5010 Ph Eur Impurity E 10-(1-methylpiperidin-4-ylidene)-5,10-dihydro- 4H-benzo [5,6] cyclohepta [1,2-b] thiophen-4- In various aspects and embodiments, the disclosure provides a solution or suspension comprising a ratio of solvents, co-solvents and polymers that produces a stable solution / suspension of indomethacin or ketotifen (e.g., ketotifen fumarate) generating minimal impurities and maintaining a homogeneous application of the active when coated onto a carrier, such as a sugar bead. In embodiments, the solution or suspension comprises indomethacin, and co- solvents. In embodiments, the co-solvents comprise about 60% to about 90% isopropyl alcohol (IPA) 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 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 DB1 / 145295370.1 6 SJP-010PC 119887-5010 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. 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). 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. 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 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 DB1 / 145295370.1 7 SJP-010PC 119887-5010 embodiments, the solution or suspension consists of indomethacin, isopropyl alcohol (IPA) 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. In embodiments, at least 90% of the indomethacin remains in the solution / suspension after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC. In embodiments, at least 95% of the indomethacin remains after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC. In embodiments, the total indomethacin impurities listed in Table 1 is less than 1.0% or less than 0.5% relative to the total of indomethacin and the impurities listed in Table 1 (e.g., after the storage). In embodiments, the total indomethacin impurities listed in Table 1 is less than 0.2% relative to the total of indomethacin and the impurities listed in Table 1 (e.g., after the storage). In aspects and embodiments, this disclosure provides 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 (IPA) 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 DB1 / 145295370.1 8 SJP-010PC 119887-5010 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, IPA, water, and povidone or HPMC (and optionally mannitol) in amounts as described. 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 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. 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. 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. 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. DB1 / 145295370.1 9 SJP-010PC 119887-5010 In embodiments, at least 90% of the ketotifen in the solution / suspension remains after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC. In embodiments, at least 95% of the ketotifen remains after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC. In embodiments, after the storage, ketotifen N-oxide impurity is less than about 0.6% by weight relative to the total of ketotifen and impurities listed in Table 2. In embodiments, total ketotifen impurities listed in Table 2 is less than 2.0% by weight relative to the total of ketotifen and impurities listed in Table 2 (e.g., after storage). 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 fillers that may be used include sugars such as lactose, dextrose, sucrose and maltose, microcrystalline cellulose and the like. In an aspect, the disclosure provides a method for making a pharmaceutical composition. The method comprises the steps of providing a solution or suspension described herein, and applying the solution or suspension to a pharmaceutically acceptable carrier via a coating process. 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. In embodiments, the pharmaceutical composition comprises a first inner drug coating prepared from the indomethacin solution or suspension, and a second outer drug coating DB1 / 145295370.1 10 SJP-010PC 119887-5010 prepared from the ketotifen (e.g., ketotifen fumarate) solution or suspension. In embodiments, the ketotifen coating has an immediate release dissolution profile as described herein (with exemplary profile shown in FIG. 3). 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 as described herein (with exemplary profile shown in FIG. 3). 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. 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., IPA) 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). In other embodiments, the beads do not comprise a protective barrier between the indomethacin and ketotifen fumarate coating. 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. 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 DB1 / 145295370.1 11 SJP-010PC 119887-5010 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. Any coating process can be used to create the coatings or bead populations. In embodiments, the coating process is a fluid bed spray coating process. In embodiments, the disclosure provides a spray coating process and drug product composition created thereby. The term “spray coating” refers to a process involving breaking up liquid mixtures into small droplets (atomization), applying these droplets to a target substrate (e.g., carrier such as a sugar bead) to be coated, and rapidly removing the solvent (aqueous or organic) from the mixture in a drying chamber where there is a strong driving force for evaporation of solvent from the droplets. The strong driving force for solvent evaporation is generally provided by counter current gas (air or nitrogen) stream up thru the coated substrates. In embodiments, the temperature and flow rate of the drying gas is chosen so that the solid content contained in the droplets of spray suspension / solution are dried on the substrate enough that they are essentially solid and the coated substrates do not stick to each other or the apparatus wall. The actual length of time to achieve this level of dryness depends on the size of the droplets and the conditions at which the process is operated. Droplet sizes may range from 1 μm to 500 μm in diameter. A general “film coating” process is illustrated in FIG.4. The Wurster coating process is illustrated in FIG.5. These embodiments employ a bottom-spray coating process that takes place in a fluidized bed. At the bottom of the fluidized bed, a distributor plate with a specific pattern of orifices determines the distribution of the hot fluidization airflow. This airflow is responsible for the motion of pellets. There are one or more two-fluid spray nozzles at the bottom of the fluidized bed. These spray nozzles supply a liquid solution as well as an atomization airflow that breaks the solution into small droplets. The spray nozzles thus form a spray region at the bottom of the fluidized bed. As the pellets travel through this region, they receive a coating solution in the form of DB1 / 145295370.1 12 SJP-010PC 119887-5010 droplets, and, as they move around in the fluidized bed, the liquid droplets are dried by the hot airflow to form a film layer on each pellet. Based on particle behavior, the fluidized bed can be divided into different regions. During coating pellets receive the coating solution in the spray zone, and then dry as they return to the spray zone after having traveled through the Wurster partition tube, the downbed, and the horizontal transport regions. This sequence of coating and drying as the pellets travel through the different regions of the fluidized bed is referred to as a particle coating cycle. The time it takes for a pellet to complete a cycle is defined as the cycle time. Similarly, the time that a pellet spends in a specific region is defined as the residence time in that region. Not only may a pellet behave differently from other pellets, but a pellet in one cycle can also behave differently from that same pellet in a different cycle. It is thus clear that pellets have both a cycle time distribution (CTD) and a residence time distribution (RTD) in different regions. The CTD and the RTD of particles in the spray zone together determine the amount of coating deposited on the pellets. Since the performance of the medicine to a great extent depends on the thickness of the coating film, it is clear that the CTD and the RTD of particles in the spray zone are critical factors in determining the coating film thickness and its variability. In embodiments, the spray coating is applied with a Wurster nozzle. For example, the process may comprise the following parameters using a Wurster nozzle: nozzle pressure is from about 5 psi to about 20 psi, or from about 10 psi to about 20 psi; acceleration pressure is from about 5 psi to about 30 psi, such as from about 20 psi to about 30 psi; air flow is from about 10 psi to about 35 psi; temperature is from about 20° C to about 45° C; and solution feed rate is from about 50 g / min to about 400 g / min. In embodiments, the spray rate is from about 1.5 g / min to about 3.0 g / min. In embodiments, the nozzle pressure is from about 10 psi to about 15 psi, the acceleration pressure is about 20 psi to about 25 psi, and the spray rate is about 1.5 g / min. to about 2.5 g / min, or from about 1.5 g / min to about 2.0 g / min. In other embodiments, the process involves a pan coating process. In embodiments, the method further comprises drying the coated carriers. In embodiments, the coated carrier is dried at a temperature in the range of 30° C to 45° C. DB1 / 145295370.1 13 SJP-010PC 119887-5010 In embodiments, the method further comprises inserting the coated carriers into a capsule suitable for oral administration. In embodiments, the capsule is gelatin or hydroxypropyl methylcellulose (HPMC), or other suitable carrier. In embodiments, the capsules are packaged with an oxygen scavenger. In embodiments, the present disclosure provides for the co-formulation of ketotifen with an NSAID, including but not limited to indomethacin. An NSAID according to the disclosure includes without limitation, aspirin (i.e., acetylsalicylic acid); ibuprofen (i.e., isobutylphenylpropanoic acid); naproxen (i.e., 6-met oxy-a-methyl-2-naphthaleneacetic acid); diclofenac (2-[(2,6-dichlorophenyl)-amino]benzene acetic acid); diflunisal (2',4'- difluoro-4-hydroxybiphenyl-3-carboxylic acid); etodolac ((1,8-Diethyl-1,3,4,9- tetrahydropyrano[3,4-b]indol-1-yl)acetic acid); indomethacin (2-{ l-[(4-Chlorophenyl)- carbonyl]- 5-methoxy-2-methyl- lH-indol-3-yl}acetic acid); ketoprofen (3-benzoyl-a- metbyI- benzeneacetic acid); ketorolac (2-amino-2-(hydroxymethyl)- l,3-propanediol); meloxicam (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-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-dioxide); salsalate (2-(2- Hydroxybenzoyl)-oxybenzoic acid); sulindac ({(lZ)-5-fluoro-2-methyl-l-[4- (methylsulfinyl)-benzylidene]-lH-indene-3-yl}acetic acid); and tolmetin ([l-methyl-5-(4- methylbenzoyl)-lH-pyrrol-2-yl] acetic acid). In particular embodiments, the NSAID comprises naproxen (6-methoxy-α-methyl- 2-naphthaleneacetic acid) and / or indomethacin (2-{l-[(4-chlorophenyl)-carbonyl]-5- methoxy-2-methyl-lH-indol-3-yl}acetic acid). In some embodiments, the disclosure provides a pharmaceutical composition comprising indomethacin and ketotifen. As used herein, an NSAID (e.g. naproxen and indomethacin) or ketotifen include 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 DB1 / 145295370.1 14 SJP-010PC 119887-5010 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 (e.g., salts of alkylamines and / or-methyl-D-glutamine), 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. In embodiments, the dissolution profile of the compositions can be determined in simulated gastric fluid or simulated intestinal fluid. For example a simulated gastric fluid will have a pH of less than 5. Simulated intestinal fluid will have a pH of greater than 5, and may be a near neutral or alkaline environment. Examples of simulated gastric fluid and simulated intestinal fluid include, but are not limited to, those disclosed in the 2005 Pharmacopeia 23NF / 28USP and as known in the art. In an aspect, the disclosure provides a pharmaceutical composition as described herein or as made by a process described herein. 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. 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 DB1 / 145295370.1 15 SJP-010PC 119887-5010 indomethacin remains after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC. For example, after the storage, ketotifen N-oxide impurity is less than about 0.6% by weight relative to the total of ketotifen and impurities listed in Table 2. In embodiments, total ketotifen impurities listed in Table 2 is less than 2.0% by weight relative to the total of ketotifen and impurities listed in Table 2. Further, in embodiments, total indomethacin impurities listed in Table 1 is less than 1.0% or less than 0.5% relative to the total of indomethacin and the impurities listed in Table 1. In embodiments, total indomethacin impurities listed in Table 1 is less than 0.2% relative to the total of indomethacin and the impurities listed in Table 1. 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 NSAID combined in unit dose. In certain embodiments, a unit dose of the disclosure comprises about 50 mg indomethacin and about 1 mg ketotifen, and the unit dose can be administered 2 or 3 times per day. In other aspects, the disclosure provides a method for treating a condition in a subject. In embodiments, the disclosure provides a method for treating or preventing an inflammatory disease or condition in a subject in need thereof. The method comprises administering the pharmaceutical composition of the present disclosure. In embodiments, the inflammatory disease or condition is an infectious disease, such as a virus infection. In embodiments, the virus infection is an influenza virus infection or a rhinovirus infection, or a common cold. The common cold is an acute, self-limiting viral infection of the upper respiratory tract involving the nose, sinuses, pharynx and larynx. Over two hundred virus strains are implicated in the cause of the common cold, with the rhinoviruses being the most common. The virus is spread by hand contact with secretions DB1 / 145295370.1 16 SJP-010PC 119887-5010 from an infected person (direct or indirect) or aerosol of the secretions and virus. The incubation period varies but is about two days for rhinovirus. Symptoms, which generally relate to the infected mucosa, typically peak at 1-3 days and last 7-10 days. Symptoms include sore throat, rhinitis, rhinorrhea, cough, malaise, runny nose, sneezing, headache, and fever. In embodiments, the inflammatory disease or condition is a coronavirus infection. Coronaviruses are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome (SARS-CoV) and Coronavirus disease 2019 (COVID-19). Coronaviruses are zoonotic, meaning that they are transmitted between animals and people. COVID-19 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 virus is an enveloped, positive-sense, single- stranded RNA beta-coronavirus. The disease has spread globally since 2019. COVID-19 is a poorly understood disease with limited effective treatments. Common symptoms of COVID-19 include fever, cough and shortness of breath. Muscle pain, sputum production and sore throat are some of the less common symptoms. While the majority of cases result in mild symptoms, some progress to pneumonia, severe acute respiratory syndrome, multi-organ failure and even death. The disease is more likely to occur in people whose immune system is impaired due to age, immunosuppressive therapy, chronic disease, psychological stress, or other factors. Accordingly, in embodiments the present disclosure provides a method of preventing or treating infection of beta- coronaviruses, such as SARS-CoV-2, and / or reducing symptoms of associated disease (e.g., COVID-19). In embodiments, therapy can be initiated before the onset of COVID-19 symptoms or after the onset of symptoms. In some embodiments, therapy is initiated soon after the first appearance of symptoms. In some embodiments, the subject is asymptomatic, but tests positive for SARS-CoV-2 (or other beta-coronavirus). In some embodiments, therapy is initiated as soon it is first suspected that the individual has an infection or disease caused by SARS-CoV-2 (or other beta-coronavirus), but before the onset of symptom(s) of the disease. In various embodiments, the subject has one or more risk factors for COVID-19. In various DB1 / 145295370.1 17 SJP-010PC 119887-5010 embodiments, the subject is experiencing one or more symptoms selected from congestion, cough, fever, loss of taste, loss of smell, muscle pain, joint pain (myalgia), fatigue, sore throat, headache, myocarditis, coagulopathy, renal injury or failure, liver damage or failure, neurological impairment, hypoxia, pneumonia with or without hypoxia, acute respiratory syndrome, or multi-organ failure. In embodiments, the inflammatory disease or condition is long COVID. Long COVID refers to a range of symptoms that can last weeks or months after a subject is first infected with SARS-CoV-2 or experiences symptoms of COVID-19. Long COVID can occur in any subject who has had COVID-19, even if the illness was mild, or if they had no initial symptoms. Long COVID symptoms include one or more of difficulty breathing or shortness of breath, tiredness or fatigue, symptoms aggravated after physical or mental activities, difficulty thinking or concentrating (sometimes referred to as “brain fog”), cough, chest or stomach pain, headache, fast-beating or pounding heart (i,e,, heart palpitations), joint or muscle pain, diarrhea, sleep problems, fever, dizziness on standing (lightheadedness), rash, mood changes, change in smell or taste, changes in menstrual cycles, among others. In embodiments, the inflammatory disease or condition is symptoms associated with a vaccination, including but not limited to vaccination for SARS-CoV-2 or Flu. Many vaccinations produce undesirable side effects, ranging from mild to severe. For example, mild side effects from the influenza vaccine include soreness, redness or swelling at the injection site; low-grade fever; and aches. For children, some side effects from the flu nasal spray can include runny nose, wheezing, headache, vomiting, muscle aches and fever. For adults, side effects include runny nose, headache, sore throat and cough. Rare but serious side effects can also occur, including allergic reactions. Further, SARS-CoV-2 vaccination has been reported to produce symptoms such as: pain and / or swelling at the injection site, tiredness, headache, muscle pain, chills, nausea, and fever. The fear of having side effects due to vaccinations discourages some individuals from obtaining vaccinations. In embodiments, the inflammatory disease or condition are symptoms associated with veisalgia (e.g., symptoms associated with alcohol intake, “hangover”). Such symptoms include, for example, substantial physical and mental fatigue, nausea, loss of appetite, DB1 / 145295370.1 18 SJP-010PC 119887-5010 tremors of the hand and limbs (the “shakes”), joint weakness / pain, dehydration, irritability, lack of coordination, concentration difficulties, sleeplessness, impaired memory and visual- spatial skills, headache, drowsiness, dry mouth, dizziness, gastro-intestinal complaints, sweating, and anxiety. In embodiments, the pharmaceutical composition can be administered as an alternative to opioids, or together with opioids to allow for dose reduction or inhibition of symptoms associated with opioid tolerance, dependence, or withdrawal. Opioids are a class of drugs that include oxycodone (OxyContin®), hydrocodone (Vicodin®), codeine, and morphine. Prescription opioid pain relievers are generally safe when taken for a short time and as prescribed by a doctor. However, due to the euphoria induced by opioids, they are frequently misused. In fact, the misuse of and addiction to opioid drugs can be initiated after exposure to prescribed medications in a clinic or physician's office. As many as 90% of patients in chronic pain management settings receive opioid pain relievers, and the prevalence of drug abuse is high among these patients. Moreover, even as prescribed by a doctor, regular use of opioids can lead to dependence. For example, withdrawal from opioid use is difficult. An addicted, or depended, individual experiences adverse symptoms including anxiety, increased pain sensitivity, poor concentration, tachycardia and flu-like symptoms during withdrawal, a syndrome reflecting physical dependence on these drugs. Such adverse withdrawal symptoms are a major contributor to the addictive nature of opioids. Current strategies for treatment of opioid withdrawal are suboptimal; they rely on the administration of controlled substances (methadone and buprenorphine), or medications with significant hemodynamic side effects (clonidine). Further, tolerance is the need for progressively higher doses of an opioid in order to maintain the same therapeutic effect, e.g., same reduction in pain. Tolerance typically develops upon sustained opioid therapy. While opioid rotation is currently used to minimize tolerance, this approach requires close monitoring due to variable cross-tolerance and side effect profiles among different patients. In its most severe form, opioid tolerance can manifest as opioid-induced hyperalgesia; that is, the opioid no longer reduces pain but instead increases or induces pain. Opioid-induced hyperalgesia is extremely difficult to treat. DB1 / 145295370.1 19 SJP-010PC 119887-5010 Opioid dependence is characterized by physical or psychological withdrawal symptoms upon discontinuation of an opioid. Dependence may be independent of addiction. However, physical dependence, or the desire to avoid withdrawal symptoms, is thought to contribute to opioid addiction, particularly at later stages of addiction; whereas, a craving for the euphoric effects of opiates may dominate in earlier stages. The somatic withdrawal signs that can occur when opioid therapy is abruptly stopped in physically dependent individuals include agitation, irritability, muscular ailments, abdominal pain, diarrhea, burning sensations, “gooseflesh,” and itching. In an effort to minimize withdrawal symptoms, patients are required to be carefully tapered off of the opioid. However, such approach requires strict monitoring throughout an extended protocol. In embodiments, the inflammatory disease or condition is an autoimmune disease. In embodiments, the inflammatory disease or condition is arthritis, which is optionally rheumatoid arthritis, osteoarthritis, or enteropathic arthritis. Enteropathic arthritis is a spondyloarthritis which occurs in patients with gastrointestinal diseases, such as, inflammatory bowel diseases (IBDs) and other diseases, such as, for example, Whipple's disease, celiac disease, and disorders resulting from intestinal bypass surgery (e.g., jejunoileal bypass). Axial spondyloarthritis, for example, is characterized by long-term inflammation of the joints of the spine, sometimes also including the joints where the spine joins the pelvis. Peripheral spondyloarthritis is characterized by inflammation of the joints in the arms and legs, most often the lower legs. Attacks or flares of the joint inflammation are typical in both forms of spondyloarthritis. These flares usually have a rapid onset, typically setting in within 48 hours. The flares sometimes disappear within about six months, but inflammation can become chronic in some people. The symptoms of gastrointestinal diseases sometimes flare along with the symptoms of spondyloarthritis in enteropathic arthritis. In embodiments, the inflammatory condition or disease is an Inflammatory bowel disease, which involves chronic inflammation of the digestive tract. The most common forms of IBD are ulcerative colitis (UC) and Crohn's disease (CD). In certain embodiments, a unit dose of the disclosure comprises 50 mg indomethacin and 1 mg ketotifen, and the unit dose is administered 2 or 3 times per day. DB1 / 145295370.1 20 SJP-010PC 119887-5010 In some embodiments, the disclosure comprises administering the NSAID (e.g., indomethacin and / or naproxen) and ketotifen at least once daily. In further embodiments, NSAID and ketotifen are administered from about once daily to about three times daily. In certain embodiments, the NSAID and ketotifen are administered for at least one week. In yet further embodiments, the NSAID and ketotifen are administered for at least two weeks. In still further embodiments, NSAID and ketotifen are administered for at least about three weeks, or about one month. In embodiments, the pharmaceutical composition is administered in a regimen such that the pharmaceutical composition is administered at least daily. The daily dose of indomethacin is about 20 mg to about 300 mg, or about 40 mg to about 200 mg, or about 75 mg to about 150 mg. In embodiments, the 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 employing naproxen as the NSAID, the daily dose of naproxen is about 100 mg to about 1600 mg, or about 200 mg to about 1400 mg, or about 400 mg to about 1200 mg, or about 600 mg to about 1000 mg, or about 700 mg to about 900 mg. As used herein, the term “about”, unless the context requires otherwise, means ±10% of an associated numerical value. 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. 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. 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.” Other aspects and embodiments will be apparent to the skilled person in view of the following working examples. DB1 / 145295370.1 21 SJP-010PC 119887-5010 EXAMPLES Example 1. Indomethacin extended release beads and preparation by pan coating process 66.268 kg Isopropyl Alcohol, USP (IPA) is added to a stainless-steel (SS) container equipped with a stirrer.1.13 kg of Povidone, USP (K30) is added to the IPA while stirring, and is mixed for fifteen minutes with stirrer speed of 1000 ± 200 rpm. Next, 1.074 kg of Mannitol USP, is added and mixed for fifteen minutes with stirrer speed of 1000 ± 300 rpm. The solution is added within five to ten minutes into a SS container used for pre-weighed 37.914 kg Indomethacin, USP, and mixed for forty-five minutes at 1000 ± 300 rpm. The Sugar Spheres are loaded into a 60” Coating Pan and following the parameters in Table 3. Example 2. Ketotifen fumarate immediate release coating and preparation by pan coating process 29.880 kg of IPA is added to a SS container, and 3.323 kg of purified water is added to the IPA and mixed for 10 minutes. 665 g of Hydroxypropyl methyl cellulose (METHOCEL E5) is slowly added in aqueous / solvent mixture under continuous mixing for 60 minutes. After mixing, the dispersion is screened through a 60-mesh screen.7.140 kg of the seal coating solution is added to 0.277 kg of ketotifen fumarate in SS container, with continued mixing for 45 minutes. The Indomethacin Spheres are loaded into the 60” Coating Pan and following the parameters in Table 3. Table 3. In-Process Parameters for Pan Coating Process Number of Coating Applications 80 to 85 ) For the last three applications, the volume of the API dispersion is adjusted to 4.2 L with Isopropyl Alcohol, USP. After the active dispersion application is complete, the beads are dried at inlet temperature (45 ± 5°C) for three hours while jogging the pan for about five rotations once every fifteen minutes. The beads are screened with a 20-mesh stainless steel DB1 / 145295370.1 22 SJP-010PC 119887-5010 screen followed by a 30-mesh stainless steel screen. The beads are mixed in the coating pan for 3 minutes. Example 3. Indomethacin extended release beads and preparation by spray coating 66.268 kg IPA is added to a SS container equipped with a stirrer. 1.13 kg of Povidone, USP (K30) is added to the IPA while stirring, and mixed for fifteen minutes with stirrer speed of 1000 ± 200 rpm. Next, 1.074 kg of Mannitol USP is added and mixed for fifteen minutes with stirrer speed of 1000 ± 300 rpm. The solution is added within five to ten minutes into a SS container having 37.914 kg Indomethacin, USP, and mixed for forty- five minutes at 1000 ± 300 rpm to create the Extended Release (ER) coating solution. The ER coating solution is sprayed onto sugar beads under the process conditions given in Table 4. The active coating solution was stirred throughout the spraying process. Example 4. Seal coating via spray coating process 29.880 kg of IPA is added to a 50L SS container and 3.323 kg of purified water is added to a separate SS container. The purified water is added to the IPA and mixed in a SS container for 10 minutes. 665 g of Hydroxypropyl methyl cellulose (METHOCEL E5) is added slowly in aqueous / solvent mixture under continuous mixing for 60 minutes. After mixing the dispersion is screened through a 60-mesh screen. The indomethacin ER intermediate 267 mg / g beads were loaded into a Wurster Coating Processor. The seal coating solution was then applied to the beads under the process conditions given in Table 4. The seal coating solution was stirred throughout the spraying process. Example 5. Ketotifen fumarate immediate release spray coating process 7.140 kg of the seal coating solution as per Example 4 is added in SS container. The seal coating solution is added to 0.277 kg of ketotifen fumarate in SS container, and mixed for 45 minutes to create the Immediate Release (IR) coating solution. The IR coating solution is sprayed to the seal coated beads under the process conditions given in Table 4. The active coating solution was stirred throughout the spraying process. Table 4. In-Process Parameters used For Spray Coating Process Air Volume 500-1500 cfm (adjust for best product movement) DB1 / 145295370.1 23 SJP-010PC 119887-5010 Exhaust Air Temperature 24°C (20-30°C) Product Bed Temperature 25°C (22-30°C) Example 6. Stability of active feed solutions and coated beads Table 5 shows the total ketotifen fumarate impurities (see Table 2) in a feed solution stored at 30° C across several pH values and using Povidone or HPMC polymer as binder. Table 5. Total ketotifen impurities (percent) Povidone HPMC0 0 5 4 Furth , methacin beads (Examples 3-5) was also determined. Storage for one month at 40°C resulted in 3.82% of impurities for pH 4.0, and 0.56% impurities for pH 6.0. Stability of ketotifen and indomethacin (% impurities) in the IR ketotifen / ER indomethacin beads was determined for ambient and accelerated stability conditions. Results are shown in Table 6. Table 6. IR ketotifen / ER indomethacin beads -- total impurities for ambient and accelerated stability conditions. 3 Month 6 Month 9 Month 12 Month C 7 0 The IR / ER profile of the ketotifen / indomethacin beads in dissolution media (phosphate buffer, pH 6.2) is shown in FIG.3. Example 7. Optimizing coating process DB1 / 145295370.1 24 SJP-010PC 119887-5010 Design of Experiments (DOE) mathematical methodology was used for planning and conducting experiments as well as analyzing and interpreting data obtained from the experiments to optimize the critical process parameters for the coating process. DOE is a branch of applied statistics that is used for conducting scientific studies of a system or process in which input variables (Xs) are manipulated to investigate its effects on measured response variable (Y). Process parameters of a spray coating process that can be critical include: (1) Chamber Air Flow, (2) Chamber Temperature, (3) Solution Spray Rate, (4) Nozzle Pressure, and (5) Acceleration Pressure. A set of experiments was conducted with a placebo to understand the optimal operating design space for the Indomethacin ER / Ketotifen IR coating process. The operating space that resulted is graphically depicted in FIG. 12A and B (where the lower, right quadrant represents an optimal process). The process is described in this example. Data from the completed DOE experiments was analyzed with DESIGN-EXPERT. Using DESIGN-EXPERT, statistical models were created for both Assay and Content Uniformity (CU) results. The Assay is the amount of mass transferred onto the sugar sphere and CU is a measure of the variability of the mass transferred throughout the bulk material. Both models were considered significant, with the assay model having an F-value of 17.2 and the CU model having an F-value of 32.05. That is, these models’ prediction of outputs, based on inputs, is statistically significant. Both models were considered to be adequate to predict and search the design space with a signal to noise ratio of 10.383 for Assay and 14.184 for CU. The Assay model indicated that the nozzle pressure was the significant factor. FIG.6. Additionally, the Assay model indicated an interaction between spray rate and nozzle pressure factors. FIG.7. The Assay Surface Response graph based on spray rate and nozzle pressure is provided in FIG.8. The CU model indicated that spray rate and accelerator pressure are significant factors, having p-values less than 0.05. FIG. 9. The CU model had a very good fit as demonstrated in FIG.10, showing predicted verses actual results. The CU Surface Response graph based on spray rate and nozzle pressure is provided in FIG.11. The analysis concluded that both the Assay and Content Uniformity models are adequate to search quantitatively within the design space investigated. The significant parameter in the Assay model is the DB1 / 145295370.1 25 SJP-010PC 119887-5010 nozzle pressure, and the mid-point (15 psi) to 10 psi is the optimal operating range. FIG. 12A and B. The significant parameters in the CU model included the acceleration pressure and the mid-point (25 psi) to 20 psi is the optimal operating range. FIG.12A, B. Also, spray rate was significant and the lower spray rate will produce the lowest CU results. FIG.12A, B. In both models there was a spray rate interaction or potential interaction. These critical parameters are summarized in Table 3. Table 7. Critical Spray Coating Process Parameters Investigated Independent Factor Parameter Low Level High Level Nozzle Pressure A 10 si 20 si the lower, left quadrant of the design space investigated, illustrated in FIG.12A, B. Example 8. Stability Study Stability study findings for three consecutive batches (D1370, D1371, and D1372) of Indomethacin ER and Ketotifen Fumarate IR Capsules (75 mg & 2 mg) were evaluated. The study evaluated impurities, assay, dissolution, and % loss on drying (LOD) under accelerated (40°C / 75% RH) and long-term (25°C / 60% RH) stability conditions. Table 8. Indomethacin ER and Ketotifen Fumarate IR Capsules Investigated Parameter API Tested Stability Conditions Time Points Impurities Profile DB1 / 145295370.1 26 SJP-010PC 119887-5010 For ketotifen fumarate impurities, results show minor increases in Impurity D and Impurity G at 3 months accelerated (40°C / 75% RH) but remained within acceptable limits. Table 9: Ketotifen Impurity Trends Over Stability Period Lot # D1370 Condition Initial 40°C / 75%RH 40°C / 75%RH 25°C / 60%RH Lot # D1371 Lot # D1372 DB1 / 145295370.1 SJP-010PC 119887-5010 ConditionInitial 40°C / 75%RH 40°C / 75%RH 25°C / 60%RHTest1 Month 3 Month 3 Month For indomethacin impurities, no significant increase observed in any major impurity under either stability condition. Assay Results (% Label Claim) Ketotifen fumarate remained within 97-104% across all conditions. Indomethacin remained within 102-103% in long-term stability and within acceptable limits. Table 11: Ketotifen Fumarate and Indomethacin Trends Over Stability Period Batch# D1370A D1371A D1372A DB1 / 145295370.1 28 SJP-010PC 119887-5010 3M, 102 97.5 101.5 98.3 100.4 106.6 25°C / 60% Dissolution Testing For ketotifen fumarate, the initial release was 100% (30 min) across all batches. There was minimal decrease in dissolution (<2%) at 3 months accelerated but still compliant with United States Pharmacopeia (USP) requirements. For indomethacin, there was an expected slow-release profile with ≥95% at 720 min. There were no significant deviations between conditions. Table 12: Ketotifen and Indomethacin Dissolution Trends Over Stability Period % DISSOLVED DB1 / 145295370.1 29 SJP-010PC 119887-5010 Individual Limit NLT 75% 2-42% 17-62% 40-90% NLT 70% t % Loss on Drying (LOD) For all batches, moisture content remained below 0.008% across all conditions, far below the NMT 4.0% specification. LOD % D1 7 D1 71 D1 72 ifi i Overall, both ketotifen fumarate and indomethacin remained stable under long-term and accelerated conditions with no significant trend in assay, impurity profile, and dissolution. There were no concerns regarding moisture content, as LOD values remained well below limits. DB1 / 145295370.1 30

Claims

SJP-010PC 119887-5010 CLAIMS:

1. A solution or suspension comprising: indomethacin, and co-solvents comprising: about 60% to about 80% isopropyl alcohol by volume, about 0% to about 10% water by volume and, one or both of povidone and mannitol at about 2% to about 5% by weight individually.

2. The solution or suspension of claim 1, wherein the isopropyl alcohol is present at less than 70% by volume.

3. The solution or suspension of claim 1 or 2, wherein the indomethacin is present up to about 70% by weight.

4. The solution or suspension of any one of claims 1 to 3, wherein the povidone is present and is a low peroxide grade.

5. The solution or suspension of any one of claims 1 to 4, wherein the concentration of indomethacin is 20% to 70% by weight.

6. The solution or suspension of any one of claims 1 to 5 having a pH in the range of 5.5 to 6.5, and optionally in the range of 5.9 to 6.

3.

7. The solution or suspension of any one of claims 1 to 6, wherein at least 90% of the indomethacin remains after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC.

8. The solution or suspension of claim 7, wherein at least 95% of the indomethacin remains after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC.

9. The solution or suspension of claim 7 or 8, wherein total indomethacin impurities listed in Table 1 is less than 1.0% or less than 0.5% relative to the total of indomethacin and the impurities listed in Table 1. DB1 / 145295370.1 31SJP-010PC 119887-5010 10. The solution or suspension of claim 9, wherein total indomethacin impurities listed in Table 1 is less than 0.2% relative to the total of indomethacin and the impurities listed in Table 1.

11. A solution or suspension comprising a co-solvent system comprising: ketotifen fumarate, and co-solvents comprising: about 70% to about 95% isopropyl alcohol by volume, about 5% to about 30% water by volume and, povidone or hydroxypropylmethylcellulose (HPMC) at about 0.5% to about 10% by weight.

12. The solution or suspension of claim 11, wherein the povidone is present and is a low peroxide grade.

13. The solution or suspension of claim 11 or 12, wherein the ketotifen fumarate is present at a concentration of about 0.1 mg / mL to about 60 mg / mL.

14. The solution or suspension of claim 13, wherein the ketotifen fumarate is present at a concentration of about 1 mg / mL to about 45 mg / mL.

15. The solution or suspension of claim 13, wherein the ketotifen fumarate is present at a concentration of about 10 mg / mL to about 30 mg / mL.

16. The solution or suspension of any one of claims 11 to 15 having a pH in the range of 6.0 to 6.5, and optionally in the range of 6.1 to 6.

4.

17. The solution or suspension of any one of claims 11 to 16, wherein at least 90% of the ketotifen fumarate or indomethacin remain after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC.

18. The solution or suspension of any one of claims 11 to 16, wherein at least 95% of the ketotifen fumarate or indomethacin remains after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC.

19. The solution or suspension of claim 17 or 18, wherein after the storage, ketotifen N- oxide impurity is less than about 0.6% by weight relative to the total of ketotifen and impurities listed in Table 2. DB1 / 145295370.1 32SJP-010PC 119887-5010 20. The solution or suspension of any one of claims 17 to 19, wherein total ketotifen impurities listed in Table 2 is less than 2.0% by weight relative to the total of ketotifen and impurities listed in Table 2.

21. The solution or suspension of any one of claims 17 to 20, wherein total indomethacin impurities listed in Table 1 is less than 1.0% or less than 0.5% relative to the total of indomethacin and the impurities listed in Table 1.

22. The solution or suspension of claim 21, wherein total indomethacin impurities listed in Table 1 is less than 0.2% relative to the total of indomethacin and the impurities listed in Table 1.

23. A method for making a pharmaceutical composition, comprising the steps: providing a solution or suspension of any one of claims 1 to 22, and applying said solution or suspension to a pharmaceutically acceptable carrier via a coating process.

24. The method of claim 23, wherein the carrier is a 25 to 32 mesh bead.

25. The method of claim 23 or 24, wherein the pharmaceutical composition comprises protective barrier between the indomethacin and ketotifen fumarate coatings.

26. The method of claim 23 or 24, wherein the pharmaceutical composition does not comprise a protective barrier between the indomethacin and ketotifen fumarate coatings.

27. The method of claim 25 or 26, wherein the indomethacin coating is an extended release coating.

28. The method of claim 25 or 26, wherein the ketotifen fumarate coating is an immediate release coating.

29. The method of any one of claims 23 to 28, wherein the coating process is a fluid bed spray coating process applied with a Wurster nozzle.

30. The method of claim 29, wherein the process comprises the following parameters: nozzle pressure is from about 10 psi to about 15 psi, acceleration pressure is from about 20 psi to about 25 psi, and spray rate is from 1.5 to 2.0 g / min. DB1 / 145295370.1 33SJP-010PC 119887-5010 31. The method of any one of claims 23 to 28, comprising a pan coating process.

32. The method of any one of claims 23 to 31, further comprising drying the coated carrier at a temperature in the range of 30° C to 45° C.

33. The method of any one of claims 23 to 32, further comprising inserting the coated carrier into a capsule suitable for oral administration.

34. The method of any one of claims 23 to 33, wherein the capsules are packaged with an oxygen scavenger.

35. A pharmaceutical composition made by the process of any one of claims 23 to 34.

36. A pharmaceutical composition comprising Ketotifen fumarate and indomethacin, wherein the ketotifen fumarate exhibits a dissolution profile in which at least 90% of the ketotifen fumarate is released at 15 minutes.

37. The pharmaceutical composition of claim 35 or 36, wherein the composition exhibits a dissolution profile in which 12% to 32% of the indomethacin is released at 1 hour.

38. The pharmaceutical composition of claim 37, wherein the composition exhibits a dissolution profile in which 27% to 52% of the indomethacin is released at 2 hours.

39. The pharmaceutical composition of claim 37 or 38, wherein the composition exhibits a dissolution profile in which 50% to 80% of the indomethacin is released at 4 hours.

40. The pharmaceutical composition of any one of claims 37 to 39, wherein the composition exhibits a dissolution profile in which at least 80% of the indomethacin is released at 12 hours.

41. The pharmaceutical composition of any one of claims 36 to 40, wherein at least 90% of the ketotifen fumarate and indomethacin remain after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC.

42. The pharmaceutical composition of claim 41, wherein at least 95% of the ketotifen fumarate and indomethacin remains after storage at 40° C and 75% relative humidity for 6 months as determined by HPLC. DB1 / 145295370.1 34SJP-010PC 119887-5010 43. The pharmaceutical composition of claim 41 or 42, wherein after the storage, ketotifen N-oxide impurity is less than about 0.6% by weight relative to the total of ketotifen and impurities listed in Table 2.

44. The pharmaceutical composition of any one of claims 41 to 43, wherein total ketotifen impurities listed in Table 2 is less than 2.0% by weight relative to the total of ketotifen and impurities listed in Table 2.

45. The pharmaceutical composition of any one of claims 41 to 44, wherein total indomethacin impurities listed in Table 1 is less than 1.0% or less than 0.5% relative to the total of indomethacin and the impurities listed in Table 1. 46 The pharmaceutical composition of claim 45, wherein total indomethacin impurities listed in Table 1 is less than 0.2% relative to the total of indomethacin and the impurities listed in Table 1.

47. The pharmaceutical composition of any one of claims 36 to 46, wherein the composition is made by the method of any one of claims 23 to 34.

48. The pharmaceutical composition of any one of claims 36 to 47, wherein the capsule is gelatin or hydroxypropyl methylcellulose (HPMC).

49. A method for treating or preventing an inflammatory disease or condition in a subject in need thereof, the method comprising administering the pharmaceutical composition of any one of claims 36 to 48.

50. The method of claim 49, wherein the inflammatory disease or condition is an infectious disease, which is optionally a virus infection.

51. The method of claim 50, wherein the inflammatory disease or condition is a coronavirus infection, which is optionally SARS-CoV-2.

52. The method of claim 49, wherein the inflammatory disease or condition is long covid.

53. The method of claim 49, wherein the inflammatory disease or condition is symptoms associated with a vaccination.

54. The method of claim 49, wherein the inflammatory disease or condition is veisalgia. DB1 / 145295370.1 35SJP-010PC 119887-5010 55. The method of claim 49, wherein the inflammatory disease or condition is symptoms associated with opioid withdrawal, dependence, or tolerance.

56. The method of claim 49, wherein the inflammatory disease or condition is an autoimmune disease.

57. The method of claim 49, wherein the inflammatory disease or condition is arthritis, which is optionally rheumatoid arthritis or enteropathic arthritis. DB1 / 145295370.1 36

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