Formulations of diclofenac

Abstract

The invention relates to aqueous, oral formulations of diclofenac that provide both rapid and sustained relief from acute pain. The invention further relates to pharmaceutical compositions comprising the compounds, methods of making the aqueous pharmaceutical compositions and methods of using the compounds treating pain, including, but not limited to migraines.

Description

Attorney Docket No.38400.0001P1FORMULATIONS OF DICLOFENACCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No. 63 / 761,802, filed on February 21, 2025, the contents of which is incorporated herein by reference in its entirety.FIELD OF INVENTION

[0002] The invention concerns pharmaceutical compositions, methods of making such pharmaceutical compositions, and methods of using pharmaceutical compositions for treating migraine and other acute pain episodes using an aqueous, oral formulation of diclofenac. The invention further concerns methods and formulations for treating symptoms that often accompany migraine and acute pain such as rebound headache, photophobia, phonophobia, nausea and vomiting.BACKGROUND

[0003] Diclofenac is a non-steroidal anti-inflammatory drug (“NSAID”) known chemically as 2-[2-(2,6-dichloroanilino)phenyl]acetic acid. The drug was developed in the 1960s by scientists at Ciba-Geigy and is sold around the world by Novartis under various trade names, including Cataflam® and Voltaren® in the United States.

[0004] Commercially available formulations provide diclofenac as a tablet, and liquid-filled capsule, a hard gelatin capsule, an extended-release (long-acting) tablet, a delayed-release (releases medication in the intestine) tablet, and as packets of powder for solution (to be mixed with water) and taken by mouth. Diclofenac liquid-filled capsules are usually taken 4 times a day and diclofenac hard gelatin capsules are usually taken 3 times a day on an empty stomach.Diclofenac extended-release tablets are usually taken once a day, and in rare cases are taken twice a day, if needed to control pain. Diclofenac tablets and diclofenac delayed-release tablets are usually taken 2, 3, or 4 times a day. Diclofenac solution is taken without food as a one dose treatment to relieve the pain of migraine headaches.

[0005] Oral liquids have long been the dosage form of choice for pediatric drug formulations. They solve the swallowability problem of solid oral dosage forms and in additioncan help to overcome administration issues with geriatric patients and those with enteral feeding tubes. The dose flexibility offered by oral liquids when used with oral syringes allows for doses that would not otherwise be attainable with most solid dosage forms.

[0006] However, diclofenac has not been supplied as a ready to use oral liquid formulation. Therefore, there exists a need for an aqueous stable diclofenac pharmaceutical composition.SUMMARY OF THE INVENTION

[0007] In one embodiment, disclosed are pharmaceutical compositions comprising diclofenac, or a pharmaceutically acceptable salt thereof, glycerin, propylene glycol, sorbitol, sucralose, hydroxypropyl betadex, viscosity increasing agent, water, optionally comprising a preservative, and optionally comprising a buffering agent.

[0008] In one embodiment, disclosed are aqueous pharmaceutical compositions, obtained by a method comprising the steps: (a) adding water at about 47% w / w to a main manufacturing vessel and warming to 45 ± 5 °C, while mixing the main manufacturing vessel, adding glycerin about 4.7% w / w and sorbitol solution about 20% w / w followed by methylparaben about 0.02% w / w to the main manufacturing vessel and stirring the mixture at 50 ± 10°C until complete dissolution, cool the main manufacturing vessel to 25 ± 5°C, adding sequentially hydroxypropyl betadex about 1% w / w and sucralose about 0.6% w / w to the main manufacturing vessel; (b) adding propylene glycol 14.5% w / v to a first side manufacturing vessel and while mixing adding diclofenac potassium 0.25% w / v; (c) combining the mixture from the first side manufacturing vessel to the main manufacturing vessel and performing a two stage rinse of the first side manufacturing vessel with propylene glycol about 1.8% w / v and water 3.6% w / w with addition of each rinse to the main manufacturing vessel; (d) adding glycerin 5% w / w to a second side manufacturing vessel, while mixing adding xanthan gum 0.025% w / w and continuing mixing until complete dissolution; (e) combining the mixture from the second side manufacturing vessel to the main manufacturing vessel and performing a rinse from the first side manufacturing vessel with water 1.8% w / w with addition of rinse to the main manufacturing vessel; (f) adding flavor 0.3% w / w to the main manufacturing vessel with mixing and additional water in an amount sufficient to obtain a pharmaceutical composition comprising about 0.25% w / v diclofenac potassium or sodium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6% w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum; wherein % w / w or %w / v in the intermediate steps are provided based on the % w / w of the final composition of the pharmaceutical composition..

[0009] In one embodiment, are methods of treating a migraine in a subject, the method comprising administering an effective amount of the disclosed pharmaceutical composition.

[0010] In one embodiment, disclosed are methods of using aqueous pharmaceutical compositions for treating migraine and other acute pain episodes using an aqueous, oral formulation of diclofenac.

[0011] In one embodiment, disclosed are methods for treating symptoms that may accompany migraine and acute pain.

[0012] In certain embodiments, the migraine is accompanied by one or more of rebound headache, photophobia, phonophobia, nausea and vomiting.DETAILED DESCRIPTION

[0013] The invention relates to pharmaceutical compositions comprising diclofenac, or a pharmaceutically acceptable salt thereof, glycerin, propylene glycol, sorbitol, sucralose, hydroxypropyl betadex, a viscosity increasing agent, water, optionally comprising a preservative, and optionally comprising a buffering agent and optionally comprising a flavoring agent. The invention also relates in part to a process for obtaining a one phase aqueous formulation that does not require reconstitution or dilution prior to administration to a patient, and that remains stable and active after a prolonged storage. Such formulations therefore avoid the cost, inconvenience, and risk of contamination or overdose that can be associated with reconstituting or diluting a concentrated diclofenac formulation prior to administration to a patient.

[0014] It is to be understood that this invention is not limited to the specific or exemplary aspects of articles, systems, and / or methods disclosed unless otherwise specified, as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0015] Those of ordinary skill in the pertinent art will recognize that many modifications and adaptations to the present invention are possible.A. DEFINITIONS

[0016] The terms used in this specification generally have their ordinary meanings in the art, within the context of this invention and in the specific context where each term is used. Certain terms are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner in describing the compositions and methods of the invention and how to make and use them.

[0017] According to the present invention, the term “diclofenac” as used herein refers to a non-steroidal anti-inflammatory drug (“NS AID”) known chemically as [(2,6-dichloro-anilino)-2-phenyl]-2-acetic acid. Diclofenac as used herein also encompasses pharmaceutically acceptable salts (e.g., diclofenac sodium salt and diclofenac potassium salt).

[0018] The terms “related compound A” or “RC-A” as used herein refers to N-(2,6-dichlorophenyl)-2-indolinone, l-(2,6-dichlorophenyl)-l,3-dihydro-2h-indol-2-one.

[0019] The term “preservative” as used herein refers to any ingredient that protects a product from the effects of microbiological contamination. Preservatives are also commonly known as antimicrobial agents or germicides. As used herein, the term “preservative” refers to any such ingredient, regardless of whether protection from microbiological contamination is the primary stated purpose of the ingredient. Non-limiting examples of preservatives can include benzalkonium chloride, ethylenediaminetetraacetic acid (EDTA) and salts thereof, benzyl alcohol, potassium sorbate, parabens, benzoic acid, sodium benzoate, and mixtures thereof.

[0020] The term “buffer” as used herein refers to any ingredients that can help maintain a constant pH within the liquid medication. Non-limiting examples of buffers can include acetic acid, sodium acetate, citric acid, sodium citrate, monobasic sodium phosphate, dibasic sodium phosphate, sodium carbonate, sodium bicarbonate, succinic acid, sodium succinate, potassium dihydrogen phosphate, and phosphoric acid, and mixtures thereof.

[0021] The term “flavoring agent,” as used herein refers to any ingredients that can help mitigate the unpleasant tastes of oral formulation in solutions and can include natural flavoring agents, artificial flavoring agents, artificial extracts, natural extracts and combination thereof. Non-limiting examples of flavoring agents can include can include: vanilla, honey lemon cherry vanilla, apple, yumberry, mangosteen, peach, honey ginger, chamomile, cherry, cherry cream, mint, vanilla mint, dark berry, black berry, raspberry, peppermint, spearmint, honey peach, acai berry, cranberry, honey cranberry, tropical fruit, dragon fruit, wolf berry, red stem mint,pomegranate, black currant, strawberry, lemon, lime, peach ginger, orange, orange cream, creamsicle, apricot, anethole, ginger, jack fruit, star fruit, blueberry, fruit punch, lemon grass, chamomile lemon grass, lavender, banana, strawberry banana, grape, blue raspberry, lemon lime, coffee, espresso, cappuccino, honey, wintergreen mint, bubble gum, tart honey lemon, sour lemon, green apple, boysenberry, rhubarb, strawberry rhubarb, persimmon, green tea, black tea, red tea, white tea, honey lime, cherry lime, apple, tangerine, grapefruit, kiwi, pear, vanillin, ethyl vanillin, maltol, ethyl-maltol, pumpkin, carrot cake, white chocolate raspberry, chocolate, white chocolate, milk chocolate, dark chocolate, chocolate marshmallow, apple pie, cinnamon, hazelnut, almond, cream, creme Brule, caramel, caramel nut, butter, butter toffee, caramel toffee, aloe Vera, whiskey, rum, cocoa, licorice, pineapple, guava, melon, watermelon, elderberry, raspberries and cream, peach mango, cool berry, lemon ice, nectar, spicy nectar, tropical mango, apple butter, peanut butter, tangerine, tangerine lime, marshmallow, cotton candy, apple cider, orange chocolate, and mixtures thereof..

[0022] The term “betadex,” as used herein refers to beta-cyclodextrin that is a cyclodextrin composed of seven alpha-(l->4) linked D-glucopyranose units. The term “hydroxypropyl betadex,” refers to a partially substituted poly(hydroxypropyl) ether of betadex. The number of hydroxypropyl groups per anhydroglucose unit expressed as molar substitution (MS).

[0023] Unless otherwise expressly stated, it is in no way intended that any method or embodiment set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect.

[0024] The present invention may be understood more readily by reference to the following detailed description of various embodiments of the invention and the examples included therein and to the Figures and their previous and following description.B. PHARMACEUTICAL COMPOSITIONS

[0025] In one embodiment, disclosed are pharmaceutical compositions comprising diclofenac, or a pharmaceutically acceptable salt thereof, glycerin, propylene glycol, sorbitol, sucralose, hydroxypropyl betadex, a viscosity increasing agent, and water, and wherein the pharmaceutical composition optionally comprising a preservative, a buffering agent, and a flavor agent.

[0026] In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous composition.

[0027] In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 25°C and 60% relative humidity for at least one month. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 25°C and 60% relative humidity for at least two months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 25°C and 60% relative humidity for at least three months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 25°C and 60% relative humidity for at least four months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 25°C and 60% relative humidity for at least five months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 25°C and 60% relative humidity for at least six months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 25°C and 60% relative humidity for at least, nine months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 25°C and 60% relative humidity for at least 12 months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 25°C and 60% relative humidity for at least 15 months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 25°C and 60% relative humidity for at least 18 months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 25°C and 60% relative humidity for at least 24 months.

[0028] In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least, one month. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least two months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least three months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least four months. In some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 40°C and 75% relative humidity for at leastfive months. Tn some embodiments, the pharmaceutical composition is a clear, one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least six months.

[0029] In some embodiments, the pharmaceutical composition comprises not more than about 0.05 %w / w to about 0.75 %w / w of related compound A. In another embodiment, the pharmaceutical composition comprises an amount of related compound A below the lowest level of detection.

[0030] In some embodiments, the pharmaceutical composition comprises not more than about 0.05 %w / w to about 1.25 %w / w of total impurities. In another embodiment, the pharmaceutical composition comprises an amount of total impurities below the lowest level of detection.

[0031] In some embodiments, the pharmaceutical composition comprises not more than 0.045 %w / w of related compound A after storage at 25°C and 60% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.043 %w / w of related compound A after storage at 25°C and 60% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.041 %w / w of related compound A after storage at 25°C and 60% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.039 %w / w of related compound A after storage at 25°C and 60% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.037 %w / w of related compound A after storage at 25°C and 60% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.035 %w / w of related compound A after storage at 25°C and 60% relative humidity after one month.

[0032] In some embodiments, the pharmaceutical composition comprises not more than 0.065 %w / w of related compound A after storage at 25°C and 60% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.063 %w / w of related compound A after storage at 25°C and 60% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.061 %w / w of related compound A after storage at 25°C and 60% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.059 %w / w of related compound A after storage at 25°C and 60% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.057%w / w of related compound A after storage at 25°C and 60% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.055 %w / w of related compound A after storage at 25°C and 60% relative humidity after three months.

[0033] In some embodiments, the pharmaceutical composition comprises not more than 0.105 %w / w of related compound A after storage at 25°C and 60% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.103 %w / w of related compound A after storage at 25°C and 60% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.101 %w / w of related compound A after storage at 25°C and 60% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.099 %w / w of related compound A after storage at 25°C and 60% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.097 %w / w of related compound A after storage at 25°C and 60% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.095 %w / w of related compound A after storage at 25°C and 60% relative humidity after six months.

[0034] In some embodiments, the pharmaceutical composition comprises not more than 0.134 %w / w of related compound A after storage at 25°C and 60% relative humidity after nine months. In some embodiments, the pharmaceutical composition comprises not more than 0.132 %w / w of related compound A after storage at 25°C and 60% relative humidity after nine months. In some embodiments, the pharmaceutical composition comprises not more than 0.130 %w / w of related compound A after storage at 25°C and 60% relative humidity after nine months. In some embodiments, the pharmaceutical composition comprises not more than 0.128 %w / w of related compound A after storage at 25°C and 60% relative humidity after nine months. In some embodiments, the pharmaceutical composition comprises not more than 0.126 %w / w of related compound A after storage at 25°C and 60% relative humidity after nine months.

[0035] In some embodiments, the pharmaceutical composition comprises not more than 0.190 %w / w of related compound A after storage at 25°C and 60% relative humidity after twelve months. In some embodiments, the pharmaceutical composition comprises not more than 0.188 %w / w of related compound A after storage at 25°C and 60% relative humidity after twelve months. In some embodiments, the pharmaceutical composition comprises not more than 0.186%w / w of related compound A after storage at 25°C and 60% relative humidity after twelve months. In some embodiments, the pharmaceutical composition comprises not more than 0.184 %w / w of related compound A after storage at 25°C and 60% relative humidity after twelve months. In some embodiments, the pharmaceutical composition comprises not more than 0.182 %w / w of related compound A after storage at 25°C and 60% relative humidity after twelve months. In some embodiments, the pharmaceutical composition comprises not more than 0.180 %w / w of related compound A after storage at 25°C and 60% relative humidity after twelve months.

[0036] In some embodiments, the pharmaceutical composition comprises not more than 0.260 %w / w of related compound A after storage at 25°C and 60% relative humidity after eighteen months. In some embodiments, the pharmaceutical composition comprises not more than 0.258 %w / w of related compound A after storage at 25°C and 60% relative humidity after eighteen months. In some embodiments, the pharmaceutical composition comprises not more than 0.256 %w / w of related compound A after storage at 25°C and 60% relative humidity after eighteen months. In some embodiments, the pharmaceutical composition comprises not more than 0.254 %w / w of related compound A after storage at 25°C and 60% relative humidity after eighteen months. In some embodiments, the pharmaceutical composition comprises not more than 0.252 %w / w of related compound A after storage at 25°C and 60% relative humidity after eighteen months. In some embodiments, the pharmaceutical composition comprises not more than 0.250 %w / w of related compound A after storage at 25°C and 60% relative humidity after eighteen months.

[0037] In some embodiments, the pharmaceutical composition comprises not more than 0.085 %w / w of total impurities after storage at 25°C and 60% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.083 %w / w of total impurities after storage at 25°C and 60% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.081 %w / w of total impurities after storage at 25°C and 60% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.079 %w / w of total impurities after storage at 25°C and 60% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.077 %w / w of total impurities after storage at 25°C and 60% relative humidity after one month. In someembodiments, the pharmaceutical composition comprises not more than 0.075 %w / w of total impurities after storage at 25°C and 60% relative humidity after one month.

[0038] In some embodiments, the pharmaceutical composition comprises not more than 0.130 %w / w of total impurities after storage at 25°C and 60% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.128 %w / w of total impurities after storage at 25°C and 60% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.126 %w / w of total impurities after storage at 25°C and 60% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.124 %w / w of total impurities after storage at 25°C and 60% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.122 %w / w of total impurities after storage at 25°C and 60% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.120 %w / w of total impurities after storage at 25°C and 60% relative humidity after three months.

[0039] In some embodiments, the pharmaceutical composition comprises not more than 0.255 %w / w of total impurities after storage at 25°C and 60% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.253 %w / w of total impurities after storage at 25°C and 60% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.251 %w / w of total impurities after storage at 25°C and 60% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.249 %w / w of total impurities after storage at 25°C and 60% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.247 %w / w of total impurities after storage at 25°C and 60% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.245 %w / w of total impurities after storage at 25°C and 60% relative humidity after six months.

[0040] In some embodiments, the pharmaceutical composition comprises not more than 0.274 %w / w of total impurities after storage at 25°C and 60% relative humidity after nine months. In some embodiments, the pharmaceutical composition comprises not more than 0.272 %w / w of total impurities after storage at 25°C and 60% relative humidity after nine months. In some embodiments, the pharmaceutical composition comprises not more than 0.270 %w / w oftotal impurities after storage at 25°C and 60% relative humidity after nine months. In some embodiments, the pharmaceutical composition comprises not more than 0.268 %w / w of total impurities after storage at 25°C and 60% relative humidity after nine months. In some embodiments, the pharmaceutical composition comprises not more than 0.266 %w / w of total impurities after storage at 25°C and 60% relative humidity after nine months.

[0041] In some embodiments, the pharmaceutical composition comprises not more than 0.350 %w / w of total impurities after storage at 25°C and 60% relative humidity after twelve months. In some embodiments, the pharmaceutical composition comprises not more than 0.348 %w / w of total impurities after storage at 25°C and 60% relative humidity after twelve months. In some embodiments, the pharmaceutical composition comprises not more than 0.346 %w / w of total impurities after storage at 25°C and 60% relative humidity after twelve months. In some embodiments, the pharmaceutical composition comprises not more than 0.344 %w / w of total impurities after storage at 25°C and 60% relative humidity after twelve months. In some embodiments, the pharmaceutical composition comprises not more than 0.342 %w / w of total impurities after storage at 25°C and 60% relative humidity after twelve months. In some embodiments, the pharmaceutical composition comprises not more than 0.340 %w / w of total impurities after storage at 25°C and 60% relative humidity after twelve months.

[0042] In some embodiments, the pharmaceutical composition comprises not more than 0.465 %w / w of total impurities after storage at 25°C and 60% relative humidity after eighteen months. In some embodiments, the pharmaceutical composition comprises not more than 0.463 %w / w of total impurities after storage at 25°C and 60% relative humidity after eighteen months. In some embodiments, the pharmaceutical composition comprises not more than 0.461 %w / w of total impurities after storage at 25°C and 60% relative humidity after eighteen months. In some embodiments, the pharmaceutical composition comprises not more than 0.459 %w / w of total impurities after storage at 25°C and 60% relative humidity after eighteen months. In some embodiments, the pharmaceutical composition comprises not more than 0.457 %w / w of total impurities after storage at 25°C and 60% relative humidity after eighteen months. In some embodiments, the pharmaceutical composition comprises not more than 0.455 %w / w of total impurities after storage at 25°C and 60% relative humidity after eighteen months.

[0043] In some embodiments, the pharmaceutical composition comprises not more than 0.165 %w / w of related compound A after storage at 40°C and 75% relative humidity after onemonth. In some embodiments, the pharmaceutical composition comprises not more than 0.163 %w / w of related compound A after storage at 40°C and 75% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.161 %w / w of related compound A after storage at 40°C and 75% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.159 %w / w of related compound A after storage at 40°C and 75% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.157 %w / w of related compound A after storage at 40°C and 75% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.155 %w / w of related compound A after storage at 40°C and 75% relative humidity after one month.

[0044] In some embodiments, the pharmaceutical composition comprises not more than 0.420 %w / w of related compound A after storage at 40°C and 75% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.418 %w / w of related compound A after storage at 40°C and 75% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.416 %w / w of related compound A after storage at 40°C and 75% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.414 %w / w of related compound A after storage at 40°C and 75% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.412 %w / w of related compound A after storage at 40°C and 75% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.410 %w / w of related compound A after storage at 40°C and 75% relative humidity after three months.

[0045] In some embodiments, the pharmaceutical composition comprises not more than 0.705 %w / w of related compound A after storage at 40°C and 75% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.703 %w / w of related compound A after storage at 40°C and 75% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.701 %w / w of related compound A after storage at 40°C and 75% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.699 %w / w of related compound A after storage at 40°C and 75% relative humidity after six months. In someembodiments, the pharmaceutical composition comprises not more than 0.697 %w / w of related compound A after storage at 40°C and 75% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 0.695 %w / w of related compound A after storage at 40°C and 75% relative humidity after six months.

[0046] In some embodiments, the pharmaceutical composition comprises not more than 0.290 %w / w of total impurities after storage at 40°C and 75% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.288 %w / w of total impurities after storage at 40°C and 75% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.286 %w / w of total impurities after storage at 40°C and 75% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.284 %w / w of total impurities after storage at 40°C and 75% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.282 %w / w of total impurities after storage at 40°C and 75% relative humidity after one month. In some embodiments, the pharmaceutical composition comprises not more than 0.280 %w / w of total impurities after storage at 40°C and 75% relative humidity after one month.

[0047] In some embodiments, the pharmaceutical composition comprises not more than 0.670 %w / w of total impurities after storage at 40°C and 75% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.668 %w / w of total impurities after storage at 40°C and 75% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.666 %w / w of total impurities after storage at 40°C and 75% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.664 %w / w of total impurities after storage at 40°C and 75% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.662 %w / w of total impurities after storage at 40°C and 75% relative humidity after three months. In some embodiments, the pharmaceutical composition comprises not more than 0.660 %w / w of total impurities after storage at 40°C and 75% relative humidity after three months.

[0048] In some embodiments, the pharmaceutical composition comprises not more than 1.200 %w / w of total impurities after storage at 40°C and 75% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 1.198 %w / w oftotal impurities after storage at 40°C and 75% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 1.196 %w / w of total impurities after storage at 40°C and 75% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 1.194 %w / w of total impurities after storage at 40°C and 75% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 1.192 %w / w of total impurities after storage at 40°C and 75% relative humidity after six months. In some embodiments, the pharmaceutical composition comprises not more than 1.190 %w / w of total impurities after storage at 40°C and 75% relative humidity after six months.

[0049] In some embodiments diclofenac, or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 0.01% w / v to about 15% w / v. In some embodiments diclofenac, or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 0.1% w / v to about 1.0% w / v. In some embodiments, diclofenac, or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 0.2% w / v to about 0.6% w / v. In some embodiments diclofenac, or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 0.25% w / v.

[0050] In some embodiments glycerin is present in the pharmaceutical composition in an amount of about 2% w / w to about 20% w / w. In some embodiments glycerin is present in the pharmaceutical composition in an amount of about 5% w / w to about 15% w / w. In some embodiments glycerin is present in the pharmaceutical composition in an amount of about 12% w / w. In some embodiments glycerin is present in the pharmaceutical composition in an amount of about 10 % w / w.

[0051] In some embodiments propylene glycol is present in the pharmaceutical composition in an amount of about 10% w / v to about 30% w / v. In some embodiments propylene glycol is present in the pharmaceutical composition in an amount of about 15% w / v to about 25% w / v. In some embodiments propylene glycol is present in the pharmaceutical composition in an amount of about 18% w / v to about 22% w / v. In some embodiments propylene glycol is present in the pharmaceutical composition in an amount of about 20 % w / v.

[0052] In some embodiments the % w / v propylene glycol in the pharmaceutical composition corresponds to about 9.0% w / w to about 27.0 % w / w, and in another embodiment 9.09% w / w toabout 27.3 % w / w. In some embodiments the % w / v propylene glycol in the pharmaceutical composition corresponds to about 13.0 % w / w to about 23.0 % w / w, and in another embodiment 13.6% w / w to about 22.7% w / w. In some embodiments the % w / v propylene glycol in the pharmaceutical composition corresponds to about 16.0% w / w to about 20.0 % w / w, and in another embodiment about 16.4% w / w to about 20% w / w. In some embodiments the % w / v propylene glycol in the pharmaceutical composition corresponds to about 18 % w / w or about 18.2 % w / w.

[0053] In some embodiments sorbitol is present in the pharmaceutical composition in an amount of about 10% w / w to about 30% w / w. In some embodiments sorbitol is present in the pharmaceutical composition in an amount of about 15% w / w to about 25% w / w. In some embodiments sorbitol is present in the pharmaceutical composition in an amount of about 18% w / w to about 22% w / w. In some embodiments sorbitol is present in the pharmaceutical composition in an amount of about 20 % w / w.

[0054] In some embodiments sucralose is present in the pharmaceutical composition in an amount of about 0.01% w / w to about 5% w / w. In some embodiments sucralose is present in the pharmaceutical composition in an amount of about 0.1% w / w to about 1% w / w. In some embodiments sucralose is present in the pharmaceutical composition in an amount of about 0.5% w / w to about 0.7% w / w. In some embodiments sucralose is present in the pharmaceutical composition in an amount of about 0.6% w / w.

[0055] In some embodiments sucralose is present in the pharmaceutical composition in an amount of about 0.1% w / w to about 10% w / w. In some embodiments sucralose is present in the pharmaceutical composition in an amount of about 0.3% w / w to about 7% w / w. In some embodiments sucralose is present in the pharmaceutical composition in an amount of about 0.4% w / w to about 2% w / w. In some embodiments sucralose is present in the pharmaceutical composition in an amount of about 1% w / w.

[0056] In some embodiments, the pharmaceutical composition comprises a viscosity increasing agent. Examples of viscosity increasing agents include, but are not limited to, xanthan gum, carob gum, guar gum, alginates, modified celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose. In some embodiments, the viscosity increasing agent is xanthan gum.

[0057] In some embodiments xanthan gum is present in the pharmaceutical composition in an amount of about 0.001% w / w to about 0.5% w / w. In some embodiments xanthan gum is present in the pharmaceutical composition in an amount of about 0.005% w / w to about 0.1% w / w. In some embodiments xanthan gum is present in the pharmaceutical composition in an amount of about 0.01% w / w to about 0.03% w / w. In some embodiments xanthan gum is present in the pharmaceutical composition in an amount of about 0.025% w / w.

[0058] In some embodiments methylparaben is present in the pharmaceutical composition in an amount of about 0.001% w / w to about 1% w / w. In some embodiments methylparaben is present in the pharmaceutical composition in an amount of about 0.005% w / w to about 0.1% w / w. In some embodiments methylparaben is present in the pharmaceutical composition in an amount of about 0.01% w / w to about 0.03% w / w. In some embodiments methylparaben is present in the pharmaceutical composition in an amount of about 0.02% w / w.

[0059] In some embodiments, the pharmaceutical composition comprises(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.01% w / v to about 15% w / v,(b) glycerin present at about 2% w / w to about 20% w / w,(c) propylene glycol present at about 10% w / v to about 30% w / v,(d) sorbitol present at about 10% w / w to about 30% w / w,(e) sucralose present at about 0.01% w / w to about 5% w / w,(f) hydroxypropyl betadex present at about 0.3% w / w to about 7% w / w, (g) methylparaben present at about 0.001% w / w to about 1% w / w,(h) xanthan gum present at about 0.01% w / w to about 0.05% w / w,(i) water at a quantity sufficient to bring composition to 100% w / w,(j) optionally a buffering agent, wherein the pH is about 6.0 to about 8.0, and (k) optionally a flavoring agent at about 0.05% to about 1% w / w.

[0060] In some embodiments, the pharmaceutical composition comprises(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.1% w / v to about 1.0% w / v,(b) glycerin present at about 5% w / w to about 15% w / w,(c) propylene glycol present at about 15% w / v to about 25% w / v,(d) sorbitol present at about 15% w / w to about 25% w / w,(e) sucralose present at about 0.1 % w / w to about 1 % w / w,(f) hydroxypropyl betadex present at about 0.1% w / w to about 10% w / w, (g) methylparaben present at about 0.01% w / w to about 0.1% w / w,(h) xanthan gum present at about 0.01% w / w to about 0.1% w / w,(i) water at a quantity sufficient to 100%,(j) optionally a buffering agent, wherein the pH is about 6.0 to about 8.0, and (k) optionally a flavoring agent at about 0.1% to about 0.5% w / w.

[0061] In some embodiments, the pharmaceutical composition comprises(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.2% w / v to about 0.6% w / v,(b) glycerin present at about 8% w / w to about 12% w / w,(c) propylene glycol present at about 18% w / v to about 22% w / v,(d) sorbitol present at about 18% w / w to about 22% w / w,(e) sucralose present at about 0.5% w / w to about 0.7% w / w,(f) hydroxypropyl betadex present at about 0.4% w / w to about 2 % w / w, (g) methylparaben present at about 0.01% w / w to about 0.03% w / w,(h) xanthan gum present at about 0.01% w / w to about 0.03% w / w,(i) water at a quantity sufficient to 100%,(j) optionally a buffering agent, wherein the pH is about 6.0 to about 8.0, and (k) optionally a flavoring agent at about 0.2% to about 0.4% w / w..

[0062] In some embodiments, the pharmaceutical composition comprises(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.25% w / v,(b) glycerin present at about 10% w / w,(c) propylene glycol present at about 20% w / v,(d) sorbitol present at about 20% w / w,(e) sucralose present at about 0.6 % w / w,(f) hydroxypropyl betadex present at about 1% w / w,(g) xanthan gum, present at about 0.025% w / w,(h) methylparaben present at about 0.02% w / w,(i) water at a quantity sufficient to 100%,(j) optionally a buffering agent, wherein the pH is about 6.0 to about 8.0, and (k) optionally a flavoring agent at about 0.3% w / w.

[0063] In one embodiment, the aqueous pharmaceutical composition is prepared by the method, comprising the steps:(a) adding water at about 47% w / w to a main manufacturing vessel and warming to 45 ± 5°C,i. while mixing the water in the main manufacturing vessel, add glycerin at about 4.7% w / w and sorbitol solution at about 20% w / w and mix until a clear solution followed by addition of methylparaben at about 0.02% w / w to the main manufacturing vessel and stirring the mixture at 50 ± 10°C until complete dissolution,ii. cooling the main manufacturing vessel to 25 ± 5°C,iii. adding sequentially hydroxypropyl betadex at about 1% w / w and sucralose at about 0.6% w / w to the main manufacturing vessel;(b) adding propylene glycol at about 14.5% w / v to a first side manufacturing vessel and while mixing, adding diclofenac potassium at about 0.25% w / v;(c) combining the mixture from the first side manufacturing vessel to the main manufacturing vessel and performing a two stage rinse of the first side manufacturing vessel with propylene glycol at about 1.8% w / v and water at about 3.6% w / w with addition of each rinse to the main manufacturing vessel;(d) adding glycerin at about 5% w / w to a second side manufacturing vessel, while mixing adding xanthan gum at about 0.025% w / w and continuing mixing until complete dissolution;(e) combining the mixture from the second side manufacturing vessel to the main manufacturing vessel and performing a rinse from the first side manufacturing vessel with water at about 1.8% w / w with addition of rinse to the main manufacturing vessel;(f) adding a flavoring agent, such as berry flavor for example, at about 0.3% w / w to the main manufacturing vessel with mixing and adding water an amount sufficient to obtain the pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6 % w / w sucralose, about 1% w / whydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum; wherein % w / w in the intermediate steps are provided based on the % w / w of the final composition of the pharmaceutical composition.

[0064] In other embodiments, the aqueous pharmaceutical composition of diclofenac is prepared by the method, comprising the steps:a. preparing a solution A, wherein the solution A is obtained by:i. combining appropriate amounts of diclofenac potassium salt, water, glycerin, and propylene glycol in a reaction vessel and stirring until complete dissolution to obtain the solution A comprising about 0.5% w / v diclofenac, about 50% w / w water, about 10% w / w glycerin, and about 40% w / v propylene glycol.b. preparing a solution B, wherein the solution B is obtained by:i. combining appropriate amounts of water, sorbitol, and methylparaben in a second reaction vessel and warming to 60°C and mixing until complete dissolution to obtain the solution B comprising about 50% w / w water, about 50%, w / w sorbitol, and about 0.05% w / w methylparaben;ii. allowing solution B to cool to 20 - 35°C,c. preparing a solution C, wherein the solution C is obtained byi. combining appropriate amounts of sucralose, sodium citrate dihydrate, and hydroxylpropyl betadex, with the solution B and continuing to mix until complete dissolution to obtain the solution C comprising about 48% w / w water, about 48%, w / w sorbitol, about 0.05% w / w methylparaben, about 1.5% w / w sucralose, about 0.24% w / w sodium citrate dihydrate, and about 2.4% w / w hydroxypropyl betadex.d. combining an appropriate amount of solution C into an appropriate amount of solution A and continuing to mix until complete dissolution to form a solution D comprising about 49% w / w water, about 5% w / w glycerin, and about 22% w / v propylene glycol, about 22%, w / w sorbitol, about 0.02% w / w methylparaben, about 0.6% w / w sucralose, about 0.1% w / w sodium citrate dihydrate, and about 1% w / w hydroxypropyl betadex.e. preparing a solution E, wherein the solution E is obtained by:i. combining appropriate amounts of glycerin and xanthan gum and mixing to obtain the solution E comprising about 0.5% w / w xanthan gum and about 99.5% w / w glycerin,f. combining an appropriate amount of the solution E with an appropriate amount of the solution D and mixing the mixture of solution E and solution D until a clear solution is obtained,g. optionally combining a flavoring agent with the solution F, andh. combining an appropriate amount of additional water in a quantity sufficient to obtain the pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6 % w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum, and about 0.1% w / w sodium citrate.C. METHODS OF MAKING A PHARMACEUTICAL COMPOSITION

[0065] In one embodiment, disclosed are methods of making an aqueous pharmaceutical composition of diclofenac, the method comprising:a. preparing a solution A, wherein the solution A is obtained by:i. combining appropriate amounts of diclofenac potassium salt, water, glycerin, and propylene glycol in a reaction vessel and stirring until complete dissolution to obtain the solution A comprising about 0.1% w / v to about 1% w / v diclofenac, about 40% w / w to about 60% w / w water, about 5% w / w to about 15% w / w glycerin, and about 30% w / w to about 50% w / v propylene glycol.b. preparing a solution B, wherein the solution B is obtained by:i. combining appropriate amounts of water, sorbitol, and methylparaben in a second reaction vessel and warming to about 60°C and mixing until complete dissolution to obtain the solution B comprising about 40% w / w to about 60% w / w water, about 40% w / w to about 60% w / w sorbitol, and about 0.01% w / w to about 0.1% w / w methylparaben;ii. allowing solution B to cool to about 20 - 35°C,c. preparing a solution C, wherein the solution C is obtained byi. combining appropriate amounts of sucralose, sodium citrate dihydrate, and hydroxylpropyl betadex, with the solution B and continuing to mix until complete dissolution to obtain the solution C comprising about 40% w / w to about 60% w / w water, about 40% w / w to about 60% w / w sorbitol, about 0.01% w / w to about 0.1% w / w methylparaben, about 0.5% w / w to about 5.0 % w / w sucralose, about 0.1 % w / w to about 0.5% w / w sodium citrate dihydrate, and about 1.0 % w / w to about 5.0% w / w hydroxypropyl betadex.d. combining an appropriate amount of solution C into an appropriate amount of solution A and continuing to mix until complete dissolution to form a solution D comprising about 0.1% w / v to about 1% w / v diclofenac, about 40% w / w to about 60% water, about 1% w / w to about 10% glycerin, and about 15% w / w to about 30% w / v propylene glycol, about 15% w / w to about 30% w / w sorbitol, about 0.01% w / w to about 0.1% w / w methylparaben, about 0.3% w / w to about 3.0 % w / w sucralose, about 0.1% w / w sodium citrate dihydrate, and about 0.5% w / w to about 1.% w / w hydroxypropyl betadex.e. preparing a solution E, wherein the solution E is obtained by:i. combining appropriate amounts of glycerin and xanthan gum and mixing to obtain the solution E comprising about 0.1% w / w to about 1.0% w / w xanthan gum and about 99% w / w to about 99.9% / w glycerin, f. combining an appropriate amount of the solution E with an appropriate amount of the solution D and mixing the mixture of solution E and solution D until a clear solution is obtained,g. optionally combining a flavoring agent with the solution F, andh. combining an appropriate amount of additional water in a quantity sufficient to obtain the pharmaceutical composition comprising about 0.1% w / v to about 1.0% w / v diclofenac potassium salt, about 40% w / w to about 60% water, about 5% w / w to about 15% w / w glycerin, about 10% w / w to about 30% w / v propylene glycol, about 10% w / w to about 30% w / w sorbitol, about 0.05% w / w to about 0.15% w / w sodium citrate dihydrate, about 0.1 % w / w to about 1.0% w / w sucralose, about0.5% w / w to about 1.5% w / w hydroxypropyl betadex, about 0.005% w / w to about 0.1% w / w methylparaben, about 0.01% w / w to about 0.05% w / w xanthan gum, and about 0.05% w / w to about 0.5% w / w sodium citrate.

[0066] In some embodiments, the method comprises:a. preparing a solution A, wherein the solution A is obtained by:i. combining appropriate amounts of diclofenac potassium salt, water, glycerin, and propylene glycol in a reaction vessel and stirring until complete dissolution to obtain the solution A comprising about 0.5% w / v diclofenac, about 50% w / w water, about 10% w / w glycerin, and about 40% w / w propylene glycol.b. preparing a solution B, wherein the solution B is obtained by:i. combining appropriate amounts of water, sorbitol, and methylparaben in a second reaction vessel and warming to 60°C and mixing until complete dissolution to obtain the solution B comprising about 50% w / w water, about 50%, w / w sorbitol, and about 0.05% w / w methylparaben;ii. allowing solution B to cool to 20 - 35°C,c. preparing a solution C, wherein the solution C is obtained byi. combining appropriate amounts of sucralose, sodium citrate dihydrate, and hydroxylpropyl betadex, with the solution B and continuing to mix until complete dissolution to obtain the solution C comprising about 48% w / w water, about 48%, w / w sorbitol, about 0.05% w / w methylparaben, about 1.5% w / w sucralose, about 0.24% w / w sodium citrate dihydrate, and about 2.4% w / w hydroxypropyl betadex.d. combining an appropriate amount of solution C into an appropriate amount of solution A and continuing to mix until complete dissolution to form a solution D comprising about 49% w / w water, about 5% w / w glycerin, and about 22% w / v propylene glycol, about 22%, w / w sorbitol, about 0.02% w / w methylparaben, about 0.6% w / w sucralose, about 0.1% w / w sodium citrate dihydrate, and about 1% w / w hydroxypropyl betadex.e. preparing a solution E, wherein the solution E is obtained by:i. combining appropriate amounts of glycerin and xanthan gum and mixing to obtain the solution E comprising about 0.5% w / w xanthan gum and about 99.5% w / w glycerin,f. combining an appropriate amount of the solution E with an appropriate amount of the solution D and mixing the mixture of solution E and solution D until a clear solution is obtained,g. optionally combining a flavoring agent with the solution F, andh. combining an appropriate amount of additional water in a quantity sufficient to obtain the pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6 % w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum, and about 0.1% w / w sodium citrate.

[0067] In one embodiment, disclosed are methods of making an aqueous pharmaceutical composition of diclofenac, the method comprising:a. adding water at about 40% w / w to about 60% w / w water to a main manufacturing vessel and warming to 45 ± 5°C,i. while mixing the water in the main manufacturing vessel, add glycerin at about 1.0% w / w to about 10.0% w / w and sorbitol solution at about 10% w / w to about 30% w / w and mix until a clear solution followed by addition of methylparaben at about 0.01% w / w to about 0.03% w / w to the main manufacturing vessel and stirring the mixture at 50 ± 10°C until complete dissolution,ii. cooling the main manufacturing vessel to 25 ± 5°C,iii. adding sequentially hydroxypropyl betadex at about 0.5% w / w to about 1.5% w / w and sucralose at about 0.2 % w / w to about 1.0% sucralose to the main manufacturing vessel;b. adding propylene glycol at about 10% w / v to about 20% w / v to a first side manufacturing vessel and while mixing, adding diclofenac potassium at about 0.1% w / v to about 1.0% w / v;c. combining the mixture from the first side manufacturing vessel to the main manufacturing vessel and performing a two stage rinse of the first side manufacturing vessel with propylene glycol at about 1.0% w / v to about 3.0% w / v and water at about 1.0% w / w to about 3.0% w / w with addition of each rinse to the main manufacturing vessel;d. adding glycerin at about 1% to about 5%w / w to a second side manufacturing vessel, while mixing adding xanthan gum at about 0.01% to about 0.05% w / w and continuing mixing until complete dissolution;e. combining the mixture from the second side manufacturing vessel to the main manufacturing vessel and performing a rinse from the first side manufacturing vessel with water at about 1.0% w / w to about 3.0% w / w with addition of rinse to the main manufacturing vessel;f. adding berry flavor at about 0.1% w / w to about 0.5% w / w / to the main manufacturing vessel with mixing and adding water an amount sufficient to obtain the pharmaceutical composition comprising about 0.1% w / v to about 1.0% w / v diclofenac potassium salt, about 40% w / w to about 60% w / w water, 5% w / w to about 15% w / w glycerin, about 10% w / w to about 30% w / v propylene glycol, about 10% w / w to about 30% w / w sorbitol, about 0.05% w / w to about 0.5% w / w sodium citrate dihydrate, about 0.2 % w / w to about 1.0% sucralose, about 0.5% w / w to about 1.5% w / w hydroxypropyl betadex, about 0.005% to about 0.05% w / w methylparaben, about 0.01% to about 0.05% w / w xanthan gum; wherein % w / w and %w / v in the intermediate steps are provided based on the % w / w and % w / v of the final composition of the pharmaceutical composition.

[0068] In some embodiments, the method comprises:a. adding water at about 47% w / w to a main manufacturing vessel and warming to 45 ± 5°C,i. while mixing the water in the main manufacturing vessel, add glycerin at about 4.7% w / w and sorbitol solution at about 20% w / w and mix until a clear solution followed by addition of methylparaben at about 0.02% w / w to the main manufacturing vessel and stirring the mixture at 50 ± 10°C until complete dissolution,ii. cooling the main manufacturing vessel to 25 ± 5°C,iii. adding sequentially hydroxypropyl betadex at about 1% w / w and sucralose at about 0.6% w / w to the main manufacturing vessel;b. adding propylene glycol at about 14.5% w / v to a first side manufacturing vessel and while mixing, adding diclofenac potassium at about 0.25% w / v; c. combining the mixture from the first side manufacturing vessel to the main manufacturing vessel and performing a two stage rinse of the first side manufacturing vessel with propylene glycol at about 1.8% w / v and water at about 3.6% w / w with addition of each rinse to the main manufacturing vessel;d. adding glycerin at about 5% w / w to a second side manufacturing vessel, while mixing adding xanthan gum at about 0.025% w / w and continuing mixing until complete dissolution;e. combining the mixture from the second side manufacturing vessel to the main manufacturing vessel and performing a rinse from the first side manufacturing vessel with water at about 1.8% w / w with addition of rinse to the main manufacturing vessel;f. adding berry flavor at about 0.3% w / w to the main manufacturing vessel with mixing and adding water an amount sufficient to obtain the pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6 % w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum; wherein % w / w in the intermediate steps are provided based on the % w / w of the final composition of the pharmaceutical composition.D. METHODS OF TREATMENT

[0069] The aqueous pharmaceutical compositions comprising diclofenac disclosed herein are useful for treatment of acute pain. Various types of acute pain may be treated including headache, including but not limited to migraine, and joint pain. The diclofenac administered using the aqueous pharmaceutical compositions disclosed herein, is disclosed in a therapeutically effective amount.

[0070] In certain embodiments, disclosed are methods of using aqueous pharmaceutical compositions for treating migraine and other acute pain episodes using an aqueous, oral formulation of diclofenac.

[0071] In certain embodiments, disclosed are methods for treating symptoms that may accompany migraine and acute pain such as rebound headache, photophobia, phonophobia, nausea and vomiting.

[0072] In certain embodiments, the migraine is accompanied by one or more of rebound headache, photophobia, phonophobia, nausea and vomiting.

[0073] In certain embodiments, the diclofenac is administered to a human patient in an amount of about 10 mg to about 200 mg. In other embodiments the diclofenac is administered to a human patient in an amount of about 25 mg to about 100 mg. In other embodiments the diclofenac is administered to a human patient in an amount of about 50 mg.

[0074] When treating migraine, the pharmaceutical compositions is administered to a human patient in an amount to deliver about 10 mg to about 200 mg of diclofenac. In other embodiments, the pharmaceutical compositions is administered to a human patient in an amount to deliver about 25 mg to about 100 mg of diclofenac. In other embodiments, the pharmaceutical compositions is administered to a human patient in an amount to deliver about 50 mg of diclofenac.

[0075] In certain embodiments, the diclofenac is administered to a human patient in an amount of about 4 mL to about 80 mL of a formulation comprising 0.25% w / v of diclofenac. In other embodiments the diclofenac is administered to a human patient in an amount of about 10 mL to about 40 mL of a formulation comprising 0.25% w / v of diclofenac. In other embodiments the diclofenac is administered to a human patient in an amount of about 20 mL of a formulation comprising 0.25% w / v of diclofenac.

[0076] In certain embodiments, the pharmaceutical composition for use to treat a patient of acute pain. Various types of acute pain may be treated including headache, including but not limited to migraine, and joint pain.

[0077] The diclofenac administered using the aqueous pharmaceutical compositions disclosed herein, is disclosed in a therapeutically effective amount.

[0078] In certain embodiments an appropriate amount of diclofenac is administered to a human patient in a volume of aqueous pharmaceutical composition of about 4 mL to about 80mL, when the concentration of diclofenac in the aqueous pharmaceutical composition is about 0.25% w / v. In other embodiments, an appropriate amount of diclofenac is administered to a human patient in a volume of aqueous pharmaceutical composition of about 10 mL to about 40 mL, when the concentration of diclofenac in the aqueous pharmaceutical composition is about 0.25% w / v. In other embodiments, an appropriate amount of diclofenac is administered to a human patient in a volume of aqueous pharmaceutical composition of about 20 mL, when the concentration of diclofenac in the aqueous pharmaceutical composition is about 0.25% w / v. E. CERTAIN EMODIMENTS

[0079] Embodiment 1, an aqueous pharmaceutical compositions comprising(a) diclofenac, or a pharmaceutically acceptable salt thereof,(b) glycerin,(c) propylene glycol,(d) sorbitol,(e) sucralose,(f) hydroxypropyl betadex,(g) a viscosity increasing agent, and(h) water, andwherein the composition optionally further comprises one or more of a stabilizing agent, buffering agent, and a flavoring agent.

[0080] Embodiment 2, the pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition is a clear one phase aqueous solution.

[0081] Embodiment 3, the pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition is a clear one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least one month.

[0082] Embodiment 4, the pharmaceutical composition of any one of embodiments 1 to 3, wherein the diclofenac, or pharmaceutically acceptable salt is present at about 0.01% w / v to about 15% w / v,

[0083] Embodiment 5, the pharmaceutical composition of any one of embodiments 1 to 3, wherein the diclofenac, or pharmaceutically acceptable salt is present at about 0.1% w / v to about 1.0% w / v.

[0084] Embodiment 6, the pharmaceutical composition of any one of embodiments 1 to 3, wherein the diclofenac, or pharmaceutically acceptable salt is present at about 0.2% w / v to about 0.6% w / v.

[0085] Embodiment 7, the pharmaceutical composition of any one of embodiments 1 to 6, wherein glycerin is present at about 2% w / w to about 20% w / w.

[0086] Embodiment 8, the pharmaceutical composition of any one of embodiments 1 to 6, wherein glycerin is present at about 5% w / w to about 15% w / w.

[0087] Embodiment 9, the pharmaceutical composition of any one of embodiments 1 to 6, wherein glycerin is present at about 8% w / w to about 12% w / w.

[0088] Embodiment 10, the pharmaceutical composition of any one of embodiments 1 to 9, wherein propylene glycol is present at about 10% w / v to about 30% w / v.

[0089] Embodiment 11, the pharmaceutical composition of any one of embodiments 1 to 9, wherein propylene glycol is present at about 15% w / v to about 25% w / v.

[0090] Embodiment 12, the pharmaceutical composition of any one of embodiments 1 to 9, wherein propylene glycol is present at about 18% w / v to about 22% w / v.

[0091] Embodiment 13, the pharmaceutical composition of any one of embodiments 1 to 12, wherein sorbitol is present at about 10% w / w to about 30% w / w.

[0092] Embodiment 14, the pharmaceutical composition of any one of embodiments 1 to 12, wherein sorbitol is present at about 15% w / w to about 25% w / w.

[0093] Embodiment 15, the pharmaceutical composition of any one of embodiments 1 to 12, wherein sorbitol is present at about 18% w / w to about 22% w / w.

[0094] Embodiment 16, the pharmaceutical composition of any one of embodiments 1 to 15, wherein sucralose is present at about 0.01% w / w to about 5% w / w.

[0095] Embodiment 17, the pharmaceutical composition of any one of embodiments 1 to 15, wherein sucralose is present at about 0.1% w / w to about 1% w / w.

[0096] Embodiment 18, the pharmaceutical composition of any one of embodiments 1 to 15, wherein sucralose is at about 0.5% w / w to about 0.7% w / w.

[0097] Embodiment 19, the pharmaceutical composition of any one of embodiments 1 to 18, wherein hydroxypropyl betadex is present at about 0.1% w / w to about 10% w / w.

[0098] Embodiment 20, the pharmaceutical composition of any one of embodiments 1 to 18, wherein hydroxypropyl betadex is present at about 0.3% w / w to about 7% w / w.

[0099] Embodiment 21, the pharmaceutical composition of any one of embodiments 1 to 18, wherein hydroxypropyl betadex is at about 0.4% w / w to about 2 % w / w.[000100] Embodiment 22, the pharmaceutical composition of any one of embodiments 1 to 21, wherein methylparaben is present at about 0.001% w / w to about 1% w / w.[000101] Embodiment 23, the pharmaceutical composition of any one of embodiments 1 to 21, wherein methylparaben is present at about 0.01% w / w to about 0.1% w / w.[000102] Embodiment 24, the pharmaceutical composition of any one of embodiments 1 to 21, wherein methylparaben is present at about 0.01% w / w to about 0.03% w / w.[000103] Embodiment 25, the pharmaceutical composition of any one of embodiments 1 to 24, wherein xanthan gum is present at about 0.01% w / w to about 0.05% w / w.[000104] Embodiment 26, the pharmaceutical composition of any one of embodiments 1 to 24, wherein xanthan gum is present at about 0.01% w / w to about 0.1% w / w.[000105] Embodiment 27, the pharmaceutical composition of any one of embodiments 1 to 24, wherein xanthan gum is present at about 0.01% w / w to about 0.03% w / w.[000106] Embodiment 28, the pharmaceutical composition of any one of embodiments 1 to 27, wherein the composition retains at least 90% w / w of total potency of diclofenac or salt thereof after storage at 40°C and 75% relative humidity for at least one month.[000107] Embodiment 29, the pharmaceutical composition of any one of embodiments 1 to 27, wherein the composition retains at least 90% w / w of total potency of diclofenac or salt thereof after storage at 40°C and 75% relative humidity for at least six months.[000108] Embodiment 30, the aqueous pharmaceutical composition according to embodiment 1 comprising;(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.01% w / w to about 15% w / w,(b) glycerin present at about 2% w / w to about 20% w / w,(c) propylene glycol present at about 10% w / v to about 30% w / v,(d) sorbitol present at about 10% w / w to about 30% w / w,(e) sucralose present at about 0.01% w / w to about 5% w / w,(f) hydroxypropyl betadex present at about 0.3% w / w to about 7% w / w,(g) methylparaben present at about 0.001% w / w to about 1% w / w,(h) xanthan gum present at about 0.01% w / w to about 0.05% w / w,(i) water at a quantity sufficient to achieve 100% of the pharmaceutical composition when combined with the other components, and(j) optionally a buffering agent,wherein the pH of the pharmaceutical composition is about 6.0 to about 8.0.[000109] Embodiment 31, the pharmaceutical composition according to embodiment 1 comprising;(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.1% w / v to about 1.0% w / v,(b) glycerin present at about 5% w / w to about 15% w / w,(c) propylene glycol present at about 15% w / v to about 25% w / v,(d) sorbitol present at about 15% w / w to about 25% w / w,(e) sucralose present at about 0.1% w / w to about 1% w / w,(f) hydroxypropyl betadex present at about 0.1% w / w to about 10% w / w,(g) methylparaben present at about 0.01% w / w to about 0.1% w / w,(h) xanthan gum present at about 0.01% w / w to about 0.1% w / w,(i) water at a quantity sufficient to achieve 100% of the pharmaceutical composition when combined with the other components, and(j) optionally a buffering agent,wherein the pH of the pharmaceutical composition is about 6.0 to about 8.0.[000110] Embodiment 32, the pharmaceutical composition of embodiment 1 comprising;(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.2% w / v to about 0.6% w / v,(b) glycerin present at about 8% w / w to about 12% w / w,(c) propylene glycol present at about 18% w / v to about 22% w / v,(d) sorbitol present at about 18% w / w to about 22% w / w,(e) sucralose present at about 0.5% w / w to about 0.7% w / w,(f) hydroxypropyl betadex present at about 0.4% w / w to about 2 % w / w,(g) methylparaben present at about 0.01% w / w to about 0.03% w / w,(h) xanthan gum present at about 0.01% w / w to about 0.03% w / w,(i) water at a quantity sufficient to achieve 100% of the pharmaceutical composition when combined with the other components, and(j) optionally a buffering agent,wherein the pH of the pharmaceutical composition is about 6.0 to about 8.0..[0001111 Embodiment 33, the pharmaceutical composition of embodiment 1 comprising;(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.25% w / v, (b) glycerin present at about 10% w / w,(c) propylene glycol present at about 20% w / v,(d) sorbitol present at about 20% w / w,(e) sucralose present at about 0.6 % w / w(f) hydroxypropyl betadex present at about 1% w / w(g) methylparaben present at about 0.02% w / w ,(h) xanthan gum, present at about 0.025% w / w,(i) water at a quantity sufficient to achieve 100% of the pharmaceutical composition when combined with the other components, and(j) optionally a buffering agent,wherein the pH of the pharmaceutical composition is between 6.0 to 8.0.[000112] Embodiment 34, the pharmaceutical composition according to any of one embodiments 30 to 33, wherein the buffering agent is sodium citrate dihydrate and is present at about 0.1% w / w.[000113] Embodiment 35, the pharmaceutical composition according to embodiment 34, wherein the pharmaceutical composition is a clear one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least three months.[000114] Embodiment 36, the aqueous pharmaceutical composition of diclofenac, obtained by the method comprising;a. preparing a solution A, wherein the solution A is obtained by:i. combining appropriate amounts of diclofenac potassium salt, water, glycerin, and propylene glycol in a reaction vessel and stirring until complete dissolution to obtain the solution A comprising about 0.5% w / v diclofenac, about 50% w / w water, about 10% w / w glycerin, and about 40% w / v propylene glycol.b. preparing a solution B, wherein the solution B is obtained by:ii. combining appropriate amounts of water, sorbitol, and solid methylparaben in a second reaction vessel and warming to 50°C and mixing until complete dissolution to obtain the solution B comprising about 50% w / w water, about 50%, w / w sorbitol, and about 0.05% w / w methylparaben;iii. allowing solution B to cool to 20 - 35°C,c. preparing a solution C, wherein the solution C is obtained byiv. combining appropriate amounts of sucralose, sodium citrate dihydrate, and hydroxylpropyl betadex, with the solution B and continuing to mix until complete dissolution to obtain the solution C comprising about 48% w / w water, about 48%, w / w sorbitol, about 0.05% w / w methylparaben, about 1.5% w / w sucralose, about 0.24% w / w sodium citrate dihydrate, and about 2.4% w / w hydroxypropyl betadex.d. combining an appropriate amount of solution C into an appropriate amount of solution A and continuing to mix until complete dissolution to form a solution D comprising about 49% w / w water, about 5% w / w glycerin, and about 22% w / v propylene glycol, about 22%, w / w sorbitol, about 0.02% w / w methylparaben, about 0.6% w / w sucralose, about 0.1% w / w sodium citrate dihydrate, and about 1% w / w hydroxypropyl betadex.e. preparing a solution E, wherein the solution E is obtained by:v. combining appropriate amounts of glycerin and xanthan gum and mixing to obtain the solution E comprising about 0.5% w / w xanthan gum and about 99.5% w / w glycerin,f. combining an appropriate amount of the solution E with an appropriate amount of the solution D and mixing the mixture of solution E and solution D until a clear solution is obtained,g. optionally combining a flavoring agent, andh. combining an appropriate amount of additional water in a quantity sufficient to obtain the pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citratedihydrate, about 0.6 % w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum, and about 0.1% w / w sodium citrate.[000115] Embodiment 37, the pharmaceutical composition according to embodiment 36, wherein the pharmaceutical composition is a clear one-phase aqueous solution.[000116] Embodiment 38, the pharmaceutical composition according to embodiment 37, wherein the pharmaceutical composition is a clear one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least one month.[000117] Embodiment 39, the pharmaceutical composition according to embodiment 36, wherein the pharmaceutical composition is a clear one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least one month.[000118] Embodiment 40, a method of treating acute pain and / or migraine in a subject in need of such treatment, the method comprising administering an effective amount of the pharmaceutical composition according to embodiments 1-39.[000119] Embodiment 41, an aqueous pharmaceutical composition of diclofenac, obtained by the method comprising;a. preparing a solution A, wherein the solution A is obtained by:vi. combining appropriate amounts of diclofenac potassium salt and propylene glycol in a reaction vessel and stirring until complete dissolution to obtain the solution A comprising about 0.5% w / v diclofenac, about 50% w / w water, about 10% w / w glycerin, and about 40% w / v propylene glycol.b. preparing a solution B , wherein the solution B is obtained by:vii. combining appropriate amounts of water, sorbitol, glycerin, and solid methylparaben in a second reaction vessel and warming to 60°C and mixing until complete dissolution to obtain the solution B comprising about 50% w / w water, about 50%, w / w sorbitol, and about 0.05% w / w methylparaben;viii. allowing solution B to cool to 20 - 35°C,c. preparing a solution C, wherein the solution C is obtained byix. combining appropriate amounts of sucralose, sodium citrate dihydrate, and hydroxylpropyl betadex, with the solution B and continuing to mix until complete dissolution to obtain the solution C comprising about 48% w / w water, about 48%, w / w sorbitol, about 0.05% w / w methylparaben, about 1.5% w / w sucralose, about 0.24% w / w sodium citrate dihydrate, and about 2.4% w / w hydroxypropyl betadex.d. combining an appropriate amount solution C into an appropriate amount solution A and continuing to mix until complete dissolution to form a solution D comprising about 49% w / w water, about 5% w / w glycerin, and about 22% w / v propylene glycol, about 22%, w / w sorbitol, about 0.02% w / w methylparaben, about 0.6% w / w sucralose, about 0.1% w / w sodium citrate dihydrate, and about 1% w / w hydroxypropyl betadex.e. preparing a solution E, wherein the solution E is obtained by:x. combining appropriate amounts of glycerin and xanthan gum and mixing to obtain the solution E comprising about 0.5% w / w xanthan gum and about 99.5% w / w glycerin,f. prepare a solution F, wherein an appropriate amount of the solution E is combined with an appropriate amount of the solution D and continue to mix until a clear solution,g. optionally combining a flavoring agent with the solution F, andh. combining an appropriate amount of additional water in a quantity sufficient to obtain the aqueous pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6 % w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum, and about 0.1% w / w sodium citrate.[000120] Embodiment 42, a method of making an aqueous pharmaceutical composition of diclofenac, the method comprising:a. preparing a solution A, wherein the solution A is obtained by:xi. combining appropriate amounts of diclofenac potassium salt, water, glycerin, and propylene glycol in a reaction vessel and stirring until complete dissolution to obtain the solution A comprising about 0.1% w / v to about 1% w / v diclofenac, about 40% w / w to about 60% w / w water, about 5%> w / w to about 15% w / w glycerin, and about 30% w / w to about 50% w / v propylene glycol.b. preparing a solution B, wherein the solution B is obtained by:xii. combining appropriate amounts of water, sorbitol, and methylparaben in a second reaction vessel and warming to about 60°C and mixing until complete dissolution to obtain the solution B comprising about 40% w / w to about 60% w / w water, about 40% w / w to about 60% w / w sorbitol, and about 0.01% w / w to about 0.1% w / w methylparaben;xiii. allowing solution B to cool to about 20 - 35°C,c. preparing a solution C, wherein the solution C is obtained byxiv. combining appropriate amounts of sucralose, sodium citrate dihydrate, and hydroxylpropyl betadex, with the solution B and continuing to mix until complete dissolution to obtain the solution C comprising about 40% w / w to about 60% w / w water, about 40% w / w to about 60% w / w sorbitol, about 0.01% w / w to about 0.1% w / w methylparaben, about 0.5% w / w to about 5.0 % w / w sucralose, about 0.1 % w / w to about 0.5% w / w sodium citrate dihydrate, and about 1.0 % w / w to about 5.0% w / w hydroxypropyl betadex.d. combining an appropriate amount of solution C into an appropriate amount of solution A and continuing to mix until complete dissolution to form a solution D comprising about 0.1% w / v to about 1% w / v diclofenac, about 40% w / w to about 60% water, about 1% w / w to about 10% glycerin, and about 15% w / w to about 30% w / v propylene glycol, about 15% w / w to about 30% w / w sorbitol, about 0.01% w / w to about 0.1% w / w methylparaben, about 0.3% w / w to about 3.0 % w / w sucralose, about 0.1% w / w sodium citrate dihydrate, and about 0.5% w / w to about l.% w / w hydroxypropyl betadex.e. preparing a solution E, wherein the solution E is obtained by:xv. combining appropriate amounts of glycerin and xanthan gum and mixing to obtain the solution E comprising about 0.1% w / w to about 1.0% w / w xanthan gum and about 99% w / w to about 99.9% / w glycerin,f. combining an appropriate amount of the solution E with an appropriate amount of the solution D and mixing the mixture of solution E and solution D until a clear solution is obtained,g. optionally combining a flavoring agent with the solution F, andh. combining an appropriate amount of additional water in a quantity sufficient to obtain the pharmaceutical composition comprising about 0.1% w / v to about 1.0% w / v diclofenac potassium salt, about 40% w / w to about 60% water, about 5% w / w to about 15% w / w glycerin, about 10% w / w to about 30% w / v propylene glycol, about 10% w / w to about 30% w / w sorbitol, about 0.05% w / w to about 0.15% w / w sodium citrate dihydrate, about 0.1 % w / w to about 1.0% w / w sucralose, about 0.5% w / w to about 1.5% w / w hydroxypropyl betadex, about 0.005% w / w to about 0.1% w / w methylparaben, about 0.01% w / w to about 0.05% w / w xanthan gum, and about 0.05% w / w to about 0.5% w / w sodium citrate.[000121] Embodiment 43, the method according embodiment 42, wherein the method comprises:a. preparing a solution A, wherein the solution A is obtained by:xvi. combining appropriate amounts of diclofenac potassium salt, water, glycerin, and propylene glycol in a reaction vessel and stirring until complete dissolution to obtain the solution A comprising about 0.5% w / v diclofenac, about 50% w / w water, about 10% w / w glycerin, and about 40% w / v propylene glycol.b. preparing a solution B, wherein the solution B is obtained by:xvii. combining appropriate amounts of water, sorbitol, and methylparaben in a second reaction vessel and warming to 60°C and mixing until complete dissolution to obtain the solution B comprising about 50% w / w water, about 50%, w / w sorbitol, and about 0.05% w / w methylparaben; xviii. allowing solution B to cool to 20 - 35°C,c. preparing a solution C, wherein the solution C is obtained byi. combining appropriate amounts of sucralose, sodium citrate dihydrate, and hydroxylpropyl betadex, with the solution B and continuing to mix until complete dissolution to obtain the solution C comprising about 48% w / w water, about 48%, w / w sorbitol, about 0.05% w / w methylparaben, about 1.5% w / w sucralose, about 0.24% w / w sodium citrate dihydrate, and about 2.4% w / w hydroxypropyl betadex.d. combining an appropriate amount of solution C into an appropriate amount of solution A and continuing to mix until complete dissolution to form a solution D comprising about 49% w / w water, about 5% w / w glycerin, and about 22% w / v propylene glycol, about 22%, w / w sorbitol, about 0.02% w / w methylparaben, about 0.6% w / w sucralose, about 0.1% w / w sodium citrate dihydrate, and about 1% w / w hydroxypropyl betadex.e. preparing a solution E, wherein the solution E is obtained by:i. combining appropriate amounts of glycerin and xanthan gum and mixing to obtain the solution E comprising about 0.5% w / w xanthan gum and about 99.5% w / w glycerin,f. combining an appropriate amount of the solution E with an appropriate amount of the solution D and mixing the mixture of solution E and solution D until a clear solution is obtained,g. optionally combining a flavoring agent with the solution F, andh. combining an appropriate amount of additional water in a quantity sufficient to obtain the pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6 % w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum, and about 0.1% w / w sodium citrate.[000122] Embodiment 44, a method of making an aqueous pharmaceutical composition of diclofenac, the method comprising:a. adding water at about 40% w / w to about 60% w / w water to a main manufacturing vessel and warming to 45 ± 5°C,i. while mixing the water in the main manufacturing vessel, add glycerin at about 1.0% w / w to about 10.0% w / w and sorbitol solution at about 10% w / w to about 30% w / w and mix until a clear solution followed by addition of methylparaben at about 0.01% w / w to about 0.03% w / w to the main manufacturing vessel and stirring the mixture at 50 ± 10°C until complete dissolution,ii. cooling the main manufacturing vessel to 25 ± 5°C,iii. adding sequentially hydroxypropyl betadex at about 0.5% w / w to about 1.5% w / w and sucralose at about 0.2 % w / w to about 1.0% sucralose to the main manufacturing vessel;b. adding propylene glycol at about 10% w / v to about 20% w / v to a first side manufacturing vessel and while mixing, adding diclofenac potassium at about 0.1% w / v to about 1.0% w / v;c. combining the mixture from the first side manufacturing vessel to the main manufacturing vessel and performing a two stage rinse of the first side manufacturing vessel with propylene glycol at about 1.0% w / v to about 3.0% w / w and water at about 1.0% w / w to about 3.0% w / w with addition of each rinse to the main manufacturing vessel;d. adding glycerin at about 1% to about 5%w / w to a second side manufacturing vessel, while mixing adding xanthan gum at about 0.01% to about 0.05% w / w and continuing mixing until complete dissolution;e. combining the mixture from the second side manufacturing vessel to the main manufacturing vessel and performing a rinse from the first side manufacturing vessel with water at about 1.0% w / w to about 3.0% w / w with addition of rinse to the main manufacturing vessel;f. adding berry flavor at about 0.1% w / w to about 0.5% w / w / to the main manufacturing vessel with mixing and adding water an amount sufficient to obtain the pharmaceutical composition comprising about 0.1% w / v to about 1.0% w / v diclofenac potassium salt, about 40% w / w to about 60% w / w water, 5% w / wto about 15% w / w glycerin, about 10% w / v to about 30% w / v propylene glycol, about 10% w / w to about 30% w / w sorbitol, about 0.05% w / w to about 0.5% w / w sodium citrate dihydrate, about 0.2 % w / w to about 1.0% sucralose, about 0.5% w / w to about 1.5% w / w hydroxypropyl betadex, about 0.005% to about 0.05% w / w methylparaben, about 0.01% to about 0.05% w / w xanthan gum; wherein % w / w and %w / v in the intermediate steps are provided based on the % w / w and %w / v of the final composition of the pharmaceutical composition.[000123] Embodiment 45, a method according to embodiment 44, wherein the method comprises:a. adding water at about 47% w / w to a main manufacturing vessel and warming to 45 ± 5°C,i. while mixing the water in the main manufacturing vessel, add glycerin at about 4.7% w / w and sorbitol solution at about 20% w / w and mix until a clear solution followed by addition of methylparaben at about 0.02% w / w to the main manufacturing vessel and stirring the mixture at 50 ± 10°C until complete dissolution,ii. cooling the main manufacturing vessel to 25 ± 5°C,iii. adding sequentially hydroxypropyl betadex at about 1% w / w and sucralose at about 0.6% w / w to the main manufacturing vessel;b. adding propylene glycol at about 14.5% w / v to a first side manufacturing vessel and while mixing, adding diclofenac potassium at about 0.25% w / v;c. combining the mixture from the first side manufacturing vessel to the main manufacturing vessel and performing a two stage rinse of the first side manufacturing vessel with propylene glycol at about 1.8% w / v and water at about 3.6% w / w with addition of each rinse to the main manufacturing vessel;d. adding glycerin at about 5% w / w to a second side manufacturing vessel, while mixing adding xanthan gum at about 0.025% w / w and continuing mixing until complete dissolution;e. combining the mixture from the second side manufacturing vessel to the main manufacturing vessel and performing a rinse from the first side manufacturing vessel with water at about 1.8% w / w with addition of rinse to the main manufacturing vessel;f. adding berry flavor at about 0.3% w / w to the main manufacturing vessel with mixing and adding water an amount sufficient to obtain the pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6 % w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum; wherein % w / w in the intermediate steps are provided based on the % w / w of the final composition of the pharmaceutical composition.[000124] Embodiment 46, the pharmaceutical composition of any one of embodiments 1 to 39, wherein the pharmaceutical composition comprises not more than 0.030 %w / w of related compound A after storage at 25°C and 60% relative humidity after one month.[000125] Embodiment 47, the pharmaceutical composition of any one of embodiments 1 to 39, wherein the pharmaceutical composition comprises not more than 0.095 %w / w of related compound A after storage at 25°C and 60% relative humidity after six months.[000126] Embodiment 48, the pharmaceutical composition of any one of embodiments 1 to 39, wherein the pharmaceutical composition comprises not more than 0.250 %w / w of related compound A after storage at 25°C and 60% relative humidity after eighteen months.[000127] Embodiment 49, the pharmaceutical composition of any one of embodiments 1 to 39, wherein the pharmaceutical composition comprises not more than 0.695 %w / w of related compound A after storage at 40°C and 75% relative humidity after six months.[000128] Embodiment 50, the pharmaceutical composition of any one of embodiments 1 to 39, wherein the pharmaceutical composition comprises not more than 0.075 %w / w of total impurities after storage at 25°C and 60% relative humidity after one month.[000129] Embodiment 51, the pharmaceutical composition of any one of embodiments 1 to 39, wherein the pharmaceutical composition comprises not more than 0.245 %w / w of total impurities after storage at 25°C and 60% relative humidity after six months.[000130] Embodiment 52, the pharmaceutical composition of any one of embodiments 1 to 39, wherein the pharmaceutical composition comprises not more than 0.455 %w / w of total impurities after storage at 25°C and 60% relative humidity after eighteen months.[000131] Embodiment 53, the pharmaceutical composition of any one of embodiments 1 to 39, wherein the pharmaceutical composition comprises not more than 1.19 %w / w of total impurities after storage at 40°C and 75% relative humidity after six months.F. EXAMPLES[000132] The following examples are put forth so as to provide those of ordinary skill in the art are exemplary of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are \not intended to limit the scope of what the inventors regard as their invention.[000133] Table 1 provides a list of the ingredients that can be used in the exemplary pharmaceutical compositions along with the functionality of the ingredients.Table 1.Example 1[000134] To a first reaction vessel was added sorbitol solution (50.0 g) and HEC (hydroxyethyl cellulose) (1.0 g) and mixed until smooth (no lumps observed) followed by addition of xanthan gum (0.25 g) and the combined solution was mixed until smooth (no lumps observed). To a second reaction vessel was added water (400 g), glycerin (200 g) and propylene glycol (150 g) followed by addition of diclofenac potassium (2.51 g) and the solution was mixed until a clear solution was observed. To the second reaction vessel was then added sequentially with mixing potassium sorbate (2.0g), sucralose (6.0 g), hydroxylpropyl betadex (2.5 g), and sorbitol solution (50 g) and a clear solution was observed after each addition. The solution of the first reaction vessel was added to the second reaction vessel with mixing and clear solution was observed with a few particles (very small lumps) floating in the mixture. Berry Flavor (1.5 g) was added to second reaction vessel with mixing and clear solution observed.Example 2[000135] To a first reaction vessel was added glycerin (25.0 g) and HEC (hydroxy ethyl cellulose) (0.50 g) and mixed until smooth (no lumps observed) To the reaction vessel was added xanthan gum (0.25 g) and the combined solution was mixed until smooth (no lumps observed). To a second reaction vessel was added water (180 g), glycerin (75 g) and propylene glycol (100 g) followed by addition of diclofenac potassium (1.25 g) and the solution was mixed until a clear solution was observed. To the second reaction vessel was then added sequentially with mixing potassium sorbate (1.0g), sucralose (3.0 g), hydroxylpropyl betadex (1.25 g), and sorbitol solution (100.0 g) ) and a clear solution was observed after each addition with the solution less clear after addition of the hydroxylpropyl betadex. The contents of the first reaction vessel was added to the second reaction vessel. The first reaction vessel was rinsed with water (11.38 g) and added to the second reaction vessel with mixing and clear solution was observed. Berry Flavor (1.5 g) was added to second reaction vessel with mixing and clear solution observed. Example 3[000136] To a first reaction vessel was added glycerin (25.0 g) and xanthan gum (0.25 g) and mixed until smooth (no lumps observed). To a second reaction vessel (main pot) was added water (200 g) and glycerin (75 g). Separately, diclofenac potassium (1.25 g) was dissolved in propylene glycol (100 g) followed by addition to the water and glycerine mixture and the solution was mixed until a clear solution was observed and few particles observed. To the second reaction vessel was then added sequentially with mixing potassium sorbate (1.0g) and sucralose (1.5 g). Hydroxylpropyl betadex (1.25 g) was predissolved in water (16.63 g) and added to the second reaction vessel and the solution was mixed until a clear solution was obtained. Sorbitol solution (100.0 g) was added to second reaction vessel and the solution was mixed until a clear solution was obtained. The contents of the first reaction vessel was added to the second reaction vessel. The first reaction vessel was rinsed with water (11.38 g) and added to the second reaction vessel with mixing and clear solution was observed. Grape flavor (1.5 g) was added to second reaction vessel with mixing and clear solution observed.Example 4[000137] To a first reaction vessel was added sorbitol solution (50.0 g) and HEC (hydroxyethyl cellulose) (1.0 g) and mixed until smooth (no lumps observed) followed by addition of xanthan gum (0.25 g) and the combined solution was mixed until smooth (no lumps observed). To a second reaction vessel was added water (200 g), glycerin (75 g). Separately, diclofenac potassium (1.25 g) was dissolved in propylene glycol (100 g) followed by addition to the water and glycerine mixture and the solution was mixed until a clear solution was observed and few particles observed. To the second reaction vessel was then added sequentially with mixing potassium sorbate (1.0g), sucralose (3.0 g), and a clear solution was observed after each addition. The contents of the first reaction vessel was added to the second reaction vessel. The first reaction vessel was rinsed with water (92.62 g) and added to the second reaction vessel with mixing and clear solution was observed with few particles observed. Berry flavor (1.5 g) was added to second reaction vessel with mixing and clear solution observed.Example 5[000138] To a first reaction vessel was added glycerin (25.0 g) and xanthan gum (0.25 g) and mixed until smooth (no lumps observed). To a second reaction vessel was added water (150 g) and glycerin (25 g) and to this solution was added diclofenac potassium (1.25 g) pre-dissolved inpropylene glycol (100 g) and the solution was mixed until a clear solution was observed and few particles observed. To a third reaction vessel was added water (50 g) and then added sequentially with mixing was potassium sorbate (1.0 g), sucralose (3.0 g), hydroxylpropyl betadex (1.25 g). The solution from the third reaction vessel was added to the first reaction vessel and stirred. To the first reaction vessel was added sorbitol solution (100.0 g) and a clear solution was observed. The solution of the first reaction vessel was added to the second reaction vessel and solution was stirred. The first reaction vessel was rinsed with water (92.62 g) and added to the second reaction vessel with mixing and clear solution was observed with few particles observed. Berry flavor (1.5 g) was added to second reaction vessel with mixing and clear solution observed.Example 6[000139] To a first reaction vessel was added glycerin (25.0 g) and hydroxyl ethyl cellulose (0.50 g) and mixed until smooth (no lumps observed). To a second reaction vessel (main pot) was added water (124.9 g) and glycerin (25 g). Separately, diclofenac potassium (1.25 g) was dissolved in propylene glycol (75 g) followed by addition to the water and glycerin mixture, an additional amount of propylene glycol (25 g) was utilized as a rinse, and the solution was mixed until a clear solution and few particles observed. To a third reaction vessel (third pot) was added water (50 g) and then sequentially was added with mixing potassium sorbate (1.0g) predissolved in water (16.63 g), sucralose (5.0 g), hydroxylpropyl betadex (1.25 g), and sorbitol solution (100.0 g) and a clear solution was observed after each addition. The contents of the third pot was added to the second reaction vessel with mixing. The contents of the first reaction vessel was added to the second reaction vessel. The first reaction vessel was rinsed with water (92.62 g) and added to the second reaction vessel with mixing and clear solution was observed with few particles observed. Berry flavor (1.5 g) was added to second reaction vessel with mixing and clear solution observed.Example 7[000140] To a first reaction vessel (main pot) was added water (2.502 kg) and glycerin (0.500 kg). Separately, in a second reaction vessel, diclofenac potassium (25 g) was dissolved in propylene glycol (1.502 kg) that was then followed by addition of the second reaction vessel to the water and glycerin containing first reaction vessel, an additional amount of propylene glycol(0.500 kg) was utilized as a rinse, and the solution was mixed until a clear solution and few particles observed. To a third reaction vessel warmed to 60°C was added water (2.004 kg) and then was added with mixing sorbitol (2.001 kg) and methylparaben (2.0 g). The third reaction vessel was allowed to cool to 25°C and then sucralose (60.0 g) and hydroxylpropyl betadex (100 g) were added with stirring. The contents of the third pot was added to the first reaction vessel with mixing. To a fourth reaction vessel was added glycerin (0.500 kg) and xanthan gum (2.5 g) and mixed until smooth (no lumps observed). The contents of the fourth reaction vessel was added to the first reaction vessel. Berry flavor (30 g) was added to first reaction vessel with mixing and clear solution observed.Example 8[000141] To a first reaction vessel (main pot) was added water (2.502 kg) and glycerin (0.500 kg). Separately, in a second reaction vessel, diclofenac potassium (25 g) was dissolved in propylene glycol (1.502 kg) that was then followed by addition of the second reaction vessel to the water and glycerin containing first reaction vessel, an additional amount of propylene glycol (0.500 kg) was utilized as a rinse, and the solution was mixed until a clear solution and few particles observed. To a third reaction vessel warmed to 60°C was added water (2.004 kg) and then was added with mixing sorbitol (2.001 kg) and methylparaben (2.0 g). The third reaction vessel was allowed to cool to 25°C and then sucralose (60.0 g), sodium citrate dihydrate (10.0 g), and hydroxylpropyl betadex (100 g) were added with stirring. The contents of the third pot was added to the first reaction vessel with mixing. To a fourth reaction vessel was added glycerin (0.500 kg) and xanthan gum (2.5 g) and mixed until smooth (no lumps observed). The contents of the fourth reaction vessel was added to the first reaction vessel. Berry flavor (30 g) was added to first reaction vessel with mixing and clear solution observed.Example 9[000142] To a first reaction vessel is added water (130 kg) and the vessel is warmed to 45 ± 5°C. Glycerin (13.0 kg) is added to the first reaction vessel and mixed at 45 ± 5°C. Sorbitol (55 kg) is added to the first reaction vessel and mixed at 45 ± 5°C. Methylparaben (0.55 kg) is added to first reaction vessel and mixed at 45 ± 5°C until a clear solution was obtained. The mixture is stirred until complete dissolution and a clear solution is obtained. The first reaction vessel is cooled to 25 ± 5°C. Sucralose (1.65 kg) is added to first reaction vessel and mixed untilcomplete dissolution. Hydroxypropyl betadex (2.75 kg) is added to first reaction vessel and mixed until complete dissolution. To a second reaction vessel is added propylene glycol (40 kg) and diclofenac potassium (0.625 kg) is stirred until complete dissolution. The solution from the second reaction vessel is added to the first reaction vessel and the second reaction vessel is rinsed with propylene glycol (10.0 kg) and water (5.0 kg) and added to the first reaction vessel and mixed until a clear solution was obtained. To a third reaction vessel is added glycerin (13.75 kg) followed by xanthan gum (68.75 g) and mixed until no lumps are observed. The xanthan gum solution from the third reaction vessel is added to the first reaction vessel and mixed at 25 ± 5°C until complete dissolution. Berry flavor (0.825 g) is added to the main manufacturing vessel and mixed at 25 ± 5°C until complete dissolution. Water is added to quantity sufficient to obtain a 25 mg / 10 ml diclofenac potassium oral solution.Example 10 Demonstration of Stability[000143] Two batches of the composition (Table 2) were evaluated for stability under storage conditions of 25°C / 60% RH and 40°C / 75% RH. The compositions were tested for diclofenac stability and for impurities at regular intervals (e.g., after one month, three months, six months, nine months, twelve months, and eighteen months). Impurities include known diclofenac degradation products, such as related compound A (RC-A)(N-(2,6-dichlorophenyl)-2-indolinone, l-(2,6-dichlorophenyl)-l,3-dihydro-2h-indol-2-one). After Tables 3-6 show the stability of Comparative Example 1 and 2Table 2.* denotes amounts of diclofenac potassium and propylene glycol are provided as % w / v[000144] The diclofenac stability of the pharmaceutical compositions under normal storage conditions (25°C / 60% RH) was evaluated over a period of one month, three months, six months, nine months, twelve months, and eighteen months (Table 3).Table 3.Example 725°C / 60% RH9 months 12 months 18 monthsw / w% w / w% w / w%Assay 1 99.9 94.3 100.6Assay 2 100.7 99.6 100.8Average 100.3 97 100.7[000145] The diclofenac stability of the pharmaceutical compositions under accelerated storage conditions (40°C / 75 % RH) was evaluated over a period of one month, three months and six months (Table 4).Table 4.[000146] The stability of the pharmaceutical compositions under accelerated storage conditions (25°C / 60% RH) was evaluated over a period of one month and three months with respect to RC- A and total impurities (Table 5).Table 5.Example 725°C / 60% RH9 months 12 months 18monthsRC-A 0.138 0.177 0.249TotalImpurities 0.263 0.336 0.451[000147] The stability of the pharmaceutical compositions under accelerated storage conditions (40°C / 75% RH) was evaluated over a period of one month and three months with respect to RC- A and total impurities (Table 6).Table 6.[000148] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

Attorney Docket No.38400.0001P1CLAIMSWhat is claimed is:

1. An aqueous pharmaceutical composition comprising(a) diclofenac, or a pharmaceutically acceptable salt thereof,(b) glycerin,(c) propylene glycol,(d) sorbitol,(e) sucralose,(f) hydroxypropyl betadex,(g) a viscosity increasing agent, and(h) water, andwherein the composition optionally further comprises one or more of a stabilizing agent, buffering agent, and a flavoring agent.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a clear one phase aqueous solution.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a clear one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least one month.

4. The pharmaceutical composition according to claim 1, wherein the diclofenac, or pharmaceutically acceptable salt is present at about 0.01% w / v to about 15% w / v,5. The pharmaceutical composition according to claim 4, wherein the diclofenac, or pharmaceutically acceptable salt is present at about 0.1% w / v to about 1.0% w / v.

6. The pharmaceutical composition according to claim 4, wherein the diclofenac, or pharmaceutically acceptable salt is present at about 0.2% w / v to about 0.6% w / v.

7. The pharmaceutical composition according to and one of claims Ithrough 6, wherein glycerin is present at about 2% w / w to about 20% w / w.

8. The pharmaceutical composition according to claim 7, wherein glycerin is present at about 5% w / w to about 15% w / w.

9. The pharmaceutical composition according to claim 8, wherein glycerin is present at about 8% w / w to about 12% w / w.

10. The pharmaceutical composition according to claim 1, wherein propylene glycol is present at about 10% w / v to about 30% w / v.

11. The pharmaceutical composition according to claim 10, wherein propylene glycol is present at about 15% w / v to about 25% w / v.

12. The pharmaceutical composition according to claim 11, wherein propylene glycol is present at about 18% w / v to about 22% w / v.

13. The pharmaceutical composition according to claim 1, wherein sorbitol is present at about 10% w / w to about 30% w / w.

14. The pharmaceutical composition according to claim 13, wherein sorbitol is present at about 15% w / w to about 25% w / w.

15. The pharmaceutical composition according to claim 14, wherein sorbitol is present at about 18% w / w to about 22% w / w.

16. The pharmaceutical composition according to claim 1, wherein sucralose is present at about 0.01% w / w to about 5% w / w.

17. The pharmaceutical composition according to claim 16, wherein sucralose is present at about 0.1% w / w to about 1% w / w.

18. The pharmaceutical composition according to claim 17, wherein sucralose is at about 0.5% w / w to about 0.7% w / w.

19. The pharmaceutical composition according to claim 1, wherein hydroxypropyl betadex is present at about 0.1% w / w to about 10% w / w.

20. The pharmaceutical composition according to claim 19, wherein hydroxypropyl betadex is present at about 0.3% w / w to about 7% w / w.

21. The pharmaceutical composition according to claim 20, wherein hydroxypropyl betadex is at about 0.4% w / w to about 2 % w / w.

22. The pharmaceutical composition according to claim 1, wherein methylparaben is present at about 0.001% w / w to about 1% w / w.

23. The pharmaceutical composition according to claim 19, wherein methylparaben is present at about 0.01% w / w to about 0.1% w / w.

24. The pharmaceutical composition according to claim 23, wherein methylparaben is present at about 0.01% w / w to about 0.03% w / w.

25. The pharmaceutical composition according to claim 1, wherein xanthan gum is present at about 0.01% w / w to about 0.05% w / w.

26. The pharmaceutical composition according to claim 25, wherein xanthan gum is present at about 0.01% w / w to about 0.1% w / w.

27. The pharmaceutical composition according to claim 26, wherein xanthan gum is present at about 0.01% w / w to about 0.03% w / w.

28. The pharmaceutical composition according to claim 1, wherein the composition retains at least 90% w / w of total potency of diclofenac or salt thereof after storage at 40°C and 75% relative humidity for at least one month.

29. The pharmaceutical composition according to claim 1, wherein the composition retains at least 90% w / w of total potency of diclofenac or salt thereof after storage at 40°C and 75% relative humidity for at least six months.

30. The aqueous pharmaceutical composition according to claim 1 comprising;(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.01% w / w to about 15% w / w,(b) glycerin present at about 2% w / w to about 20% w / w,(c) propylene glycol present at about 10% w / v to about 30% w / v,(d) sorbitol present at about 10% w / w to about 30% w / w,(e) sucralose present at about 0.01% w / w to about 5% w / w,(f) hydroxypropyl betadex present at about 0.3% w / w to about 7% w / w,(g) methylparaben present at about 0.001% w / w to about 1% w / w,(h) xanthan gum present at about 0.01% w / w to about 0.05% w / w,(i) water at a quantity sufficient to achieve 100% of the pharmaceutical composition when combined with the other components, and(j) optionally a buffering agent,wherein the pH of the pharmaceutical composition is about 6.0 to about 8.0.

31. The pharmaceutical composition according to claim 1 comprising;(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.1% w / v to about 1.0% w / v,(b) glycerin present at about 5% w / w to about 15% w / w,(c) propylene glycol present at about 15% w / v to about 25% w / v,(d) sorbitol present at about 15% w / w to about 25% w / w,(e) sucralose present at about 0.1% w / w to about 1% w / w,(f) hydroxypropyl betadex present at about 0.1% w / w to about 10% w / w,(g) methylparaben present at about 0.01% w / w to about 0.1% w / w,(h) xanthan gum present at about 0.01% w / w to about 0.1% w / w,(i) water at a quantity sufficient to achieve 100% of the pharmaceutical composition when combined with the other components, and(j) optionally a buffering agent,wherein the pH of the pharmaceutical composition is about 6.0 to about 8.0.

32. The pharmaceutical composition of claim 1 comprising;(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.2% w / v to about 0.6% w / v,(b) glycerin present at about 8% w / w to about 12% w / w,(c) propylene glycol present at about 18% w / v to about 22% w / v,(d) sorbitol present at about 18% w / w to about 22% w / w,(e) sucralose present at about 0.5% w / w to about 0.7% w / w,(f) hydroxypropyl betadex present at about 0.4% w / w to about 2 % w / w,(g) methylparaben present at about 0.01% w / w to about 0.03% w / w,(h) xanthan gum present at about 0.01% w / w to about 0.03% w / w,(i) water at a quantity sufficient to achieve 100% of the pharmaceutical composition when combined with the other components, and(j) optionally a buffering agent,wherein the pH of the pharmaceutical composition is about 6.0 to about 8.0..

33. The pharmaceutical composition of claim 1 comprising;(a) diclofenac, or a pharmaceutically acceptable salt thereof, present at about 0.25% w / v, (b) glycerin present at about 10% w / w,(c) propylene glycol present at about 20% w / v,(d) sorbitol present at about 20% w / w,(e) sucralose present at about 0.6 % w / w(f) hydroxypropyl betadex present at about 1% w / w(g) methylparaben present at about 0.02% w / w ,(h) xanthan gum, present at about 0.025% w / w,(i) water at a quantity sufficient to achieve 100% of the pharmaceutical composition when combined with the other components, and(j) optionally a buffering agent,wherein the pH of the pharmaceutical composition is between 6.0 to 8.0.

34. The pharmaceutical composition according to any of one claims 30 to 33, wherein the buffering agent is sodium citrate dihydrate and is present at about 0.1% w / w.

35. The pharmaceutical composition according to any of one claims 30 to 33, wherein the pharmaceutical composition is a clear one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least three months.

36. An aqueous pharmaceutical composition of diclofenac, obtained by the method comprising;a. preparing a solution A, wherein the solution A is obtained by:i. combining appropriate amounts of diclofenac potassium salt, water, glycerin, and propylene glycol in a reaction vessel and stirring until complete dissolution to obtain the solution A comprising about 0.5% w / v diclofenac, about 50% w / w water, about 10% w / w glycerin, and about 40% w / v propylene glycol.b. preparing a solution B, wherein the solution B is obtained by:ii. combining appropriate amounts of water, sorbitol, and solid methylparaben in a second reaction vessel and warming to 50°C and mixing until complete dissolution to obtain the solution B comprising about 50% w / w water, about 50%, w / w sorbitol, and about 0.05% w / w methylparaben;iii. allowing solution B to cool to 20 - 35°C,c. preparing a solution C, wherein the solution C is obtained byiv. combining appropriate amounts of sucralose, sodium citrate dihydrate, and hydroxylpropyl betadex, with the solution B and continuing to mix until complete dissolution to obtain the solution C comprising about 48% w / wwater, about 48%, w / w sorbitol, about 0.05% w / w methylparaben, about 1.5% w / w sucralose, about 0.24% w / w sodium citrate dihydrate, and about 2.4% w / w hydroxypropyl betadex.d. combining an appropriate amount of solution C into an appropriate amount of solution A and continuing to mix until complete dissolution to form a solution D comprising about 49% w / w water, about 5% w / w glycerin, and about 22% w / v propylene glycol, about 22%, w / w sorbitol, about 0.02% w / w methylparaben, about 0.6% w / w sucralose, about 0.1% w / w sodium citrate dihydrate, and about 1% w / w hydroxypropyl betadex.e. preparing a solution E, wherein the solution E is obtained by:v. combining appropriate amounts of glycerin and xanthan gum and mixing to obtain the solution E comprising about 0.5% w / w xanthan gum and about 99.5% w / w glycerin,f. combining an appropriate amount of the solution E with an appropriate amount of the solution D and mixing the mixture of solution E and solution D until a clear solution is obtained,g. optionally combining a flavoring agent, andh. combining an appropriate amount of additional water in a quantity sufficient to obtain the pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6 % w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum, and about 0.1% w / w sodium citrate.

37. The pharmaceutical composition according to claim 36, wherein the pharmaceutical composition is a clear one-phase aqueous solution.

38. The pharmaceutical composition according to claim 37, wherein the pharmaceutical composition is a clear one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least one month.

39. The pharmaceutical composition according to claim 36, wherein the pharmaceutical composition is a clear one-phase aqueous solution after storage at 40°C and 75% relative humidity for at least one month.

40. A method of treating acute pain and / or migraine in a subject in need of such treatment, the method comprising administering an effective amount of the pharmaceutical composition according to claim any one of claims 1-39.

41. The method of claim 40, wherein the migraine is accompanied by one or more of rebound headache, photophobia, phonophobia, nausea and vomiting.

42. An aqueous pharmaceutical composition of diclofenac, obtained by the method comprising;a. preparing a solution A, wherein the solution A is obtained by:i. combining appropriate amounts of diclofenac potassium salt and propylene glycol in a reaction vessel and stirring until complete dissolution to obtain the solution A comprising about 0.5% w / v diclofenac, about 50% w / w water, about 10% w / w glycerin, and about 40% w / v propylene glycol.b. preparing a solution B , wherein the solution B is obtained by:ii. combining appropriate amounts of water, sorbitol, glycerin, and solid methylparaben in a second reaction vessel and warming to 60°C and mixing until complete dissolution to obtain the solution B comprising about 50% w / w water, about 50%, w / w sorbitol, and about 0.05% w / w methylparaben;iii. allowing solution B to cool to 20 - 35°C,c. preparing a solution C, wherein the solution C is obtained byiv. combining appropriate amounts of sucralose, sodium citrate dihydrate, and hydroxylpropyl betadex, with the solution B and continuing to mix until complete dissolution to obtain the solution C comprising about 48% w / w water, about 48%, w / w sorbitol, about 0.05% w / w methylparaben, about 1.5% w / w sucralose, about 0.24% w / w sodium citrate dihydrate, and about 2.4% w / w hydroxypropyl betadex.d. combining an appropriate amount solution C into an appropriate amount solution A and continuing to mix until complete dissolution to form a solution D comprising about 49% w / w water, about 5% w / w glycerin, and about 22% w / v propylene glycol, about 22%, w / w sorbitol, about 0.02% w / w methylparaben, about 0.6% w / w sucralose, about 0.1% w / w sodium citrate dihydrate, and about 1% w / w hydroxypropyl betadex.e. preparing a solution E, wherein the solution E is obtained by:v, combining appropriate amounts of glycerin and xanthan gum and mixing to obtain the solution E comprising about 0.5% w / w xanthan gum and about 99.5% w / w glycerin,f. prepare a solution F, wherein an appropriate amount of the solution E is combined with an appropriate amount of the solution D and continue to mix until a clear solution,g. optionally combining a flavoring agent with the solution F, andh. combining an appropriate amount of additional water in a quantity sufficient to obtain the aqueous pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6 % w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum, and about 0.1% w / w sodium citrate.

43. A method of making a aqueous pharmaceutical composition of diclofenac, the method comprising:a. preparing a solution A, wherein the solution A is obtained by:i. combining appropriate amounts of diclofenac potassium salt, water, glycerin, and propylene glycol in a reaction vessel and stirring until complete dissolution to obtain the solution A comprising about 0.1% w / v to about 1% w / v diclofenac, about 40% w / w to about 60% w / w water, about 5% w / w to about 15% w / w glycerin, and about 30% w / w to about 50% w / v propylene glycol.b. preparing a solution B, wherein the solution B is obtained by:ii. combining appropriate amounts of water, sorbitol, and methylparaben in a second reaction vessel and warming to about 60°C and mixing until complete dissolution to obtain the solution B comprising about 40% w / w to about 60% w / w water, about 40% w / w to about 60% w / w sorbitol, and about 0.01% w / w to about 0.1% w / w methylparaben;iii. allowing solution B to cool to about 20 - 35°C,c. preparing a solution C, wherein the solution C is obtained byiv. combining appropriate amounts of sucralose, sodium citrate dihydrate, and hydroxylpropyl betadex, with the solution B and continuing to mix until complete dissolution to obtain the solution C comprising about 40% w / w to about 60% w / w water, about 40% w / w to about 60% w / w sorbitol, about 0.01% w / w to about 0.1% w / w methylparaben, about 0.5% w / w to about 5.0 % w / w sucralose, about 0.1 % w / w to about 0.5% w / w sodium citrate dihydrate, and about 1.0 % w / w to about 5.0% w / w hydroxypropyl betadex.d. combining an appropriate amount of solution C into an appropriate amount of solution A and continuing to mix until complete dissolution to form a solution D comprising about 0.1% w / v to about 1% w / v diclofenac, about 40% w / w to about 60% water, about 1% w / w to about 10% glycerin, and about 15% w / w to about 30% w / v propylene glycol, about 15% w / w to about 30% w / w sorbitol, about 0.01% w / w to about 0.1% w / w methylparaben, about 0.3% w / w to about 3.0 % w / w sucralose, about 0.1% w / w sodium citrate dihydrate, and about 0.5% w / w to about 1.% w / w hydroxy propyl betadex.e. preparing a solution E, wherein the solution E is obtained by:v. combining appropriate amounts of glycerin and xanthan gum and mixing to obtain the solution E comprising about 0.1% w / w to about 1.0% w / w xanthan gum and about 99% w / w to about 99.9% / w glycerin, f. combining an appropriate amount of the solution E with an appropriate amount of the solution D and mixing the mixture of solution E and solution D until a clear solution is obtained,g. optionally combining a flavoring agent with the solution F, andh. combining an appropriate amount of additional water in a quantity sufficient to obtain the pharmaceutical composition comprising about 0.1% w / v to about 1.0% w / v diclofenac potassium salt, about 40% w / w to about 60% water, about 5% w / w to about 15% w / w glycerin, about 10% w / w to about 30% w / v propylene glycol, about 10% w / w to about 30% w / w sorbitol, about 0.05% w / w to about 0.15% w / w sodium citrate dihydrate, about 0.1 % w / w to about 1.0% w / w sucralose, about 0.5% w / w to about 1.5% w / w hydroxypropyl betadex, about 0.005% w / w to about 0.1% w / w methylparaben, about 0.01% w / w to about 0.05% w / w xanthan gum, and about 0.05% w / w to about 0.5% w / w sodium citrate.

44. The method according claim 43, wherein the method comprises:a. preparing a solution A, wherein the solution A is obtained by:i. combining appropriate amounts of diclofenac potassium salt, water, glycerin, and propylene glycol in a reaction vessel and stirring until complete dissolution to obtain the solution A comprising about 0.5% w / v diclofenac, about 50% w / w water, about 10% w / w glycerin, and about 40% w / v propylene glycol.b. preparing a solution B, wherein the solution B is obtained by:ii. combining appropriate amounts of water, sorbitol, and methylparaben in a second reaction vessel and warming to 60°C and mixing until complete dissolution to obtain the solution B comprising about 50% w / w water, about 50%, w / w sorbitol, and about 0.05% w / w methylparaben;iii. allowing solution B to cool to 20 - 35°C,c. preparing a solution C, wherein the solution C is obtained byii. combining appropriate amounts of sucralose, sodium citrate dihydrate, and hydroxylpropyl betadex, with the solution B and continuing to mix until complete dissolution to obtain the solution C comprising about 48% w / w water, about 48%, w / w sorbitol, about 0.05% w / w methylparaben, about 1.5% w / w sucralose, about 0.24% w / w sodium citrate dihydrate, and about 2.4% w / w hydroxypropyl betadex.d. combining an appropriate amount of solution C into an appropriate amount of solution A and continuing to mix until complete dissolution to form a solution Dcomprising about 49% w / w water, about 5% w / w glycerin, and about 22% w / v propylene glycol, about 22%, w / w sorbitol, about 0.02% w / w methylparaben, about 0.6% w / w sucralose, about 0.1% w / w sodium citrate dihydrate, and about 1% w / w hydroxypropyl betadex.e. preparing a solution E, wherein the solution E is obtained by:ii. combining appropriate amounts of glycerin and xanthan gum and mixing to obtain the solution E comprising about 0.5% w / w xanthan gum and about 99.5% w / w glycerin,f. combining an appropriate amount of the solution E with an appropriate amount of the solution D and mixing the mixture of solution E and solution D until a clear solution is obtained,g. optionally combining a flavoring agent with the solution F, andh. combining an appropriate amount of additional water in a quantity sufficient to obtain the pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20% w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6 % w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum, and about 0.1% w / w sodium citrate.

45. A method of making an aqueous pharmaceutical composition of diclofenac, the method comprising:a. adding water at about 40% w / w to about 60% w / w water to a main manufacturing vessel and warming to 45 ± 5°C,iv. while mixing the water in the main manufacturing vessel, add glycerin at about 1.0% w / w to about 10.0% w / w and sorbitol solution at about 10% w / w to about 30% w / w and mix until a clear solution followed by addition of methylparaben at about 0.01% w / w to about 0.03% w / w to the main manufacturing vessel and stirring the mixture at 50 ± 10°C until complete dissolution,v. cooling the main manufacturing vessel to 25 ± 5°C,vi. adding sequentially hydroxypropyl betadex at about 0.5% w / w to about 1.5% w / w and sucralose at about 0.2 % w / w to about 1.0% sucralose to the main manufacturing vessel;b. adding propylene glycol at about 10% w / v to about 20% w / v to a first side manufacturing vessel and while mixing, adding diclofenac potassium at about 0.1% w / v to about 1.0% w / v;c. combining the mixture from the first side manufacturing vessel to the main manufacturing vessel and performing a two stage rinse of the first side manufacturing vessel with propylene glycol at about 1.0% w / v to about 3.0% w / v and water at about 1.0% w / w to about 3.0% w / w with addition of each rinse to the main manufacturing vessel;d. adding glycerin at about 1% to about 5%w / w to a second side manufacturing vessel, while mixing adding xanthan gum at about 0.01% to about 0.05% w / w and continuing mixing until complete dissolution;e. combining the mixture from the second side manufacturing vessel to the main manufacturing vessel and performing a rinse from the first side manufacturing vessel with water at about 1.0% w / w to about 3.0% w / w with addition of rinse to the main manufacturing vessel;f. adding a flavoring agent at about 0.1% w / w to about 0.5% w / w / to the main manufacturing vessel with mixing and adding water an amount sufficient to obtain the pharmaceutical composition comprising about 0.1% w / v to about 1.0% w / v diclofenac potassium salt, about 40% w / w to about 60% w / w water, 5% w / w to about 15% w / w glycerin, about 10% w / w to about 30% w / v propylene glycol, about 10% w / w to about 30% w / w sorbitol, about 0.05% w / w to about 0.5% w / w sodium citrate dihydrate, about 0.2 % w / w to about 1.0% sucralose, about 0.5% w / w to about 1.5% w / w hydroxypropyl betadex, about 0.005% to about 0.05% w / w methylparaben, about 0.01% to about 0.05% w / w xanthan gum; wherein % w / w and %w / v in the intermediate steps are provided based on the % w / w and %w / v of the final composition of the pharmaceutical composition.

6. The method according to claim 45, wherein the method comprises:a. adding water at about 47% w / w to a main manufacturing vessel and warming to 45 ± 5°C,iv. while mixing the water in the main manufacturing vessel, add glycerin at about 4.7% w / w and sorbitol solution at about 20% w / w and mix until a clear solution followed by addition of methylparaben at about 0.02% w / w to the main manufacturing vessel and stirring the mixture at 50 ± 10°C until complete dissolution,v. cooling the main manufacturing vessel to 25 ± 5°C,vi. adding sequentially hydroxypropyl betadex at about 1% w / w and sucralose at about 0.6% w / w to the main manufacturing vessel;b. adding propylene glycol at about 14.5% w / v to a first side manufacturing vessel and while mixing, adding diclofenac potassium at about 0.25% w / v;c. combining the mixture from the first side manufacturing vessel to the main manufacturing vessel and performing a two stage rinse of the first side manufacturing vessel with propylene glycol at about 1.8% w / v and water at about 3.6% w / w with addition of each rinse to the main manufacturing vessel;d. adding glycerin at about 5% w / w to a second side manufacturing vessel, while mixing adding xanthan gum at about 0.025% w / w and continuing mixing until complete dissolution;e. combining the mixture from the second side manufacturing vessel to the main manufacturing vessel and performing a rinse from the first side manufacturing vessel with water at about 1.8% w / w with addition of rinse to the main manufacturing vessel;f. adding a flavoring agent at about 0.3% w / w to the main manufacturing vessel with mixing and adding water an amount sufficient to obtain the pharmaceutical composition comprising about 0.25% w / v diclofenac potassium salt, about 48% w / w water, about 10% w / w glycerin, about 20% w / v propylene glycol, about 20%w / w sorbitol, about 0.1% w / w sodium citrate dihydrate, about 0.6 % w / w sucralose, about 1% w / w hydroxypropyl betadex, about 0.02% w / w methylparaben, about 0.025% xanthan gum; wherein % w / w in the intermediate steps are provided based on the % w / w of the final composition of the pharmaceutical composition.

47. The pharmaceutical composition of any one of claims 1 to 39, wherein the pharmaceutical composition comprises not more than 0.030 %w / w of related compound A after storage at 25°C and 60% relative humidity after one month.

48. The pharmaceutical composition of any one of claims 1 to 39, wherein the pharmaceutical composition comprises not more than 0.095 %w / w of related compound A after storage at 25°C and 60% relative humidity after six months.

49. The pharmaceutical composition of any one of claims 1 to 39, wherein the pharmaceutical composition comprises not more than 0.250 %w / w of related compound A after storage at 25°C and 60% relative humidity after eighteen months.

50. The pharmaceutical composition of any one of claims 1 to 39, wherein the pharmaceutical composition comprises not more than 0.695 %w / w of related compound A after storage at 40°C and 75% relative humidity after six months.

51. The pharmaceutical composition of any one of claims 1 to 39, wherein the pharmaceutical composition comprises not more than 0.075 %w / w of total impurities after storage at 25°C and 60% relative humidity after one month.

52. The pharmaceutical composition of any one of claims 1 to 39, wherein the pharmaceutical composition comprises not more than 0.245 %w / w of total impurities after storage at 25°C and 60% relative humidity after six months.

53. The pharmaceutical composition of any one of claims 1 to 39, wherein the pharmaceutical composition comprises not more than 0.455 %w / w of total impurities after storage at 25°C and 60% relative humidity after eighteen months.

54. The pharmaceutical composition of any one of claims 1 to 39, wherein the pharmaceutical composition comprises not more than 1.19 %w / w of total impurities after storage at 40°C and 75% relative humidity after six months.

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