Rapid-dissolving softgel capsules containing ibuprofen

Abstract

The invention describes in certain embodiments a soft gel capsule including a filler material including ibuprofen or a pharmaceutically acceptable salt thereof, and a shell composition comprising a non-gelatinous bio-based polymer, the film dissolving completely in less than 30 minutes when subjected to dissolution with a USP Apparatus I at 75-200 rpm basket speed or a USP Apparatus II with paddle speed at 75 RPM in 900 ml of 50 mM phosphate buffer (pH 7.2) and deionized water at 37 degrees C.

Description

34896-584 FAST DISSOLVING SOFTGEL CAPSULES INCLUDING IBUPROFEN CROSS REFERENCE TO RELATED APPLICATION(S)

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 538,952, filed on September 18, 2023. The entire contents of which are incorporated by reference in its entirety. FIELD OF THE INVENTION

[0002] The present disclosure relates to a softgel capsule including a fill formulation including ibuprofen or a pharmaceutically acceptable salt thereof and a shell composition including a non-gelatin biobased polymer. The softgel capsule film includes a non-gelatin biobased polymer. BACKGROUND

[0003] Softgel capsules are ubiquitously utilized in both pharmaceutical and nutraceutical industries. Gelatin is the most abundantly used ingredient for a softgel shell due to its advantages including high aqueous solubility, flexibility and mechanical robustness. Today, there is a high demand in gelatin, causing a deficit supply to meet the growing demand. Additionally, a shell composition including gelatin has its shortcomings, such as low melting temperature, causing leaking in a capsule when subject to higher temperatures. Additionally, it has been found that crosslinking may occur resulting in dissolution failure and that the shells cannot tolerate high pH, which limits the solubility and larger capsules. To mitigate such dependence on gelatin, plant-based softgel capsules have been developed using carrageenan (seaweed extract) in combination with starch.

[0004] In order for a compound to serve as a shell material in softgel applications, it must satisfy two important criteria: (1) shell must be robust enough to hold the fill and shape, physically stable and (2) shell needs to be soluble in aqueous medium (or physiological media) to release the active pharmaceutical ingredient upon consumption. For an immediate release pharmaceutical dosage form, the expectation is to have at least 80% of the contents release within 30 minutes.

[0005] It has been found that such immediate drug release is challenging to achieve with starch and carrageenan because of their poor aqueous solubility. One downside to this approach is that starch has poor water solubility, thereby limiting its use in an immediate release dosage form.34896-584

[0006] Accordingly, there is a need for improved non-gelatin softgel capsule formulations that have higher aqueous solubility that meet or exceeds immediate release dosage form dissolution requirements and are amenable to high-speed manufacturing as a reliable and commercially viable alternate to gelatin based softgel capsules. BRIEF SUMMARY

[0007] According to various embodiments, disclosed herein is a softgel capsule including a fill formulation including ibuprofen and a shell composition including a non-gelatin biobased polymer. In certain embodiments, the shell composition dissolves in less than 20 minutes when subject to a dissolution with a USP Apparatus II with paddles at 75 RPM in 250 ml or 900 ml of 50 mM phosphate buffer (pH 7.2). BRIEF DESCRIPTION OF DRAWINGS

[0008] FIG.1 illustrates the burst strength data for Lot 22MC-41 according to an embodiment of the Example;

[0009] FIG.2 illustrates the burst strength data for Lot 22MC-97 according to an embodiment of the Example;

[0010] FIG. 3 illustrates the water activity results for Lot 22MC-41 according to an embodiment of the Example;

[0011] FIG. 4 illustrates the water activity results for Lot 22MC-97 according to an embodiment of the Example;

[0012] FIG. 5 illustrates the Fiberoptic dissolution results for Lot 22MC-41 according to an embodiment of the Example;

[0013] FIG. 6 illustrates the Fiberoptic dissolution results for Lot 22MC-97 according to an embodiment of the Example;

[0014] FIG. 7 illustrates the Fiberoptic dissolution results for Lot 5198000D according to an embodiment of the Example;

[0015] FIG. 8 illustrates the Fiberoptic dissolution results using USP Apparatus II for Lot 5384199B according to an embodiment of the Example;

[0016] FIG. 9 illustrates the dissolution profile of Lot 5384199B with various post-treatment according to an embodiment of the Example;

[0017] FIG.10 illustrates the comparative dissolution results using USP Apparatus III for Lot 5384199B according to an embodiment of the Example; and34896-584

[0018] FIG. 11 illustrates the Fiberoptic dissolution results using USP Apparatus II for Lot 5384199B according to an embodiment of the Example. DETAILED DESCRIPTION

[0019] Described herein are various embodiments of softgel capsule formulations including ibuprofen and methods of preparation and use thereof. It is to be understood that the invention is not limited to the details of construction or process steps set forth in the following description. The invention is capable of other embodiments and of being practiced or being carried out in a variety of ways.

[0020] Reference throughout this specification to “one embodiment,” “certain embodiments,” “one or more embodiments” or “an embodiment” means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases such as “in one or more embodiments,” “in certain embodiments,” “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily referring to the same embodiment of the invention. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0021] As used herein, the singular forms “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise. Thus, for example, reference to “a softgel capsule” includes a single softgel capsule as well as two or more softgel capsules.

[0022] As used herein, “free or substantially free,” refers to a composition that comprises less than about 1 wt%, less than about 0.5 wt%, less than about 0.25 wt%, less than about 0.1 wt%, less than about 0.05 wt%, less than about 0.01 wt%, or 0 wt% of said component.

[0023] As used herein, “about” refers to any values that are within a variation of ± 10%, such that “about 10” would include from 9 to 11. As used herein, “a,” “an,” or “the” refers to one or more, unless otherwise specified. Thus, for example, reference to "an excipient" includes a single excipient as well as a mixture of two or more different excipients, and the like.

[0024] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.34896-584

[0025] The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to illuminate certain materials and methods and does not pose a limitation on scope. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods.

[0026] As used herein, the term “film,” “film composition,” “shell” or “shell composition” refers to the shell of a softgel capsule which encapsulates a fill material.

[0027] Although the disclosure herein is with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the compositions and methods without departing from the spirit and scope of the invention. Thus, it is intended that the invention include modifications and variations that are within the scope of the appended claims and their equivalents.

[0028] Disclosed herein is a softgel capsule including a fill material including ibuprofen or a pharmaceutically acceptable salt thereof and a shell composition including a non-gelatin biobased polymer. In certain embodiments, the shell composition may completely dissolve in less than 20 minutes when subject to a dissolution with a USP Apparatus II with paddles at 75 RPM in 250 ml or 900 ml of 50 mM phosphate buffer (pH 7.2). The shell composition may dissolve in less than 15 minutes, less than 10 minutes, or less than 5 minutes.

[0029] In certain embodiments, about 80% of ibuprofen or a pharmaceutically acceptable salt thereof releases from the softgel capsule in less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes.

[0030] In certain embodiments of the softgel capsule, the non-gelatin biobased polymer may include carrageenan, maltodextrin, pullulan, or a combination thereof.

[0031] In certain embodiments of the softgel capsule, the non-gelatin biobased polymer may be included in an amount of about 1% to about 70% (w / w), about 2% to about 65% (w / w), about 5% to about 60% (w / w), about 10% to about 55% (w / w), about 15% to about 50% (w / w), about 20 to about 45% (w / w), about 25 to about 40% (w / w), or about 30 to about 35% (w / w) of the shell composition, or any range, sub-range or value within.

[0032] In certain embodiments, the non-gelatin biobased polymer may be pullulan. In other embodiments, the non-gelatin biobased polymer may be maltodextrin. In yet another embodiment, the non-gelatin biobased polymer may be pullulan and maltodextrin.

[0033] In certain embodiments, pullulan may be included in the shell composition in an amount of about 1% to about 30%, about 2% to about 25%, about 4% to about 20%, about 5% to about34896-584 15%, or about 7.5% to about 12.5% (w / w) of the shell composition, or any range, sub-range or value within.

[0034] In some embodiments, maltodextrin may be included in the shell composition in an amount of about 10% to about 50%, about 15% to about 45%, about 20% to about 40%, or about 25% to about 35% (w / w) of the shell composition, or any range, sub-range or value within.

[0035] In some embodiments, pullulan and maltodextrin may be included in the shell composition in an amount of about 1% to about 70% (w / w), about 2% to about 65% (w / w), about 5% to about 60% (w / w), about 10% to about 55% (w / w), about 15% to about 50% (w / w), about 20 to about 45% (w / w), about 25 to about 40% (w / w), or about 30 to about 35% (w / w) of the shell composition, or any range, sub-range or value within.

[0036] In certain embodiments, the shell composition of the softgel capsule may further include a synthetic polymer. The synthetic polymer may include polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft co-polymer, high molecular weight polyethylene glycol, povidone, a surfactant, a nonionic triblock copolymer or a combination thereof. In some embodiments, the synthetic polymer may be a nonionic triblock copolymer. The nonionic triblock copolymer may include polyethylene oxide and polypropylene oxide blocks. In some embodiments, the surfactant may include sodium lauryl sulfate.

[0037] In certain embodiments, the shell composition may further include a non-animal derived gelling agent. The non-animal derived gelling agent may include starch, pregelatinized starch, xanthan gum, agar, pectin, sugar, sugar alcohol, a cellulose derivative, a cellulosic polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, silicon dioxide, curdlan, furcelleran, egg white powder, lacto albumin, soy protein, chitosan or a combination thereof.

[0038] In certain embodiments, the non-animal derived gelling agent may include carrageenan. In some embodiments of the softgel capsule, the carrageenan may be iota carrageenan, kappa carrageenan, lambda carrageenan, or a combination thereof.

[0039] In certain embodiments, the non-animal gelling agent does not include a starch.

[0040] In certain embodiments, the non-animal gelling agent may be in an amount of from about 10% to about 50% (w / w) of the shell composition. In some embodiments, the non- animal gelling agent may be included in an amount of from about 15% to about 45%, about 20% to about 40%, about 25% to about 35%, or about 30% to about 50% (w / w) of the shell composition. In some embodiments, the shell composition may include carrageenan in an34896-584 amount of about 2% to about 30%, about 5% to about 25%, or about 10% to about 20% (w / w) of the shell composition.

[0041] In other embodiments, the shell composition may include less than 10%, less than 5% or less than 1% (w / w) of an animal derived gelling agent. In certain embodiments, the shell composition of the softgel capsule does not include an animal derived gelling agent.

[0042] In certain embodiments, the shell composition of the softgel capsule may also include a plasticizer. In other embodiments, the shell composition may also include a buffer agent. In other embodiments, the shell composition may further include a plasticizer and a buffer agent.

[0043] In some embodiments, the plasticizer may be glycerol, glycerin, sorbitol, sorbitol sorbitan solution, propylene glycol, triacetin, polysorbate or combinations thereof. In some embodiments, the polysorbate may include polysorbate 20 also known as Tween 20, polysorbate 80 also known as Tween 80, or a combination thereof. In certain embodiments of the shell composition, the plasticizer may be included in an amount of about 15% to about 75%, about 20% to about 70%, about 25% to about 65%, about 30% to about 60%, about 35% to about 55%, or about 40% to about 50% (w / w) of the shell composition.

[0044] In some embodiments, the buffer agent may be dibasic sodium phosphate, monobasic sodium phosphate, sodium bicarbonate, sodium citrate, disodium phosphate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, potassium phosphate or a combination thereof. In some embodiments of the shell composition, the buffer agent may be in an amount of about 0.1% to about 5% (w / w) of the shell composition. In other embodiments, the buffer agent may be included in an amount of about 0.1% to about 5%, about 0.3% to about 4.5%, about 0.5% to about 4%, about 1% to about 3.5%, or about 1.5% to about 3% (w / w), or any value or sub- range herein.

[0045] In certain embodiments, the fill formulation may further include a solvent, an ionizing agent, or a combination thereof. In some embodiments, the solvent may be polyethylene glycol, water, or a combination thereof. In some embodiments, the ionizing agent may include potassium hydroxide, sodium hydroxide, or a combination thereof.

[0046] In certain embodiments, ibuprofen may be included in the fill formulation in an amount of about 15% to about 65%, about 20% to about 60%, about 25% to about 55%, about 30% to about 50%, or about 35% to about 45% (w / w) of the fill formulation.

[0047] In certain embodiments, the solvent may be included in the fill formulation in an amount of about 20% to about 70%, about 25% to about 65%, about 30% to about 60%, about 35% to about 55%, or about 40% to about 50% (w / w) of the fill formulation.34896-584

[0048] In certain embodiments, polyethylene glycol may be included in the fill formulation in an amount of about 20% to about 65%, about 25% to about 60%, about 30% to about 55%, or about 35% to about 50% (w / w) of the fill formulation.

[0049] In certain embodiments, water may be included in the fill formulation in an amount of about 0.1% to about 55%, about 0.5% to about 50%, about 1% to about 45%, about 5% to about 40%, about 10% to about 35%, about 15% to about 30%, about 20% to about 25%, about 0.1% to about 20%, about 0.5% to about 15%, or about 1% to about 10% (w / w) of the fill formulation.

[0050] In certain embodiments, the ionizing agent may be included in the fill formulation in an amount of about 0.5% to about 15%, about 1% to about 12%, about 2% to about 10%, or about 5% to about 8% of the fill formulation.

[0051] In certain embodiments, the softgel capsule may have a stability of at least 99%, at least 97%, at least 95%, at least 93%, or at least 90% at 30°C / 65%RH at 1 month, 3 months, 6 months or 12 months. In some embodiments, the stability may be an assay stability.

[0052] In some embodiments, the softgel capsule may have a stability of at least 99%, at least 97%, at least 95%, at least 93%, or at least 90% at 25°C / 60%RH at 1 month, 3 months, 6 months or 12 months. In some embodiments, the stability may be an assay stability.

[0053] In some embodiments, the softgel capsule may have a stability of at least 99%, at least 97%, at least 95%, at least 93%, or at least 90% at 40°C / 75%RH at 1 month, 3 months, 6 months or 12 months. In some embodiments, the stability may be an assay stability.

[0054] In certain embodiments, ibuprofen or a pharmaceutically acceptable salt thereof may be included in the softgel capsule in an amount of about 150 mg to about 1000 mg. In other embodiments, ibuprofen or a pharmaceutically acceptable salt thereof may be included in an amount of about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg.

[0055] Also disclosed in certain embodiments is a method of treating pain or inflammation including administering to a subject in need thereof a softgel capsule as described herein.

[0056] In certain embodiments, a softgel capsule is an immediate release softgel capsule. The immediate release softgel capsule includes a fill material including ibuprofen or a pharmaceutically acceptable salt thereof encapsulated by a shell composition including a non- gelatin biobased polymer, wherein at least 80% of the fill material releases within 30 minutes.34896-584 In some embodiment, at least 80% of the fill material may release within 25 minutes, within 20 minutes, within 15 minutes, within 12 minutes, within 10 minutes, or within 5 minutes.

[0057] The shell composition as disclosed herein may also contain at least one of a buffering agent, a plasticizer and water. Softgel capsule formulations as described herein can be vegetarian and free of animal derived materials such as gelatin. The immediate release softgel capsule may include a shell composition as described above in the present disclosure.

[0058] In certain embodiments, the shell composition disclosed herein completely dissolves in less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes when subject to a dissolution with a USP Apparatus II with paddles at 75 RPM in 250 ml or 900 ml of 50 mM phosphate buffer (pH 7.2).

[0059] In an embodiment, the shell composition / film of the softgel capsule may optionally comprise additional agents such as coloring agents, flavorings agents, sweetening agents, fillers, antioxidants, diluents, pH modifiers or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides.

[0060] Exemplary suitable coloring agents may include, but not be limited to, colors such as e.g., white, black, yellow, blue, green, pink, red, orange, violet, indigo, and brown. In specific embodiments, the color of the dosage form can indicate the contents (e.g., one or more active ingredients) contained therein.

[0061] Exemplary suitable flavoring agents may include, but not be limited to, “flavor extract” obtained by extracting a part of a raw material, e.g., animal or plant material, often by using a solvent such as ethanol or water; natural essences obtained by extracting essential oils from the blossoms, fruit, roots, etc., or from the whole plants.

[0062] Additional exemplary flavoring agents that may be in the dosage form may include, but not be limited to, breath freshening compounds like menthol, spearmint, and cinnamon, coffee beans, other flavors or fragrances such as fruit flavors (e.g., cherry, orange, grape, etc.), especially those used for oral hygiene, as well as actives used in dental and oral cleansing such as quaternary ammonium bases. The effect of flavors may be enhanced using flavor enhancers like tartaric acid, citric acid, vanillin, or the like.

[0063] Exemplary sweetening agents may include, but not be limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof. Artificial sweeteners include, e.g., acesulfame and its various salts such as the potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet®and Equal®), salt of aspartame-acesulfame (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts such34896-584 as the sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose such as sucralose (available as Kaltame®and Splenda®), and mogrosides. Natural sweeteners include, e.g., glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); Stevia rebaudiana (Stevioside), natural intensive sweeteners, such as Lo Han Kuo, polyols such as sorbitol, mannitol, xylitol, erythritol, and the like.

[0064] The fill formulation of the softgel capsule as disclosed herein may further include at least one of rapeseed oil, medium chain triglyceride oil, polyethylene glycol and combinations thereof. Lipophilic and / or hydrophilic and / or alcohol fill compositions could also be encapsulated with the softshell capsule formulations as described herein.

[0065] In some embodiments, the lipids in the dosage form may be selected, without limitations, from the group consisting of almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, colza oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, walnut oil, and watermelon seed oil. Other oil and fats may include, but not be limited to, fish oil (omega-3), krill oil, animal or vegetable fats, e.g., in their hydrogenated form, free fatty acids and mono-, di-, and tri-glycerides with C8-, C10-, C12-, C14-, C16-, C18-, C20- and C22-fatty acids, and combinations thereof.

[0066] Examples of other possible active agents include, but are not limited to, non-steroidal anti-inflammatory agents (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprin, azapropazone, benorilate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicyl salicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, pharmaceutically acceptable salts thereof and mixtures thereof.34896-584

[0067] The dosage forms according to the disclosure include ibuprofen and its pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like, and metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′- dibenzylethylenediamine salt and the like.

[0068] Suitable fill materials comprise ibuprofen and can be made according to known methods. In addition to the at least one active ingredient, suitable fill materials may comprise additional fill components such as flavoring agents, sweetening agents, coloring agents and fillers or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides. Suitable amounts of pharmaceutically active ingredient and pharmaceutically acceptable excipients can be readily determined by one of ordinary skill in the art.

[0069] In certain embodiments, the disintegration tests disclosed herein may be performed at about 37 °C ± 2 °C at a volume of fluid of 1000 mL. Disintegration test fluid 1 (also referred to herein as “artificial gastric juice”) was 2 g / L sodium chloride-hydrochloric acid solution having a pH of 1.2. Disintegration test fluid 2 (also referred to herein as “artificial intestinal fluid”) was 0.2 mol / L potassium dihydrogen phosphate – 0.2 mol / L sodium hydroxide solution having a pH of 6.8.

[0070] In certain embodiments, the disintegration test with the first fluid was carried out for about 120 minutes by placing one unit in each of the six tubes of the basket, immersing the basket (and consequently the units) in the first test fluid, and lifting the basket from the fluid to observe whether the units disintegrated. Disintegration is defined as that state at which the unit is broken or the enteric shell composition is ruptured or broken. The test is met if none of the six units is disintegrated. A similar test is performed with the second disintegration test fluid for the selected duration.

[0071] In some embodiments, the disintegration test may be performed for about 150 minutes, about 120 minutes, about 105 minutes, about 90 minutes, about 75 minutes, about 60 minutes, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, or about 5 minutes.34896-584

[0072] In certain embodiments, USP Apparatus I, USP Apparatus II and USP Apparatus III were used for performing the dissolution tests. Dissolution test medium was 50 mM phosphate buffer solution having a pH of 7.2.

[0073] In some embodiments, the dissolution test may be performed for about 150 minutes, about 120 minutes, about 105 minutes, about 90 minutes, about 75 minutes, about 60 minutes, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, or about 5 minutes.

[0074] In some embodiments, the softgel capsule may have a burst strength of about 4 kg to about 20 kg, 8 kg to about 15 kg, about 10 kg to about 15 kg, about 4 kg, about 6 kg, about 8 kg, about 10 kg, about 12 kg, or about 15 kg at 1 month, 3 months, 6 months or 12 months at 40°C / 75% RH.

[0075] In some embodiments, the softgel capsule may have a burst strength of about 4 kg to about 20 kg, 8 kg to about 15 kg, about 10 kg to about 15 kg, about 4 kg, about 6 kg, about 8 kg, about 10 kg, about 12 kg, or about 15 kg at 1 month, 3 months, 6 months or 12 months at 30°C / 65% RH.

[0076] In some embodiments, the softgel capsule may release 80% of the fill material after about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, or about 55 minutes, e.g, in a dissolution test in 900 mL phosphate buffer (50 mM, pH 7.2), e.g., at 37 degrees Celsius, using USP APP II with paddle speed at 75RPM or dissolution with a USP Apparatus II with paddles at 75 RPM in 900 ml of 0.1N HCL and deionized water, or deionized water, e.g., at 37 degrees Celsius. In certain embodiments, the above results may also be achieved for a softgel capsule under accelerated / various stability conditions of 25°C / 60% RH, 30°C / 65% RH, or 40°C / 75% RH at 1 month, 3 months, 6 months, 12 months, 18 months, 22 months, or 24 months. In certain embodiments, after any of the accelerated storage conditions disclosed herein, the dissolution does not change from time 0 by more than 20%, by more than 10% or by more than 5% at 1 hour, 4 hours or 8 hours.

[0077] In some embodiments of the softgel capsule, the softgel capsule may have a water activity (Aw) may be about 0.3 to about 1.0, about 0.3 to about 0.8, about 0.4 to about 0.9, about 0.4 to about 0.6, about 0.5 to about 0.8, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1.0 at 1 month, 3 months, 6 months, or 12 months at 40°C / 75% RH.

[0078] In some embodiments of the softgel capsule, the softgel capsule may have a water activity (Aw) may be about 0.3 to about 1.0, about 0.4 to about 0.9, about 0.4 to about 0.8, about 0.5 to about 0.8, about 0.3 , about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1.0 at 1 month, 3 months, 6 months, or 12 months at 30°C / 65% RH.34896-584 Methods of Preparing the Dosage Forms

[0079] Disclosed herein are methods of preparing a softgel capsule film and capsule formulation as disclosed herein. The methods include combining a non-gelatin biobased polymer and optionally at least one of a synthetic polymer, non-animal derived gelling agent, buffering agent, a plasticizer and water to form a combination.

[0080] The method may also further include transferring the combination to an encapsulation apparatus. In certain embodiments, the method may include encapsulating a fill material within a softgel capsule formed from the combination to form a plurality softgel capsule dosage forms. The method may also further include drying the plurality of softgel capsule dosage forms in a tumble dryer. Certain embodiments further include packaging the plurality of softgel capsule dosage forms. Examples Example 1 – Formulation Development

[0081] A shell composition was developed using a non-animal shell formulation according to an embodiment of the present disclosure. The shell composition of the Example has been developed by replacing starch of previous formulations with more soluble natural polymers, including pullulan and maltodextrins. The shell formulation is presented in Table 1, and the fill formulation is present in Table 2. Table 1. Fast Dissolving Shell Formulation Ingredient % (Dry Basis, weight of Function th h ll t34896-584 Table 2. Fill Formulation for 200 mg Ibuprofen Softgel Capsules Ingredient % (based on weight of fill) Function Ibuprofen 20.0 – 60.0 Drug Substance

[0082] The softgel capsule of the Example was manufactured using commercial scale equipment. The manufacturing process can be divided into six (6) separate unit operations: shell mass preparation, fill compounding, encapsulation, drying, inspection and finishing. Shell Mass Preparation

[0083] The shell mass preparation can be divided into three (3) separate steps: maltodextrin and pullulan addition, carrageenan addition, mixing and shell mass deaeration followed by shell mass discharge.

[0084] The shell mass was prepared using the Olsa Gel Melter. The shell mass was discharged into two (2) gel receivers evenly. The shell mass was kept at ambient conditions and melt at approximately 85 - 95°C during the entire batch production. Fill Material Preparation

[0085] The fill material containing Ibuprofen was used for preparing all the batches. The fill was prepared using an enclosed mixing vessel. Polyethylene glycol 600 was used as the main solvent. Potassium hydroxide solution was added to the fill mix to partially ionize Ibuprofen molecules to improve the solubility. The fill mix was continuously mixed until all Ibuprofen was fully dissolved. The fill mix was then deaerated under vacuum to remove any trapped air. After the deaearation, the fill mix was blanked with nitrogen until encapsulation. Encapsulation

[0086] The softgel capsules of the Example were encapsulated into two (2) sublots, designated by the letters A and B, respectively. Table 3 presents a summary of the encapsulation sublots and the parameters for each sublot.34896-584

[0087] All sublots (A and B) were encapsulated using dies with matching wedges and distribution plates. The target shell weight of the capsules was dependent on the ribbon thickness (0.028” and 0.026”). The alert limits in the range of ± 12% of target shell weight due to high degree of shell shrinkage upon drying and high-water percentage of the shell formulation. The machine speed was set to 3.0 – 4.5 RPM in each sublot and standard tumbler drying setting was used to remove some moisture prior to tray drying in drying tunnels.

[0088] Finished capsules were subjected to physical and analytical testing including shell mass characterization, finished product burst strength, Fiberoptic dissolution and analytical testing using methods in the draft state. Informal stability studies were performed on selected batches on demand. Table 3. Fast-dissolving Ibuprofen Capsules Sublot Parameter Table Sublot Ribbon Encapsulation Run Time Theor. Qty Thickness Speed (Hour) (softgels)Ribbon Thickness Study

[0089] A ribbon thickness study was conducted for the 200 mg Ibuprofen softgel capsules with different ribbon thicknesses as shown in Table 3 above. The tensile strength of wet ribbons (with different thicknesses) was evaluated using Texture Analyzer with tensile grip fixtures.

[0090] The in-process parameters of the shell / fill weight referenced in the batch record were recorded at the beginning, every 60 minutes and at the end of the encapsulation. Average of ten (10) wet softgel burst strength were recorded at the beginning, every 30 minutes and at the end of the encapsulation using Texture Analyzer. Water Activity Testing

[0091] After drying, a composite capsule sample obtained from top, middle and bottom of the stack was collected from each product (including sublots) (at any timepoint). Water activity was assessed on five (5) sets of softgel samples. Fill Moisture Testing34896-584

[0092] After drying, a composite capsule sample obtained from top, middle and bottom of the stack was collected from each product (including sublots) (at any timepoint). Extended Drying

[0093] Extended  drying studies were conducted to evaluate the drying behaviors of the capsules by keeping the softgel capsules in the drying tunnels for up to two weeks (14 days). Minimum five (5) trays were left in the drying tunnel for up to two weeks and water activity and fill moisture of composite samples were collected every two (2) days and recorded in the batch record. Mechanical Testing of Softgels (Burst Strength)

[0094] After reaching the water activity requirement, softgels were collected from each product at specified time intervals. Sampling was requested by the scientist to the shift assistant and collected samples were analyzed for bursting capability using a Texture Analyzer by the scientist. Capsule Finishing / Bulk Packaging

[0095] Capsules were washed with ethanol and phosal or lecithin wash solution and bulk packaged in the Pilot Plant. All sublots were washed and packaged per corresponding batch record. Segregation between each sublot were maintained during washing and packaging. A representative sample of capsules was obtained by a finishing operator or designee and inspected. Acceptable Quality Limits (AQL) Inspection during bulk packaging of each sublot. AQL Level II inspection results were recorded for each sublot.

[0096] All sublots were washed and packaged per the production batch record. The capsules were 100% inspected per the batch record.

[0097] Sampling of the capsules for each sublot testing occurred per corresponding batch records. Table 4 presents the sampling plan during packaging and testing for these samples. Table 4. Sampling and Testing Sample Quantity Test Acceptance34896-584 Three (3) composite Fast Dissolving samples of 160 capsules Ib f S ft l ll t d O f Appearance (Color,R t R ltsS

[0098] Product stability was initiated for ibuprofen softgel capsules. The softgel capsules from different lots were packaged into HDPE bottles (30-50 capsules per 120 ml bottle) and placed into stability chambers (40°C / 75%RH and 30°C / 65%RH) up to 12 months to evaluate the stability performance. Testing Results and Discussion Appearance and Burst Strength

[0099] The appearance of the softgel capsules according to the Example including shape and color looked normal, similar to those of gelatin based softgel capsules. The burst strength data for Lots 22MC-41 and 22MC-97 are summarized in Figure 1 and Figure 2, respectively.

[0100] The physical robustness of the softgel capsules was acceptable, ensuring the long-term physical stability. Water Activity

[0101] Water activity is an indicator for the product moisture and environmental sensitivity. The water activity was monitored during the manufacturing and stability timepoint. Figures 3 and 4 show the water activity data on stability for lots 22MC-41 and 22MC-97, respectively.

[0102] Water activity values increased on the stability study because of the absorption of moisture from the environment but still remain within the acceptable level without compromising the physical and chemical stability of the capsules. Fiberoptic Dissolution

[0103] The softgel capsules of the Example were subjected to rigorous in vitro dissolution34896-584 testing to evaluate the drug release performance. Figures 5, 6 and 7 summarized the results of dissolution testing of lots 22MC-41, 22MC-97 and 519800D, respectively, for T0, T1, T3 and T6 under various stability conditions.

[0104] An additional lot, Lot 5384199B was also subjected to rigorous in-vitro dissolution testing utilizing both USP Apparatus II and USP Apparatus III, the results of which are shown in Figures 8 and 10.

[0105] The changes of dissolution profiles while on stability were shown in Figure 11 for over a period of 12 months for lot 5384199B.

[0106] Some of the softgel capsules of the additional lot (Lot 5384199B) were also subjected to a post treatment. The post treatment includes polishing the capsules with either an oil solution of 3% lecithin, or 1% steric acid at ambient conditions. The post treatment was performed to prevent the capsules from sticking together. These capsules were also subjected to an accelerated stability conditions. An additional dissolution test was performed to analyze how the post treatment effects the capsules. The results of which are shown in Figure 9. Chemical Stability

[0107] Product stability is critical to ensure quality, safety and efficacy. Table 5 presents the analytical results for both batches of products on stability. The softgel capsules of the Example were found to be chemically stable under intermediate stability condition (30°C / 65% RH) up to T=6 month time point. Table 5. Analytical Testing Results 22MC-41 22MC-41 22MC-97 22MC-97 22MC-97 T t 22MC-41 T1M T3M 22MC-97 T1M T3M T6M %34896-584 4-iso- butylacetopheno0.0% 0.0% NotDete0.0% 0.0% 0% 0%nectedTable 6. Results of Chemical Stability for Lot 5384199B Test Specifications Results H B)

[0108] The softgel capsule of the Example utilized a non-animal based shell has been developed to meet the need of patients. The softgel capsules including Ibuprofen of the Example were both physically and chemically stable. The use of natural polymers including carrageenan, pullulan and maltodextrin provides several benefits and advantages, such as, but not limited to: 1. Elimination of potential crosslinking that could result in product failures. 2. Higher pH tolerance that could increase the pH of the fill materials, so that higher drug loading could be achieved. This will lead to reduced fill weight and smaller capsule34896-584 sizes. 3. Higher temperature tolerance leads to more stable softgel products in warm climate. 4. Lower raw material cost results in lower product costs and higher profit margins. 5. Abundant supplies of natural materials reduce the demand for animal derived gelatin, which is in short supply.

[0109] The preceding description sets forth numerous specific details such as examples of specific systems, components, methods, and so forth, in order to provide a good understanding of several embodiments of the present invention. It will be apparent to one skilled in the art, however, that at least some embodiments of the present invention may be practiced without these specific details. In other instances, well-known components or methods are not described in detail in order to avoid unnecessarily obscuring the present invention. Thus, the specific details set forth are exemplary. Particular embodiments may vary from these exemplary details and still be contemplated to be within the scope of the present invention.

[0110] Although the operations of the methods herein are described in a particular order, the order of the operations of each method may be altered so that certain operations may be performed in an inverse order or so that certain operation may be performed, at least in part, concurrently with other operations. In another embodiment, instructions or sub-operations of distinct operations may be in an intermittent and / or alternating manner.

[0111] It is to be understood that the above description is intended to be illustrative, and not restrictive. Many other embodiments will be apparent to those of skill in the art upon reading and understanding the above description. The scope of the invention should, therefore, be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

34896-584 WHAT IS CLAIMED IS:

1. A softgel capsule comprising: a fill formulation comprising ibuprofen; and a shell composition comprising a non-gelatin biobased polymer; wherein the shell composition dissolves in less than 20 minutes according to a dissolution test using USP Apparatus paddle II at 75 rpm in 250 mL of 50 mM phosphate buffer (pH 7.2).

2. The softgel capsule of claim 1, wherein at least 80% of the fill formulation is released in less than 25 minutes.

3. The softgel capsule of claim 1, wherein the non-gelatin biobased polymer comprises carrageenan, maltodextrin, pullulan, or a combination thereof.

4. The softgel capsule of claim 1, wherein the shell composition further comprises a synthetic polymer.

5. The softgel capsule of claim 4, wherein the synthetic polymer is polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft co-polymer, high molecular weight polyethylene glycol, povidone, a surfactant, a nonionic triblock copolymer or a combination thereof.

6. The softgel capsule of claim 5, wherein the synthetic polymer is a nonionic triblock copolymer.

7. The softgel capsule of claim 6, wherein the nonionic triblock copolymer comprises polyethylene oxide and polypropylene oxide blocks.

8. The softgel capsule of claim 5, wherein the surfactant is sodium lauryl sulfate.

9. The softgel capsule of claim 1, wherein the shell composition further comprises a non- animal derived gelling agent.34896-584 10. The softgel capsule of claim 9, wherein the non-animal derived gelling agent comprises starch, pregelatinized starch, xanthan gum, agar, pectin, sugar, sugar derived alcohol, a cellulose derivative, a cellulosic polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, silicon dioxide, curdlan, furcelleran, egg white powder, lacto albumin, soy protein, chitosan or a combination thereof.

11. The softgel capsule of claim 1, wherein the shell composition further comprises a plasticizer.

12. The softgel capsule claim 1, wherein the shell composition further comprises a buffer agent.

13. The softgel capsule of claim 1, wherein the shell composition dissolves in less than 15 minutes, less than 10 minutes, or less than 5 minutes.

14. The softgel capsule of claim 9, wherein the non-animal derived gelling agent comprises carrageenan.

15. The softgel capsule of claim 14, wherein the carrageenan comprises iota carrageenan, kappa carrageenan, lambda carrageenan or a combination thereof.

16. The softgel capsule of claim 9, wherein the non-animal gelling agent does not comprise a starch.

17. The softgel capsule of claim 9, wherein the non-animal gelling agent is in an amount of from about 10% to about 50% (w / w) of the shell composition.

18. The softgel capsule of claim 14, wherein the carrageenan is in an amount of about 2 to about 30% (w / w).

19. The softgel capsule of claim 1, comprising less than 10%, less than 5%, or less than 1% of an animal derived gelling agent.34896-584 20. The softgel capsule of claim 1, wherein the film does not comprise an animal derived gelling agent.

21. The softgel capsule of claim 11, wherein the plasticizer comprises glycerol, glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate or combinations thereof.

22. The softgel capsule of claim 21, wherein the polysorbate comprises Tween 20, Tween 80 or a combination thereof.

23. The softgel capsule of claim 11, wherein the plasticizer is in an amount of from about 15 to about 75% (w / w) of the shell composition.

24. The softgel capsule of claim 12, wherein the buffer agent is in an amount of from about 0.1 to about 5% (w / w) of the shell composition.

25. The softgel capsule of claim 12, wherein the buffer agent comprises dibasic sodium phosphate, monobasic sodium phosphate, sodium bicarbonate, sodium citrate, disodium phosphate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, potassium phosphate, or a combination thereof.

26. The softgel capsule of claim 1, wherein the polymer is included an amount of from about 1 to about 70% (w / w), about 2 to about 65% (w / w), about 5 to about 60% (w / w), about 10 to about 55% (w / w), about 15 to about 50% (w / w), about 20 to about 45% (w / w), about 25 to about 40% (w / w) or about 30 to about 35% (w / w) of the shell composition.

27. The softgel capsule of claim 3, wherein the polymer is pullulan.

28. The softgel capsule film of claim 27, wherein pullulan is in an amount of about 1 to about 30% (w / w), about 2 to about 25% (w / w), about 4 to about 20% (w / w), about 5 to about 15% (w / w), or about 7.5 to about 12.5% (w / w) of the shell composition.

29. The softgel capsule of claim 3, wherein the polymer is maltodextrin.34896-584 30. The softgel capsule of claim 29, wherein maltodextrin is in an amount of about 10 to about 50% (w / w), about 15 to about 45% (w / w), about 20 to about 40% (w / w), or about 25 to about 35% (w / w) of the shell composition.

31. The softgel capsule of claim 3, wherein the polymer is pullulan and maltodextrin.

32. The softgel capsule of claim 31, wherein the polymer is in an amount of about 1 to about 70% (w / w), about 5 to about 65% (w / w), about 10 to about 60% (w / w), about 15 to about 55% (w / w), about 20 to about 50% (w / w), about 25 to about 45% (w / w) or about 30 to about 40% (w / w) of the shell composition.

33. The softgel capsule of claim 1, wherein the fill formulation further comprises a solvent, an ionizing agent, or a combination thereof.

34. The softgel capsule of claim 33, wherein the solvent comprises polyethylene glycol, water, or a combination thereof.

35. The softgel capsule of claim 33, wherein the ionizing agent comprises potassium hydroxide, sodium hydroxide, or a combination thereof.

36. The softgel capsule of claim 1, wherein the ibuprofen is included in an amount of about 15 to about 65% (w / w) of the fill formulation.

37. The softgel capsule of claim 33, wherein the solvent is included in an amount from about 20 to about 70% (w / w) of the fill formulation.

38. The softgel capsule of claim 34, wherein polyethylene glycol is included in amount from about 20 to about 65% (w / w) of the fill formulation.

39. The softgel capsule of claim 34, wherein the water is included in an amount from about 0.1 to about 55 % (w / w) of the fill formulation.34896-584 40. The softgel capsule of claim 33, wherein the ionizing agent is included in an amount of about 0.5 to about 15% (w / w) of the fill formulation.

41. The softgel capsule of claim 1, wherein the softgel capsule has a stability of at least 99%, at least 97%, at least 95%, at least 93%, or at least 90% at 30°C / 65%RH at 1 month, 3 months, 6 months or 12 months.

42. The softgel capsule of claim 1, wherein the softgel capsule has a stability of at least 99%, at least 97%, at least 95%, at least 93%, or at least 90% at 25°C / 60%RH at 1 month, 3 months, 6 months or 12 months.

43. The softgel capsule of claim 1, wherein the softgel capsule has a stability of at least 99%, at least 97%, at least 95%, at least 93%, or at least 90% at 40°C / 75%RH at 1 month, 3 months, 6 months or 12 months.

44. The softgel capsule of claim 1, wherein ibuprofen is included in an amount of about 150 mg to about 1000 mg.

45. A method of treating pain or inflammation comprising administering to a subject in need thereof a softgel capsule of any one of claims 1-44.

46. A method of preparing a softgel capsule comprising: preparing a shell composition comprising a non-gelatin biobased polymer; preparing a fill formulation comprising ibuprofen; and encapsulating the fill formulation in the shell composition.

47. A softgel capsule comprising: a fill formulation comprising ibuprofen or a pharmaceutically acceptable salt thereof; and a shell composition comprising a non-gelatin biobased polymer; wherein the shell composition dissolves in less than 20 minutes according to a dissolution test using USP Apparatus I at 75 – 200 rpm of basket speed or USP Apparatus II at34896-584 50-100 rpm of paddle speed in 200-1000 mL or 200-400 mL of 50 mM phosphate buffer (pH 7.2).

48. A softgel capsule comprising: a fill formulation comprising ibuprofen or a pharmaceutically acceptable salt thereof; and a shell composition comprising a non-gelatin biobased polymer; wherein the shell composition dissolves in less than 20 minutes according to a dissolution test using USP Apparatus III at 30-100 DPM or USP Apparatus paddle III at 50- 100 rpm in 200-400 mL of 50 mM phosphate buffer (pH 7.2).

49. A softgel capsule comprising: a fill formulation comprising ibuprofen; and a shell composition comprising a non-gelatin biobased polymer; wherein the shell composition dissolves in less than 20 minutes according to a dissolution test using USP Apparatus II at 75 rpm paddle speed in 900 mL of 50 mM phosphate buffer (pH 7.2).