Softgel capsule including a non-steroidal Anti-inflammatory drug and acetaminophen

Abstract

Described herein is a softgel capsule including a fill material and a shell composition. The fill material may include an alkali metal salt of a NSAID. acetaminophen and does not include povidone. The shell composition may include a film forming material. The softgel capsule may have an assay stability of at least about 99% at room temperature after 12 months.

Description

SOFTGEL CAPSULE INCLUDING A NON-STEROIDAL ANTIINFLAMMATORY DRUG AND ACETAMINOPHENCROSS REFERENCE TO RELATED APPLICATION(S)

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 533,473 filed on August 18, 2023, the entire contents of which are incorporated in its entirety.FIELD OF THE INVENTION

[0002] The present invention relates to a softgel capsule including (a) a fill material comprising an alkali metal salt of a nonsteroidal anti-inflammatory drug (“NS AID’") and acetaminophen, as well as corresponding methods of manufacture and methods of treatment.BACKGROUND OF THE INVENTION

[0003] Capsule dosage forms are commonly used for oral administration of a variety of pharmaceuticals. The capsules can be, for example, soft gelatin shell or hard shell (animal or vegetable variety). Softgel capsules provide numerous advantages including fast dissolution, taste-masking, ease of swallowing, fewer excipients as compared to tablets, delivery of a liquid matrix that solubilizes and improves oral bioavailability of a marginally hydrophilic compound, delivery' of low and ultra-low doses of a compound, delivery of low melting temperature compounds and minimization of dust generation during manufacturing and thus, improved safety for production personnel.

[0004] Soft capsules, in particular, soft gelatin capsules (or softgel capsules), provide a dosage form which is more readily accepted by patients, since the capsules are easy to swallow and need not be flavored in order to mask any unpleasant taste of the active agent. Softgel encapsulation of drugs further provides the potential to improve the bioavailability of the pharmaceutical agents. For example, active ingredients may be rapidly released in liquid form as soon as the gelatin shell ruptures.

[0005] NS AIDs and acetaminophen are first line treatments for ailments such as fever, pain relief and / or inflammatory conditions.

[0006] There continues to exist a need in the art for a combination NS AID / acetamin ophen formulation that are useful for the treatment of patients in need thereof.SUMMARY OF THE INVENTION

[0007] In some embodiments of the invention, a softgel capsule includes (a) a fill material including an alkali metal salt of a NSAID, acetaminophen, and polyalkylene glycol, wherein the fill material does not include povidone, and (b) a shell composition including a film forming material comprising a plasticizer. In some embodiments, the fill material is free flowing at room temperature. In some embodiments, the shell composition includes a plasticizer that decreases drying time during processing.

[0008] In some embodiments, a softgel capsule includes (a) a fill material including an alkali metal salt of a NSAID, acetaminophen, and polyalkylene glycol, and (b) a shell composition including from about 10% to about 80% gelatin and a plasticizer. In some embodiments, the combination of gelatin and a plasticizer in the shell composition decreases drying time during processing.

[0009] In some embodiments, a softgel capsule includes (a) a fill material including an alkali metal salt of aNSAID, acetaminophen, and polyalkylene glycol, wherein the fill material does not include povidone and (b) a shell composition including a film forming material, wherein the temperature during manufacture of the fill material does not exceed 60°C. In some embodiments, the temperature may solubilize the acetaminophen. If the temperature is greater than 60°C, then it may increase the potential formation of an acetaminophen degradation product such as 4-aminophenol.

[0010] In some embodiments, the softgel capsule may further include free acid NSAID.

[0011] In some embodiments, the ratio of alkali metal salt of NSAID to free acid NSAID is from about 75:25 to about 100.

[0012] In some embodiments, the ratio of alkali metal salt of NSAID to free acid NSAID is from about 88: 12 to about 92:8.

[0013] In some embodiments, the ratio of alkali metal salt of NSAID to acetaminophen is from about 0.3:1 to about 0.5: 1.

[0014] In some embodiments, the ratio of alkali metal salt of NSAID to acetaminophen is from about 0.35 to about 0.45: 1.

[0015] In some embodiments, the alkali metal salt of NSAID is a potassium NSAID such as potassium ibuprofen. In other embodiments, the alkali metal salt of NSAID is a sodium NSAID such as sodium ibuprofen

[0016] In some embodiments, the free acid NSAID is ibuprofen.

[0017] In some embodiments, a process for preparing a softgel capsule may include (a) combining an NSAID with an alkali metal hydroxide to form an alkali metal salt of the NSAID; (b) solubilizing acetaminophen with the alkali metal salt of the NSAID to form a fill material; and (c) encapsulating the fill material in a softgel capsule at room temperature.

[0018] In some embodiments, a process for preparing a softgel capsule may include (a) combining an NSAID with an alkali metal hydroxide to form an alkali metal salt of the NSAID; (b) solubilizing acetaminophen with the alkali metal salt of the NSAID to form a fill material; and (c) encapsulating the fill material in a softgel capsule shell including about 10% to about 80% gelatin and a plasticizer. In some embodiments, the plasticizer may include sorbitol and glycerin, e.g., at a ratio of glycerin to sorbitol of about 0.5 to about 1 to about 3 to about 1 or a ratio of about 1 : 1 to about 1.5 to 1, e.g., in a low sulfate content gel.

[0019] In some embodiments, a process for preparing a softgel capsule including (a) combining an NSAID with an alkali metal hydroxide to form an alkali metal salt of the NSAID; (b) solubilizing acetaminophen with the alkali metal salt of the NSAID to form a fill material; and (c) encapsulating the fill material in a softgel capsule shell including from about 10% to about 80% gelatin and plasticizer.

[0020] In some embodiments, the film forming material comprises an animal derived polymer or a non-animal derived polymer. In certain embodiments, the animal derived polymer comprises a low sulfate content gelatin. In other embodiments, the non-animal derived polymer comprises alginate.

[0021] In some embodiments, the shell composition further comprises dextrose.

[0022] In some embodiments, the shell comprises an enteric polymer such as pectin. In certain embodiments, the pectin is an amidated pectin, a non-amidated pectin or combinations thereof. In some embodiments, the shell composition comprises from about 2 wt% to about 5 wt% of pectin. In some embodiments, the shell composition comprises non-amidated pectin.

[0023] In some embodiments, the shell composition of the softgel capsule comprises about 30 wt% to about 80 wt% of a gelatin. In some embodiments, the shell composition of the softgel capsule comprises about 2 wt% to about 20 wt% of pectin. In some embodiments, the shell composition of the softgel capsule comprises about 0.01 wt% to about 4 wt% of dextrose. In some embodiments, the shell composition comprises about 2 wt% to about 40 wt% of a plasticizer.

[0024] In certain embodiments, the film forming material includes gelatin, wherein the gelatin comprises Type A gelatin, Type B gelatin and mixtures thereof. In some embodiments, the gelatin comprises fish gelatin, hide gelatin, bone gelatin and mixtures thereof.

[0025] In some embodiments, the shell composition further includes a plasticizer, wherein the plasticizer comprises glycerol, glycerin, sorbitol and combinations thereof. In some embodiments, the plasticizer may include glycerin and sorbitol at a glycerin to sorbitol ratio of about 0.5 to about 1 to about 3 to about 1 or a ratio of about 1 : 1 to about 1.5 to 1, e.g., in a low sulfate content gel.

[0026] In some embodiments, the shell composition of the softgel capsule further comprises water. In some embodiments, the shell composition comprises from about 10 wt% to about 50 wt% of water.DETAILED DESCRIPTION OF THE INVENTION

[0027] The inventors of the present disclosure have developed an NSAID / acetaminophen combination softgel capsule. It has been found that if one of skill in the art were to mix the NS AID and acetaminophen at the same time, followed by adding an alkali metal salt such as KOH / potassium acetate would result in a very viscous fill solution. Thus, in order to encapsulate such a fill material, the material would need to be heated. Further, such mixing steps would cause unnecessary ions because of the addition of the potassium acetate and any side reactions that may occur. To avoid these issues, the inventors have found that by converting the NSAID to an alkali metal NSAID such as potassium ibuprofen before addition of acetaminophen, the alkali metal NSAID can act as a solubilizing agent for the acetaminophen. Thus, the inventive process eliminates the step of adding an alkali metal salt, and also eliminates the adverse processing issues discussed above.

[0028] Further the present inventors have found that a NSAID can be neutralized, e g., at a 0.9 to 1 mole ratio (i.e., 90% ionized) with an alkali metal salt such as KOH. This would result in an approximately 0.33 to 1 mole ratio of alkali metal NSAID to acetaminophen. Because of the higher concentration of alkali metal NSAID to acetaminophen, the acetaminophen quickly dissolves at a temperature, e.g. of about 45°C. Thus, the fill material of the present disclosure does not have to be heated to higher temperatures, such as 65°C, nor does the fill material have to be mixed for anextended period of time because of the improved solubility of certain embodiments of the present invention. Further, by using a lower temperature, it has been found that the formation of acetaminophen impurities, such as 4-aminophenol, can be reduced or eliminated. Also, the fill material of certain embodiments of the present invention has a lower viscosity, then what would be expected, and allows for encapsulation to occur at room temperature.

[0029] The present invention advances the state of the art by developing a softgel capsule including a combination of an alkali metal salt of a non-steroidal antiinflammatory drugs (“NSAID”) and acetaminophen. The softgel capsule of the present invention includes a fill material that is free flowing at room temperature and the shell composition has lower drying time than conventional softgel capsules. Such mechanism is beneficial for encapsulation of a fill material including an alkali metal salt of a NSAID and acetaminophen.

[0030] As used herein, "NSAID" refers to a nonsteroidal anti-inflammatory drug or compound that may be used in the diagnosis, cure, mitigation, treatment, or prevention of a condition. The term “condition” or “conditions” refers to those medical conditions that can be treated or prevented by administration to a subject of an effective amount of a NSAID.

[0031] As used herein, the terms “therapeutically effective” and an “effective amount” refer to the amount of active agent or the rate at which it is administered which is needed to produce a desired therapeutic result.

[0032] As used herein, “shell” or “shell composition” refers to the shell of a softgel capsule which encapsulates a fill material.

[0033] All references to wt% throughout the specifications and the claims refer to the weight of the component in reference to the weight of the entire composition and may also be designated as w / w.

[0034] As used herein, “fill material” or “fill” refers to the composition that is encapsulated by the capsule shell and contains at least one pharmaceutically active ingredient.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] According to an embodiment, a softgel capsule may include (a) a fill material including an alkali metal salt of a NSAID, acetaminophen, and polyalkylene glycol, wherein the fill material does not include povidone and (b) a shell composition including a film forming material including a plasticizer. The fill material of the softgel capsule may be free flowing at room temperature. In some embodiments, the fill material may have a viscosity of about 1000 cP to about 10,000 cP or about 1000 cP top about 5000 cP or about 2000 cP to about 3000 cP at 25°C as determined by a HAAKE RheoWin viscometer. In some embodiments, the fill material may have a viscosity of about 2000 cP. about 2100 cP. about 2200 cP, about 2300 cP, about 2400 cP, about 2500 cP, about 2600 cP, about 2700 cP, about 2800 cP, about 2900 cP, or about 3000 cP at 25 °C as determined by a HAAKE RheoWin viscometer. The film forming material in the shell composition of the present disclosure decreases the drying time.

[0039] In some embodiments, the fill material may include the alkali metal salt of a NSAID in an amount of about 5 wt% to about 40 wt%, about 10 wt% to about 35 wt%, about 15 wt% to about 30 wt%, or about 20% to about 25 wt%, based on total weight of the fill material. In some embodiments, the acetaminophen may be included in an amount of about 10 wt% to about 50 wt%, about 15 wt% to about 45 wt%, about 20 wt% to about 40 wt%, or about 25 wt% to about 35 wt%, based on total weight of the fill material.

[0040] In some embodiments, the fill material may include polyalkylene glycol in an amount of about 30 wt% to about 70 wt%, about 35 wt% to about 65 wt%, about 40wt% to about 60 wt%, or about 45 wt% to about 55 wt%, based on total weight of the fill material.

[0041] NSAIDs are a large group of therapeutic compounds. NSAIDs may reduce inflammation by blocking cyclooxygenase. NSAIDs may include, without limitation, aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxipirin, aminophenazone, antraphenine, aspirin, azapropazone, benorilate, benoxaprofen, benzydamine. butibufen. celecoxib, chlorthenoxacin. choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole; etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxylethyl salicylate, ibuprofen, indomethacin, indoprofen. ketoprofen, ketorolac, lactyl phenetidin, loxoprofen, lumiracoxib. mefenamic acid, meloxicam, metamizole, metiazinic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxametacin, phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone. protizinic acid, rofecoxib, salicylamide, salsalate, sulindac, suprofen, tiaramide. tinoridine, tolfenamic acid, valdecoxib, and zomepirac.

[0042] NSAIDs may be classified based on their chemical structure or mechanism of action. Non-limiting examples of NSAIDs include a salicylate derivative NSAID, a p- amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) inhibitor, and a selective cyclooxygenase 2 (COX 2) inhibitor. A NSAID may be a profen. Examples of a suitable salicylate derivative NSAID include, without limitation, acetylsalicylic acid (asprin), diflunisal, and salsalate. Examples of a suitable p-amino phenol derivative NSAID include, without limitation, paracetamol and phenacetin. Examples of a suitable propionic acid derivative NSAID include, without limitation, alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen. Examples of a suitable acetic acid derivative NSAID include, without limitation, aceclofenac. acemetacin, actarit, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indometacin, ketorolac, metiazinic acid, mofezolac, nabumetone, naproxen, oxametacin, sulindac, and zomepirac. Examples of a suitable enolic acid (Oxicam) derivative NSAID include, without limitation, droxicam, isoxicam, lomoxicam, meloxicam, piroxicam, and tenoxicam. Examples of a suitable fenamic acidderivative NS AID include, without limitation, flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid. Examples of a suitable selective COX-2 inhibitors include, without limitation, celecoxib, etoricoxib, firocoxib, lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.

[0043] According to another embodiment, a softgel capsule may include (a) a fill material including an alkali metal salt of a NSAID, acetaminophen, and polyalkylene glycol and (b) a shell composition including from about 10% to about 80% gelatin and a plasticizer.

[0044] According to another embodiment, a softgel capsule may include (a) a fill material including an alkali metal salt of a NSAID, acetaminophen, and polyalkylene glycol, wherein the fill material does not include povidone, and (b) a shell composition including a film forming material, wherein the temperature during manufacture of the fill material does not exceed about 60°C, the temperature of manufacture of the fill material may also reduce the formation of 4-aminophenol, which is more likely to form when the temperature is greater than 60°C.

[0045] The total dose of acetaminophen in the dosage form may be. e.g., from about 50 mg to about 1000 mg, from about 100 mg to about 750 mg, about 200 mg to about 500 mg or about 300 mg to about 400 mg. In certain embodiments, total dose of ibuprofen in the dosage form (equivalent to free base) may be, e.g., about 100 mg, about 200 mg, about 250 mg, about 300 mg. about 325 mg. about 400 mg. about 500 mg or about 750 mg.

[0046] In some embodiments, the softgel capsule of the present disclosure may further include free acid NSAID. In some embodiments, the ratio of alkali metal salt of NS AID to free acid NSAID may be from about 75:25 to about 100. In other embodiments, the ratio of alkali metal salt of NSAID to free acid NSAID may be from about 88: 12 to about 92:8. In some embodiments, the ratio of alkali metal salt of NSAID to free acid NSAID may be from about 75:25, about 80:20, about 85: 15, about 88: 12, about 90: 10. about 92:8, about 95:5, or about 100.

[0047] In some embodiments, the alkali metal salt of the NSAID may be potassium ibuprofen or sodium ibuprofen.

[0048] In some embodiments, the free acid NSAID may be ibuprofen.

[0049] The total dose of ibuprofen in the dosage form (equivalent to free base) may be, e.g.. from about 50 mg to about 1000 mg, from about 100 mg to about 800 mg, about 200 mg to about 600 mg or about 250 mg to about 500 mg. In certainembodiments, total dose of ibuprofen in the dosage form (equivalent to free base) may be, e.g.. about 100 mg. about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 600 mg or about 800 mg.

[0050] In other embodiments, the fill material may include additional fill components such as flavoring agents, sweetening agents, coloring agents and fillers, an antioxidant or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides.

[0051] In an embodiment, the gelatin in the shell composition may include Type A gelatin, Type B gelatin, a hide or skin gelatin and / or a bone gelatin used alone or in combination. In some embodiments, the gelatin may be a low sulfate gelatin. In one embodiment, the gelatin may be a pigskin gelatin or a Type B. In another embodiment, there may be only one type of gelatin. In yet another embodiment, the gelatin may be a combination of at least two ty pes of gelatins. In an embodiment, the amount of gelatin in the shell composition may be about 10 wt% to about 80 wt%, or from about 20 wt% to about 70 wt%, or from about 30 wt% to about 60 wt%, or from about 40 wt% to about 50 wt%.

[0052] In one embodiment, the shell composition may include dextrose. In an embodiment, the amount of dextrose in the shell composition is about 0.005 \vt% or about 0.01 wt% to about 4 wt%, or from about 0.1 wt% or about 0.15 wt% to about 3 wt%, or from about 0. 15 wt % or about 0.2 wt% to about 2 wt%, or from about 0.1 wt% to about 0.2 wt%.

[0053] In some embodiments, the shell composition may include pectin. In some embodiments, the pectin may be a low methoxy pectin. In some embodiments, the pectin may be an amidated pectin, non-amidated pectin or a combination thereof. In an embodiment, the pectin is low methylester (LM) pectin with Degree of Esterification lower than 50. In some embodiments, the pectin is LMS-318, SPL-12, LM-102 AS-Z and / or LM-12 CG-Z. In other embodiments, the low methoxy (LM) pectin may be LM Pectin (P-25), LM Pectin (445C), LM Pectin (100C) or a combination thereof. In an embodiment, an amount of pectin in the shell composition is about 2 wt% to about 20 wt%, from about 3 wt% to about 15 wt%, from about 3 wt% to about 5.5 wt%, and from about 5 wt% to about 10 wt%.

[0054] In an embodiment, the plasticizer in the shell composition may include glycerol, glycerin, sorbitol and combinations thereof. In an embodiment, the plasticizer may include a combination of sorbitol and glycerin, e.g., at a ratio ofglycerin to sorbitol of about 0.5 to about 1 to about 3 to about 1 or a ratio of about 1: 1 to about 1.5 to 1, e.g., in a low sulfate content gel. Sorbitol may be including to reduce the potential for forming esters with the ibuprofen free acid. Other suitable plasticizers may include, but not be limited to, sugar alcohol plasticizer such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizer such as diglycerin, ethylene glycol, diethylene glycol, triethyleneglycol, tetraethylene glycol, dipropylene glycol, a polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-l,3- propanediol, trimethylolpropane, a polyether polyol, ethanol amines; and mixtures thereof. Other exemplary plasticizers may also include, without limitations, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, polypropylene glycol), multi-block polymers, single block polymers, citrate ester-type plasticizers, and triacetin. Such plasticizers may include 1,2- butylene glycol, 2.3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyltributylcitrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.

[0055] In an embodiment, the amount of plasticizer in the shell composition is about 2 wt% to about 40 wt%, or from about 5 wt % to about 35 vrt%, or from about 10 wt% to about 30 wt%, or from about 15 wt% to about 25 wt%.

[0056] In an embodiment, the shell composition may also include a gelling agent. In some embodiments, the gelling agent may be a gellan gum. For example, the gellan gum may be a Kelcogel CG-LA gellan gum.

[0057] The shell composition may also include water. In some embodiments, water may be included in the shell composition in an amount of 10 wt% to about 60 wt%. or from about 20 wt% to about 50 wt%, or about 30 wt% to about 45 wt% based on the total shell composition.

[0058] In an embodiment, the shell composition 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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 such 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.

[0063] In some embodiments, the softgel capsule may have a stability of at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least 96%, at least 97%, at least about 98% or at least 99% when tested at 25 °C / 60%RH at 1 month, 2 months, 3 months, 6 months, 9 months or 12 months. In some embodiments, the softgel capsule may have a stability of at leastabout 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least 96%, at least 97%, at least about 98% or at least 99% when tested at 30 °C / 65%RH at 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months. In some embodiments, the softgel capsule may have a stability of at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least 96%, at least 97%, at least about 98% or at least 99% when tested at 40 °C / 75%RH at 1 month, 2 months, 3 months, 6 months, or 9 months. As used herein, stability is measured as the amount of active agent remaining after an accelerated time period stored at a temperature and relative humidity.

[0064] In some embodiments, the amount of 4-aminophenol may be less than about 0.2%, less than about 0.1%, less than about 0.05%, less than about 0.02%, less than about 0.01%, or is nondetectable in the softgel capsule at 25 °C / 60%RH at 1 month, 2 months, 3 months, 6 months, 9 months or 12 months; at 30 °C / 65%RH at 1 month, 2 months, 3 months, 6 months, 9 months or 12 months; or at 40°C / 75%RH at 1 month,2 months, 3 months, 6 months, 9 months or 12 months. In some embodiments, the amount of ibuprofen-PEG ester in the softgel capsule may be less than about 0.2%, less than about 0.1%, less than about 0.05%, less than about 0.02%, less than about 0.01%, or less than about 0.001% at 25 °C / 60%RH at 1 month, 2 months, 3 months, 6 months, 9 months or 12 months; at 30 °C / 65%RH at 1 month, 2 months, 3 months, 6 months, 9 months or 12 months; or at 40°C / 75%RH at 1 month, 2 months, 3 months, 6 months, 9 months or 12 months. In some embodiments, the amount of ibuprofen- sorbitol ester in the softgel capsule may be less than about 0.2%, less than about 0.1%, less than about 0.05%, less than bout 0.02%, less than about 0.01%, or less than abut 0.001%. In some embodiments, the amount of total impurities may be less than about 0.1%, less than about 0.05%, less than about 0.02%, less than about 0.01%, less than about 0.005%, or less than about 0.001% at 25 °C / 60%RH at 1 month, 2 months,3 months, 6 months, 9 months or 12 months; at 30 °C / 65%RH at 1 month, 2 months, 3 months, 6 months, 9 months or 12 months; or at 40°C / 75%RH at 1 month, 2 months, 3 months, 6 months, 9 months or 12 months.

[0065] According to an embodiment, the softgel capsule is prepared by (a) combining an NSAID with an alkali metal hydroxide to form an alkali metal salt of the NSAID; (b) solubilizing acetaminophen with the alkali metal salt of the NSAID to form a fillmaterial; and (c) encapsulating the fill composition in a shell composition at room temperature.

[0066] According to another embodiment, a process for preparing a softgel capsule including (a) combining an NS AID with an alkali metal hydroxide to form an alkali metal salt of the NSAID; (b) solubilizing acetaminophen with the alkali metal salt of the NSAID to form a fill material; and (c) encapsulating the fill material in a shell composition including from about 10% to about 80% gelatin in combination with a plasticizer. The plasticizer may include sorbitol and glycerin at glycerin to sorbitol ratio of about 0.5 to about 1 to about 3 to about 1 or a ratio of about 1: 1 to about 1.5 to 1, e.g., in a low sulfate content gel.

[0067] According to another embodiment, a process for preparing a softgel capsule includes (a) combining a NSAID with an alkali metal hydroxide to form an alkali metal salt of the NSAID; (b) solubilizing acetaminophen with the alkali metal salt of the NSAID to form a fdl material; and (c) encapsulating the fill material in a shell composition including about 10% to about 80% gelatin and plasticizer.

[0068] In some embodiments, the fill material may include free acid NSAID. The ratio of alkali metal salt of NSAID to free acid NSAID is from about 75:25 to about 100. In some embodiments, the ratio of alkali metal salt of NSAID to free acid NSAID is from about 88:12 to about 92:8.

[0069] In some embodiments, the ratio of alkali metal salt of NSAID to acetaminophen is from about 0.35: 1 to about 0.5: 1. In some embodiments, the ratio of alkali metal salt of NSAID to acetaminophen is from about 0.35: 1 to about 0.45: 1. In some embodiments, the alkali metal salt of NSAID may be potassium ibuprofen. In some embodiments, the free acid NSAID may be ibuprofen.

[0070] According to an embodiment, the softgel capsule described herein may be used as a method of treating pain, reducing inflammation and / or reducing a fever. In some embodiments, a method of treating a headache may include administering a softgel capsule as described herein. In some embodiments, a method of treating pain associated with a sprain or strain may include administering a softgel capsule as described herein. In some embodiments, a method of treating a cold or flu may include administering a softgel capsule as described herein. In some embodiments, a method of reducing inflammation may include administering a softgel capsule as described herein.EXAMPLES

[0071] Specific embodiments of the invention will now be demonstrated by reference to the following examples. It should be understood that these examples are disclosed solely by way of illustrating the invention and should not be taken in any way to limit the scope of the present invention.Method of Preparing a softgel capsule

[0072] In one study, a softgel capsule according to an embodiment of the present disclosure was prepared. To begin preparing the softgel capsule, deionized water was added to an approximately 40 gallon closed mixing vessel with bottom mixer. The water was cooled to approximately 15°C. Full vacuum was obtained on the vessel and while mixing at approximately 100 RPM, potassium hydroxide was slowly vacuum transferred into the vessel maintaining the temperature at less than 40°C. The potassium hydroxide was mixed until completely dissolved. The temperature of the solution was maintained between 20°C and 25°C.

[0073] Polyethylene Glycol 400 was vacuum transferred into an approximately 300 gallon closed mixing vessel. The jacket of the closed vessel was set at 27°C. While mixing under vacuum with the disperser set at 1200 RPM and the sweep set at 20 RPM, the ibuprofen was vacuum transferred into the closed mixing vessel and mixed until homogenous while still under vacuum.

[0074] After completion of mixing, the potassium hydroxide solution is slowly vacuum transferred into the 300-gallon closed mixing tank through a 0.125 inch orifice plate while mixing with disperser at 1200 RPM and sweep at 20 RPM. The temperature was not allowed to exceed 50°C.

[0075] The temperature of the fill material was set to 45°C. After mixing for approximately 15 minutes, the acetaminophen was vacuum transferred into the closed mixing tank. The mixture was mixed for not less than 30 minutes at 45°C until all the acetaminophen was completely dissolved.

[0076] The fill material was set to 27°C and the fill material was deaerated for not less than 45 minutes. The fill material was then transferred into receivers and the receivers transferred to a rotary die encapsulation machine. The fill material was then encapsulation into a 12 oblong die using a low sulfate fast diying gel formula.

[0077] The softgel capsules were dried to a fill moisture of 7.0% to 7.5%.Table 1. Fill FormulationTable 2. Gel Formula / Shell FormulationStability and Dissolution Study

[0078] Stability and dissolution studies were conducted of a soft gel capsule including 250 mg of acetaminophen and 125 mg of ibuprofen under 40°C / 75%RH accelerated stability in bottles (LOT 22PP-33), 30°C / 65%RH intermediate stability in bottles and blisters, and 25°C / 60%RH ambient stability in bottles and blisters. The amount of impurities present in the samples were also tested. The results of the studies are presented in Tables 3, 4, 5 and 6.Table 3. Accelerated Stability Study Results in BottlesLot 22PP-33 40°C / 75%RH Accelerated Stability (Bottles)Table 4. Intermediate Condition Stability Results in Bottles and BlistersLot 22PP-33 30°C / 65%RH Intermediate StabilityTable 5. Ambient Condition Stability Results in BottlesLot 22PP-33 25°C / 60%RH Room Temperature Stability (Bottles)Table 6. Ambient Condition Stability Results in BlistersLot 22PP-33 25°C / 60%RH Room Temperature Stability (Blisters)

Claims

WHAT IS CLAIMED IS:

1. A softgel capsule comprising:(a) a fill material comprising an alkali metal salt of a non-steroidal antiinflammatory drug (“NSAID”). acetaminophen, and polyalkylene glycol, wherein the fill material does not include povidone; and(b) a shell composition comprising a film forming material comprising a plasticizer, wherein the softgel capsule has a stability after 1 month at room temperature of at least 99%.

2. A softgel capsule comprising:(a) a fill material comprising an alkali metal salt of a NSAID, acetaminophen, and polyalkylene glycol, and(b) a shell composition comprising from about 10% to about 80% gelatin and a plasticizer.

3. A softgel capsule comprising:(a) a fill material comprising an alkali metal salt of a NSAID, acetaminophen, and polyalkylene glycol, wherein the fill material does not include povidone; and(b) a shell composition comprising a film forming material; wherein the temperature during manufacture of the fill material does not exceed 60°C.

4. The softgel capsule of any of claims 1-3, further comprising free acid NSAID.

5. The softgel capsule of claim 4, wherein the ratio of alkali metal salt of NSAID to free acid NSAID is from about 75:25 to about 100.

6. The softgel capsule of claim 4, wherein the ratio of alkali metal salt of NSAID to free acid NSAID is from about 88: 12 to about 92:

87. The softgel capsule of any of claims 1-3, wherein the ratio of alkali metal salt of NSAID to acetaminophen is from about 0.35: 1 to about 0.5: 1.

8. The softgel capsule of any of claims 1-3, wherein the ratio of alkali metal salt of NSAID to acetaminophen is from about 0.35: 1 to about 0.45:

19. The softgel capsule of any of claims 1-8, wherein the alkali metal salt of ibuprofen is potassium ibuprofen.

10. The softgel capsule of claim 4, wherein the free NS AID is ibuprofen.

11. The softgel capsule of any one of claims 1-10, wherein the fill material has a viscosity of about 2000 cP to about 3000cP at 25°C.

12. The softgel capsule of any one of claims 1-10, wherein the fill material is free flowing at room temperature.

13. The softgel capsule of any one of claims 1-12, wherein the plasticizer comprises glycerin and sorbitol.

14. The softgel capsule of claim 13, wherein the glycerin and the sorbitol are at a ratio of 1 to 1 to 1.5 to 1.

13. A process for preparing a softgel capsule comprising:(a) combining an NSAID with an alkali metal hydroxide to form an alkali metal salt of the NSAID;(b) solubilizing acetaminophen with the alkali metal salt of the NSAID to form a fill material;(c) encapsulating the fill material in a softgel capsule shell at room temperature; the softgel capsule having stability after 1 month at room temperature of at least 99%.

14. A process for preparing a softgel capsule comprising:(a) combining an NSAID with an alkali metal hydroxide to form an alkali metal salt of the NSAID;(b) solubilizing acetaminophen with the alkali metal salt of the NSAID to form a fill material;(c) encapsulating the fill material in a softgel capsule shell comprising from about 10% to about 80% gelatin and a plasticizer.

15. A process for preparing a softgel capsule comprising:(a) combining an NSAID with an alkali metal hydroxide to form an alkali metal salt of the NSAID;(b) solubilizing acetaminophen with the alkali metal salt of the NSAID to form a fill material;(c) encapsulating the fill material in a softgel capsule shell comprising from about 10% to about 80% gelatin.

16. The process of any of claims 13-15, wherein the fill material further comprises free acid NSAID.

17. The process of claim 16, wherein the ratio of alkali metal salt of NSAID to free acid NSAID is from about 75:25 to about 100.

18. The process of claim 16, wherein the ratio of alkali metal salt of NSAID to free acid NSAID is from about 88: 12 to about 92:

819. The process of any of claims 13-15, wherein the ratio of alkali metal salt of NSAID to acetaminophen is from about 0.35: 1 to about 0.5: 1.

20. The process of any of claims 13-15, wherein the ratio of alkali metal salt of NSAID to acetaminophen is from about 0.35: 1 to about 0.45:

121. The process of any of claims 13-20, wherein the alkali metal salt of ibuprofen is potassium ibuprofen.

21. The process of claim 13, wherein the free acid NSAID is ibuprofen.

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