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 potassium acetate. The shell composition may include a film forming material. The softgel capsule may have a stability of at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% at room temperature after 1 month.

Description

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

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 533,476, 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 ( ‘NSAID”) 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 NSAID / acetaminophen 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 NS AID, acetaminophen, and potassium acetate, and (b) a shell composition including a film forming material. The softgel capsule may have a stability of at least about 90%, at least about 92%. at least about 95%, at least about 97%, or at least about 99% after 1 month at room temperature.

[0008] In some embodiments, the fill material may further include water, propylene glycol, or a combination thereof.

[0009] In some embodiments, the fill material may include about 10% to about 40% acetaminophen.

[0010] In some embodiments, the fill material may include about 0.1% to about 10% potassium acetate.

[0011] In some embodiments, the fill material may include about 0.5 / o to about 5 / o propylene glycol.

[0012] In some embodiments, the fill material may include about 1% to about 8% water.

[0013] In some embodiments, the fill material may further include a free acid NSAID.

[0014] In some embodiments, the ratio of alkali metal salt of NSAID to free acid NSAID is from about 75:25 to about 100.

[0015] In some embodiments, the ratio of alkali metal salt of NSAID to acetaminophen may be from about 0.3: 1 to about 0.5: 1.

[0016] In some embodiments, the ratio of alkali metal salt of NSAID to acetaminophen may be from about 0.35 to about 0.45: 1.

[0017] In some embodiments, the ratio of potassium acetate to acetaminophen may be about 0.15:1 to about 0.25: 1.

[0018] In some embodiments, the alkali metal salt of NSAID may be a potassium NSAID, such as potassium ibuprofen. In other embodiments, the alkali metal salt of NSAID may be a sodium NSAID, such as sodium ibuprofen.

[0019] In some embodiments, the free acid NSAID is ibuprofen.

[0020] 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. In certain embodiments, the softgel capsule has a stability7of at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% after 1 month.DETAILED DESCRIPTION OF THE INVENTION

[0021] The inventors of the present disclosure have developed an NSAID / acetaminophen combination softgel capsule.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] As used herein, “shell” or “shell composition” refers to the shell of a softgel capsule which encapsulates a fill material.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] According to an embodiment, a softgel capsule may include (a) a fill material including an alkali metal salt of a NSAID, acetaminophen, and potassium acetate, and (b) a shell composition including a film forming material, wherein the softgel capsule has a stability of at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% after 1 month. 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 16500 cPs at 25°C and 2400 cPs at 45°C measured with a Haake Viscotester 550V. In some embodiments, the fill material may have a viscosity of about 10000 cPs to about 25000 cPs at 25°C, about 11000 cPs to about 24000 cPs, about 12000 cPs to about 23000 cPs, about 13000 cPs to about 22000 cPs, about 14000 cPs to about 21000 cPs, about 15000 cPs to about 20000 cPs, or about 16000 to about 19000 cPs at 25°C measured with a Haake Viscotester 550V. In some embodiments, the fill material may have a viscosity of about 2000 cPs to about 8000 cPs, about 3000 cPs to about 7000 cPs, or about 4000 cPs to about 6000 cPs at 45°C measured with a Haake Viscotester 550V.

[0032] 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.

[0033] NS AIDs 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, acety lsalicylic 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 acid derivative NSAID 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.

[0034] In some embodiments, the fill material may further include water, propylene glycol or combination thereof.

[0035] In some embodiments, the fill material may include about 10% to about 40% acetaminophen based on total weight of the fill material. In other embodiments, the fill material may include about 15% to about 35%, about 20% to about 30%, or about 22% to about 27% of acetaminophen based on total weight of the fill material. In yet another embodiment, the fill material may include about 10%. about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% acetaminophen based on total weight of the fill material.

[0036] 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.

[0037] In some embodiments, the fill material may include about 0.1% to about 10% potassium acetate, based on total weight of the fill material. In other embodiments, the fill material may include about 1% to about 9%, about 2% to about 8%, about 3% to about 7%, or about 4% to about 6% potassium acetate, based on total weight of the fill material. In another embodiment, the fill material may include about 0.1%, about 0.5%, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% potassium acetate, based on total weight of the fill material.

[0038] In some embodiments, the fill material may include about 0.5% to about 5% propylene glycol, based on total weight of the fill material. In some embodiments, the fill material may include about 0.7% to about 4.5%, about 1% to about 4%, about 1.5% to about 3.5% or about 2% to about 3% propylene glycol, based on total weight of the fill material. In some embodiments, the fill material may include about 0.5%, about 1%. about 1.5%, about 2%. about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% propylene glycol, based on total weight of the fill material.

[0039] In some embodiments, the fill material may include about 1% to about 8% water, based on total weight of the fill material. In some embodiments, the fill material may include about 2% to about 7%, about 3% to about 6%. or about 4% to about 5% water, based on total weight of the fill material. In other embodiments, thefill material may include about 1%, about 2%. about 3%, about 4%, about 5%, about 6%, about 7%, or about 8% water, based on total weight of the fill material.

[0040] 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.

[0041] In some embodiments, the alkali metal salt of the NSAID may be potassium ibuprofen or sodium ibuprofen.

[0042] In some embodiments, the free acid NSAID may be ibuprofen.

[0043] 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 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 400 mg, about 600 mg or about 800 mg.

[0044] In some embodiments, the ratio of potassium acetate to acetaminophen maybe about 0.15: 1 to about 0.25: 1, or about 0.17: 1.

[0045] 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.

[0046] 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 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 types 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%. In some embodiments, the amount of gelatin in the shell composition may be about 10 wt%. about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%.about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, or about 80 wt%.

[0047] In one embodiment, the shell composition may include dextrose. In an embodiment, the amount of dextrose in the shell composition is about 0.005 wt% 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%. In some embodiments, the amount of dextrose in the shell composition may be about 0.005 wt%, about 0.01 wt%, about 0.1 wt%, about 0.15 v %, about 0.2 vrt.%, about 0.25 wt%, about 0.5 wt%, about 0.75 wt%, about 1 v %, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, or about 4 wt%.

[0048] 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%. In some embodiments, the amount of pectin in the shell composition may be about 2 wt%, about 3 wt%, about 5 wt%, about 5.5 wt%, about 7.5 wt%, about 10 wt%, about 12 wt%, about 15 wt%, or about 20 wt%.

[0049] In an embodiment, the film forming material may include a plasticizer. In some embodiments, 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. Sorbitol may be included 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, penlaerythntol. 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, apolyether 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-ty pe 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.

[0050] 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 wt%, or from about 10 wt% to about 30 wt%, or from about 15 wt% to about 25 wt%. In some embodiments, the amount of plasticizer in the shell composition may be about 2 wt%, about 5 wt%, about 8 wt%. about 10 wt%, about 15 wt%. about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, or about 40 wt%.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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 plantmaterial, 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.

[0056] 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.

[0057] 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 SweefN 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.

[0058] 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 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 30 °C / 65%RH at 1 month, 2 months, 3 months, 6 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 12 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.

[0059] 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 fill material; and (c) encapsulating the fill composition in a shell composition, wherein the softgel capsule has a stabi li ty of at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% at 1 month at room temperature. The encapsulation of the fill composition occurs at a temperature of about 30°C to about 45°C, about 32°C to about 40°C, or about 34°C to about 37°C. In some embodiments, the encapsulation of the fill composition may occur at a temperature of about 30°C, about 32°C, about 34°C. about 36°C, about 38°C, about 40°C, about 42°C, or about 45°C.

[0060] 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.

[0061] 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.

[0062] 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

[0063] 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

[0064] In one study, a softgel capsule according to an embodiment of the present disclosure was prepared. To begin preparing the softgel capsule, a premix of potassium hydroxide and potassium acetate was prepared in water and propylene glycol. The softgel was prepared by combining an NSAID, such as ibuprofen, and acetaminophen into a mixer in the same step to improve the solubility of ibuprofen prior to the addition of the premix. The premix of potassium hydroxide and potassium acetate was then added to the mixer. This was found to prevent degradation of the propylene glycol.

[0065] The solution was then mixed to form a fill material.

[0066] 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 dry ing gel formula.

[0067] The fill material of the Example had a fill formulation according to Table 1. Table 1 Fill Formulation

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 potassium acetate; and(b) a shell composition comprising a film forming material, wherein the softgel capsule has a stability after 1 month at room temperature of at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99%.

2. The softgel capsule of claim 1, wherein the fill material further comprises water, propylene glycol or a combination thereof.

3. The softgel capsule of claim 1 or 2, wherein the fill material comprises about 10% to about 40% acetaminophen, based on total weight of the fill material.

4. The softgel capsule of any one of claims 1-3, wherein the fill material comprises about 0.1% to about 10% potassium acetate, based on total weight of the fill material.

5. The softgel capsule of claim 2. wherein the fill material comprises about 0.5% to about 5% propylene glycol, based on total weight of the fill material.

6. The softgel capsule of claim 2, wherein the fill material comprises about 1% to about 8% water, based on total weight of the fill material.

7. The softgel capsule of any one of claims 1-6, wherein the film forming material comprises a plasticizer.

8. The softgel capsule of claim 1. 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 any one of claims 1-9, further comprising a free acid NSAID.

11. The softgel capsule of claim 10, wherein the free acid NSAID is ibuprofen.

12. The softgel capsule of any one of claims 1-11, wherein the alkali metal salt of ibuprofen is potassium ibuprofen.

13. The softgel capsule of any one of claims 1-12, wherein the ratio of potassium acetate to acetaminophen is about 0.15: 1 to about 0.25: 1.

14. The softgel capsule of any one of claims 1-13, wherein the fill material has a viscosity of about 10000 cPs to about 25000 cPs at 25°C measured with a Haake Viscotester 550V.

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 potassium acetate and mixing 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 about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99%.

16. The process of claim 15, wherein the encapsulation is performed at a temperature of about 30°C to about 45°C.

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