Softgel capsules containing nonsteroidal anti-inflammatory drugs and acetaminophen

Abstract

This specification describes softgel capsules comprising a filler material and a shell composition. The filler material may include an alkali metal salt of an NSAID, acetaminophen, and potassium acetate. The shell composition may include a film-forming material. The softgel capsules may have at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% stability at room temperature after one month.

Description

[[Technical Field]]

[0001] Cross-Reference to Related Applications This application claims the priority benefit of U.S. Provisional Patent Application No. 63 / 533,476, filed on August 18, 2023, the entire content of which is incorporated herein in its entirety.

[0002] The present invention relates to (a) a softgel capsule comprising a fill material comprising an alkali metal salt of a non-steroidal anti-inflammatory drug ("NSAID") and acetaminophen, as well as corresponding methods of manufacture and methods of treatment. [[Background Art]]

[0003] Capsule dosage forms are commonly used for oral administration of various pharmaceutical products. Capsules can be, for example, soft gelatin shells or hard shells (of animal or vegetable origin). Softgel capsules offer a number of advantages, including rapid dissolution, taste masking, ease of swallowing, fewer excipients compared to tablets, solubilization of slightly hydrophilic compounds and delivery of a liquid matrix that improves their oral bioavailability, delivery of low and ultra-low doses of compounds, delivery of low-melting temperature compounds, and minimization of dust generation during manufacturing, thus improving the safety of manufacturing personnel.

[0004] Soft capsules, particularly soft gelatin capsules (or softgel capsules), provide a dosage form that is more readily accepted by patients because the capsule is easy to swallow and does not require flavoring to mask any unpleasant taste of the active agent. Softgel encapsulation of drugs further offers the potential to improve the bioavailability of the drug. For example, as soon as the gelatin shell ruptures, the active ingredient can be rapidly released in liquid form.

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

[0006] In this technology field, there remains a need for NSAID / acetaminophen combination formulations that are useful for treating patients who require treatment. [Overview of the project]

[0007] In some embodiments of the present invention, the softgel capsule comprises (a) a filling material comprising an alkali metal salt of an NSAID, acetaminophen, and potassium acetate, and (b) a shell composition comprising a film-forming material. The softgel capsule may have at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% stability at room temperature after one month.

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

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

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

[0011] In some embodiments, the filler material may contain about 0.5% to about 5% propylene glycol.

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

[0013] In some embodiments, the filler material may further contain free acid NSAIDs.

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

[0015] In some embodiments, the ratio of alkali metal salt of NSAID to acetaminophen may be 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 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 the NSAID may be an NSAID potassium, such as ibuprofen potassium. In other embodiments, the alkali metal salt of the NSAID may be an NSAID sodium, such as ibuprofen sodium.

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

[0020] In some embodiments, the process for preparing the 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 together with the alkali metal salt of the NSAID to form a filler material, and (c) encapsulating the filler material in a softgel capsule. In certain embodiments, 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 one month. [Modes for carrying out the invention]

[0021] The inventors of this disclosure have developed a softgel capsule containing both NSAID and acetaminophen.

[0022] The present invention advances the state of the art by developing softgel capsules comprising a combination of an alkali metal salt of a non-steroidal anti-inflammatory drug ("NSAID") and acetaminophen. The softgel capsules of the present invention comprise a fill material that is free-flowing at room temperature, and the shell composition has a shorter drying time than conventional softgel capsules. Such a mechanism is beneficial for the encapsulation of fill materials comprising an alkali metal salt of an NSAID and acetaminophen.

[0023] As used herein, "NSAID" refers to a non-steroidal anti-inflammatory drug or compound that can be used for the diagnosis, cure, mitigation, treatment, or prevention of a symptom. The term "condition" or "conditions" refers to those medical conditions that can be treated or prevented by administering an effective amount of an NSAID to a subject.

[0024] As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount of active agent, or the rate at which it is administered, necessary to produce the desired therapeutic result.

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

[0026] All references to weight percent throughout the specification and claims refer to the weight of the ingredient relative to the total weight of the composition, and may also be designated as w / w.

[0027] As used herein, "fill material" or "fill" refers to a composition that is encapsulated by a capsule shell and contains at least one pharmaceutically active ingredient.

[0028] As used herein, the term "about" refers to any value within a variation of ±10%, such that "about 10" includes 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 mixtures of two or more different excipients, and the like.

[0029] The recitation of ranges of values herein is 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] Any and all examples provided herein, or the use of exemplary language (e.g., "such as"), is merely intended to clarify certain materials and methods, and does not impose a limitation on the scope. No language in the specification should be construed as indicating any element that is not claimed as essential to the practice of the materials and methods of the present disclosure.

[0031] According to one embodiment, the softgel capsule may comprise (a) a filler material comprising an alkali metal salt of an NSAID, acetaminophen, and potassium acetate, and (b) a shell composition comprising 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 one month. The filler material of the softgel capsule can flow freely at room temperature. In some embodiments, the filler material may have a viscosity of 16,500 cPs at 25°C and 2,400 cPs at 45°C, as measured with Haake Viscotester 550V. In some embodiments, the filler material may have a viscosity of approximately 10,000 cPs to approximately 25,000 cPs, approximately 11,000 cPs to approximately 24,000 cPs, approximately 12,000 cPs to approximately 23,000 cPs, approximately 13,000 cPs to approximately 22,000 cPs, approximately 14,000 cPs to approximately 21,000 cPs, approximately 15,000 cPs to approximately 20,000 cPs, or approximately 16,000 to approximately 19,000 cPs at 25°C, as measured with Haake Viscotester 550V. In some embodiments, the filler 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, as measured with Haake Viscotester 550V.

[0032] NSAIDs are a large group of therapeutic compounds. NSAIDs can reduce inflammation by blocking cyclooxygenase. Examples of NSAIDs include, but are not limited to, aceclofenac, acemetacin, actarit, alcofenac, aluminoprofen, amfenac, aloxipirin, aminophenazone, anthraphenine, aspirin, azapropazon, benolilate, benoxaprofen, benzydamine, butibufen, celecoxib, chlortenoxazine, choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorphazon, epirizole; etodolac, etricoxib, feclobuzone, felbinac, fenbufen, and fenclofen. Examples include Enac, flurbiprofen, graphenin, hydroxyethyl salicylate, ibuprofen, indomethacin, indoprofen, ketoprofen, ketrolac, lactylphenetidine, loxoprofen, lumiracoxib, mefenamic acid, meloxicam, metamisole, methiadic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, nifluminic acid, oxamethacin, phenacetin, pipebuzone, pranoprofen, propifenazone, procazone, brotidic acid, lofecoxib, salicylamide, sarsalat, sulindac, suprofen, tiaramide, tinoridine, tolfenamic acid, valdecoxib, and zomepirac.

[0033] NSAIDs can be classified based on their chemical structure or mechanism of action. Non-limiting examples of NSAIDs include salicylic acid derivative NSAIDs, p-aminophenol derivative NSAIDs, propionic acid derivative NSAIDs, acetic acid derivative NSAIDs, enolic acid derivative NSAIDs, fenamic acid derivative NSAIDs, non-selective cyclooxygenase (COX) inhibitors, selective cyclooxygenase 1 (COX1) inhibitors, and selective cyclooxygenase 2 (COX2) inhibitors. NSAIDs can also include profens. Preferred salicylic acid derivative NSAIDs include, but are not limited to, acetylsalicylic acid (aspurine), diflunisal, and salsalate. Preferred p-aminophenol derivative NSAIDs include, but are not limited to, paracetamol and phenacetin. Suitable propionic acid derivative NSAIDs include, but are not limited to, aluminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen. Suitable acetate derivative NSAIDs include, but are not limited to, aceclofenac, acemetacin, actarit, alcofenac, amfenac, clometac, diclofenac, etodolac, felbinac, fenclofenac, indomethacin, ketorolac, methiadic acid, mofezolac, nabumetone, naproxen, oxamethacin, sulindac, and zomepirac. Suitable enolic acid (oxicam) derivative NSAIDs include, but are not limited to, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam. Suitable fenamic acid derivative NSAIDs include, but are not limited to, flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid. Suitable selective COX-2 inhibitors include, but are not limited to, celecoxib, etoricoxib, firocoxib, lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.

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

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

[0036] The total dose of acetaminophen in the dosage form may be, for example, about 50 mg to about 1000 mg, 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, the total dose of ibuprofen in the dosage form (corresponding to free base) may be, for example, 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 filler material may contain about 0.1% to about 10% potassium acetate based on the total weight of the filler material. In other embodiments, the filler material may contain 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 the total weight of the filler material. In yet another embodiment, the filler material may contain 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 the total weight of the filler material.

[0038] In some embodiments, the filler material may contain about 0.5% to about 5% propylene glycol based on the total weight of the filler material. In some embodiments, the filler material may contain 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%, based on the total weight of the filler material. In some embodiments, the filler material may contain 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%, based on the total weight of the filler material.

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

[0040] In some embodiments, the softgel capsules of the present disclosure may further contain free acid NSAIDs. In some embodiments, the ratio of alkali metal salt of NSAID to free acid NSAID may be about 75:25 to about 100. In other embodiments, the ratio of alkali metal salt of NSAID to free acid NSAID may be about 88:12 to about 92:8. In some embodiments, the ratio of alkali metal salt of NSAID to free acid NSAID may be 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 ibuprofen potassium or ibuprofen sodium.

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

[0043] The total dose of ibuprofen in the dosage form (corresponding to free bases) may be, for example, about 50 mg to about 1000 mg, 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, the total dose of ibuprofen in the dosage form (corresponding to free bases) may be, for example, 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 may be about 0.15:1 to about 0.25:1, or about 0.17:1.

[0045] In other embodiments, the filler material may include additional filler components, such as flavoring agents, sweeteners, colorants and fillers, antioxidants, or other pharmaceutically acceptable excipients, or additives such as synthetic dyes and inorganic oxides.

[0046] In one embodiment, the gelatin in the shell composition may include type A gelatin, type B gelatin, skin or dermal gelatin, and / or bone gelatin, used alone or in combination. In one embodiment, the gelatin may be porcine skin gelatin or type B. In another embodiment, only one type of gelatin may be present. In yet another embodiment, the gelatin may be a combination of at least two types of gelatin. In one embodiment, the amount of gelatin in the shell composition may be about 10% to about 80% by weight, or about 20% to about 70% by weight, or about 30% to about 60% by weight, or about 40% to about 50% by weight. In some embodiments, the amount of gelatin in the shell composition may be about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, or about 80% by weight.

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

[0048] In some embodiments, the shell composition may contain pectin. In some embodiments, the pectin may be low-methoxypectin. In some embodiments, the pectin may be amidated pectin, unamidated pectin, or a combination thereof. In one embodiment, the pectin is low-methyl ester (LM) pectin having a degree of esterification of less than 50. In some embodiments, the pectin is LMS-318, SPL-12, LM-102AS-Z, and / or LM-12CG-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 one embodiment, the amount of pectin in the shell composition is about 2% to about 20% by weight, about 3% to about 15% by weight, about 3% to about 5.5% by weight, and about 5% to about 10% by weight. In some embodiments, the amount of pectin in the shell composition may be about 2% by weight, about 3% by weight, about 5% by weight, about 5.5% by weight, about 7.5% by weight, about 10% by weight, about 12% by weight, about 15% by weight, or about 20% by weight.

[0049] In one 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 one embodiment, the plasticizer may include a combination of sorbitol and glycerin. Sorbitol may be included to reduce the possibility of ester formation in ibuprofen free acid. Other suitable plasticizers include, but are not limited to, sugar alcohol plasticizers such as isomalt, maltitol, xylitol, erythritol, adonitol, dalcitol, pentaerythritol, or mannitol, or polyol plasticizers such as diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine, and mixtures thereof. Other exemplary plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, singleblock polymers, citrate ester-type plasticizers, and triacetins. Examples of 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, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.

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

[0051] In one embodiment, the shell composition may also include a gelling agent. In some embodiments, the gelling agent may be gellan gum. For example, the gellan gum may be Kelcogel CG-LA gellan gum.

[0052] The shell composition may also contain water. In some embodiments, water may be included in the shell composition in an amount of 10% to about 60% by weight, or about 20% to about 50% by weight, or about 30% to about 45% by weight, based on the total shell composition.

[0053] In one embodiment, the shell composition may optionally contain additional agents, such as colorants, flavoring agents, sweeteners, fillers, antioxidants, diluents, pH modifiers, or other pharmaceutically acceptable excipients, or additives such as synthetic dyes and mineral oxides.

[0054] Examples of suitable colorants include, but are not limited to, white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown. In certain embodiments, the color of the dosage form may indicate the contents contained therein (e.g., one or more active ingredients).

[0055] Examples of suitable flavoring agents include, but are not limited to, "flavor extracts" obtained by extracting a portion of a raw material, such as animal or plant material, often using a solvent such as ethanol or water; and natural essences obtained by extracting essential oils from flowers, fruits, roots, or the whole plant.

[0056] Additional exemplary flavoring agents that may be in dosage form include, but are not limited to, breath-freshening compounds such as menthol, spearmint, and cinnamon; other flavorings or fragrances such as coffee beans and fruit flavorings (e.g., cherry, orange, grape, etc.), particularly those used for oral hygiene; and active substances used in dental and oral hygiene, such as quaternary ammonium bases. The effect of the flavoring agent may be enhanced using flavor enhancers such as tartaric acid, citric acid, and vanillin.

[0057] Examples of sweeteners include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Examples of artificial sweeteners include acesulfame and various salts thereof, e.g., potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salts (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and various salts thereof, e.g., sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose, e.g., sucralose (available as Kaltame® and Splenda®), and mogrosides. Examples of natural sweeteners include glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); stevia rebaudiana (stevioside), monk fruit, sorbitol, mannitol, xylitol, erythritol, and other polyols, which are natural sweeteners with high sweetness levels.

[0058] In some embodiments, the softgel capsule may have 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% stability when tested at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, or 12 months. In some embodiments, the softgel capsule may have 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% stability when tested at 30°C / 65%RH for 1 month, 2 months, 3 months, 6 months, or 12 months. In some embodiments, softgel capsules may have 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% stability when tested at 40°C / 75%RH for 1 month, 2 months, 3 months, 6 months, or 12 months. As used herein, stability is measured as the amount of activator remaining after an accelerated period of storage at a certain temperature and relative humidity.

[0059] According to one embodiment, a 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 together with the alkali metal salt of the NSAID to form a filler material, and (c) encapsulating the filler composition in a shell composition, the softgel capsule having at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% stability at room temperature after one month. Encapsulation of the filler composition occurs at temperatures 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, encapsulation of the filler composition may occur at temperatures 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 filler material may contain free acid NSAIDs. The ratio of alkali metal salt to free acid NSAID is about 75:25 to about 100. In some embodiments, the ratio of alkali metal salt to free acid NSAID is about 88:12 to about 92:8.

[0061] In some embodiments, the ratio of alkali metal salt of NSAID to acetaminophen is about 0.35:1 to about 0.5:1. In some embodiments, the ratio of alkali metal salt of NSAID to acetaminophen is about 0.35:1 to about 0.45:1. In some embodiments, the alkali metal salt of NSAID may be ibuprofen potassium. In some embodiments, the free acid NSAID may be ibuprofen.

[0062] According to one embodiment, the softgel capsules described herein may be used as a method for treating pain, reducing inflammation, and / or reducing fever. In some embodiments, a method for treating a headache may include administering the softgel capsules described herein. In some embodiments, a method for treating pain associated with a sprain or muscle strain may include administering the softgel capsules described herein. In some embodiments, a method for treating a cold or influenza may include administering the softgel capsules described herein. In some embodiments, a method for reducing inflammation may include administering the softgel capsules described herein. [Examples]

[0063] Herein, specific embodiments of the present invention are shown by reference to the following examples. These examples are disclosed solely for illustrative purposes and should not be understood in any way as limiting the scope of the invention.

[0064] Method for preparing softgel capsules In one test, softgel capsules were prepared according to one embodiment of the present disclosure. To begin the preparation of the softgel capsules, a premix of potassium hydroxide and potassium acetate was prepared in water and propylene glycol. Before adding the premix, a softgel was prepared by combining an NSAID such as ibuprofen and acetaminophen in the same process into a mixer to improve the solubility of ibuprofen. The premix of potassium hydroxide and potassium acetate was then added to the mixer. It was found that this prevented the decomposition of propylene glycol.

[0065] Next, the solutions were mixed to form the filler material.

[0066] Next, the filler material was transferred to a receiver, and the receiver was transferred to a rotary die encapsulation machine. Then, using a low-sulfuric acid, fast-drying gel formulation, the filler material was encapsulated into 12 oval dies.

[0067] The filler material in the example had the filler formulation shown in Table 1. [Table 1]

Claims

1. It is a soft gel capsule, (a) A filler material comprising an alkali metal salt of a nonsteroidal anti-inflammatory drug ("NSAID"), acetaminophen, and potassium acetate, (b) A soft gel capsule comprising a shell composition containing a film-forming material, wherein the soft gel capsule has at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% stability at room temperature after one month.

2. The soft gel capsule according to claim 1, wherein the filling material further comprises water, propylene glycol, or a combination thereof.

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

4. The soft gel capsule according to any one of claims 1 to 3, wherein the filling material contains about 0.1% to about 10% potassium acetate based on the total weight of the filling material.

5. The soft gel capsule according to claim 2, wherein the filling material contains about 0.5% to about 5% propylene glycol based on the total weight of the filling material.

6. The soft gel capsule according to claim 2, wherein the filling material contains about 1% to about 8% water based on the total weight of the filling material.

7. The soft gel capsule according to any one of claims 1 to 6, wherein the film-forming material contains a plasticizer.

8. The softgel capsule according to claim 1, wherein the ratio of alkali metal salt of NSAID to acetaminophen is about 0.35:1 to about 0.45:

1.

9. The softgel capsule according to any one of claims 1 to 8, wherein the alkali metal salt of ibuprofen is ibuprofen potassium.

10. A softgel capsule according to any one of claims 1 to 9, further comprising a free acid NSAID.

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

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

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

1.

14. The soft gel capsule according to any one of claims 1 to 13, wherein the filling material has a viscosity of about 10,000 cPs to about 25,000 cPs at 25°C, as measured by a Haake Viscotester 550V.

15. A process for preparing softgel capsules, (a) Combining an NSAID with an alkali metal hydroxide to form an alkali metal salt of the NSAID, (b) Solubilizing acetaminophen together with potassium acetate and mixing it with the alkali metal salt of the NSAID to form a filler material. (c) Encapsulating the filling material in a soft gel capsule shell at room temperature, A process wherein the softgel capsule has at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% stability at room temperature after one month.

16. The process according to claim 15, wherein the encapsulation is carried out at a temperature of approximately 30°C to approximately 45°C.

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