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 contain alkali metal salts of NSAIDs and acetaminophen, but may not contain povidone. The shell composition may contain a film-forming material. The softgel capsules may have at least about 99% assay stability at room temperature after 12 months.

Description

Technical Field

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[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 533,473, filed on August 18, 2023, the entire content of which is incorporated herein by reference in its entirety.

[0002] The present invention relates to (a) soft - gel capsules containing a filling material comprising an alkali metal salt of a non - steroidal anti - inflammatory drug ( "NSAID") and acetaminophen, and corresponding manufacturing and treatment methods.

Background Art

[0003] The capsule dosage form is commonly used for oral administration of various pharmaceuticals. Capsules can be, for example, of soft gelatin shell or hard shell (animal or plant variety). Soft - gel capsules offer many advantages, including rapid dissolution, taste masking, ease of swallowing, fewer excipients compared to tablets, delivery of a liquid matrix that solubilizes slightly hydrophilic compounds and improves their oral bioavailability, delivery of compounds at low and ultra - low doses, delivery of compounds with low melting temperatures, and minimization of dust generation during manufacturing, thus improved safety for manufacturing personnel.

[0004] Soft capsules, particularly soft gelatin capsules (or soft - gel capsules), provide a dosage form that is more readily acceptable to patients because the capsule is easy to swallow and there is no need to flavor it to mask any unpleasant taste of the active agent. Encapsulating a drug in a soft - gel capsule 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 diseases 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 filler material comprising an alkali metal salt of an NSAID, acetaminophen, and polyalkylene glycol, wherein the filler material is povidone-free, and (b) a shell composition comprising a film-forming material containing a plasticizer. In some embodiments, the filler material is free-flowing at room temperature. In some embodiments, the shell composition contains a plasticizer that reduces drying time during processing.

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

[0009] In some embodiments, the softgel capsule comprises (a) a filler material comprising an alkali metal salt of an NSAID, acetaminophen, and a polyalkylene glycol, wherein the filler material is povidone-free, and (b) a shell composition comprising a film-forming material, wherein the temperature during the manufacture of the filler material does not exceed 60°C. In some embodiments, the temperature may solubilize acetaminophen. If the temperature is higher than 60°C, this may increase the potential formation of acetaminophen degradation products such as 4-aminophenol.

[0010] In some embodiments, the softgel capsule may further contain free acid NSAIDs.

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

[0012] In some embodiments, the ratio of alkali metal salts of NSAIDs to free acid NSAIDs is approximately 88:12 to approximately 92:8.

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

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

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

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

[0017] In some embodiments, the process for preparing softgel capsules 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 at room temperature.

[0018] In some embodiments, the process for preparing softgel capsules 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 containing about 10% to about 80% gelatin and a plasticizer. In some embodiments, the plasticizer may, for example, in a low sulfuric acid gel, contain sorbitol and glycerin in a glycerin to sorbitol ratio of about 0.5:about 1 to about 3:about 1, or in a ratio of about 1:1 to about 1.5:1.

[0019] In some embodiments, the process for preparing a softgel capsule includes (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 containing about 10% to about 80% gelatin and a 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 alginic acid.

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

[0022] In some embodiments, the shell comprises an enteric-coated polymer such as pectin. In certain embodiments, the pectin is amidated pectin, unamidated pectin, or a combination thereof. In some embodiments, the shell composition comprises about 2% to about 5% by weight of pectin. In some embodiments, the shell composition comprises unamidated pectin.

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

[0024] In certain embodiments, the film-forming material includes gelatin, and the gelatin includes type A gelatin, type B gelatin, and mixtures thereof. In some embodiments, the gelatin includes fish gelatin, skin gelatin, bone gelatin, and mixtures thereof.

[0025] In some embodiments, the shell composition further comprises a plasticizer, the plasticizer comprising glycerol, glycerin, sorbitol, and combinations thereof. In some embodiments, the plasticizer may comprise glycerin and sorbitol in a ratio of about 0.5 to about 1 to about 3 to about 1, or in a ratio of about 1:1 to about 1.5 to 1, for example, in a low sulfuric acid content gel.

[0026] In some embodiments, the shell composition of the softgel capsule further contains water. In some embodiments, the shell composition contains about 10% to about 50% by weight of water. [Modes for carrying out the invention]

[0027] The inventors of the present disclosure have developed a soft gel capsule containing a combination of an NSAID and acetaminophen. It has been found that when a person skilled in the art mixes an NSAID and acetaminophen simultaneously and subsequently adds an alkali metal salt such as KOH / potassium acetate, a very viscous filling solution can be obtained. Therefore, in order to encapsulate such a filling material, it may be necessary to heat the material. Further, such a mixing process may cause unnecessary ions due to the addition of potassium acetate and any possible side effects. To avoid these problems, the inventors have found that by converting the NSAID to an alkali metal NSAID such as potassium ibuprofen before adding acetaminophen, the alkali metal NSAID can act as a solubilizing agent for acetaminophen. Therefore, the process of the present invention eliminates the step of adding an alkali metal salt and also eliminates the problem of the above-mentioned harmful treatment.

[0028] Furthermore, the inventors have found that the NSAID can be neutralized with an alkali metal salt such as KOH at a molar ratio of 0.9 to 1 (i.e., 90% ionization). This results in a molar ratio of approximately 0.33 to 1 of alkali metal NSAID to acetaminophen. Due to the high concentration of the alkali metal NSAID relative to acetaminophen, acetaminophen dissolves rapidly at a temperature of, for example, about 45°C. Therefore, the filling material of the present disclosure does not need to be heated to a higher temperature such as 65°C, and also does not need to be mixed for a long time due to the improved solubility of certain embodiments of the present invention. Further, it has been found that by using a lower temperature, the formation of acetaminophen impurities such as 4-aminophenol can be reduced or eliminated. Also, the filling material of certain embodiments of the present invention has a lower viscosity than expected, enabling encapsulation to occur at room temperature.

[0029] The present invention advances the state of the art by developing a soft gel capsule comprising a combination of an alkali metal salt of a nonsteroidal anti-inflammatory drug (「NSAID」) and acetaminophen. The soft gel capsule of the present invention contains a filling material that is free-flowing at room temperature, and the shell composition has a lower drying time than conventional soft gel capsules. Such mechanism is beneficial for the encapsulation of the filling material containing the alkali metal salt of NSAID and acetaminophen.

[0030] As used herein, 「NSAID」 refers to a nonsteroidal anti-inflammatory drug or compound that can be used for the diagnosis, cure, mitigation, treatment, or prevention of a condition. The term 「condition」 or 「conditions」 refers to those medical states that can be treated or prevented by administering an effective amount of NSAID to a subject.

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

[0032] As used herein, 「shell」 or 「shell composition」 refers to the shell of a soft gel capsule that encapsulates a filling material.

[0033] All references to weight % throughout the specification and claims refer to the weight of the component relative to the weight of the entire composition, and may be designated as w / w.

[0034] As used herein, 「filling material」 or 「filling」 refers to a composition that is encapsulated by a capsule shell and contains at least one pharmaceutically active ingredient.

[0035] As used herein, “about” refers to any value within a ±10% variation, 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, a reference to “excipient” includes a single excipient, as well as mixtures of two or more different excipients.

[0036] The enumeration of value ranges in this Specified is intended to function merely as a simplified way of referring individually to each distinct value within the range, unless otherwise indicated herein, and each distinct value is incorporated herein as if it were individually enumerated herein. All methods described herein may be carried out in any preferred order, unless otherwise indicated herein or unless it is clearly inconsistent with the context.

[0037] Any and all examples or illustrative language provided herein (e.g., "etc.") are intended solely to illustrate certain materials and methods, and not to limit their scope. Nothing in this specification should be construed as indicating any element not claimed to be essential to the performance of the materials and methods of this disclosure.

[0038] According to one embodiment, the softgel capsule comprises (a) a filler material comprising an alkali metal salt of an NSAID, acetaminophen, and polyalkylene glycol, wherein the filler material is povidone-free, and (b) a shell composition comprising a film-forming material containing a plasticizer. The filler material of the softgel capsule can flow freely at room temperature. In some embodiments, the filler material may have a viscosity of about 1,000 cP to about 10,000 cP, or about 1,000 cP to about 5,000 cP, or about 2,000 cP to about 3,000 cP at 25°C, as determined by a HAAKE RheoWin viscometer. In some embodiments, the filler 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 this disclosure reduces drying time.

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

[0040] In some embodiments, the filler material may contain polyalkylene glycol in amounts of about 30% to about 70% by weight, about 35% to about 65% by weight, about 40% to about 60% by weight, or about 45% to about 55% by weight, based on the total weight of the filler material.

[0041] 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.

[0042] 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.

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

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

[0045] 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.

[0046] 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.

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

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

[0049] 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.

[0050] 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.

[0051] 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 some embodiments, the gelatin may be low-sulfate gelatin. 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.

[0052] 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.

[0053] 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.

[0054] In one embodiment, the plasticizer in the shell composition may include glycerol, glycerin, sorbitol, and combinations thereof. In one embodiment, the plasticizer may include, for example, a combination of sorbitol and glycerin in 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, in a low sulfuric acid content gel. 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 also 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 triacetin. Examples of such plasticizers 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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).

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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, 9 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, 9 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 9 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.

[0064] In some embodiments, the amount of 4-aminophenol in the softgel may be less than approximately 0.2%, less than approximately 0.1%, less than approximately 0.05%, less than approximately 0.02%, less than approximately 0.01%, or undetectable at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months; less than approximately 0.05%, less than approximately 0.02%, less than approximately 0.01% at 40°C / 75%RH for 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 approximately 0.2%, less than approximately 0.1%, less than approximately 0.05%, less than approximately 0.02%, less than approximately 0.01%, or less than approximately 0.001% at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months; less than approximately 0.05%, less than approximately 0.01%, less than approximately 0.01%, or less than approximately 0.001% at 40°C / 75%RH for 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 approximately 0.2%, less than approximately 0.1%, less than approximately 0.05%, less than approximately 0.02%, less than approximately 0.01%, or less than approximately 0.001%. In some embodiments, the total amount of 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 for 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months; less than about 0.01%, less than about 0.005%, or less than about 0.001% at 40°C / 75%RH for 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months.

[0065] 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 filling material, and (c) encapsulating the filling composition in a shell composition at room temperature.

[0066] According to another embodiment, a process for preparing a softgel capsule comprises (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 filler material; and (c) encapsulating the filler material in a shell composition containing about 10% to about 80% gelatin in combination with a plasticizer. The plasticizer may, for example, in a low sulfuric acid gel, contain sorbitol and glycerin in a ratio of about 0.5:1 to about 3:1 glycerin to sorbitol, or in a ratio of about 1:1 to about 1.5 to 1.

[0067] According to another embodiment, a process for preparing a softgel capsule includes (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 shell composition containing about 10% to about 80% gelatin and a plasticizer.

[0068] 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.

[0069] 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.

[0070] 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]

[0071] 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.

[0072] 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, deionized water was added to a sealed mixing vessel of approximately 40 gallons equipped with a bottom mixer. The water was cooled to approximately 15°C. With a complete vacuum obtained over the vessel, potassium hydroxide was slowly transferred under vacuum into a vessel maintained at a temperature of less than 40°C while mixing at approximately 100 RPM. Mixing continued until the potassium hydroxide was completely dissolved. The temperature of the solution was maintained at 20°C to 25°C.

[0073] Polyethylene glycol 400 was vacuum-transferred into a sealed mixing container of approximately 300 gallons. The jacket of the sealed container was set to 27°C. With the disperser set to 1200 RPM and the sweep set to 20 RPM, ibuprofen was vacuum-transferred into the sealed mixing container while mixing under vacuum, and continued mixing under vacuum until homogeneous.

[0074] After mixing is complete, the potassium hydroxide solution is slowly vacuum-transferred through a 0.125-inch orifice plate into a 300-gallon sealed mixing tank while mixing with a disperser at 1200 RPM and a sweep at 20 RPM. The temperature was kept below 50°C.

[0075] The temperature of the filling material was set to 45°C. After mixing for approximately 15 minutes, acetaminophen was vacuum-transferred into a sealed mixing tank. The mixture was mixed at 45°C for at least 30 minutes until all of the acetaminophen was completely dissolved.

[0076] The filler material was set to 27°C and degassed for at least 45 minutes. The filler material was then transferred to a receiver, and the receiver was transferred to a rotary die encapsulator. The filler material was then encapsulated into 12 oval dies using a low-sulfuric acid, fast-drying gel formulation.

[0077] The softgel capsules were dried to a moisture content of 7.0% to 7.5%. [Table 1] [Table 2]

[0078] Stability and dissolution tests The stability and dissolution of softgel capsules containing 250 mg of acetaminophen and 125 mg of ibuprofen were tested under accelerated stability conditions at 40°C / 75%RH in the bottle (lot 22PP-33), intermediate stability conditions at 30°C / 65%RH in the bottle and blister pack, and ambient stability conditions at 25°C / 60%RH in the bottle and blister pack. The amount of impurities present in the samples was also tested. The test results are shown in Tables 3, 4, 5, and 6. [Table 3] [Table 4] [Table 5] Table 6

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 polyalkylene glycol, wherein the filler material is a filler material that does not contain povidone, (b) A soft gel capsule comprising a shell composition containing a film-forming material containing a plasticizer, wherein the soft gel capsule has at least 99% stability at room temperature after one month.

2. It is a soft gel capsule, (a) A filler material comprising an alkali metal salt of an NSAID, acetaminophen, and polyalkylene glycol, (b) A soft gel capsule comprising a shell composition containing approximately 10% to approximately 80% gelatin and a plasticizer.

3. It is a soft gel capsule, (a) A filler material comprising an alkali metal salt of an NSAID, acetaminophen, and polyalkylene glycol, wherein the filler material does not contain povidone, (b) A shell composition comprising a film-forming material, A soft gel capsule in which the temperature of the filling material during manufacturing does not exceed 60°C.

4. A softgel capsule according to any one of claims 1 to 3, further comprising a free acid NSAID.

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

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

8.

7. A softgel capsule according to any one of claims 1 to 3, wherein the ratio of alkali metal salt of NSAID to acetaminophen is about 0.35:1 to about 0.5:

1.

8. A softgel capsule according to any one of claims 1 to 3, 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. The softgel capsule according to claim 4, wherein the free NSAID is ibuprofen.

11. The soft gel capsule according to any one of claims 1 to 10, wherein the filling material has a viscosity of about 2000 cP to about 3000 cP at 25°C.

12. The soft gel capsule according to any one of claims 1 to 10, wherein the filling material is free-flowing at room temperature.

13. The soft gel capsule according to any one of claims 1 to 12, wherein the plasticizer comprises glycerin and sorbitol.

14. The soft gel capsule according to claim 13, wherein the glycerin and sorbitol are in a ratio of 1:1 to 1.5:

1.

13. 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 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 by which the softgel capsule has at least 99% stability at room temperature after one month.

14. 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 with the alkali metal salt of the NSAID to form a filler material. (c) A process comprising encapsulating the filler material in a soft gel capsule shell containing about 10% to about 80% gelatin and a plasticizer.

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 with the alkali metal salt of the NSAID to form a filler material. (c) A process comprising encapsulating the filling material in a soft gel capsule shell containing about 10% to about 80% gelatin.

16. The process according to any one of claims 13 to 15, wherein the filler further comprises a free acid NSAID.

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

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

8.

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

1.

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

1.

21. The process according to any one of claims 13 to 20, wherein the alkali metal salt of ibuprofen is ibuprofen potassium.

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

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