Modified-release valproic acid softgel capsules

Abstract

The softgel capsule comprises a fill composition and a shell composition, the fill composition comprising valproic acid, and the shell composition comprising gelatin, a plasticizer, and an enteric polymer. The softgel capsule further comprises a dose of 125 mg to 1000 mg of valproic acid. Methods for producing the softgel capsule using gel mass and rotary die encapsulation are also provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 311,559, filed February 18, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to an enteric coated softgel capsule comprising a shell composition and a fill composition. Specifically, the enteric coated softgel capsule comprises valproic acid in the fill composition. Methods of preparation of such dosage forms and methods of use thereof are also disclosed. [Background technology]

[0003] Capsule dosage forms are commonly used for oral administration of various pharmaceuticals. Capsules can be, for example, soft gelatin shell or hard shell (animal or plant varieties). Soft gel capsules offer many advantages, including fast dissolution, taste masking, ease of swallowing, fewer excipients compared to tablets, delivery of a liquid matrix that solubilizes compounds with slight hydrophilicity and improves their oral bioavailability, delivery of low and very low doses of compounds, delivery of compounds with low melting temperatures, and minimization of dusting during manufacturing and thus improved safety for manufacturing personnel.

[0004] Soft capsules, especially soft gelatin capsules (or soft gel capsules), provide a dosage form that is easy to swallow and does not require flavoring to mask any unpleasant taste of active drugs, making it more acceptable to patients.Soft gel encapsulation of drugs also offers the possibility of improving the bioavailability of the pharmaceutical agent.For example, the active ingredient can be released quickly in the form of liquid or solution as soon as the gelatin shell is ruptured. Summary of the Invention

[0005] The present invention advances the state of the art by developing delayed release oral dosage forms, particularly delayed release softgel capsules, that contain enteric polymers. The delayed release softgel capsules of the present invention relate to a fill material and a shell composition, where the fill material comprises valproic acid.

[0006] In one embodiment of the present disclosure, the softgel capsule comprises a fill material and a shell composition, where the fill material comprises valproic acid and the shell composition comprises gelatin, a plasticizer, and an enteric polymer.

[0007] In some embodiments of the softgel capsule, the shell composition further comprises dextrose. In some embodiments of the softgel capsule, the enteric polymer may be pectin. In certain embodiments, the pectin may be amidated pectin, non-amidated pectin, or a combination thereof.

[0008] In some embodiments of the softgel capsule, the shell composition may comprise about 25 wt% to about 55 wt% gelatin. In some embodiments of the softgel capsule, the shell composition may comprise about 3 wt% to about 22 wt% pectin. In some embodiments of the softgel capsule, the shell composition may comprise about 0.01 wt% to about 1.0 wt% dextrose.

[0009] In certain embodiments of the softgel capsule, the gelatin may be selected from the group consisting of type A gelatin, type B gelatin, and mixtures thereof. In certain embodiments of the softgel capsule, the gelatin may be selected from the group consisting of fish gelatin, hide gelatin, bone gelatin, and mixtures thereof.

[0010] In some embodiments of the softgel capsule, the plasticizer may be selected from the group consisting of glycerin, aqueous sorbitol and sorbitan solutions, and combinations thereof. In certain embodiments, the plasticizer may be glycerin, aqueous sorbitol and sorbitan solutions, or combinations thereof.

[0011] In some embodiments of the softgel capsule, the shell composition can further comprise water. In certain embodiments of the softgel capsule, the shell composition can comprise from about 10 wt% to about 50 wt% water.

[0012] In some embodiments of the softgel capsule, the shell composition may further comprise a gelling agent. In certain embodiments, the shell composition may comprise from about 0.2 wt% to about 8 wt% of a gelling agent. In certain embodiments, the gelling agent may be gellan gum.

[0013] In some embodiments, the fill composition may include an antioxidant. In some embodiments, the fill composition may include butylated hydroxytoluene (BHT). In some embodiments, the fill composition may include butylated hydroxyanisole (BHA).

[0014] In some embodiments of the softgel capsule, the fill composition may contain from about 125 mg to about 1000 mg, from about 250 mg to about 750 mg, or from about 350 mg to about 550 mg of valproic acid, or any subrange or value within the range.

[0015] In some embodiments of the softgel capsule, the shell composition may include nonamidated pectin. In certain embodiments of the softgel capsule, the shell composition may further include a methacrylic acid copolymer.

[0016] In some embodiments of the softgel capsule, the softgel capsule may have at least about 90% stability when tested at 25° C. / 60% RH at 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months. In certain embodiments, the softgel capsule may have at least about 92% stability when tested at 25° C. / 60% RH at 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months. In certain embodiments, the softgel capsule may have at least about 94% stability when tested at 25° C. / 60% RH at 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months. In certain embodiments, the softgel capsule may have at least about 96% stability when tested at 25° C. / 60% RH at 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months. In certain embodiments, the softgel capsules may have a stability of at least about 98% when tested at 25° C. / 60% RH at 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months. In certain embodiments, the softgel capsules may have a stability of at least about 99% when tested at 25° C. / 60% RH at 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0017] In some embodiments, the softgel capsule may have at least about 90% stability when tested at 30° C. / 65% RH at 1 month, 2 months, 3 months, 6 months, or 12 months. In certain embodiments, the softgel capsule may have at least about 92% stability when tested at 30° C. / 65% RH at 1 month, 2 months, 3 months, 6 months, or 12 months. In certain embodiments, the softgel capsule may have at least about 94% stability when tested at 30° C. / 65% RH at 1 month, 2 months, 3 months, 6 months, or 12 months. In certain embodiments, the softgel capsule may have at least about 96% stability when tested at 30° C. / 65% RH at 1 month, 2 months, 3 months, 6 months, or 12 months. In certain embodiments, the softgel capsules may have a stability of at least about 98% when tested at 1 month, 2 months, 3 months, 6 months, or 12 months at 30° C. / 65% RH. In some embodiments, the softgel capsules may have a stability of at least about 99% when tested at 1 month, 2 months, 3 months, 6 months, or 12 months at 30° C. / 65% RH.

[0018] In some embodiments, the softgel capsule may have at least about 90% stability when tested at 40° C. / 75% RH at 1 month, 2 months, 3 months, or 6 months. In certain embodiments, the softgel capsule may have at least about 92% stability when tested at 40° C. / 75% RH at 1 month, 2 months, 3 months, or 6 months. In certain embodiments, the softgel capsule may have at least about 94% stability when tested at 40° C. / 75% RH at 1 month, 2 months, 3 months, or 6 months. In certain embodiments, the softgel capsule may have at least about 96% stability when tested at 40° C. / 75% RH at 1 month, 2 months, 3 months, or 6 months. In certain embodiments, the softgel capsule may have at least about 98% stability when tested at 40° C. / 75% RH at 1 month, 2 months, 3 months, or 6 months. In certain embodiments, the softgel capsules may have a stability of at least about 99% when tested at 40° C. / 75% RH at 1 month, 2 months, 3 months, or 6 months.

[0019] In some embodiments, the softgel capsules may remain unchanged for at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours in an acidic medium, and the dissolution test is performed in a USP Apparatus II using paddles at a speed of 50 rpm in a medium of pH 1.2.

[0020] In some embodiments, the softgel capsule is capable of disintegrating in about 60 minutes or less, about 45 minutes or less, about 30 minutes or less, about 20 minutes or less, about 10 minutes or less, or about 5 minutes or less in a buffer solution of pH 6.8.

[0021] In some embodiments, the softgel capsule may remain unchanged for at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours in a pH 1.2 medium, the dissolution test is performed in a USP Apparatus II using paddles at a speed of 50 rpm in a pH 1.2 medium, and the softgel capsule may disintegrate in about 60 minutes or less, about 45 minutes or less, about 30 minutes or less, about 20 minutes or less, about 10 minutes or less, or about 5 minutes or less in a pH 6.8 buffer solution.

[0022] In some embodiments of the softgel capsule, the total impurities may not exceed about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, or 0.01%, where the total impurities are measured according to current USP monograph test methods. In certain embodiments of the softgel capsule, the total impurities do not exceed about 0.3%.

[0023] In some embodiments of the present disclosure, a process for producing a softgel capsule of the present disclosure includes encapsulating a fill composition into a shell composition to form a softgel capsule and drying the softgel capsule. In some embodiments of the process, gel conversion of the shell composition is performed prior to encapsulation.

[0024] In some embodiments, a method for treating seizures may include administering a softgel capsule of the present disclosure. In certain embodiments, a method for treating bipolar disorder may include administering a softgel capsule of the present disclosure. In certain embodiments, a method for treating migraine headaches may include administering a softgel capsule of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The present invention advances the state of the art by developing a modified or delayed release oral dosage form, particularly a delayed release softgel capsule, that contains an enteric polymer.The delayed release softgel capsule of the present invention does not dissolve in the stomach environment of the stomach, but rather dissolves in the intestine.Such a mechanism is beneficial for the delivery of active ingredients that may be subject to gastric irritation or degradation in the acidic environment of the stomach.

[0026] As used herein, "active pharmaceutical ingredient" refers to a drug or compound that can 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 of an effective amount of an active agent to a subject.

[0027] As used herein, the term "active ingredient" refers to any substance intended to provide a therapeutic, prophylactic, or other intended effect, regardless of whether it has been approved for that purpose by a governmental agency. This term, with respect to a particular agent, includes the pharmacologic active agent and all pharmacologic acceptable salts, solvates, and crystal forms thereof, which salts, solvates, and crystal forms are pharmacologic active.

[0028] As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount or rate of active agent administered that is necessary to bring about the desired therapeutic result.

[0029] As used herein, "shell" or "shell composition" refers to the shell of a softgel capsule that encapsulates the fill material.

[0030] All references to wt % throughout this specification and claims refer to the weight of the component with respect to the weight of the total composition, which may also be expressed as w / w.

[0031] As used herein, "fill material" or "fill" refers to the composition encapsulated by the capsule shell and containing at least one pharma- ceutical active ingredient.

[0032] As used herein, "about" refers to any value within a variance of ±10%, so that "about 10" would include 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.

[0033] Recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each individual value falling within the range, unless otherwise indicated herein, and each individual value is incorporated herein as if it were individually recited herein. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order.

[0034] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to clarify particular materials and methods and is not limiting in scope. No language in the specification should be construed as implying that any non-claimed element is essential to the practice of the disclosed materials and methods.

[0035] In some embodiments, the drug substance may be valproic acid or a salt thereof, hi some embodiments, the drug substance may include a valproate salt, sodium valproate, or semisodium valproate.

[0036] According to one embodiment, the softgel capsule may include a fill composition and a shell composition, the fill composition may include an active pharmaceutical ingredient, and the shell composition includes gelatin, a plasticizer, and an enteric polymer. In some embodiments, the enteric polymer may be amidated pectin, non-amidated pectin, or a combination thereof. In some embodiments, the plasticizer may be glycerin.

[0037] In some embodiments, the fill composition may include a pharma- ceutical active ingredient, while in other embodiments, the fill composition may include additional fill ingredients such as flavorings, sweeteners, colorants, and fillers, antioxidants, or other pharma- ceutically acceptable excipients or additives such as synthetic dyes and mineral oxides.

[0038] In some embodiments, the antioxidant may be butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), alpha tocopherol, vitamin E TPGS, propyl gallate, cysteine, sodium metabisulfite, or combinations thereof.

[0039] In some embodiments, the fill composition may contain the active pharmaceutical ingredient in an amount of about 125 mg, about 250 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, or about 1300 mg. In some embodiments, the fill composition may contain the active pharmaceutical ingredient in an amount of about 125 mg to about 1000 mg, about 250 mg to about 750 mg, or about 350 mg to about 550 mg, or any subrange or value therein.

[0040] In some embodiments, an antioxidant may be included in the fill composition in an amount of about 0.001 parts by weight to about 2 parts by weight based on 100 parts by weight of the fill composition.

[0041] In one embodiment, the gelatin in the shell composition may include type A gelatin, type B gelatin, hide or skin gelatin, and / or bone gelatin used alone or in combination. In one embodiment, the gelatin may be pigskin gelatin or type B. In another embodiment, only one type of gelatin may be included. 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 20 wt% to about 80 wt%, or about 30 wt% to about 60 wt%, or about 25 wt% to about 55 wt%.

[0042] In one embodiment, the shell composition includes dextrose. In one embodiment, the amount of dextrose in the shell composition is about 0.005 wt% to about 5 wt%, or about 0.01 wt% to about 4 wt%, or about 0.01 wt% to about 3 wt%, or about 0.01 wt% to about 2 wt%, or about 0.01 wt% to about 1 wt%, or about 0.1 wt% to about 3 wt%, or about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%, or about 0.15 wt% to about 2 wt%, or about 0.15 wt% to about 1 wt%. Dextrose may be added to the capsule shell to mitigate the possibility of loss of gel strength. The concentration of dextrose in the shell composition may be an effective amount to improve its enteric properties, but not so high that it may prevent the softgel capsule from bursting.

[0043] In some embodiments, the shell composition may include pectin. In some embodiments, the pectin may be low methoxyl pectin. In some embodiments, the pectin may be amidated pectin, nonamidated pectin, or a combination thereof. In one embodiment, the pectin is a low methoxyl (LM) pectin having a degree of esterification 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 methoxyl (LM) pectin may be LM pectin (P-25), LM pectin (445C), LM pectin (100C), or a combination thereof. Too much pectin in the dosage form may reduce the gel strength of the softgel capsule, which may subsequently adversely affect the sealability of the softgel capsule. Thus, pectin may be added to the dosage form at a concentration high enough to form a delayed release dosage form, and at the same time at a concentration low enough to mitigate the loss of gel strength. In one embodiment, the amount of pectin in the shell composition is from about 2 wt% to about 25 wt%, from about 3 wt% to about 25 wt%, from about 4 wt% to about 25 wt%, or from about 5 wt% to about 25 wt%, or from about 5 wt% to about 20 wt%, or from about 5 wt% to about 15 wt%, or from about 5 wt% to about 10 wt%.

[0044] In one embodiment, the shell composition may also include a plasticizer. In some embodiments, the plasticizer in the shell composition may include glycerin, aqueous sorbitol and sorbitan solution, and combinations thereof. Other suitable plasticizers may include, but are not limited to, sugar alcohol plasticizers such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers such as diglycerin, dipropylene glycol, polyethylene glycols 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 with aliphatic hydroxyl groups, ester-based plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single block polymers, citrate ester-based 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, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0045] In one embodiment, the amount of plasticizer in the shell composition is from 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%.

[0046] In one embodiment, the shell composition may also include a gelling agent. In some embodiments, the gelling agent may be gellan gum, agar, alginate, guar gum, or locust bean gum. For example, the gellan gum may be a low acyl gellan gum, such as Kelcogel CG-LA.

[0047] The shell composition may also include water, hi some embodiments, the water may be included in the shell composition in an amount of from about 5 wt% to about 30 wt%, or from about 10 wt% to about 25 wt%, or from about 15 wt% to about 20 wt%, based on the total shell composition.

[0048] In one embodiment, the shell composition may optionally include additional agents such as colorants, flavoring agents, sweeteners, fillers, antioxidants, diluents, pH adjusters, or other pharma- ceutically acceptable excipients or additives such as synthetic dyes and mineral oxides.

[0049] Exemplary suitable colorants may include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, violet, indigo, and brown. In certain embodiments, the color of the dosage form may be indicative of the contents (e.g., one or more active ingredients) contained therein.

[0050] Exemplary suitable flavoring agents may include, but are not limited to, "flavor extracts" obtained by extracting a source, e.g., a portion of an animal or plant material, often using a solvent such as ethanol or water; natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from the entire plant.

[0051] Additional exemplary flavoring agents that may be present in the dosage form may include, but are not limited to, breath freshening compounds such as menthol, spearmint, and cinnamon, other flavors or fragrances such as coffee bean, fruit flavors (e.g., cherry, orange, grape, etc.), particularly those used for oral hygiene, as well as actives used in cleaning teeth and the oral cavity such as quaternary ammonium bases. The effect of the flavoring agents may be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, and the like.

[0052] Exemplary sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof. Artificial sweeteners include, for example, acesulfame and its various salts, such as potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salt (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as sodium salt (available as Sweet'N Low®), chloro derivatives of sucrose, such as stevia, sucralose (available as Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); natural intense sweeteners such as Stevia rebaudiana (stevioside), Monk fruit, polyols such as sorbitol, mannitol, xylitol, erythritol, and the like.

[0053] In some embodiments, a methacrylic acid copolymer may be included in the shell composition. In one embodiment, the shell composition may include a methacrylic acid copolymer in an amount of about 0.1 wt% to about 5 wt%, or about 1 wt% to about 4 wt%, or about 2 wt% to about 3 wt%, based on the total weight of the shell composition. In some embodiments, the methacrylic acid copolymer may be Kollicoat MAE100P. Without being limited by theory, the inventors believe that the methacrylic acid copolymer enhances the enteric properties of the shell composition.

[0054] In some embodiments, the softgel capsule may allow for delayed or controlled release of the active agent.

[0055] In some embodiments, the shell composition and / or softgel capsule may be tested with a dissolution test. In one embodiment, the dissolution test is a two-stage dissolution. Dissolution may be performed in a USP apparatus II with paddles at a speed of 50 rpm to 100 rpm in a pH 1.2 medium (with or without pepsin) or gastric fluid. The softgel capsule according to this embodiment may remain unchanged for at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours in an acidic medium, and may disintegrate in about 60 minutes or less, about 45 minutes or less, about 30 minutes or less, about 20 minutes or less, about 10 minutes or less, or about 5 minutes or less in a pH 6.8 buffer or intestinal fluid. The acidic medium may be 0.1 N HCl.

[0056] In some embodiments, the shell composition and / or softgel capsule may be tested in a disintegration test performed in a USP / EP disintegration apparatus in a pH 1.2 medium (with or without pepsin) or artificial gastric fluid. The softgel capsule according to the present embodiments may remain unchanged for at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours in an acidic medium, and may disintegrate in about 60 minutes or less, about 45 minutes or less, about 30 minutes or less, about 20 minutes or less, about 10 minutes or less, or about 5 minutes or less in a pH 6.8 buffer or intestinal fluid.

[0057] In some embodiments, the dissolution test may be performed for about 150 minutes, about 120 minutes, about 105 minutes, about 90 minutes, about 75 minutes, about 60 minutes, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, or about 5 minutes.

[0058] In some embodiments, the softgel capsule may be ethanol tolerant. Ethanol tolerance is evaluated using a USP dissolution apparatus II with a medium containing 10%, 20%, 30%, 40%, or 50% ethanol. The softgel capsule may remain unchanged for about 150 minutes, about 120 minutes, about 105 minutes, about 90 minutes, about 75 minutes, about 60 minutes, about 45 minutes, about 30 minutes, or about 15 minutes.

[0059] 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, 12 months, or 24 months. In some embodiments, the softgel capsule may have a stability of about 90% to about 110%, about 92% to about 108%, about 94% to about 106%, about 96% to about 104%, about 98% to about 102%, or about 99% to about 101% when tested at 25° C. / 60% RH at 1 month, 2 months, 3 months, 6 months, 12 months, or 24 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 about 90% to about 110%, about 92% to about 108%, about 94% to about 106%, about 96% to about 104%, about 98% to about 102%, or about 99% to about 101% when tested at 30° C. / 65% RH at 1 month, 2 months, 3 months, 6 months, or 12 months. In some embodiments, the softgel capsules 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, or 6 months.In some embodiments, the softgel capsules may have a stability of about 90% to about 110%, about 92% to about 108%, about 94% to about 106%, about 96% to about 104%, about 98% to about 102%, or about 99% to about 101% when tested at 1 month, 2 months, 3 months, or 6 months at 40° C. / 75% RH. As used herein, stability is assessed as the amount of valproic acid remaining after an accelerated period of storage at a given temperature and relative humidity.

[0060] In certain embodiments, any of the compositions described herein may exhibit any of the above chemical stabilities upon storage at a relative humidity in the range of about 20% to about 75% at a temperature in the range of about 5° C. to about 50° C., about 10° C. to about 40° C., about 20° C. to about 30° C., or any subrange or single value therein, for an extended period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, or 24 months, or any subrange or single value therein).

[0061] In certain embodiments, any of the compositions described herein may exhibit physical stability upon storage for an extended period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, or 24 months, or any subrange or single value therein) at a relative humidity in the range of about 20% to about 75% at a temperature in the range of about 5° C. to about 50° C., about 10° C. to about 40° C., about 20° C. to about 30° C., or any subrange or single value therein.

[0062] In certain embodiments, the physical stability of the delayed release softgel capsule can be demonstrated by the dissolution profile of the capsule in acidic and buffered media.For example, the dissolution profile of the capsule in acidic and buffered media is substantially equivalent (or within specification) after storage for up to 12 months, up to 6 months, up to 3 months, or up to 1 month (during any of these periods under ambient conditions or stress conditions of 40°C and 75% relative humidity) compared to the dissolution profile of the capsule before storage.

[0063] The term "substantially equivalent" may refer to a particular value being within about 30%, within about 25%, within about 20%, within about 15%, within about 10%, within about 5%, or within about 1% of a corresponding comparative value. The percentages are calculated based on the apparent value of the comparative value. For example, a range of dissolution times from 27 minutes to 33 minutes may be considered within 10% of a comparative dissolution time of 30 minutes.

[0064] In some embodiments, the amount of the impurity RRT0.152 in the softgel is at most about 0.05%, at most about 0.04%, at most about 0.03%, at most about 0.02%, or at most about 0.01%, or about 0.001% to about 0.05%, about 0.01% to about 0.04%, or about 0.02% to about 0.03%, or any subrange or single value therein. In some embodiments, the amount of the impurity butyric acid in the softgel is at most about 0.05%, at most about 0.04%, at most about 0.03%, at most about 0.02%, or at most about 0.01%, or about 0.001% to about 0.05%, about 0.01% to about 0.04%, or about 0.02% to about 0.03%, or any subrange or single value therein. In some embodiments, the amount of valeric acid impurity in the softgel is at most about 0.05%, at most about 0.04%, at most about 0.03%, at most about 0.02%, or at most about 0.01%, or about 0.001% to about 0.05%, about 0.01% to about 0.04%, or about 0.02% to about 0.03%, or any subrange or single value therein. In some embodiments, the amount of impurity RRT0.545 in the softgel is at most about 0.05%, at most about 0.04%, at most about 0.03%, at most about 0.02%, or at most about 0.01%, or about 0.001% to about 0.05%, about 0.01% to about 0.04%, or about 0.02% to about 0.03%, or any subrange or single value therein. In some embodiments, the amount of impurity RRT0.873 in the softgel is at most about 0.05%, at most about 0.04%, at most about 0.03%, at most about 0.02%, or at most about 0.01%, or from about 0.001% to about 0.05%, from about 0.01% to about 0.04%, or from about 0.02% to about 0.03%, or any subrange or single value therein.In some embodiments, the amount of impurity RRT1.397 in the softgel is at most about 0.05%, at most about 0.04%, at most about 0.03%, at most about 0.02%, or at most about 0.01%, or from about 0.001% to about 0.05%, from about 0.01% to about 0.04%, or from about 0.02% to about 0.03%, or any subrange or single value therein.

[0065] In some embodiments, the total impurities present in the softgel capsules do not exceed about 0.01%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, or any subrange or single value therein. In some embodiments, the total impurities present in the softgel capsules may be in an amount of about 0.0001% to about 0.5%, about 0.001% to about 0.4%, about 0.01% to about 0.3%, or about 0.1% to about 0.2%, or any subrange or single value therein.

[0066] Encapsulation of the fill material may be accomplished in any conventional manner. As an example, rotary die encapsulation may be used. In some embodiments, gel conversion may be used to encapsulate the fill composition. In some embodiments, the gel conversion includes the shell composition, an opacifier, and a colorant. The opacifier may be titanium dioxide. The colorant may include FD&C Yellow #6. The gel conversion may also include water. In some embodiments, the colorant may be included in an amount of about 0.5 g to about 2.5 g per kilogram of the shell composition. In some embodiments, the opacifier may be included in an amount of about 2 g to about 10 g per kilogram of the shell composition. In other embodiments, the water may be included in an amount of about 40 grams to about 60 grams per kilogram of the shell composition.

[0067] According to one embodiment, the softgel capsule is prepared by (a) preparing a fill composition comprising a pharma- ceutical active ingredient, and (b) encapsulating the fill composition in a shell composition. The encapsulation process may also include a substep of preparing a shell composition, for example, by mixing gelatin, dextrose, pectin, and optionally a plasticizer. The shell composition may further undergo gel conversion before encapsulation by adding colorants and water.

[0068] The softgel capsules of the present disclosure may be packaged in a blister pack, bottle, or volume pack. EXAMPLES

[0069] Specific embodiments of the present invention will now be illustrated by reference to the following examples, which should be understood to be disclosed solely for the purpose of illustrating the present invention and should not be construed as limiting the scope of the present invention in any way.

[0070] A shell composition according to one embodiment of the present disclosure was prepared and is shown in Table 1.

[0071] [Table 1]

[0072] A batch of softgel capsules according to one embodiment of the present disclosure was produced. A Ross melter was used to prepare the shell composition in Table 1. Valproic acid was used as the drug substance. Valproic acid was dispensed into a stainless steel hopper under nitrogen blanket. A rotary die encapsulation machine was used to encapsulate the valproic acid into the shell composition.

[0073] A drying chamber was used to dry the softgel capsules. After drying was complete, the softgel capsules were inspected for defects and washed using a lecithin / ethanol solution.

[0074] Stability studies were performed on the softgel capsules, which were packaged in 200cc HDPE bottles and placed under various stability conditions: 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH.

[0075] The softgel capsules were subjected to a two-stage dissolution to evaluate their enteric properties, USP <711> The dissolution test was in accordance with USP APPII using a 50 RPM paddle speed. The softgel capsules were expected to remain unchanged for 2 hours in 0.1N HCl and to burst within 45 minutes in pH 6.8 phosphate buffer. The results of the two-stage dissolution test are shown in Table 2.

[0076] [Table 2]

[0077] These results demonstrated that the softgel capsules were stable over a period of 6 months under 40°C / 75% RH conditions and 27 months under 25°C / 60% RH conditions.

[0078] Analytical testing for impurities was also performed on samples stored for 27 months under 25°C / 60% RH conditions. The test methods were performed according to the current USP monograph for valproic acid. The test results are summarized in Table 3.

[0079] [Table 3]

[0080] Test results of 0.11% total impurities after 27 months under ambient conditions indicated that the valproic acid softgel product was chemically stable. These results indicate that the softgel capsule according to one embodiment of the present disclosure is a stable product with reliable enteric properties and chemical stability.

Claims

1. (a) a filler material; and (b) Shell Composition A softgel capsule comprising: the filler material comprises valproic acid or a salt thereof; A softgel capsule, wherein the shell composition comprises gelatin, a plasticizer, and an enteric polymer.

2. 10. The softgel capsule of claim 1, wherein the shell composition further comprises dextrose.

3. 10. The softgel capsule of claim 1, wherein the enteric polymer is pectin.

4. 4. The softgel capsule of claim 3, wherein the pectin is an amidated pectin, a non-amidated pectin, or a combination thereof.

5. 10. The softgel capsule of claim 1, wherein the shell composition comprises 25 wt% to 55 wt% gelatin.

6. 10. The softgel capsule of claim 1, wherein the shell composition comprises 3 wt% to 22 wt% pectin.

7. 10. The softgel capsule of claim 1, wherein the shell composition comprises 0.01 wt% to 1.0 wt% dextrose.

8. 10. The softgel capsule of claim 1, wherein the gelatin is selected from the group consisting of type A gelatin, type B gelatin, and mixtures thereof.

9. 10. The softgel capsule of claim 1, wherein the gelatin is selected from the group consisting of fish gelatin, hide gelatin, bone gelatin, and mixtures thereof.

10. 10. The softgel capsule of claim 1, wherein the plasticizer is selected from the group consisting of glycerin, aqueous sorbitol and sorbitan solutions, and combinations thereof.

11. 10. The softgel capsule of claim 1, wherein the shell composition comprises 10 wt% to 50 wt% water.

12. 10. The softgel capsule of claim 1, wherein the shell composition comprises 0.2 wt% to 8 wt% of a gelling agent.

13. 13. The softgel capsule of claim 12, wherein the gelling agent is gellan gum.

14. 10. The softgel capsule of claim 1, wherein the fill composition further comprises an antioxidant.

15. 15. The softgel capsule of claim 14, wherein the fill composition further comprises butylated hydroxytoluene (BHT).

16. 15. The softgel capsule of claim 14, wherein the fill composition further comprises butylated hydroxyanisole (BHA).

17. 10. The softgel capsule of claim 1, wherein the fill composition comprises 125 mg to 1000 mg of valproic acid.

18. 4. The softgel capsule of claim 3, wherein the shell composition comprises non-amidated pectin.

19. 20. The softgel capsule of claim 18, wherein the shell composition further comprises a methacrylic acid copolymer.

20. 10. The softgel capsule of claim 1, wherein the softgel capsule has a stability of at least 90% when tested at 25°C / 60% RH at 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

21. 10. The softgel capsule of claim 1, wherein the softgel capsule has a stability of at least 90% when tested at 30°C / 65% RH at 1 month, 2 months, 3 months, 6 months, or 12 months.

22. 10. The softgel capsule of claim 1, wherein the softgel capsule has a stability of at least 90% when tested at 40°C / 75% RH at 1 month, 2 months, 3 months, or 6 months.

23. 10. The softgel capsule of claim 1, wherein the softgel capsule remains unchanged in an acidic medium for at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, or at least 5 hours, and the dissolution test is performed in a pH 1.2 medium using a USP Apparatus II with paddles at a speed of 50 rpm.

24. 10. The softgel capsule of claim 1, wherein the softgel capsule disintegrates in a pH 6.8 buffer solution in 60 minutes or less, 45 minutes or less, 30 minutes or less, 20 minutes or less, 10 minutes or less, or 5 minutes or less.

25. 10. The softgel capsule of claim 1, wherein the softgel capsule remains unchanged in a medium of pH 1.2 for at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, or at least 5 hours, and is capable of disintegrating in a buffer solution of pH 6.8 in 60 minutes or less, 45 minutes or less, 30 minutes or less, 20 minutes or less, 10 minutes or less, or 5 minutes or less.

26. 10. The softgel capsule of claim 1, wherein total impurities do not exceed 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or 0.01%, wherein the total impurities are measured according to current USP monograph test methods.

27. A softgel capsule according to any one of claims 1 to 26 for treating seizures.

28. A softgel capsule according to any one of claims 1 to 26 for treating bipolar disorder.

29. A softgel capsule according to any one of claims 1 to 26 for treating migraine headaches.

30. 10. A method for making the softgel capsule of claim 1, comprising encapsulating a fill composition in the shell composition to form a softgel capsule, and drying the softgel capsule.

31. 31. The method of claim 30, wherein the shell composition is subjected to gel conversion prior to encapsulation.