Enteric-coated bisacodyl soft gel capsules

Abstract

The soft gel capsule includes a filling material and a shell composition, where the filling composition includes bisacodyl and the shell composition includes a film-forming material and an enteric polymer. The soft gel capsule further includes 5 parts by weight of bisacodyl based on 100 parts by weight of the filling material. Also provided is a method for producing the soft gel capsule using gel conversion.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 351,761, filed on June 13, 2022, the entire content of which is incorporated herein by reference in its entirety.

[0002] The present invention relates to enteric - coated soft - gel capsules comprising a shell composition and a filling composition. Specifically, the enteric - coated soft - gel capsule contains bisacodyl in the filling composition. Methods of preparing such dosage forms and methods of using the same are also disclosed.

Background Art

[0003] Capsule dosage forms are commonly used for the oral administration of various pharmaceuticals. Capsules can be, for example, soft gelatin shells or hard shells (animal or plant species). Soft - gel capsules offer many advantages, including rapid dissolution, flavor masking, ease of swallowing, fewer excipients compared to tablets, delivery of a slightly hydrophilic compound in a liquid matrix to improve its oral bioavailability, delivery of low and ultra - low doses of compounds, delivery of low - melting - point compounds, and minimization of dust generation during manufacturing, thus improving the safety of production 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 capsules are easy to swallow and do not require flavoring to mask any unpleasant flavors of the active agent. Soft - gel encapsulation of drugs further offers the potential to improve the bioavailability of pharmaceuticals. For example, the active ingredient can be rapidly released in liquid form as soon as the gelatin shell ruptures.

Summary of the Invention

[0005] In some embodiments, the soft gel capsule comprises a filling material and a shell composition, wherein the filling material comprises bisacodyl or a pharmaceutically acceptable salt thereof, and the shell composition comprises a film-forming material and an enteric polymer.

[0006] 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 gelatin. In other embodiments, the non-animal-derived polymer comprises pectin.

[0007] In some embodiments, the shell composition further comprises dextrose. In some embodiments, the shell composition further comprises a plasticizer.

[0008] In some embodiments, the enteric polymer is pectin. In certain embodiments, the pectin is amidated pectin, non-amidated pectin, or a combination thereof. In some embodiments, the shell composition comprises about 2 wt% to about 20 wt% pectin. In some embodiments, the shell composition comprises non-amidated pectin.

[0009] In some embodiments, the shell composition of the soft gel capsule comprises about 30 wt% to about 80 wt% gelatin. In some embodiments, the shell composition of the soft gel capsule comprises about 2 wt% to about 20 wt% pectin. In some embodiments, the shell composition of the soft gel capsule comprises about 0.01 wt% to about 4 wt% dextrose. In some embodiments, the shell composition comprises about 2 wt% to about 40 wt% plasticizer.

[0010] In certain embodiments, the film-forming material comprises gelatin, where the gelatin comprises type A gelatin, type B gelatin, and mixtures thereof. In some embodiments, the gelatin comprises fish gelatin, skin gelatin, bone gelatin, and mixtures thereof.

[0011] In some embodiments, the shell composition further comprises a plasticizer, where the plasticizer includes glycerol, glycerin, sorbitol, and solutions of sorbitol and sorbitan, and combinations thereof.

[0012] In some embodiments, the shell composition of the soft gel capsule further comprises water. In some embodiments, the shell composition comprises from about 8 wt% to about 20 wt% water.

[0013] In some embodiments, the shell composition of the soft gel capsule further comprises a gelling agent. In some embodiments, the shell composition comprises from about 0.1 wt% to about 2 wt% of the gelling agent. In certain embodiments, the gelling agent is gellan gum.

[0014] In some embodiments, the filling material further comprises an antioxidant. In certain embodiments, the filling material further comprises butylated hydroxytoluene (BHT). In certain embodiments, the filling material further comprises butylated hydroxyanisole (BHA). In some embodiments, the filling material comprises from about 0.001 parts by weight to about 2 parts by weight of the antioxidant based on 100 parts by weight of the filling material. In some embodiments, the filling material comprises from about 0.001 parts by weight to about 0.5 parts by weight of BHT based on 100 parts by weight of the filling material. In some embodiments, the filling material comprises from about 0.1 parts by weight to about 2 parts by weight of BHT based on 100 parts by weight of the filling material.

[0015] In some embodiments, the filling material further comprises a lipid. In some embodiments, the lipid is soybean oil. In some embodiments, the filling material comprises from about 90 wt% to about 95 wt% of the lipid based on the total composition of the filling material. In some embodiments, the filling material may further comprise a suspending agent, where the suspending agent is a hydrogenated vegetable oil.

[0016] In some embodiments, the filling material comprises from about 5 parts by weight to about 10 parts by weight of bisacodyl based on 100 parts by weight of the filling material.

[0017] In some embodiments, the shell composition further comprises a methacrylic acid copolymer.

[0018] In some embodiments, when tested at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, the soft gel capsule may disintegrate in a pH 6.8 buffer solution 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.

[0019] In some embodiments, when tested at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, the soft gel capsule may remain intact in a pH 1.2 medium 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, and may disintegrate in a pH 6.8 buffer solution 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.

[0020] In some embodiments, when tested at 30°C / 65%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, the soft gel capsule may disintegrate in a pH 6.8 buffer solution 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.

[0021] In some embodiments, the soft gel capsule may remain intact 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 medium of pH 1.2 when tested at 30°C / 65% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, and may disintegrate in a buffer of pH 6.8 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.

[0022] In some embodiments, the soft gel capsule may disintegrate in a buffer of pH 6.8 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 when tested at 49°C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0023] In some embodiments, the soft gel capsule may remain intact 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 medium of pH 1.2 when tested at 40°C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, and may disintegrate in a buffer of pH 6.8 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.

[0024] In some embodiments, the soft gel capsule may have at least about 90% assay stability when tested at 25°C / 60% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0025] In some embodiments, the soft gel capsule may have an assay stability of at least about 92% when tested at 25°C / 60% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0026] In some embodiments, the soft gel capsule may have an assay stability of at least about 94% when tested at 25°C / 60% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0027] In some embodiments, the soft gel capsule may have an assay stability of at least about 96% when tested at 25°C / 60% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0028] In some embodiments, the soft gel capsule may have an assay stability of at least about 98% when tested at 25°C / 60% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0029] In some embodiments, the soft gel capsule may have an assay stability of at least about 99% when tested at 25°C / 60% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0030] In some embodiments, the soft gel capsule may have an assay stability of at least about 90% when tested at 30°C / 65% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0031] In some embodiments, the soft gel capsule may have an assay stability of at least about 92% when tested at 30°C / 65% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0032] In some embodiments, the soft gel capsules can have an assay stability of at least about 94% when tested at 30°C / 65% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0033] In some embodiments, the soft gel capsules can have an assay stability of at least about 96% when tested at 30°C / 65% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0034] In some embodiments, the soft gel capsules can have an assay stability of at least about 98% when tested at 30°C / 65% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0035] In some embodiments, the soft gel capsules can have an assay stability of at least about 99% when tested at 30°C / 65% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0036] In some embodiments, the soft gel capsules can have an assay stability of at least about 90% when tested at 40°C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0037] In some embodiments, the soft gel capsules can have an assay stability of at least about 92% when tested at 40°C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0038] In some embodiments, the soft gel capsules can have an assay stability of at least about 94% when tested at 40°C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0039] In some embodiments, the soft gel capsule may have an assay stability of at least about 96% when tested at 40 °C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0040] In some embodiments, the soft gel capsule may have an assay stability of at least about 98% when tested at 40 °C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0041] In some embodiments, the soft gel capsule may have an assay stability of at least about 99% when tested at 40 °C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0042] In some embodiments, the soft gel capsule may remain intact 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, where the dissolution test is performed in a USP apparatus II using a paddle at 50 rpm in a medium of pH 1.2.

[0043] In some embodiments, the soft gel capsule may remain intact 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, where the disintegration test is performed in a USP apparatus II using a paddle at 50 rpm in a medium of pH 1.2.

[0044] In some embodiments, the soft gel capsule may disintegrate in a pH 6.8 buffer 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.

[0045] In some embodiments, the soft gel capsule may remain intact in a medium of pH 1.2 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, and may disintegrate in a buffer of pH 6.8 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.

[0046] In some embodiments, the total impurities do not exceed about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, or about 0.01%, where the total impurities are measured according to the current USP monograph test method.

[0047] In some embodiments, the total impurities do not exceed about 0.3%.

[0048] In another embodiment, a method of producing a soft gel capsule comprising a filling material and a shell composition (where the filling material comprises bisacodyl and the shell composition comprises a film-forming material and an enteric polymer) includes encapsulating a filling composition in the shell composition to form a soft gel capsule and drying the soft gel capsule. In another embodiment, the method further includes performing a gel conversion on the shell composition before encapsulation.

Mode for Carrying Out the Invention

[0049] The present invention advances the state of the art by developing a delayed-release oral dosage form containing an enteric polymer, particularly a delayed-release soft gel capsule. The delayed-release soft gel capsule of the present invention does not dissolve in the gastric environment but dissolves in the intestine. Such a mechanism is beneficial for the delivery of active ingredients that may cause gastric inflammation or are highly sensitive to the acidic environment of the stomach.

[0050] As used herein, "pharmaceutically active ingredient" refers to a drug or compound that can be used for the diagnosis, cure, mitigation, treatment, or prevention of a condition. The term "condition(s)" refers to a medical condition that can be treated or prevented by administration of an effective amount of an active agent to a subject.

[0051] As used herein, the term "active ingredient" refers to any material intended to produce a therapeutic, prophylactic, or other desired effect, whether or not approved by a governmental agency for a particular purpose. This term includes, with respect to a particular agent, the pharmaceutically active agent, as well as all of its pharmaceutically acceptable salts, solvates, and crystalline forms, where the salts, solvates, and crystalline forms are pharmaceutically active.

[0052] As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount of the active agent or the rate at which it is administered necessary to produce the desired therapeutic result.

[0053] As used herein, "shell" or "shell composition" refers to the shell of a soft gel capsule that encapsulates a filling material.

[0054] All references to weight percent refer throughout this specification and the claims to the weight of the component with reference to the total weight of the composition and may be referred to as w / w.

[0055] As used herein, "filling material" or "fill" refers to a composition encapsulated by a capsule shell and containing at least one pharmaceutically active ingredient.

[0056] As used herein, "about" refers to any value within a variation of ±10% such that "about 10" includes from 9 to 11. As used herein, "a", "an", or "the" refers to one or more, unless otherwise specified. Thus, for example, references to "an excipient" include a single excipient, as well as mixtures of two or more different excipients, and the like.

[0057] 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 herein 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.

[0058] Any and all examples, or exemplary language (e.g., "such as") provided herein are intended merely to clarify the particular materials and methods and are not intended to be limiting. The language in the specification should not be construed as indicating that any non-claimed element is essential to the practice of the disclosed materials and methods.

[0059] In some embodiments, the active pharmaceutical ingredient can be bisacodyl or a salt thereof.

[0060] According to one embodiment, the soft gel capsule may include a filling material and a shell composition, wherein the filling material may include bisacodyl or a pharmaceutically acceptable salt thereof, and the shell composition includes a film-forming material and an enteric polymer. In some embodiments, the enteric polymer may be amidated, non-amidated, or a combination thereof.

[0061] In some embodiments, the filling material may include bisacodyl or a pharmaceutically acceptable salt thereof and a lipid. In other embodiments, the filling material may further include additional filling components such as a suspending agent, a flavoring agent, a sweetening agent, a coloring agent and a filler, an antioxidant or other pharmaceutically acceptable excipients or additives such as synthetic dyes and metal oxides. In some embodiments, the suspending agent may be a hydrogenated vegetable oil.

[0062] In some embodiments, the lipid in the dosage form may be selected from the group consisting of almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hydrogenated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, walnut oil, and watermelon seed oil, but is not limited thereto. Other oils and fats include fish oil (omega-3), krill oil, for example, animal or vegetable fats in hydrogenated form, fractionated coconut oil, medium-chain triglycerides, free fatty acids and monoglycerides, diglycerides, and triglycerides of C8-, C10-, C12-, C14-, C16-, C18-, C20- and C22-fatty acids, and combinations thereof, but are not limited thereto.

[0063] In some embodiments, the antioxidant may be butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or a combination thereof.

[0064] In some embodiments, the filling material may contain bisacodyl in an amount of about 1 mg to about 25 mg per capsule, or about 2 mg to about 20 mg per capsule, or about 5 mg to about 15 mg per capsule, or about 5 mg to about 10 mg per capsule, or about 7.5 mg to about 10 mg per capsule. In one embodiment, bisacodyl may be contained in an amount of about 5 parts by weight to about 10 parts by weight based on 100 parts by weight of the filling material.

[0065] In some embodiments, the lipid may be contained in an amount of about 85 parts by weight, about 90 parts by weight or about 95 parts by weight based on 100 parts by weight of the filling material.

[0066] In some embodiments, the antioxidant may be included in the filling material. The antioxidant may be contained in an amount of about 0.001 parts by weight to about 2 parts by weight based on 100 parts by weight of the filling material.

[0067] In one embodiment, the gelatin in the shell composition may include type A gelatin, type B gelatin, skin or hide gelatin and / or bone gelatin, which are used alone or in combination. In one embodiment, the gelatin may be porcine skin gelatin or type B gelatin. 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 20 wt% to about 80 wt%, or about 30 wt% to about 60 wt%, or about 35 wt% to about 55 wt%.

[0068] In one embodiment, the shell composition comprises dextrose. In one embodiment, the amount of dextrose in the shell composition is from about 0.005 wt% to about 5 wt%, or from about 0.01 wt% to about 4 wt%, or from about 0.1 wt% to about 3.5 wt%, or from about 0.15 wt% to about 3 wt%, or from about 0.15 wt% to about 2.5 wt% or from about 0.2 wt% to about 2 wt%, or from about 0.1 wt% to about 1.5 wt%, or from about 0.2 wt% to about 1 wt%. Dextrose can be added to the capsule shell to reduce the potential for a decrease in gel strength. The concentration of dextrose in the shell composition can be an amount effective to improve gel strength, but not so high as to interfere with the seal.

[0069] In some embodiments, the shell composition may comprise pectin. In some embodiments, the pectin can be low-methoxy pectin. In some embodiments, the pectin can be amidated pectin, non-amidated pectin, or a combination thereof. In one embodiment, the pectin is a low-methyl ester (LM) pectin having an esterification degree of less than 50. In some embodiments, the pectin is LMS-318, SPL-12, LM-102 AS-Z and / or LM-12 CG-Z. In other embodiments, the low-methoxy (LM) pectin can be LM pectin (P-25), LM pectin (445C), LM pectin (100C) or a combination thereof. If there is too much pectin in the dosage form, the gel strength of the soft gel capsule may decrease, which can subsequently have an adverse effect on the sealability of the soft gel capsule. Therefore, pectin can be added to the dosage form at a concentration high enough to form a delayed-release dosage form and at the same time low enough to reduce the decrease in gel strength. In one embodiment, the amount of pectin in the shell composition is from about 2 wt% to about 20 wt%, from about 3 wt% to about 15 wt%, from about 2 wt% to about 12 wt%, from about 3 wt% to about 5.5 wt%, from about 5 wt% to about 10 wt%.

[0070] In one embodiment, the shell composition may also include a plasticizer. In some embodiments, the plasticizer in the shell composition may include glycerol, glycerin, sorbitol, and solutions of sorbitol and sorbitan, and combinations thereof. Other suitable plasticizers may include sugar alcohol plasticizers such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol, or polyol plasticizers such as diglycerin, dipropylene glycol, polyethylene glycol with a maximum molecular weight of 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyol, ethanolamine, and mixtures thereof, but are not limited thereto. Also, other exemplary plasticizers may include 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, single-block polymers, citrate ester-type plasticizers, and triacetin, but are not limited thereto. 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.

[0071] In one embodiment, the amount of the 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%.

[0072] In one embodiment, the shell composition may also include a gelling agent. In some embodiments, the gelling agent can be gellan gum, agar, alginate, guar gum, or locust bean gum. For example, the gellan gum can be Kelcogel CG-LA gellan gum.

[0073] The shell composition may also include water. In some embodiments, the water can be included in the shell composition in an amount of 5 wt% to about 60 wt%, 10 wt% to about 50 wt%, or about 20 wt% to about 40 wt%, or about 5 wt% to about 25 wt%, or about 8 wt% to about 20 wt%, or about 30 wt% to about 45 wt% based on the total shell composition.

[0074] In one embodiment, the shell composition may optionally include additional agents such as colorants, flavoring agents, sweetening agents, fillers, antioxidants, diluents, pH adjusters, or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides.

[0075] Exemplary suitable colorants can 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 can indicate the contents contained therein (e.g., one or more active ingredients).

[0076] Exemplary suitable flavoring agents can include, but are not limited to, "flavor extracts" obtained by extracting raw materials, often using a solvent such as ethanol or water, e.g., a part of an animal or plant material; natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from the whole plant.

[0077] Additional exemplary flavoring agents that may be present in the dosage form include, but are not limited to, bad breath deodorizing compounds such as menthol, spearmint, and cinnamon, other flavors or fragrances such as coffee beans, fruit flavors (e.g., cherry, orange, grape, etc.), especially those used in oral hygiene, and active substances used in dentistry and oral rinses such as quaternary ammonium bases. The effect of the flavor may be enhanced using flavor enhancing agents such as tartaric acid, citric acid, and vanillin.

[0078] Exemplary sweetening agents may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Artificial sweeteners include, for example, acesulfame and its various salts, such as the potassium salt (available as Sunett™), alitame, aspartame (available as NutraSweet® and Equal®), the salt of aspartame - acesulfame (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as the sodium salt (available as Sweet’N Low®), stevia, chloro derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®), and mogroside. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); Stevia rebaudiana (stevioside), natural high - potency sweeteners such as Lo Han Kuo, and polyols such as sorbitol, and sorbitol and sorbitan, mannitol, xylitol, erythritol.

[0079] In some embodiments, the methacrylic acid copolymer may be included in the shell composition. In one embodiment, the shell composition may contain the 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 MAE 100P. Without being limited by theory, the inventors believe that the methacrylic acid copolymer enhances the enteric properties of the shell composition.

[0080] In some embodiments, the shell composition and / or the soft gel capsule may be tested in a dissolution test performed in a USP apparatus II using a paddle at a speed of 50 rpm in a medium of pH 1.2 or simulated gastric fluid. The soft gel capsule according to this embodiment may remain intact 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 a buffer of pH 6.8 or simulated intestinal fluid in about 30 minutes or less, about 20 minutes or less, about 10 minutes or less, or about 5 minutes or less.

[0081] In some embodiments, the shell composition and / or the soft gel capsule may be tested in a disintegration test performed in a USP / EP disintegration apparatus in a medium of pH 1.2 or simulated gastric fluid. The soft gel capsule according to this embodiment may remain intact 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 a buffer of pH 6.8 or simulated intestinal fluid in about 30 minutes or less, about 20 minutes or less, about 10 minutes or less, or about 5 minutes or less.

[0082] In some embodiments, the shell composition and / or soft gel capsule can be tested in a two-stage dissolution test performed in a USP Apparatus II using a paddle at 50 rpm in a pH 1.2 0.1N HCl medium or simulated gastric fluid maintained at 37°C in 750 ml. The soft gel capsules according to this embodiment remain intact in the acidic medium 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, and can disintegrate in a buffer of pH 6.8 or simulated intestinal fluid in 1000 ml in about 60 minutes or less, 45 minutes or less, 30 minutes or less, about 20 minutes or less, about 10 minutes or less, or about 5 minutes or less.

[0083] In some embodiments, the shell composition and / or soft gel capsule can be tested in a two-stage disintegration test performed in a USP / EP disintegration apparatus in a pH 1.2 0.1N HCl medium or simulated gastric fluid maintained at 37°C. The soft gel capsules according to this embodiment can remain intact in the acidic medium 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, and can disintegrate in a buffer of pH 6.8 or simulated intestinal fluid in about 60 minutes or less, 45 minutes or less, 30 minutes or less, about 20 minutes or less, about 10 minutes or less, or about 5 minutes or less.

[0084] In some embodiments, the disintegration test can 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.

[0085] In some embodiments, the soft gel capsule may have an assay stability of at least about 80%, at least 85%, at least 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 for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months. In some embodiments, the soft gel capsule may have an assay stability of at least about 80%, at least 85%, at least 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least 97%, at least about 98% or at least 99% when tested at 30°C / 65% RH for 1 month, 2 months, 3 months, 6 months or 12 months. In some cases, the soft gel capsule may have an assay stability of at least about 80%, at least 85%, at least 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, 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 for 1 month, 2 months, 3 months, 6 months or 12 months. As used herein, the assay stability is measured as the amount of bisacodyl remaining after the accelerated period of storage at the specified temperature and relative humidity.

[0086] The amount of impurities can also be measured and analyzed, for example, after an accelerated period of about 1 month, about 2 months, about 3 months, about 6 months or about 12 months. In some embodiments, the soft gel capsule may have less than about 2.0%, or less than about 1.75%, or less than about 1.5%, or less than about 1.25%, or less than about 1%, or less than about 0.75%, or less than about 0.5%, or less than about 0.25%, or 0% total impurities. In certain embodiments, the soft gel capsule may contain less than about 0.1%, less than about 0.075%, less than about 0.05%, less than about 0.025%, or 0% of impurity RRT 0.822. In certain embodiments, the soft gel capsule may have less than about 0.1%, or less than about 0.075%, or less than about 0.05%, or less than about 0.025% or 0% of impurity RRT 0.935.

[0087] Encapsulation of the filling material can be carried out in any conventional manner. By way of example, a rotary die encapsulation machine may be used. In some embodiments, gel conversion may be used to color the gel mass and encapsulate the filling composition. In some embodiments, the gel conversion comprises a shell composition, an opacifying agent and a colorant. The opacifying agent can be titanium dioxide. The opacifying agent can also be iron oxide. The colorant can include FD&C Yellow No. 6. The gel conversion may also include water and a plasticizer. In some embodiments, the colorant can 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 opacifying agent can be included in an amount of about 2 g to about 5 g per kilogram of the shell composition. In other embodiments, water can be included in an amount of about 40 grams to about 60 grams per kilogram of the shell composition.

[0088] According to one embodiment, the soft gel capsule is prepared by (a) preparing a filling composition containing a pharmaceutically active ingredient and (b) encapsulating the filling composition in a shell composition. The encapsulation process may also include sub-steps of preparing the shell composition, for example, by mixing gelatin, dextrose, pectin, a plasticizer, and optionally, a gum or a synthetic polymer. The shell composition may further undergo gel conversion before encapsulation.

[0089] Enumeration of items 1. (a) A filling material, (b) A shell composition A soft gel capsule comprising: wherein the filling material contains bisacodyl or a pharmaceutically acceptable salt, and the shell composition contains a film-forming material and an enteric polymer, the soft gel capsule.

[0090] 2. The soft gel capsule according to item 1, wherein the film-forming material contains an animal-derived polymer or a non-animal-derived polymer.

[0091] 3. The soft gel capsule according to item 2, wherein the animal-derived polymer contains gelatin.

[0092] 4. The soft gel capsule according to item 2, wherein the non-animal-derived polymer contains gellan gum.

[0093] 5. The soft gel capsule according to any one of the preceding items, wherein the shell composition further contains dextrose.

[0094] 6. The soft gel capsule according to any one of the preceding items, wherein the shell composition further contains a plasticizer.

[0095] 7. The soft gel capsule according to any one of the preceding items, wherein the enteric polymer is pectin.

[0096] 8. The soft gel capsule according to any one of items 1 to 6, wherein the enteric polymer is a copolymer of methylacrylic acid.

[0097] 9. The soft gel capsule according to item 7, wherein the pectin is amidated pectin, non-amidated pectin, or a combination thereof.

[0098] 10. The soft gel capsule according to item 3, wherein the shell composition contains about 30% to about 80% by weight of gelatin.

[0099] 11. The soft gel capsule according to item 7, wherein the shell composition contains about 2% to about 20% by weight of pectin.

[0100] 12. The soft gel capsule according to item 8, wherein the shell composition contains about 2% to about 16% by weight of the copolymer of methylacrylic acid.

[0101] 13. The soft gel capsule according to item 5, wherein the shell composition contains about 0.01% to about 4% by weight of dextrose.

[0102] 14. The soft gel capsule according to item 6, wherein the shell composition contains about 2% to about 40% by weight of a plasticizer.

[0103] 15. The soft gel capsule according to item 3, wherein the gelatin includes type A gelatin, type B gelatin, and a mixture thereof.

[0104] 16. The soft gel capsule according to item 3, wherein the gelatin includes fish gelatin, skin gelatin, bone gelatin, and a mixture thereof.

[0105] 17. The soft gel capsule according to item 6, wherein the plasticizer includes glycerol, glycerin, sorbitol, a sorbitol and sorbitan solution, and a combination thereof.

[0106] 18. The soft gel capsule according to any one of items 1 to 17, wherein the shell composition further contains water.

[0107] 19. The soft gel capsule of item 18, wherein the shell composition contains about 8% to about 20% by weight of water.

[0108] 20. The soft gel capsule of any one of items 1 to 19, wherein the shell composition further contains a gelling agent.

[0109] 21. The soft gel capsule of item 7, wherein the shell composition contains about 2% to about 12% by weight of pectin.

[0110] 22. The soft gel capsule of item 20, wherein the shell composition contains about 0.1% to about 2% by weight of a gelling agent.

[0111] 23. The soft gel capsule of item 18 or 22, wherein the gelling agent is gellan gum.

[0112] 24. The soft gel capsule of any of the preceding items, wherein the filling material further contains an antioxidant.

[0113] 25. The soft gel capsule of item 24, wherein the filling material further contains butylated hydroxytoluene (BHT).

[0114] 26. The soft gel capsule of claim 24 or 25, wherein the filling material further contains butylated hydroxyanisole (BHA).

[0115] 27. The soft gel capsule of any one of items 1 to 26, wherein the filling material further contains a lipid.

[0116] 28. The soft gel capsule of item 27, wherein the lipid is soybean oil.

[0117] 29. The soft gel capsule of any one of items 1 to 28, wherein the filling material further contains a suspending agent.

[0118] 30. The soft gel capsule of item 29, wherein the suspending agent is hydrogenated vegetable oil.

[0119] 31. The soft gel capsule of item 27, wherein the filling material contains about 90 wt% to about 95 wt% lipid based on the total composition of the filling material.

[0120] 32. The soft gel capsule of any of the preceding items, wherein the filling material contains about 5 parts by weight to about 10 parts by weight of bisacodyl based on 100 parts by weight of the filling material.

[0121] 33. The soft gel capsule of item 24, wherein the filling material contains about 0.001 parts by weight to about 2 parts by weight of an antioxidant based on 100 parts by weight of the filling material.

[0122] 34. The soft gel capsule of item 25, wherein the filling material contains about 0.001 parts by weight to about 0.5 parts by weight of BHT based on 100 parts by weight of the filling material.

[0123] 35. The soft gel capsule of item 26, wherein the filling material contains about 0.1 parts by weight to about 2 parts by weight of BHT based on 100 parts by weight of the filling material.

[0124] 36. The soft gel capsule of item 9, wherein the shell composition contains non-amidated pectin.

[0125] 37. When tested at 25 °C / 60% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, it disintegrates in a buffer solution of pH 6.8 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. The soft gel capsule of any one of the preceding items.

[0126] When tested at 38.25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, it remains intact in a medium of pH 1.2 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, and disintegrates in a buffer solution of pH 6.8 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. The soft gel capsule of any one of the above items.

[0127] When tested at 39.30°C / 65%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, it disintegrates in a buffer solution of pH 6.8 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. The soft gel capsule of any one of the above items.

[0128] When tested at 40.30°C / 65%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, it remains intact in a medium of pH 1.2 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, and disintegrates in a buffer solution of pH 6.8 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. The soft gel capsule of any one of the above items.

[0129] When tested at 41.49°C / 75%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, it disintegrates in a buffer solution of pH 6.8 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, any one of the soft gel capsules of the above items.

[0130] When tested at 42.40°C / 75%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, it remains intact in a medium of pH 1.2 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, and disintegrates in a buffer solution of pH 6.8 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, any one of the soft gel capsules of the above items.

[0131] Any one of the soft gel capsules of items 37 to 42, wherein the enteric polymer is amidated pectin.

[0132] When tested at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, any one of the soft gel capsules of the above items having at least about 90% assay stability.

[0133] When tested at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, any one of the soft gel capsules of the above items having at least about 92% assay stability.

[0134] When tested at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, any one of the soft gel capsules of the above items having at least about 94% assay stability.

[0135] When tested at 47.25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, any one of the soft gel capsules of the foregoing items having at least about 96% assay stability.

[0136] When tested at 48.25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, any one of the soft gel capsules of the foregoing items having at least about 98% assay stability.

[0137] When tested at 49.25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, any one of the soft gel capsules of the foregoing items having at least about 99% assay stability.

[0138] When tested at 50.30°C / 65%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, any one of the soft gel capsules of the foregoing items having at least about 90% assay stability.

[0139] When tested at 51.30°C / 65%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, any one of the soft gel capsules of the foregoing items having at least about 92% assay stability.

[0140] When tested at 52.30°C / 65%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, any one of the soft gel capsules of the foregoing items having at least about 94% assay stability.

[0141] When tested at 53.30°C / 65%RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months, any one of the soft gel capsules of the foregoing items having at least about 96% assay stability.

[0142] A soft gel capsule of any one of the foregoing items having at least about 98% assay stability when tested at 54.30°C / 65% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0143] A soft gel capsule of any one of the foregoing items having at least about 99% assay stability when tested at 55.30°C / 65% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0144] A soft gel capsule of any one of the foregoing items having at least about 90% assay stability when tested at 56.40°C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0145] A soft gel capsule of any one of the foregoing items having at least about 92% assay stability when tested at 57.40°C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0146] A soft gel capsule of any one of the foregoing items having at least about 94% assay stability when tested at 58.40°C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0147] A soft gel capsule of any one of the foregoing items having at least about 96% assay stability when tested at 59.40°C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0148] A soft gel capsule of any one of the foregoing items having at least about 98% assay stability when tested at 60.40°C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0149] A soft gel capsule of any one of the foregoing items having at least about 99% assay stability when tested at 61. 40°C / 75% RH for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months.

[0150] 62. A soft gel capsule of any of the foregoing items, wherein the soft gel capsule remains intact 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 carried out in a USP apparatus II using a paddle at a speed of 50 rpm in a medium of pH 1.2.

[0151] 63. A soft gel capsule of any one of the foregoing items, wherein the soft gel capsule remains intact 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, and the disintegration test is carried out in a USP apparatus II using a paddle at a speed of 50 rpm in a medium of pH 1.2.

[0152] 64. A soft gel capsule of any one of the foregoing items that disintegrates in a buffer solution of pH 6.8 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.

[0153] 65. A soft gel capsule of any of the foregoing items, wherein the soft gel capsule remains intact 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 medium of pH 1.2 and disintegrates in a buffer solution of pH 6.8 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.

[0154] 66. A soft gel capsule of any of the foregoing items, wherein the total impurities do not exceed about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1% or about 0.01% and are measured according to the current USP monograph test method.

[0155] 67. A soft gel capsule of any of the foregoing items, wherein the total impurities do not exceed about 0.3%.

[0156] 68. A method for producing a soft gel capsule of any one of items 1 to 67, comprising encapsulating a filling composition in a shell composition to form a soft gel capsule and drying the soft gel capsule.

[0157] 69. The method of item 68, wherein a gel conversion is performed on the shell composition before encapsulation.

Examples

[0158] Here, certain embodiments of the present invention are demonstrated with reference to the following examples. It should be understood that these examples are disclosed only for the purpose of illustrating the present invention and should not be construed as limiting the scope of the present invention in any way.

[0159] Shell compositions using various enteric polymers were developed. The shell compositions are presented in Tables 1 and 2.

[0160]

Table 1

[0161]

Table 2

[0162] The gel conversion of the shell compositions is shown in Table 3.

[0163]

Table 3

[0164] Also, two filling compositions were developed and encapsulated using the shell compositions in Tables 1 and 2. The filling compositions are shown in Tables 4 and 5.

[0165]

Table 4

[0166]

Table 5

[0167] The gel mass was prepared using a melter. The colorant was added directly to the melter during the preparation of the gel mass. The filling material was mixed using a mixing container. Two filling batches were prepared and divided into four (4) finished product sublots / batches. Encapsulation of the four (4) finished product sublots / batches was carried out. The theoretical batch size was 5000 soft gels for all four batches. The results of the in-process seal thickness inspection are summarized in Table 6 below.

[0168]

Table 6

[0169] Drying was carried out using a drying cabinet. After 24 hours, the hardness of all the capsules in the four lots reached the drying completion requirement. After drying was completed, the bisacodyl soft gel 5 mg capsules were inspected for defects, washed using a lecithin / ethanol solution, and packaged in sealed plastic bags.

[0170] All four finished product batches were packaged in 100 cc HDPE bottles (100 soft gels per bottle), induction sealed, and stability studies were carried out under various stability conditions of 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. The four batches are summarized in Table 7.

[0171]

Table 7

[0172] Two - stage dissolution test Table 8 summarizes the results of the two - stage dissolution test for enteric - coated bisacodyl 5 mg soft gels at T0. Batches 1 and 2 met the USP requirements for the first - stage dissolution at the T0 time point. Both lots were encapsulated using gel masses prepared using amidated pectin as described in Table 1. Capsules made with non - amidated pectin, namely Batches 3 and 4, were found to require an additional hardening process to enhance the interaction between gelatin and pectin to meet the USP dissolution requirements. Also, Batches 3 and 4, similarly, met the USP requirements for the two - stage dissolution at the T0 time point.

[0173]

Table 8

[0174] The test results at T12 months are presented in Table 9. The two - stage visual dissolution test includes visually inspecting the capsules to confirm whether the capsules opened and released any fillings at the acidic stage or the buffer stage, and whether the capsules completely released their contents at the buffer stage.

[0175]

Table 9

[0176] Disintegration test The disintegration test was also performed on batches. Table 10 summarizes the results of the disintegration test for enteric-coated bisacodyl 5 mg soft gels at the stability time points of T0, T1, and T2. Batch 1 was found to meet the USP requirements for disintegration at T0 and T1, as well as the EP requirements at T2. Batch 2 met the EP requirements for the disintegration test at all experimental points T0, T1, and T2. Both batches were encapsulated using a shell composition having amidated pectin. Batches 3 and 4 failed the disintegration test at all stability time points. Without being limited to theory, the inventors believe that this was due to the use of non-amidated pectin in the shell composition. Further test results are presented in Tables 11 to 15.

[0177]

Table 10

[0178]

Table 11

[0179] Table 12 summarizes the results of the 1-hour USP disintegration test at the T3 time point.

[0180]

Table 12

[0181] Table 13 summarizes the results of the 2-hour EP disintegration test at the T6 stability time point. Batch 1 met the EP requirements for disintegration at the T6 time point. Batches 2 to 4 still failed the disintegration test at the T6 time point.

[0182]

Table 13

[0183] Table 14 summarizes the results of the 2-hour EP dissolution test at the T12 stability time point. Batch 2 met the EP requirements for dissolution at the T12 time point. Batches 1, 3, and 4 still failed the dissolution test at the T12 time point.

[0184]

Table 14

[0185] Table 15 summarizes the results of the 1-hour USP dissolution test at the T12 stability time point.

[0186]

Table 15

[0187] As can be seen from the above results, Batches 1 and 2 met the USP requirements for dissolution at the T12 time point. Batches 3 and 4 still failed the dissolution test at the T12 time point. The difference in these batches was the type of pectin used. As described above, Batches 1 and 2 were prepared using amidated pectin, while Batches 3 and 4 were prepared using non-amidated pectin.

[0188] Table 16 summarizes the results of the 2-hour EP dissolution test at the T24 stability time point. Both Batches 1 and 2 met the EP requirements for dissolution at the T24 time point.

[0189]

Table 16

[0190] Table 17 summarizes the results of the 1-hour USP dissolution test at the T24 stability time point. Both Batches 1 and 2 met the USP requirements for dissolution at the T24 time point.

[0191]

Table 17

[0192] Chemical stability test The stability tests for Batches 1 to 4 were also conducted in the same manner.

[0193] Tables 18 to 21 summarize the chemical stability data for the samples under various stability conditions at the time points of T = 0, 6, 12, 18, and 24 months. For the analysis, LOQ = 0.05% and LOD = 0.03%. According to the ICH guidelines, the proposed specification for individual unknown impurity levels is 0.15%, and the proposed specification for total impurity levels is 2.0%.

[0194]

Table 18

[0195]

Table 19

[0196]

Table 20

[0197]

Table 21

[0198] Under all stability conditions (40°C / 75%RH, 30°C / 65%RH, and 25°C / 60%RH), all four lots of the enteric-coated bisacodyl 5 mg soft gel product are chemically stable with or without antioxidant, and as expected, a slight increase in impurities is observed at 40°C / 75%RH.

[0199] From these results, it was found that the enteric-coated bisacodyl soft gel products were physically and chemically stable. All batches / lots of the bisacodyl soft gel products were chemically stable, with and without antioxidants. The soft gel products encapsulated using amidated pectin met either the USP dissolution requirements or the EP dissolution requirements. The soft gel products encapsulated using non-amidated pectin met the requirements of the second-stage visual dissolution test.

Claims

1. A softgel capsule, (a) A filling material comprising a suspending agent comprising bisacodyl or a pharmaceutically acceptable salt thereof, lipids including soybean oil, and hydrogenated vegetable oil; and (b) A shell composition comprising a film-forming material, a plasticizer comprising sorbitol and sorbitan, and an enteric polymer comprising pectin; The filling material contains 5 to 10 parts by weight of bisacodyl based on 100 parts by weight of the filling material. The filler material contains 90% to 95% by weight of lipids based on the total composition of the filler material. When a disintegration test was performed using a USP apparatus II with a paddle moving at 50 rpm in a pH 1.2 medium, the softgel capsule remained intact for at least 15 minutes, and, When tested at 40°C / 75% RH for one month, the softgel capsules exhibit at least 90% assay stability. The aforementioned softgel capsule.

2. The softgel capsule according to claim 1, wherein the film-forming material comprises an animal-derived polymer or a non-animal-derived polymer.

3. The softgel capsule according to claim 2, wherein the animal-derived polymer contains gelatin.

4. The softgel capsule according to claim 2, wherein the non-animal-derived polymer comprises gellan gum.

5. The softgel capsule according to claim 1, wherein the shell composition further comprises dextrose.

6. The softgel capsule according to claim 1, wherein the enteric-coated polymer is a methylacrylic acid copolymer.

7. The softgel capsule according to claim 3, wherein the shell composition comprises 30% to 80% by weight of gelatin.

8. The softgel capsule according to claim 1, wherein the shell composition contains 2% to 20% by weight of pectin.

9. The softgel capsule according to claim 6, wherein the shell composition comprises 2% to 16% by weight of a methylacrylic acid copolymer.

10. The softgel capsule according to claim 5, wherein the shell composition contains 0.01% to 4% by weight of dextrose.

11. The softgel capsule according to claim 3, wherein the gelatin comprises type A gelatin, type B gelatin, and mixtures thereof.

12. The softgel capsule according to claim 1, wherein the shell composition further comprises water.

13. The softgel capsule according to claim 1, wherein the filling material further comprises an antioxidant.

14. The softgel capsule according to claim 13, wherein the filling material further comprises butylated hydroxytoluene (BHT).

15. The softgel capsule according to claim 13, wherein the filling material further comprises butylated hydroxyanisole (BHA).

16. The softgel capsule according to claim 13, wherein the filling material contains 0.001 to 2 parts by weight of an antioxidant based on 100 parts by weight of the filling material.

17. The softgel capsule according to claim 14, wherein the filling material contains 0.001 to 0.5 parts by weight of BHT based on 100 parts by weight of the filling material.

18. The softgel capsule according to claim 15, wherein the filling material contains 0.1 to 2 parts by weight of BHT based on 100 parts by weight of the filling material.

19. The softgel capsule according to claim 1, which has at least 90% assay stability when tested at 25°C / 60% RH for one month.

20. The softgel capsule according to claim 1, which has at least 90% assay stability when tested at 30°C / 65% RH for one month.

21. The softgel capsule according to claim 1, which remains intact for at least 15 minutes in a medium of pH 1.2 and disintegrates in a buffer solution of pH 6.8 in 60 minutes or less.

22. The softgel capsule according to claim 1, wherein the total impurities do not exceed 0.5%, and the total impurities are measured according to the current USP monograph test method.