Soft gel capsule

Abstract

A soft gel capsule is provided that can be used with a fill composition that contains a high alcohol content. The soft gel capsule includes a shell composition that includes a film-forming polymer and a plasticizer. The fill composition includes at least about 20 wt.% alcohol. The soft gel capsule has a weight loss change of less than about 10% after storage at ambient conditions for 30 days, 90 days, 6 months, 9 months, or 12 months.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 218,579, filed July 6, 2021, which is incorporated by reference in its entirety.

[0002] The present invention relates to a soft gel capsule for enclosing a fill composition comprising alcohol, more particularly, the present invention relates to a soft gel capsule for enclosing a fill composition comprising, for example, at least about 20 wt.% alcohol. [Background technology]

[0003] Alcohol is a common ingredient in a variety of pharmaceutical and personal care products, such as disinfectants. Ethyl alcohol is commonly used in pharmaceutical products to solubilize active pharmaceutical ingredients and to increase the bioavailability of pharmaceutical products. In personal care products, alcohol is commonly used as a disinfectant in hand sanitizer gels.

[0004] There are many dosage forms in which pharmaceutical products and personal care products are prepared. Soft gelatin capsules (also called liquid gels or soft gels) are a unique drug delivery system that can provide clear advantages over traditional dosage forms such as tablets, hard gelatin capsules and liquids. Soft gels are usually sealed one-piece capsules with liquid or semi-solid fillings. Soft gels usually include two main components: a shell composition and a fill composition. An exemplary shell composition may include a film-forming polymer such as gelatin. The fill composition can include a wide variety of vehicles, for example, it can be a solution or a suspension.

[0005] Soft gel capsules often use alcohol to solubilize pharmaceutical products. Having alcohol in the soft gel fill composition has proven challenging in preparing a stable product suitable for commercialization. Recently, there has been a high demand for single-use alcohol-based hand sanitizers due to the ongoing COVID-19 pandemic. Current single-use dose hand sanitizers are packaged using plastic or plastic / aluminum laminated film pouches to prevent alcohol loss. However, these packaging materials are not biodegradable, which is an environmental concern. There is a continuing need in the art for green and environmentally acceptable packaging for soft gels and alcohol-based products suitable for alcohol-containing fill compositions. Summary of the Invention

[0006] It is an object of some embodiments of the present invention to provide a soft gel capsule that includes a fill composition that includes alcohol.

[0007] It is an object of some embodiments of the present invention to provide a soft gel capsule comprising a fill composition that includes an active agent solubilized in alcohol.

[0008] It is an object of some embodiments of the present invention to provide a soft gel capsule comprising a fill composition that includes a sanitizing agent (e.g., a hand sanitizer).

[0009] It is an object of some embodiments of the present invention to provide a method for preparing a soft gel capsule as disclosed herein.

[0010] It is an object of some embodiments of the present invention to provide a method of treating a disease or condition with a soft gel capsule as disclosed herein.

[0011] It is an object of some embodiments of the present invention to provide a method of disinfecting a surface (e.g., a bodily surface) with the soft gel capsule fill composition disclosed herein.

[0012] One or more of the above and other objects of the present invention may be met by several embodiments of the present invention.

[0013] In some embodiments, the present invention is directed to a soft gel capsule comprising a shell comprising a film-forming polymer and a plasticizer, and a fill composition comprising at least about 20 wt.% alcohol.

[0014] In some embodiments, the present invention is directed to a soft gel capsule comprising a shell comprising a film-forming polymer and a plasticizer, and a fill composition comprising at least about 20 wt.% alcohol, wherein after 30 days, 90 days, 6 months, 9 months, or 12 months of storage at ambient conditions, the soft gel capsule has a weight loss change of less than about 10%.

[0015] In some embodiments, the present invention is directed to a method of treating a disease or condition comprising administering to a subject or patient in need thereof a soft gel comprising an active agent as disclosed herein.

[0016] In some embodiments, the present invention is directed to a method of preparing a soft gel as disclosed herein comprising encapsulating a fill composition comprising at least about 20 wt.% alcohol in a shell comprising a film-forming polymer and a plasticizer.

[0017] In some embodiments, the present invention is directed to a method of disinfecting a surface comprising dispensing an alcoholic composition from a soft gel disclosed herein and applying the composition to a surface.

[0018] The present invention is illustrated by way of example and not by way of limitation in the figures of the accompanying drawings, in which: [Brief description of the drawings]

[0019] [Figure 1] 1 is a graph showing the weight loss results of Example 5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The detailed description set forth below is intended merely as a description of the presently preferred embodiments of the invention, and is not intended to represent the only manner in which the invention may be constructed or used. The description sets forth the functions, means, and methods of carrying out the invention in connection with the illustrated embodiments. However, it should be understood that the same or equivalent functions and features may be accomplished by different embodiments that are also intended to be encompassed within the spirit and scope of the claims.

[0021] As used herein, the singular forms "a," "an," and "the" include references to the plural unless the context clearly indicates otherwise. Thus, for example, reference to an "active pharmaceutical ingredient" includes a single active pharmaceutical ingredient as well as mixtures of two or more different active pharmaceutical ingredients, reference to an "excipient" includes a single excipient as well as mixtures of two or more different excipients, and so forth.

[0022] As used herein, the term "about" in connection with a measured quantity refers to normal variation in the measured quantity as would be expected by a person of ordinary skill in the art making the measurements and exercising a level of care appropriate to the purpose of the measurement and the precision of the measuring equipment. In some embodiments, the term "about" includes the recited number ±5%, such that "about 10" would include 9.5 to 10.5.

[0023] The recitation of ranges of values ​​herein is intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0024] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to highlight particular materials and methods and does not pose a limitation on the scope of the invention. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods.

[0025] As used herein, the terms "active agent," "active ingredient," "active pharmaceutical ingredient," "API," and "drug" refer to any material intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose. These terms, with respect to specific agents, include all pharma- ceutically active agents, all pharma- ceutically acceptable salts, complexes, stereoisomers, crystalline forms, cocrystals, ethers, esters, hydrates, solvates, and mixtures thereof, which form is pharma- ceutically active.

[0026] As used herein, "shell" or "shell composition" refers to the shell of a soft gel capsule that encapsulates the fill material.

[0027] As used herein, "filling material" or "fill" refers to the composition that is encapsulated by the shell.

[0028] As used herein, "ambient conditions" refers to a temperature range of 15.0°C (59°F) to 30.0°C (86°F) and a relative humidity range of 20% to 50%.

[0029] In some embodiments, the present invention is directed to soft gel capsules that can be used with fills having high alcohol content (e.g., greater than about 20%). In some embodiments, the soft gel capsules can be spherical, oval, rectangular, or twist-off. In some embodiments, after 30 days, 90 days, 6 months, 9 months, or 12 months of storage at ambient conditions, the soft gel capsules have a weight loss change of less than about 10%.

[0030] In some embodiments, the shell may include a film-forming polymer and optionally a plasticizer. The film-forming polymer may be an animal-derived polymer, a non-animal-derived polymer, or a combination thereof. The animal-derived polymer may include gelatin. The gelatin in the shell composition may include, but is not limited to, type A gelatin, type B gelatin, hide gelatin, fish gelatin, pork gelatin, and / or bone gelatin, used alone or in combination. In an embodiment, the gelatin is a type A medium bloom gelatin to high bloom gelatin. In an embodiment, the gelatin is a type B medium bloom gelatin to high bloom gelatin. Medium bloom is when the bloom is about 70 grams to about 160 grams. High bloom is when the bloom is about 175 grams or more, or about 175 grams to about 300 grams. In one embodiment, the gelatin is a 250 bloom gelatin. In another embodiment, the gelatin is only one type. In yet another embodiment, the gelatin is a combination of at least two types of gelatin. The non-animal derived polymer may include carrageenan.

[0031] The plasticizer can be glycerol, glycerin, sorbitol, polyethylene sorbitan monooleate or combinations thereof.Other suitable plasticizers can 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, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyol, 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 hydroxyls, ester-based plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single block polymers, citrate-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.

[0032] The shell may also include additional ingredients. The additional ingredients may include a thickener, a buffer, water, or a combination thereof. The shell may further include pullulan.

[0033] The shell composition may include gelatin in an amount of about 35 wt.% to about 75 wt.%. In some embodiments, the gelatin may be included in an amount of about 40 wt.% to about 70 wt.%, about 45 wt.% to about 65 wt.%, or about 50 wt.% to about 60 wt.%. In some embodiments, the gelatin may be included in an amount of at least about 30 wt.%, at least about 35 wt.%, at least about 40 wt.%, at least about 45%, at least about 50 wt.%, at least about 55 wt.%, at least about 60 wt.%, at least about 65 wt.%, at least about 70 wt.%, or at least about 75 wt.%.

[0034] The shell composition may contain a sorbitol solution or a sorbitol sorbitan solution, POLYSORB® 85 / 70 / 00 or Sorbitol Special®, in an amount of about 5 wt.% to about 35 wt.%, or about 5 wt.% to about 25 wt.%, or about 10 wt.% to about 30 wt.%, or about 15 wt.% to about 25 wt.%, or about 18 wt.% to about 35 wt.%, or about 20 wt.% to about 30 wt.%. Glycerin (e.g., anhydrous glycerin) may also be present in the shell composition in an amount of about 10 wt.% to about 40 wt.%, or about 15 wt.% to about 40 wt.%, or about 10 wt.% to about 20 wt.%, or about 10 wt.% to about 30 wt.%, or about 15 wt.% to about 30 wt.%, or about 15 wt.% to about 25 wt.%. Sodium alginate may also be included in the shell composition in an amount of about 1 wt.% to about 10 wt.%, or about 2 wt.% to about 9 wt.%, or about 3 wt.% to about 8 wt.%, or about 4 wt.% to about 7 wt.%, or about 5 wt.% to about 6 wt.%. The shell composition may also include purified water in an amount of about 8 wt.% to about 25 wt.%, or about 8 wt.% to about 20 wt.%, or about 10 wt.% to about 20 wt.%, or about 12 wt.% to about 20 wt.%, or about 10 wt.% to about 15 wt.%.

[0035] In some embodiments, the amount of sorbitol or sorbitol sorbitan solution in the shell composition may be at least about 5 wt.%, at least about 10 wt.%, at least about 15 wt.%, at least about 20 wt.%, at least about 25 wt.%, at least about 30 wt.%, or at least about 35 wt.%. In some embodiments, the amount of glycerin (e.g., anhydrous glycerin) in the shell composition may be at least about 10 wt.%, at least about 15 wt.%, at least about 20 wt.%, at least about 25 wt.%, at least about 30 wt.%, at least about 35 wt.%, or at least about 40 wt.%. In some embodiments, the amount of sodium alginate may be included in the shell composition in an amount of at least about 1 wt.%, at least about 2 wt.%, at least about 3 wt.%, at least about 4 wt.%, at least about 5 wt.%, at least about 6 wt.%, at least about 7 wt.%, at least about 8 wt.%, at least about 9 wt.%, or at least about 10 wt.%. In some embodiments, the amount of purified water may be at least about 8 wt.%, at least about 10 wt.%, at least about 13 wt.%, at least about 15 wt.%, at least about 18 wt.%, at least about 20 wt.%, at least about 22.5 wt.%, or at least about 25 wt.%.

[0036] The thickening / film-forming agent may be a starch, a starch derivative or a modified starch. The starch or starch derivative may be hydroxypropylated tapioca starch, hydroxypropylated corn starch, potato starch, or pregelatinized modified corn starch. Modified starches include starches such as hydroxypropylated starch, acid thinned starch, and the like. In general, modified starches are products prepared by chemically processing starch, such as, for example, acid-treated starch, enzyme-treated starch, oxidized starch, cross-bonding starch, and other starch derivatives.

[0037] The buffering agent and / or alkalizing agent may be, but is not limited to, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate and / or disodium phosphate. In one embodiment, the buffering agent is disodium phosphate.

[0038] In some embodiments, the soft gel capsule fill composition comprises at least about 20 wt.% alcohol, at least about 30 wt.% alcohol, at least about 40 wt.% alcohol, at least about 50 wt.% alcohol, at least about 60 wt.% alcohol, or at least about 75 wt.% alcohol. In some embodiments, the alcohol is present in an amount of about 20 wt.% to about 75 wt.%, about 25 wt.% to about 70 wt.%, about 30 wt.% to about 65 wt.%, about 35 wt.% to about 60 wt.%, about 40 wt.% to about 55 wt.%, or about 45 wt.% to about 50 wt.%, or any range or sub-range therein.

[0039] The alcohol in the fill composition may be ethanol, ethyl alcohol or isopropanol. In some embodiments, the ethanol may be 40% ethanol, 50% ethanol (100 proof), 60% ethanol, 65% ethanol, 70% ethanol, 75% ethanol, 80% ethanol, or 100% ethanol (200 proof). In some embodiments, the ethyl alcohol may be 70% ethyl alcohol, 75% ethyl alcohol, 80% ethyl alcohol, 85% ethyl alcohol, or 90% ethyl alcohol. In some embodiments, the isopropanol may be 60% isopropanol, 65% isopropanol, 70% isopropanol, 75% isopropanol, 80% isopropanol, or 85% isopropanol.

[0040] The fill composition of the softgel composition may further comprise additional ingredients, which may be water, acrylates copolymer, xanthan gum, carbomer, glycerin, butylene glycol, aminomethylpropanol, aloe barbaensis leaf extract, an active pharmaceutical ingredient, or combinations thereof.

[0041] In some embodiments, the present invention is directed to a soft gel capsule comprising a shell comprising a film-forming polymer and a plasticizer, and a fill composition comprising at least about 20 wt.% alcohol, wherein after 30 days, 90 days, 6 months, 9 months, or 12 months of storage at ambient conditions, the soft gel capsule has a weight loss change of less than about 10%.

[0042] In some embodiments of the invention, after 30 days of storage at ambient conditions, the soft gel capsules have a weight loss change of less than about 8%, less than about 5%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.25%.

[0043] In some embodiments of the invention, after 2 months of storage at ambient conditions, the soft gel capsules have a weight loss change of less than about 8%, less than about 5%, less than about 3%, less than about 1%, less than about 0.5%, or less than about 0.25%.

[0044] In some embodiments of the invention, after 6 months of storage at ambient conditions, the soft gel capsules have a weight loss change of less than about 8%, less than about 5%, less than about 3%, less than about 1%, less than about 0.5%, or less than about 0.25%.

[0045] In some embodiments of the invention, after 9 months of storage at ambient conditions, the soft gel capsules have a weight loss change of less than about 8%, less than about 5%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.25%.

[0046] In some embodiments of the invention, after 12 months of storage at ambient conditions, the soft gel capsules have a weight loss change of less than about 8%, less than about 5%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.25%.

[0047] In some embodiments of the invention, storage at ambient conditions is in a sealed container.

[0048] In other embodiments of the invention, storage at ambient conditions is in an open container.

[0049] In some embodiments of the present invention, the film-forming polymer comprises an animal-derived polymer or a non-animal-derived polymer.

[0050] In some embodiments of the present invention, the animal derived polymer comprises gelatin.

[0051] In some embodiments of the present invention, the non-animal derived polymer comprises alginate, carrageenan, pullulan, or a combination thereof.

[0052] In some embodiments of the present invention, the alcohol comprises ethanol, isopropanol, or a combination thereof.

[0053] In some embodiments of the present invention, the shell further comprises a thickening agent.

[0054] In some embodiments of the invention, the shell further comprises a buffering agent.

[0055] In some embodiments of the present invention, the shell further comprises a gelling salt, which may be calcium chloride, sodium chloride, potassium chloride, sodium citrate, calcium acetate, calcium citrate, calcium gluconate, calcium lactate, sodium phosphate, or potassium phosphate.

[0056] In some embodiments of the present invention, the shell further comprises water.

[0057] In some embodiments of the present invention, the plasticizer comprises glycerin, sorbitol, polyethylene sorbitan monooleate, or a combination thereof.

[0058] In some embodiments of the present invention, the shell further comprises pullulan.

[0059] In some embodiments of the present invention, the thickening / film-forming agent comprises starch or a starch derivative.

[0060] In some embodiments of the invention, the buffer comprises sodium phosphate.

[0061] In some embodiments of the present invention, the shell contains from about 0.1 grams to about 2 grams of the fill composition. In other embodiments, the shell may contain from about 0.1 grams to about 1.75 grams of the fill composition, or from 0.25 grams to about 1.5 grams, or from about 0.5 grams to about 1.25 grams, or from about 0.75 grams to about 1 gram. In some embodiments, the shell may contain at least about 0.1 grams of the fill composition, at least about 0.25 grams of the fill composition, at least about 0.5 grams of the fill composition, at least about 0.75 grams of the fill composition, at least about 1 gram of the fill composition, at least about 1.25 grams of the fill composition, at least about 1.5 grams of the fill composition, at least about 1.75 grams of the fill composition, or at least about 2 grams of the fill composition.

[0062] In some embodiments of the present invention, the fill composition further comprises water, acrylates copolymer, xanthan gum, glycerin, butylene glycol, aminomethylpropanol, aloe barbaensis leaf extract, or combinations thereof.

[0063] In some embodiments of the invention, after 3 months, 6 months or 12 months, the soft gel capsule has a weight loss change of less than about 10%. In some embodiments of the invention, after 1 month, 2 months, 3 months, 6 months, 9 months or 12 months, the soft gel capsule has a weight loss change of less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.25%.

[0064] In some embodiments of the present invention, the soft gel may be spherical, elliptical, rectangular or twist-off.

[0065] In some embodiments of the present invention, the softgel further comprises an active agent.

[0066] In some embodiments of the present invention, the active agent is solubilized in alcohol.

[0067] In some embodiments of the present invention, the capsule disintegrates in a gastric environment in less than about 60 minutes, less than about 45 minutes, less than about 30 minutes, less than about 20 minutes, less than about 10 minutes, or less than about 5 minutes based on disintegration testing performed in a USP Apparatus II with paddles at a speed of 50 rpm in a pH 1.2 buffer.

[0068] In some embodiments of the invention, the capsule disintegrates in 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 basic medium, based on disintegration testing performed in a basket rack assembly NT-40H model apparatus in a 1000 mL beaker at about 37° C.±2° C.

[0069] In some embodiments of the present invention, the shell comprises an enteric material.

[0070] In some embodiments of the present invention, the capsule dissolves / disintegrates in an acidic medium in 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 based on dissolution / disintegration tests performed in 0.1N HCl, optionally containing pepsin, or in simulated gastric fluid in a USP Apparatus II using paddles at a speed of 50 rpm.

[0071] In some embodiments of the present invention, the capsule dissolves / disintegrates in an intestinal environment after at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, or between about 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes and about 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 75 minutes, or 90 minutes, based on dissolution / disintegration testing performed in a pH 6.8 phosphate buffer, optionally containing pancreatin, or in simulated gastric fluid in a USP Apparatus II using paddles at a speed of 50 rpm.

[0072] In some embodiments, the present invention is directed to a method of treating a disease or condition comprising administering a soft gel as disclosed herein to a subject or patient in need thereof.

[0073] In some embodiments, the present invention is directed to a method of preparing a soft gel as disclosed herein comprising encapsulating a fill composition comprising at least about 20 wt.% alcohol in a shell comprising a film-forming polymer and a plasticizer.

[0074] In some embodiments, the present invention is directed to a method of disinfecting a surface comprising dispensing an alcoholic composition from a soft gel as disclosed herein and applying the composition to a surface.

[0075] In some embodiments, the surface is the skin of a subject (eg, on one or more hands).

[0076] In some embodiments, the surface is on a non-living object (eg, a counter surface).

[0077] Alternative Embodiments In some embodiments, the shell comprises a pH-dependent polymer that is solubilized at a pH of less than about 5.5, less than about 5.0, less than about 4.5, or less than about 4.0.

[0078] In some embodiments, the pH dependent polymer is an acrylic polymer or a cellulose polymer.

[0079] In some embodiments, the pH dependent polymer is an acrylic polymer, such as an amino methacrylate copolymer.

[0080] In some embodiments, the shell composition comprises the pH-dependent polymer in an amount (w / w) of about 1% to about 90%, about 2% to about 60%, about 5% to about 50%, about 10% to about 40%, or about 15% to about 35%. In other embodiments, the shell composition may comprise the pH-dependent polymer in an amount (w / w) of at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition.

[0081] In some embodiments, the shell composition comprises gelatin in an amount (w / w) of about 5% to about 75%, about 10% to about 60%, about 15% to about 50%, or about 20% to about 40%. In some embodiments, the shell composition may comprise gelatin in an amount (w / w) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or at least about 75%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition.

[0082] In some embodiments, the shell composition further comprises a solubilizing agent, such as an organic acid, such as, for example, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, phthalic acid, isophthalic acid, terephthalic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, cinnamic acid, lactic acid, benzoic acid, salicylic acid, gallic acid, or toluic acid. In certain embodiments, the organic acid is lactic acid.

[0083] In some embodiments, the shell composition comprises a solubilizer in an amount (w / w) of about 0.0001% to about 1%, about 0.001% to about 0.5%, or about 0.005% or about 0.1%. In some embodiments, the shell composition may comprise a solubilizer in an amount (w / w) of about 0.01% to about 0.5%, about 0.1% to about 1%, or any range or value therein. In some embodiments, the shell composition may comprise a solubilizer in an amount of at least about 0.0001%, at least about 0.001%, at least about 0.005%, at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, or at least about 1%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition.

[0084] In some embodiments, the shell composition further comprises a plasticizer in an amount (w / w) of, for example, about 0.1 wt.% to about 50 wt.%, about 5% to about 45%, about 10% to about 40%, or about 15% to about 35%. In some embodiments, the shell composition may comprise a plasticizer in an amount of at least about 0.1 wt.%, at least about 1 wt.%, at least about 2.5 wt.%, at least about 5 wt.%, at least about 10 wt.%, at least about 15 wt.%, at least about 20 wt.%, at least about 25 wt.%, at least about 30 wt.%, at least about 35 wt.%, at least about 40 wt.%, at least about 45 wt.%, at least about 50 wt.%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition.

[0085] In some embodiments, the plasticizer is selected from glycerol, glycerin, sorbitol solution, sorbitol sorbitan solution, or combinations thereof.

[0086] In some embodiments, the gelatin is selected from type A gelatin, type B gelatin, or a mixture thereof.

[0087] In some embodiments, the gelatin is selected from the group consisting of fish gelatin, animal skin gelatin, bone gelatin, or mixtures thereof.

[0088] In some embodiments, the liquid medium is water, a polyol, a glycol, an alcohol, or a combination thereof. The polyol can be glycerol, the glycol can be polyethylene glycol, and the alcohol can be ethanol.

[0089] In some embodiments, the fill composition comprises alcohol in an amount of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. In some embodiments, the fill composition comprises alcohol in an amount of 20%-50%, about 50%-about 70%, or about 70%-about 95%.

[0090] In some embodiments, the capsule disintegrates in a gastric environment in less than about 60 minutes, less than about 45 minutes, less than about 30 minutes, less than about 20 minutes, less than about 10 minutes, or less than about 5 minutes, based on disintegration testing performed in a USP Apparatus II with paddles at a speed of 50 rpm in a pH 1.2 buffer.

[0091] In some embodiments, the capsule disintegrates in 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 basic medium, based on disintegration testing performed in a basket rack assembly NT-40H model apparatus in a 1000 mL beaker at about 37° C.±2° C.

[0092] Suitable fill materials may include additional fill ingredients such as flavorants, sweeteners, colorants and fillers or other pharma- ceutically acceptable excipients, or additives such as synthetic dyes and mineral oxides.

[0093] In some embodiments, the fill material (with or without an active agent) in a dosage form according to the present disclosure has a pH of greater than about 3. For example, the pH of the fill material is greater than about 3, greater than about 4, greater than about 5, greater than about 6, greater than about 7, greater than about 8, greater than about 9, or from about 4 to about 14, from about 4 to about 6, from about 5 to about 7, from about 6 to about 8, from about 7 to about 9, from about 8 to about 10, from about 9 to about 11, from about 10 to about 12, from about 11 to about 13, from about 12 to about 14, from about 10 to about 14, from about 10 to about 13, from about 10 to about 12, or any individual pH or subrange within these ranges.

[0094] In embodiments, the gelatin in the shell composition may include type A gelatin, type B gelatin, animal hide or skin gelatin, and / or bone gelatin used alone or in combination. In one embodiment, the gelatin is 250 bloom gelatin. In another embodiment, there is only one type of gelatin. In yet another embodiment, the gelatin is a combination of at least two types of gelatin. In embodiments, the amount of gelatin in the shell composition is about 5 wt.% to about 90 wt.%, about 10 wt.% to about 80 wt.%, about 20 wt.% to about 80 wt.%, about 40 wt.% to about 80 wt.%, or about 45 wt.% to about 75 wt.%, or about 50 wt.% to about 70 wt.%. In some embodiments, the amount of gelatin can be at least about 5 wt.%, at least about 10 wt.%, at least about 15 wt.%, at least about 20 wt.%, at least about 25 wt.%, at least about 30 wt.%, at least about 35 wt.%, at least about 40 wt.%, at least about 45 wt.%, at least about 50 wt.%, at least about 55 wt.%, at least about 60 wt.%, at least about 65 wt.%, at least about 70 wt.%, at least about 75 wt.%, at least about 80 wt.%, at least about 85 wt.%, or at least about 90 wt.%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition.

[0095] In one embodiment, the shell composition may include dextrose. In an embodiment, the amount of dextrose in the pH-dependent capsule shell composition is about 0.005 wt.% or about 0.01 wt.% to about 4 wt.%, or about 0.1 wt.% or about 0.15 wt.% to about 3 wt.%, or about 0.15 wt.% or about 0.2 wt.% to about 2 wt.%, or about 0.1 wt.% to about 0.2 wt.%. In some embodiments, the amount of dextrose in the pH dependent capsule shell composition can be at least about 0.005 wt.%, at least about 0.01 wt.%, at least about 0.1 wt.%, at least about 0.15 wt.%, at least about 0.2 wt.%, at least about 0.5 wt.%, at least about 1 wt.%, at least about 2 wt.%, at least about 3 wt.%, or at least about 4 wt.%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition.

[0096] In embodiments, the plasticizer in the shell composition may include glycerol, glycerin, sorbitol solution, sorbitol 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, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 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 hydroxyls, ester-based plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single block polymers, citrate-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.

[0097] In embodiments, the amount of plasticizer in the shell composition is about 0.1 wt.% to about 50 wt.%, about 15 wt.% to about 40 wt.%, or about 20 wt.% to about 35 wt.%, or about 25 wt.% to about 30 wt.%. In some embodiments, the amount of plasticizer can be at least about 0.1 wt.%, at least about 1 wt.%, at least about 5 wt.%, at least about 10 wt.%, at least about 15 wt.%, at least about 20 wt.%, at least about 25 wt.%, at least about 30 wt.%, at least about 35 wt.%, at least about 40 wt.%, at least about 45 wt.%, or at least about 50 wt.%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition.

[0098] In embodiments, the shell composition may optionally include additional agents such as colorants, flavorants, sweeteners, fillers, antioxidants, diluents, pH adjusters or other pharma- ceutically acceptable excipients, or additives such as synthetic dyes and mineral oxides.

[0099] Exemplary suitable colorants may include, but are not limited to, colors such as, for example, white, black, yellow, blue, green, pink, red, orange, violet, indigo, and brown, etc. In specific embodiments, the color of the dosage form may be indicative of the contents (e.g., one or more active ingredients) contained therein.

[0100] Exemplary suitable flavoring agents may include, but are not limited to, "flavor extracts," obtained by extracting a portion of a raw material, such as an animal or plant material, often by using a solvent such as ethanol or water; natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from whole plants.

[0101] 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, and actives used in tooth and oral cleaning such as quaternary ammonium bases. The effect of the flavoring agents may be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

[0102] Exemplary sweeteners 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 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®), stevia, chloro derivatives of sucrose, such as 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 trademark MagnaSweet®); natural intense sweeteners such as Stevia rebaudiana (stevioside), swingle fruit, and polyols such as sorbitol, mannitol, xylitol, and erythritol.

[0103] Encapsulation of the fill material may be accomplished in any conventional manner. By way of example, a rotary die encapsulation machine may be used.

[0104] According to embodiments, the pH dependent soft gel capsule is prepared by a method comprising the steps of (a) preparing a fill material as disclosed herein, said fill material optionally comprising at least one pharma- ceutical active ingredient, and (b) encapsulating the fill material of step (a) in a shell composition as disclosed herein. The encapsulation method according to step (b) may further comprise the sub-step of preparing the shell composition, for example, by mixing a film-forming polymer and a plasticizer.

[0105] Non-Animal Film Formers In some embodiments, the shell composition comprises a non-animal film former, such as carrageenan, pullulan, starch, pregelatinized starch, xanthan gum, agar, pectin, alginate, sugar, sugar-derived alcohol, monosaccharide, disaccharide, oligosaccharide, cellulose derivative, cellulose polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, arbopol, silicon dioxide, curdlan, furcelleran, albumin (e.g., from egg or lacto), soy protein, chitosan, guar gum, tamarind seed polysaccharide, glucomannan, chitin, pullulan, inulin, cyclodextrin, or combinations thereof.

[0106] The carrageenan can be at least one of iota carrageenan, kappa carrageenan, and lambda carrageenan.

[0107] The starch can be modified or native starch, sweet potato starch, potato starch, corn starch, tapioca starch, pea starch, hydroxypropylated starch, hydroxyalkylated starch, acid treated starch, dextrin, high amylose unmodified corn starch, modified waxy corn starch, non-granular starch, modified high amylose corn starch, pregelatinized rice flour and combinations thereof. As used herein and in the claims, the term "modified starch" includes starches such as hydroxypropylated starch, acid diluted starch, etc. In general, modified starches are products prepared by chemically processing starch, such as, for example, acid treated starch, enzyme treated starch, oxidized starch, cross-linked starch, and other starch derivatives. Modified starches are preferably derivatized so that the side chains are modified with hydrophilic or hydrophobic groups, thereby forming more complex structures with strong interactions between the side chains.

[0108] In some embodiments, the non-animal film former is present in the shell composition in an amount of, for example, about 2 wt.% to about 20 wt.%, about 2 wt.% to about 15 wt.%, about 2 wt.% to about 40 wt.%, about 10 wt.% to about 80 wt.%, or about 15 wt.% to about 75 wt.%, or about 20 wt.% to about 70 wt.%, or about 25 wt.% to about 60 wt.%, or about 25 wt.% to about 45 wt.%, or about 20 wt.% to about 35 wt.%, or about 30 wt.% to about 40 wt.%, or about 32 wt.%, or about 35 wt.%, or about 38 wt.%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition. In some embodiments, the non-animal film former is present in the shell composition in an amount of at least about 2 wt.%, at least about 5 wt.%, at least about 10 wt.%, at least about 15 wt.%, at least about 20 wt.%, at least about 25 wt.%, at least about 30 wt.%, at least about 32 wt.%, at least about 35 wt.%, at least about 38 wt.%, at least about 40 wt.%, at least about 45 wt.%, at least about 50 wt.%, at least about 55 wt.%, at least about 60 wt.%, at least about 65 wt.%, at least about 70 wt.%, at least about 75 wt.%, at least about 80 wt.%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition.

[0109] In one embodiment, the non-animal gelling agents include carrageenan but do not include starch (or modified starch). In one embodiment, the soft gel shell composition is substantially free or free of starch (or modified starch).

[0110] enteric coated material In some embodiments, the shell composition comprises an enteric polymeric material, such as acrylic and methacrylic acid polymers, which may be available under the trade names EUDRAGIT®, Kollicoat® MAE100P, and other acid-insoluble polymers, such as methyl acrylate-methacrylic acid copolymers. Other acid-insoluble polymers include, but are not limited to, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), alginates, such as sodium alginate and potassium alginate, stearic acid, and shellac. Other enteric materials include pectin, pectin derivatives, gellan gum, and gellan gum derivatives.

[0111] Activator Any pharmacologic active ingredient that is alcohol soluble may be used for the purposes of the present invention. Suitable pharmacologic active ingredients include analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigouts, antihypertensives, antimalarials, antimigraine, antimuscarinics, antineoplastics and immunosuppressants, antiprotozoal agents, antirheumatics, antithyroids, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropics, and the like. These include, but are not limited to, therapeutic agents, corticosteroids, antitussives, cytotoxic, decongestants, diuretics, enzymes, antiparkinsonian drugs, gastrointestinal drugs, histamine receptor antagonists, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritionals, opioid analgesics, oral vaccines, protein, peptide and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and combinations thereof.

[0112] In some embodiments, the active pharmaceutical ingredient may be selected from the group consisting of, but is not limited to, dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurin, asimadoline, beclomethasone, apremilast, sapacitabine, linsitinib, abiraterone, vitamin D analogs (e.g., calcifediol, calcitriol, paricalcitol, doxercalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, pharmaceutically acceptable salts thereof, and combinations thereof.

[0113] According to some embodiments, active agents may include lipid-lowering agents, including, but not limited to, statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), fibrates (e.g., clofibrate, ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil), niacin, bile acid sequestrants, ezetimibe, lomitapide, plant sterols, and pharma- ceutically acceptable salts, hydrates, solvates, and prodrugs thereof, mixtures of any of the foregoing, and the like.

[0114] Suitable dietary supplement actives may include, but are not limited to, 5-hydroxytryptophan, acetyl L-carnitine, alpha lipoic acid, alpha ketoglutaric acid, honeybee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), dimethylaminoethanol, fumaric acid, germanium sesquioxide, glandular products, glucosamine HCI, glucosamine sulfate, hydroxymethylbutyrate, immunoglobulins, lactic acid, L-carnitine, liver products, malic acid, maltose anhydrous, mannose (d-mannose), methylsulfonylmethane, plant sterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0115] Suitable nutritional supplement actives may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements or combinations thereof.

[0116] Suitable vitamin active agents may include, but are not limited to, the following: ascorbic acid (vitamin C), vitamin B, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbates, mixed tocopherols, niacin (vitamin B3), orotic acid, para-aminobenzoic acid, pantothenate, pantothenic acid (vitamin B5), pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamine (vitamin B1), tocotrienols, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oils and oil-soluble vitamins.

[0117] Suitable herbal supplement actives may include, but are not limited to, the following: arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginko biloba, ginseng, goldenrod, hawthorn, kava kava, licorice, milk thistle, psyllium, rauwolfia, senna, soybean, hypericum perforatum, saw palmetto, turmeric, and valerian.

[0118] Mineral activators may include, but are not limited to, the following: boron, calcium, chelated minerals, chloride, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvate, zinc and other minerals.

[0119] Examples of other possible active agents include antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), nonsteroidal anti-inflammatory agents (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprenaline, and the like). muroprofen, trioxaprofen, suprofen, aminoprofen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprine, azapropazone , benorylate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicylate salicylate acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., phenyloin, meprobmate, and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem, and nicardipine), antitussives and expectorants (e.g., codeine phosphate), antiasthmatics (e.g., theophylline), antacids,These include, but are not limited to, antispasmodics (e.g., atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluthiazide), anti-hypotensives (e.g., propranolol, clonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibacterials (e.g., tetracycline), antihemorrhoidal, hypnotics, psychotropic drugs, antidiarrheals, mucolytics, sedatives, decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine) and cannabinoids, as well as pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof. ,

[0120] The active agent may be a benzodiazepine, a barbiturate, a stimulant, or a mixture thereof. The term "benzodiazepine" refers to drugs that are benzodiazepines and derivatives of benzodiazepines that can depress the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Benzodiazepine antagonists that may be used as the active agent include, but are not limited to, flumazenil, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0121] The term "barbiturates" refers to sedative-hypnotic drugs derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists that can be used as active agents include, but are not limited to, amphetamine, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0122] The term "stimulant" includes, but is not limited to, amphetamines, such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, and pharmaceutically acceptable salts, hydrates, and solvates and mixtures thereof. Stimulant antagonists that may be used as the active agent include, but are not limited to, benzodiazepines, and pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.

[0123] The dosage forms according to the present disclosure include various active agents and their pharma- ceutically acceptable salts. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonate salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; amino acid salts such as arginate, asparginate, glutamate, etc.; metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc. EXAMPLES

[0124] The present invention will now be described more fully with reference to the accompanying examples, however, it should be understood that the following description is merely illustrative and should not be taken as limiting the present invention in any manner.

[0125] [Example 1] An alginate / gelatin shell hand sanitizer softgel was prepared. The shell composition included anhydrous glycerin, sodium alginate, anhydrous dextrose, gelatin, and purified water. The shell composition is shown in Table 1 below. The air-filled softgel was dried and 1 gram of hand sanitizer was injected into the air-filled softgel and the injection hole was blocked using the same gel mass.

[0126] [Table 1]

[0127] The ingredients and formulation of the hand sanitizer are shown in Table 2 below.

[0128] [Table 2]

[0129] The filled softgels were then stored, half with lids, i.e. in closed glass vials, and the other half without lids, i.e. in open glass vials. The weight and physical changes of the softgels were observed over a period of 15 days. It was found that there was weight loss in both the softgels stored in open and closed containers. The weight loss results are shown in Table 3.

[0130] [Table 3]

[0131] The weight loss of the alginate / gelatin shell hand sanitizer softgel in the open vial was significantly higher than that of the alginate / gelatin shell hand sanitizer softgel in the closed vial. This indicated that the alginate / gelatin shell was fairly permeable to alcohol and water vapor. Without being limited by theory, the inventors believe that this may be due to the use of glycerin in the gel mass.

[0132] [Example 2] A non-animal polymer shell hand sanitizer softgel was prepared. The shell composition included modified starch, carrageenan, sodium phosphate, POLYSORB® 85 / 70 / 00, pullulan and purified water. The shell composition is shown in Table 4 below. The air-filled softgel was dried and 1 gram of hand sanitizer was injected into the air-filled softgel and the injection hole was blocked using the same gel mass.

[0133] [Table 4]

[0134] The filled softgels were then stored, half with lids, i.e. in glass vials in closed containers, and the other half without lids, i.e. in glass vials in open containers. The weight and physical changes of the softgels were observed over a period of 30 days. It was found that there was weight loss in both the softgels stored in open containers and the softgels stored in closed containers. The weight loss results are shown in Table 5.

[0135] [Table 5]

[0136] [Example 3] Another batch of non-animal hand sanitizer soft gel was prepared. This batch was prepared with the same composition as that described in Example 2. Half of this batch was filled with hand sanitizer from a commercial source without adding glycerin or other excipients, while the other half was filled with hand sanitizer from a commercial source with the addition of 5% anhydrous glycerin. The theoretical fill weight of the soft gel was 1000 mg per capsule. After encapsulation, the soft gel was spread on a shallow tray and dried in a drying cabinet. It was observed that a portion of the hand sanitizer fill was lost during the drying process, creating air bubbles in the capsule. After drying, the capsules filled with hand sanitizer were inspected, washed, and packed into sealed plastic bags.

[0137] Stability tests were conducted to observe the weight loss of the hand sanitizer-loaded soft gels during storage under ambient conditions. Therefore, the hand sanitizer-loaded soft gels were placed in open and closed glass vials under ambient conditions. The weight loss was checked periodically by weighing the soft gels and is shown in Tables 6 and 7.

[0138] [Table 6]

[0139] [Table 7]

[0140] The soft gel capsules filled with hand sanitizer continuously lost weight when stored at ambient conditions. However, the weight loss of the soft gel capsules filled with hand sanitizer stored in a closed container was significantly less than that of the soft gel capsules filled with hand sanitizer stored in an open container. Also, the rate of weight loss gradually decreased over time.

[0141] [Example 4] Regression analyses were also performed to predict the percentage of hand sanitizer remaining after various periods of storage in both closed and open containers, as shown in Tables 8 and 9.

[0142] [Table 8]

[0143] [Table 9]

[0144] Based on the extrapolated data, it can be concluded that the hand sanitizer softgel without glycerin can retain about 90% (89.1%) of the hand sanitizer fill material for one year at ambient conditions. On the other hand, the hand sanitizer containing glycerin may not be suitable for long-term retention of ethanol in capsules, potentially due to increased shell permeability caused by migration of glycerin into the shell, resulting in loss of volatile fill content such as ethanol. Further optimization of the manufacturing process parameters, including fill formulation, rate and extent of drying, and final bulk pack size type and headspace, etc., may help retain even more than 90% of the fill at the end of a one-year storage period in a sealed container.

[0145] [Example 5] Stability studies were also performed. Thirty (30) high ethanol (hand sanitizer containing 70% ethanol by volume) capsules from two different sublots (21MC-33A and 21MC-33B) were packaged in sealed 100 cc glass bottles to mimic real world use. 21MC-33A was manufactured using commercial hand sanitizer. 21MC-33B was manufactured using commercial hand sanitizer with the addition of 5% glycerin. The bottles were stored at ambient conditions. The capsules were measured at various time intervals up to 12 months. The results of the measurements are shown in Table 10 and in the figures.

[0146] [Table 10]

[0147] Based on the weight change data, the high ethanol capsules were stable with only slight weight loss during storage in a closed container. Also, both sublots showed similar trends in weight loss. Therefore, the effect of adding glycerin is not significant. Furthermore, all capsules were of acceptable appearance with no leaking capsules or other physical defects.

[0148] Thus, the high ethanol capsules were stable with only slight weight loss during storage in a closed container, and both sublots showed similar trends in weight loss. Thus, the capsules have good barrier properties against ethanol and offer a viable option for the encapsulation of fill materials containing high concentrations of alcohol.

Claims

1. A soft gel capsule formulation comprising: a shell containing a film-forming polymer and a plasticizer; a filling composition containing at least about 20 wt.% alcohol; wherein after 30 days of storage under ambient conditions, the soft gel capsule formulation has a weight loss change of less than about 10%.

2. The soft gel capsule formulation according to claim 1, wherein the filling composition contains at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, or at least about 75 wt.% alcohol.

3. The soft gel capsule formulation according to claim 1, wherein after 30 days of storage under ambient conditions, the soft gel capsule formulation has a weight loss change of less than about 8%, less than about 5%, less than about 3%, less than about 1%, less than about 0.5%, or less than about 0.25%.

4. The soft gel capsule formulation according to claim 1, wherein the storage under ambient conditions is carried out in a sealed container or an open container.

5. The soft gel capsule formulation according to claim 1, wherein the film-forming polymer contains an animal-derived polymer or a non-animal-derived polymer.

6. The soft gel capsule formulation according to claim 5, wherein the animal-derived polymer contains gelatin.

7. The soft gel capsule formulation according to claim 6, wherein the gelatin is contained in an amount of about 35 wt.% to about 70 wt.%.

8. The soft gel capsule formulation according to claim 5, wherein the non-animal-derived polymer contains alginate, carrageenan, or pullulan.

9. The soft gel capsule formulation according to claim 8, wherein the carrageenan is contained in an amount of about 5 wt.% to about 20 wt.%.

10. The soft gel capsule formulation according to claim 1, wherein the alcohol contains ethanol or isopropanol.

11. The soft gel capsule formulation according to claim 1, wherein the shell further contains a thickening agent or a buffering agent.

12. The soft gel capsule formulation according to claim 1, wherein the shell further contains water.

13. The soft gel capsule formulation according to claim 12, wherein the water is contained in an amount of about 8 wt.% to about 25 wt.%.

14. The soft gel capsule formulation according to claim 1, wherein the plasticizer contains glycerin, a sorbitol sorbitan solution, polyethylene sorbitan monooleate, or a combination thereof.

15. The soft gelatin capsule preparation according to claim 1, wherein the shell further contains pullulan.

16. The soft gelatin capsule preparation according to claim 11, wherein the thickening agent contains starch or a starch derivative.

17. The soft gelatin capsule preparation according to claim 11, wherein the buffering agent contains sodium phosphate.

18. The soft gelatin capsule preparation according to claim 1, wherein the shell contains from about 0.1 gram to about 10 grams of the filling composition.

19. The soft gelatin capsule preparation according to claim 1, wherein the filling composition further contains water, an acrylate copolymer, xanthan gum, carbomer, glycerin, butylene glycol, aminomethylpropanol, aloe barbaensis leaf extract, or a combination thereof.

20. The soft gelatin capsule preparation according to claim 1, which has a weight loss change of less than about 10% after 3 months, 6 months, or 12 months.

21. The soft gelatin capsule preparation according to claim 1, which can be spherical, oval, rectangular, or twist-off.

22. The soft gelatin capsule preparation according to claim 1, which disintegrates in less than about 60 minutes, less than about 45 minutes, less than about 30 minutes, less than about 20 minutes, less than about 10 minutes, or less than about 5 minutes in a gastric environment based on a disintegration test conducted in USP Apparatus II using a paddle at a speed of 50 rpm in a pH 1.2 buffer.

23. The soft gelatin capsule preparation according to claim 1, which disintegrates in 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 basic medium based on a disintegration test conducted in a basket rack assembly NT-40H model apparatus in a 1000 mL beaker at about 37°C ± 2°C.

24. The soft gelatin capsule preparation according to claim 1, wherein the shell contains an enteric material.

25. A method for preparing a soft gel according to claim 1, comprising the step of encapsulating an encapsulating filling composition containing at least about 20 wt.% alcohol in a shell containing a film-forming polymer and a plasticizer.

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