Non-animal soft gel capsule formulations, methods for preparing same, and methods for using same

Abstract

In certain embodiments, a softgel composition is disclosed, which comprises a fill material encapsulated in a shell composition. The shell composition has a non-animal-derived gelling agent and a water-soluble polymer. When subjected to dissolution in 900 mL of 0.1 N HCl and deionized water at 37° C. using a USP Apparatus II with paddles at 75 RPM, the shell composition completely dissolves in less than 30 minutes.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 912,886, filed October 9, 2019, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to non-animal softgel capsule formulations. Methods for preparing and using such softgel capsules are also disclosed herein. [Background technology]

[0003] The encapsulation of a solution or dispersion of a nutritional or pharmaceutical agent in a liquid carrier into a softgel capsule offers many advantages over other dosage forms, such as compressed, coated, or uncoated solid tablets or bulk liquids. Such encapsulation of a solution or dispersion allows for accurate delivery of a unit dose, which is particularly important when relatively small amounts of an active ingredient must be administered. Furthermore, uniformity is more difficult to achieve in the tableting process, where solids must be uniformly mixed and compressed, or in the introduction of the total dose of an active ingredient into a bulk liquid carrier, which must be measured out before each oral administration.

[0004] In addition, softgel capsules, most commonly soft gelatin capsules, provide a dosage form that is more acceptable to patients because they are easy to swallow and do not require flavoring to mask the unpleasant taste of the active agent. Softgel capsules are also easier for patients to carry than bulk liquids because only the required number of doses need to be removed from the packaging.

[0005] Softgel encapsulation of drugs also has the potential to improve the bioavailability of pharmaceutical agents. As soon as the capsule shell ruptures, the active ingredient is rapidly released in liquid form. Complete disintegration of the capsule is not essential for the active ingredient to become absorbable, as is the case with tableted compositions. Furthermore, relatively insoluble active ingredients can be dispersed in a liquid carrier to provide more rapid absorption.

[0006] Compared to softgel capsules made from animal-derived gelatin, which take between 5 and 15 minutes to burst, current non-animal softgels (e.g., Vegicaps® and OptiShell® softgels) take between 20 and 40 minutes to burst in dissolution media. For immediate-release products where rapid relief is required (e.g., pain relievers, antihistamines / allergy medications), such long dissolution times can be problematic for patients.

[0007] Therefore, there is a need for improved non-animal softgel capsule formulations that have shorter dissolution and / or disintegration times. Summary of the Invention [Means for solving the problem]

[0008] According to various embodiments, softgel compositions are disclosed herein that include a fill material encapsulated in a shell composition. The shell composition includes a non-animal derived gelling agent and a water-soluble polymer. In certain embodiments, the shell composition completely dissolves in less than 30 minutes when subjected to dissolution testing using a USP Apparatus II paddle at 75 RPM in 900 mL of 0.1 N HCl and deionized water at 37°C.

[0009] According to certain embodiments, softgel compositions are disclosed that include a fill material comprising an active pharmaceutical or cosmetic agent and encapsulated by a shell composition, the shell composition comprising a non-animal derived gelling agent comprising carrageenan, starch, or a combination thereof, and a water soluble polymer comprising polyvinyl alcohol, pullulan gum, polylactic acid, polyvinyl alcohol-polyethylene glycol graft copolymer, high molecular weight polyethylene glycol, povidone, a surfactant, or a combination thereof.

[0010] Also disclosed herein are various embodiments relating to methods for preparing softgel compositions comprising a non-animal derived gelling agent and a water-soluble polymer.

[0011] According to further embodiments, disclosed herein are softgel compositions comprising a fill material comprising an active agent (or cosmetic agent), the fill material encapsulated by a shell composition comprising a non-animal derived gelling agent and a water soluble polymer, as well as methods for making and processing the same.

[0012] According to still further embodiments, disclosed herein are methods of treating a condition treatable by an active agent or cosmetic agent described herein by administering any of the softgel compositions described herein to a subject in need thereof.

[0013] The above and other features of the present disclosure, its nature and various advantages will become apparent from a consideration of the following detailed description taken in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0014] [Figure 1] 1 illustrates the release profile of an active agent (e.g., ibuprofen) from a conventional non-gelatin capsule compared to a softgel capsule according to certain embodiments. The release profile is also illustrative of the dissolution profile of a conventional non-gelatin capsule shell composition compared to a softgel shell composition according to certain embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0015] Various embodiments of softgel compositions, e.g., softgel capsule film compositions encapsulating fill materials, methods for preparing same, and methods for using same are described herein. It is to be understood that the invention is not limited to the details of the compositions or process steps set forth in the following description. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0016] Throughout this specification, references to "one embodiment," "a particular embodiment," "one or more embodiments," or "an embodiment" mean that a particular feature, structure, material, or characteristic described in connection with an embodiment is included in at least one embodiment of the invention. Thus, the appearances of phrases such as "in one or more embodiments," "in a particular embodiment," "in one embodiment," or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment of the invention. Furthermore, particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0017] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to a "polymer" includes mixtures of two or more polymers as well as a single polymer.

[0018] As used herein, the term "about" in connection with a measured quantity refers to the normal variation in that measured quantity that would be expected by one of ordinary skill in the art making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measuring device. In certain embodiments, the term "about" includes the recited number ±10%, such that "about 10" would include 9 to 11.

[0019] The term "at least about" in connection with a measured quantity refers to normal variations in that measured quantity and any higher quantities, as would be expected by one of ordinary skill in the art making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measurement device. In certain embodiments, the term "at least about" includes the recited number minus 10% and any higher quantity, such that "at least about 10" would include 9 and any number greater than 9. The term can also be expressed as "about 10 or greater." Similarly, the term "less than about" typically includes the recited number plus 10% and any lower quantity, such that "less than about 10" would include 11 and any number less than 11. The term can also be expressed as "about 10 or less."

[0020] The term "immediate release" refers to a dosage form (e.g., a softgel capsule formulation) disclosed herein that releases at least about 85 wt.%, at least about 90 wt.%, or at least about 95 wt.% of the active agent (or cosmetic agent) encapsulated within its shell composition within about 30 minutes, within about 45 minutes, or within about 60 minutes, as measured by in vivo dissolution in a USP Apparatus II at about 50 RPM to about 250 RPM in 900 mL of 0.1 N HCl (optionally containing pepsin) at 37°C.

[0021] The term "controlled release" refers to a dosage form (e.g., a softgel capsule formulation) disclosed herein that releases an active agent (or cosmetic agent) encapsulated within its shell composition over a period of time, for example, to provide a once-daily or twice-daily dosage form.

[0022] As used herein, the term "soft gel" does not necessarily mean that gelatin is part of its shell composition (or film composition) and / or its fill material (or fill composition). In certain embodiments, the shell composition (or film composition) may include gelatin, while in other embodiments, the shell composition may not include gelatin. Similarly, in certain embodiments, the fill material (or fill composition) may include gelatin, while in other embodiments, the fill material may not include gelatin. The term "soft gel" may be used interchangeably with the term "soft shell" throughout this description.

[0023] The term "shell composition" may be used interchangeably throughout this description with the terms "film composition," "shell," and "film," which refer to the outer portion of a softgel composition (e.g., these terms refer to the shell of a softgel capsule that encapsulates the fill material).

[0024] The term "fill material" may be used interchangeably throughout this description with the terms "fill composition" and "fill." These terms refer to the interior of a softgel composition that is encapsulated by a shell composition (e.g., the interior of a softgel capsule).

[0025] The term "softgel composition" may be used interchangeably with the terms "softgel formulation" and "dosage form" throughout this description. In certain embodiments, the term "softgel composition" or "softgel formulation" may be used interchangeably with the term "softgel capsule composition" or "softgel capsule formulation," respectively.

[0026] Unless otherwise indicated, all parts and percentages are by weight. Unless otherwise indicated, weight percent (wt.%) is based on the total composition, excluding any volatile materials, i.e., on dry solids.

[0027] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each individual value falling within the range, unless otherwise indicated herein, and each individual value is incorporated herein as if it were individually recited herein. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order.

[0028] Any examples or use of exemplary language (e.g., "such as") provided herein are intended to facilitate understanding of particular materials and methods only and are not intended to limit the scope. No language herein should be construed as indicating any element not claimed as essential to the practice of the disclosed materials and methods.

[0029] Although the present disclosure refers to particular embodiments herein, it should be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the compositions and methods of the present invention without departing from the spirit and scope of the invention. It is therefore intended that the present invention cover modifications and variations that come within the scope of the appended claims and their equivalents.

[0030] Softgel capsule formulation Disclosed herein is a softgel capsule shell composition comprising a non-animal-derived gelling agent and a water-soluble polymer. In certain embodiments, the shell composition dissolves completely in less than 30 minutes when subjected to dissolution in 900 mL of 0.1 N HCl and deionized water at 37° C. using a USP Apparatus II with paddles at 50-250 RPM (e.g., 75 RPM). In certain embodiments, the softgel capsule shell composition dissolves in less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes.

[0031] In certain embodiments of the softgel capsule shell composition, the non-animal-derived gelling agent comprises carrageenan and starch. The weight ratio of carrageenan to starch in the softgel capsule shell composition can be, for example, about 1:1 to about 1:10, about 1:1 to about 1:8, about 1:1 to about 1:5, or about 1:2.5 to about 1:4.5. In certain embodiments, the inclusion of a water-soluble polymer in the softgel capsule shell composition contributes to the weight ratio of carrageenan to starch, but this is less important (e.g., for dissolution, disintegration, resilience, strength, etc.) than if the softgel capsule shell composition did not include the water-soluble polymer described herein.

[0032] In certain embodiments, softgel capsule formulations are also disclosed, which include a fill material containing an active agent, the fill material being encapsulated by the shell composition disclosed herein.The fill material can include, for example, a hydrophilic material, a lipophilic material, an amphiphilic material, or a combination thereof, optionally with a surfactant.The fill material can be a solution, a suspension, a semi-solid, or a solid, and can further include an active agent (e.g., an active pharmaceutical ingredient or a dietary supplement) or a cosmetic agent.

[0033] The shell composition disclosed herein may contain at least one of a buffer, a plasticizer, and water. The softgel capsule formulations described herein may be vegetarian and free of animal-derived materials such as gelatin. In certain embodiments, the shell composition may contain less than 10 wt.%, less than 5 wt.%, less than 1 wt.%, or 0 wt.% of an animal-derived gelling agent.

[0034] In certain embodiments, the shell compositions disclosed herein completely dissolve in less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes when subjected to dissolution in a USP Apparatus II with paddles at about 50 RPM to about 250 RPM (e.g., about 50 RPM, about 75 RPM, about 100 RPM, about 150 RPM, about 200 RPM, or about 250 RPM) in 900 mL of 0.1 N HCl and deionized water (optionally containing pepsin) at 37°C.

[0035] In certain embodiments, the shell compositions disclosed herein completely dissolve in about 5, 8, 10, 12, or 15 minutes to about 20, 23, 25, 28, 30, or 35 minutes when subjected to dissolution in a USP Apparatus II with paddles at about 50 RPM to about 250 RPM (e.g., about 50 RPM, about 75 RPM, about 100 RPM, about 150 RPM, about 200 RPM, or about 250 RPM) in 900 mL of 0.1 N HCl and deionized water (optionally containing pepsin) at 37° C.

[0036] In certain embodiments, the shell compositions disclosed herein begin to dissolve in less than 15 minutes, less than 10 minutes, less than 9 minutes, less than 8 minutes, or less than 7 minutes when subjected to dissolution in a USP Apparatus II with paddles at about 50 RPM to about 250 RPM (e.g., about 50 RPM, about 75 RPM, about 100 RPM, about 150 RPM, about 200 RPM, or about 250 RPM) in 900 mL of 0.1 N HCl and deionized water (optionally containing pepsin) at 37°C.

[0037] In certain embodiments, the shell compositions disclosed herein, when subjected to dissolution in a USP Apparatus II with paddles at about 50 RPM to about 250 RPM (e.g., about 50 RPM, about 75 RPM, about 100 RPM, about 150 RPM, about 200 RPM, or about 250 RPM) in 900 mL of 0.1 N HCl and deionized water (optionally containing pepsin) at 37° C., begin to dissolve at about any of about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes, to about any of about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, or about 15 minutes.

[0038] In certain embodiments, softgel compositions (e.g., softgel capsules) comprising a fill material encapsulated with a shell composition disclosed herein begin to rupture in less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes when subjected to disintegration in a USP disintegration apparatus using paddles at about 50 RPM to about 250 RPM (e.g., about 50 RPM, about 75 RPM, about 100 RPM, about 150 RPM, about 200 RPM, or about 250 RPM) in 900 mL of 0.1 N HCl and deionized water (optionally containing pepsin) at 37°C.

[0039] In certain embodiments, softgel compositions (e.g., softgel capsules) comprising a fill material encapsulated with a shell composition disclosed herein, when subjected to disintegration in a USP disintegration apparatus using paddles at about 50 RPM to about 250 RPM (e.g., about 50 RPM, about 75 RPM, about 100 RPM, about 150 RPM, about 200 RPM, or about 250 RPM) in 900 mL of 0.1 N HCl and deionized water (optionally containing pepsin) at 37° C., begin to rupture in about any of the following: 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, or about 7 minutes, to about any of the following: 8 minutes, about 9 minutes, about 10 minutes, about 15 minutes, or about 20 minutes.

[0040] In certain embodiments, a softgel composition (e.g., a softgel capsule) comprising a fill material encapsulated with a shell composition disclosed herein completely dissolves in less than 45 minutes, less than 40 minutes, less than 35 minutes, less than 30 minutes, or less than 25 minutes when subjected to disintegration in a USP disintegration apparatus using paddles at about 50 RPM to about 250 RPM (e.g., about 50 RPM, about 75 RPM, about 100 RPM, about 150 RPM, about 200 RPM, or about 250 RPM) in 900 mL of 0.1 N HCl and deionized water (optionally containing pepsin) at 37°C.

[0041] In certain embodiments, softgel compositions (e.g., softgel capsules) comprising a fill material encapsulated with a shell composition disclosed herein, when subjected to disintegration in a USP disintegration apparatus using paddles at about 50 RPM to about 250 RPM (e.g., about 50 RPM, about 75 RPM, about 100 RPM, about 150 RPM, about 200 RPM, or about 250 RPM) in 900 mL of 0.1 N HCl and deionized water (optionally containing pepsin) at 37° C., completely dissolve in about any of the following: 15 minutes, about 18 minutes, about 20 minutes, about 22 minutes, or about 25 minutes, to about any of the following: 30 minutes, about 35 minutes, about 40 minutes, or about 45 minutes.

[0042] It should be understood that the dissolution and / or disintegration time of the shell composition may be independent of the dissolution and / or disintegration time of its fill material. The release profile of an active agent from a dosage form may vary depending on its shell composition and fill composition. The dissolution and / or disintegration time of the shell composition may, at least in part, indicate the release profile of the active agent from the dosage form. According to embodiments described herein, the dosage form may be formulated as an immediate-release dosage form (e.g., by formulating an immediate-release shell composition with an immediate-release fill material) or as a controlled-release dosage form (e.g., by formulating an immediate-release shell composition with a controlled-release fill material).

[0043] According to certain embodiments, the water-soluble polymer may include, for example, polyvinyl alcohol (PVA), pullulan gum, polylactic acid, polyvinyl alcohol-polyethylene glycol graft copolymer (PVA-PEG copolymer), high molecular weight polyethylene glycol, povidone, a surfactant (e.g., sodium lauryl sulfate), or a combination thereof. In one embodiment, the water-soluble polymer is PVA. In one embodiment, the water-soluble polymer is PVA-PEG copolymer. In one embodiment, the water-soluble polymer is pullulan gum. The high molecular weight polyethylene glycol may be polyethylene glycol having a number average molecular weight ranging from about 600 Da to about 2,000,000 Da, or any number average molecular weight therein (e.g., PEG600, PEG800, PEG1000, PEG1500, PEG3350, PEG4000, PEG6000, PEG8000, etc.). In certain embodiments, the water-soluble polymer is present in the shell composition in an amount of, for example, about 0.5 wt.% to about 10 wt.%, about 0.5 wt.% to about 12 wt.%, about 1 wt.% to about 15 wt.%, about 1 wt.% to about 20 wt.%, about 2 wt.% to about 22 wt.%, about 2 wt.% to about 7 wt.%, about 0.5 wt.% to about 8 wt.%, about 3 wt.% to about 9 wt.%, about 2.5 wt.% to about 3 0 wt.%, about 10 wt.% to about 50 wt.%, about 20 wt.% to about 40 wt.%, about 15 wt.% to about 30 wt.%, about 15 wt.%, about 18 wt.%, about 20 wt.%, about 22 wt.%, about 25 wt.%, about 28 wt.%, about 30 wt.%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition.

[0044] According to embodiments, the non-animal gelling agent may include, for example, carrageenan, starch, pregelatinized starch, xanthan gum, agar, pectin, alginate, sugar, sugar-derived alcohol, monosaccharide, disaccharide, oligosaccharide, cellulose derivative, cellulosic polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol™, silicon dioxide, curdlan, furcellaran, albumin (e.g., egg-derived or lacto-derived), soy protein, chitosan, guar gum, tamarind seed polysaccharide, glucomannan, chitin, pluran, cyclodextrin, or combinations thereof.

[0045] The carrageenan can be at least one of iota carrageenan, kappa carrageenan, and lambda carrageenan.

[0046] 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-thinned starch, etc. Generally, modified starches are products prepared by chemical treatment of starch, such as acid-treated starch, enzyme-treated starch, oxidized starch, crosslinked starch, and other starch derivatives. Preferably, this modified starch is derivatized so that the side chains are modified with hydrophilic or hydrophobic groups to form more complex structures with strong interactions between the side chains.

[0047] In certain embodiments, the non-animal gelling agent is present in the shell composition in an amount, for example, from about 2 wt.% to about 20 wt.%, from about 2 wt.% to about 15 wt.%, from about 2 wt.% to about 40 wt.%, from about 10 wt.% to about 80 wt.%, from about 15 wt.% to about 75 wt.%, from about 20 wt.% to about 70 wt.%, from about 25 wt.% to about 60 wt.%, from about 25 wt.% to about 45 wt.%, from about 20 wt.% to about 35 wt.%, from about 30 wt.% to about 40 wt.%, about 32 wt.%, about 35 wt.%, about 38 wt.%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition. In one embodiment, the non-animal gelling agent comprises carrageenan and is free of starch (or modified starch). In one embodiment, the softgel shell composition is substantially free of starch (or modified starch) or is free of starch (or modified starch).

[0048] In certain embodiments, the weight ratio of water-soluble polymer (e.g., PVA, PVA-PEG copolymer, pullulan, or a combination thereof) to non-animal gelling agent (e.g., carrageenan, starch, or a combination thereof) can range from about 20:1 to about 1:20, from about 15:1 to about 1:15, from about 10:1 to about 1:10, from about 8:1 to about 1:8, from about 5:1 to about 1:5, from about 3:1 to about 1:3, or from about 2:1 to about 1:2, or can be about 1:1. While not intended to be limiting, it is believed that the weight ratio of water-soluble polymer to non-animal gelling agent contributes to the dissolution time of the softgel shell compositions described herein.

[0049] According to embodiments, the buffering agent comprises at least one of dibasic sodium phosphate, monobasic sodium phosphate, sodium bicarbonate, sodium citrate, disodium phosphate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, monobasic potassium phosphate, and dibasic potassium phosphate. In embodiments, the buffering agent comprises dibasic sodium phosphate. In embodiments, the buffering agent is present in the shell composition in an amount of about 0.01 wt.% to about 5 wt.%, about 0.05 wt.% to about 4 wt.%, about 0.1 wt.% to about 3 wt.%, about 0.5 wt.% to about 3 wt.%, about 1.0 wt.%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition.

[0050] According to various embodiments, the plasticizer may include, for example, glycerin, sorbitol, a solution of sorbitol and sorbitan, triacetin, polysorbate, propylene glycol, sodium lauryl sulfate (SLS), a sugar alcohol (e.g., maltitol), or a combination thereof. In certain embodiments, the plasticizer is glycerin. In one embodiment, the plasticizer is sorbitol. In one embodiment, the plasticizer is SLS. In embodiments, the plasticizer is present in the shell composition in an amount of about 0.5 wt.% to about 40.0 wt.%, 10 wt.% to about 30.0 wt.%, about 12 wt.% to about 28 wt.%, about 15 wt.% to about 30 wt.%, about 18 wt.% to about 23 wt.%, about 18 wt.%, about 20 wt.%, about 22 wt.%, about 25 wt.%, about 28 wt.%, about 30 wt.%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition.

[0051] In certain embodiments, the softgel capsule shell composition contains water. Water may be present in the shell composition in an amount of about 30 wt.% to about 60 wt.%, about 35 wt.% to about 55 wt.%, about 40 wt.% to about 50 wt.%, about 42 wt.%, about 43 wt.%, about 44 wt.%, about 45 wt.%, about 45.5 wt.%, about 46 wt.%, about 47 wt.%, about 48 wt.%, or any subrange or single concentration value therein, all wt.% being based on the total weight of the shell composition. According to certain embodiments, the weight ratio of water to non-animal gelling agent in the shell composition is about 1:5 to about 5:1, about 1:4 to about 4:1, about 1:3 to about 3:1, about 1:1, about 2:1, about 3:1, about 4:1, or about 5:1.

[0052] In certain embodiments, the softgel shell compositions described herein have a film strength of greater than about 5.0 kg, greater than about 5.2 kg, or greater than about 5.4 kg, as measured by a texture analyzer according to the details described in the Examples. In certain embodiments, the softgel shell compositions described herein have a film strength in a range from about 3.5 kg, about 4.0 kg, about 4.5 kg, about 5.0 kg, or about 5.5 kg to about 6.0 kg, about 6.5 kg, about 7.0 kg, about 7.5 kg, about 8.0 kg, about 8.5 kg, about 9.0 kg, about 9.5 kg, about 10.0 kg, about 10.5 kg, about 11.0 kg, about 11.5 kg, or about 12.0 kg, or any single value or subrange therein. In certain embodiments, the softgel shell compositions described herein have a film strength ranging from about 3.5 kg to about 12.0 kg, from about 5.0 kg to about 12.0 kg, from about 5.2 kg to about 10.0 kg, or from about 5.0 kg to about 7.0 kg.

[0053] In certain embodiments, the softgel shell compositions described herein have a springiness of greater than about 7.7 mm, greater than about 8.0 mm, or greater than about 8.2 mm, as measured by a texture analyzer according to the details described in the Examples. In certain embodiments, the softgel shell compositions described herein have a springiness ranging from about 6 mm, about 6.5 mm, about 7.0 mm, about 7.5 mm, about 8.0 mm, or about 8.5 mm to about 9.0 mm, about 9.5 mm, about 10.0 mm, about 10.5 mm, about 11.0 mm, about 11.5 mm, or about 12.0 mm, or any single value or subrange therein. In certain embodiments, the softgel shell compositions described herein have a springiness of about 6.0 mm to about 12.0 mm, about 7.0 mm to about 10.0 mm, about 8.0 mm to about 12.0 mm, or about 8.0 mm to about 10.0 mm.

[0054] In certain embodiments, the softgel shell compositions described herein are sufficiently elastic to allow for the formation of capsules, yet strong enough to be handled in an encapsulation machine (e.g., a rotary die), and provide good sealing properties at temperatures below the melting point of the softgel shell composition, all without compromising the dissolution or disintegration profile of the softgel shell composition and the capsule.

[0055] The softgel capsule formulations disclosed herein may further comprise a fill material. The fill material may comprise at least one of rapeseed oil, medium-chain triglyceride oil, polyethylene glycol, and combinations thereof. Lipophilic and / or hydrophilic and / or alcoholic fill materials may be encapsulated with the softgel capsule fill material described herein.

[0056] Active Agent Any pharmaceutically active ingredient may be used for the purposes of the present invention, including both water-soluble and sparingly water-soluble ones. Suitable pharmaceutically active ingredients include, but are not limited to, analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterial agents, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarials, antimigraine agents, antimuscarinic agents, antitumor and immunosuppressants, antiprotozoal agents, antirheumatic agents, antithyroid agents, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics. These include drugs, beta-blockers, cardiac inotropes, corticosteroids, antitussives, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritional agents, opioid analgesics, oral vaccines, protein, peptide and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and combinations thereof.

[0057] In some embodiments, the active pharmaceutical ingredient may be selected from the group consisting of, but 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.

[0058] In some embodiments, the lipid in the dosage form may be selected from the group including, but not limited to, almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, palm oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, flaxseed 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. Other oils and fats may include, but are not limited to, fish oil (omega-3), krill oil, animal or vegetable fats, such as their hydrogenated forms, free fatty acids, and mono-, di-, and tri-glycerides with C8-, C10-, C12-, C14-, C16-, C18-, C20-, and C22-fatty acids, and combinations thereof.

[0059] According to certain 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, phytosterols, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof, mixtures of any of the foregoing, and the like.

[0060] Suitable dietary supplement active agents may include, but are not limited to, 5-hydroxytryptophan, acetyl L-carnitine, alpha lipoic acid, alpha-ketoglutarate, honeybee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristotriate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin 812), dimethylaminoethanol, fumaric acid, germanium sesquioxide, glandular products, glucosamine HCl, glucosamine sulfate, hydroxymethylbutyrate, immunoglobulins, lactic acid, L-carnitine, liver products, malic acid, maltose anhydrous, mannose (d-mannose), methylsulfonylmethane, phytosterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0061] Suitable nutritional supplement active agents may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, or combinations thereof.

[0062] Suitable vitamin active agents may include, but are not limited to, the following: ascorbic acid (vitamin C), B vitamins, 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.

[0063] Suitable herbal supplement active agents 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, ginkgo biloba, ginseng, goldenrod, hawthorn, kava kava, licorice, milk thistle, plantain, Indian jasmine, senna, soybean, St. John's wort, saw palmetto, turmeric, and valerian.

[0064] Mineral active agents 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, malate, pyruvate, zinc, and other minerals.

[0065] Examples of other possible active agents include, but are not limited to, antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and d-chlorpheniramine maleate), nonsteroidal anti-inflammatory drugs (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, pyroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, amitriptyline ... Noprofen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxipinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprine, azapropazone, benorilate, bronfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, flu Eislamin, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, pharmaceutically acceptable salts thereof, and mixtures thereof, acetaminophen phenytoin, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., phenytoin, meprobamate, and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem, and nicardipine), antitussives and expectorants (e.g., codeine phosphate), antiasthmatics (e.g., theophylline), antacids, antispasmodics (e.g., atropine, scopolamine), antidiabetic drugs (e.g., insulin), diuretics (e.g., ethacrynic acid, bendroflumethiazide), antihypertensives (e.g., propranolol, clonidine),Included are antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibacterials (e.g., tetracycline), antihemorrhoids, 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.

[0066] The active agent may be a benzodiazepine, a barbiturate, a stimulant, or a mixture thereof. The term "benzodiazepine" refers to benzodiazepines and drugs that are derivatives of benzodiazepines and 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, methylphenidate, as well as their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Benzodiazepine antagonists that can be used as active agents include, but are not limited to, flumazenil, as well as their pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0067] The term "barbiturates" refers to sedative-hypnotic drugs derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbital, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, and secobarbital, as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists that may be used as active agents include, but are not limited to, amphetamine, as well as pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0068] The term "stimulant" includes, but is not limited to, amphetamines, such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, as well as pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof. Stimulant antagonists that may be used as active agents include, but are not limited to, benzodiazepines, as well as pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0069] The softgel capsule formulations described herein contain various active agents and their pharmaceutically acceptable salts, including, but not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; amino acid salts such as arginate, aspartate, glutamate, etc.; metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

[0070] Method for preparing a softgel capsule formulation Disclosed herein are methods for preparing softgel shell compositions and softgel capsule formulations as disclosed herein. The methods include blending a non-animal gelling agent, a water-soluble polymer, and optionally at least one of a buffer, a plasticizer, or water to form a composition. The methods further include heating the composition to form a molten mass. In embodiments, the molten mass is a homogeneous molten mass. The methods may further include extruding the molten mass to form a ribbon. Additionally, the methods may include using a rotary die encapsulation device to cast the ribbon onto a drum to form a soft capsule shell. In embodiments, the ribbon may be, for example, about 0.001 inch to about 0.100 inch (about 0.0254 mm to about 2.54 mm), about 0.001 inch to about 0.070 inch (about 0.0254 mm to about 1.78 mm), about 0.001 inch to about 0.050 inch (about 0.0254 mm to about 1.27 mm), about 0.005 inch to about 0.030 inch (about 0.127 mm to about 0.762 mm), or about 0.010 inch to about 0.025 inch. (about 0.254 mm to about 0.635 mm), about 0.015 inches to about 0.021 inches (about 0.381 mm to about 0.533 mm), about 0.017 inches (about 0.432 mm), about 0.018 inches (about 0.457 mm), about 0.019 inches (about 0.483 mm), about 0.020 inches (about 0.508 mm), about 0.021 inches (about 0.533 mm), or about 0.022 inches (about 0.559 mm). In certain embodiments, a netting can be formed from the compound. This netting can then be melted and reused to form ribbons.

[0071] In one embodiment, the method may further include, when both a plasticizer and water are present, mixing the plasticizer with water to form a plasticizer solution. The method may further include mixing a synthetic polymer, a non-animal (natural) gelling agent, and a buffering agent (if present) with the plasticizer solution. In the same or an alternative embodiment, the combining may further include mixing the plasticizer with the non-animal gelling agent to form a solution, mixing the solution with water to form a plasticizer solution, and mixing the water-soluble polymer and buffering agent with the plasticizer solution (including the non-animal gelling agent therein). The combining may include placing the water-soluble polymer, non-animal gelling agent, buffering agent, plasticizer, and water, respectively, in a low-shear mixer. In embodiments, the blending may be performed for about 1 minute to about 3 hours, about 5 minutes to about 2.5 hours, about 15 minutes to about 2.0 hours, about 20 minutes to about 1.5 hours, about 30 minutes to 1.0 hour, or about 5 minutes to about 30 minutes. The blending may be performed at a temperature of about 45°C to about 90°C, about 50°C to about 85°C, about 55°C to about 80°C, about 60°C to about 70°C, about 55°C, about 60°C, or about 65°C. The blending may further include increasing the temperature to about 95°C to about 125°C, about 100°C to about 120°C, about 105°C to about 115°C, about 95°C, about 96°C, about 97°C, about 98°C, about 99°C, or about 100°C.

[0072] According to certain embodiments, the method may further include transferring the formulation to a receiving vessel. The formulation or material in the receiving vessel may be transferred to a heated vessel for heating the material therein. In certain embodiments, the heated vessel may heat the formulation to a temperature of about 80°C to about 115°C, about 85°C to about 100°C, or about 88°C to about 95°C. According to certain embodiments, the method may include injecting a colorant into the formulation.

[0073] The method may further include transferring the formulation to an encapsulation device. In certain embodiments, the method may include encapsulating a fill material within a softgel capsule fill material formed from any of the above formulations to form a plurality of softgel capsule dosage forms. The method may further include drying the plurality of softgel capsule dosage forms in a tumble dryer. Certain embodiments may further include packaging the plurality of softgel capsule dosage forms.

[0074] treatment method Disclosed herein are methods for treating, preventing, minimizing, or ameliorating in a subject in need thereof a condition treatable by an active agent contained in the fill material of a softgel capsule described herein, the method comprising administering any of the softgel capsules described herein to a subject in need thereof, wherein administration of the softgel capsule treats, prevents, minimizes, ameliorate, or alleviates the condition.

[0075] The terms "treatment of" and "treating" include the administration of an active agent for the purpose of lessening the severity of a condition.

[0076] The terms "prevention of" and "preventing" include the avoidance of the onset of a condition by prophylactic administration of an active agent.

[0077] The term "condition" or "conditions" may refer to a medical condition that can be treated, prevented, minimized, or ameliorated by administration of an effective amount of any of the active agents or cosmetic agents described herein. In certain embodiments, the term "condition" or "conditions" may refer to pain.

[0078] In certain embodiments, the softgel capsules described herein (e.g., those comprising a non-animal derived gelling agent, a water soluble polymer, and at least one of a buffer, a plasticizer, and water) exhibit a faster T than softgel capsules that do not include one of the ingredients listed herein above (such as a water soluble polymer). max contribute to.

[0079] T max is the plasma concentration of the active drug at C max refers to the time it takes to reach

[0080] C max refers to the peak plasma concentration of the active drug.

[0081] As used herein, the term "effective amount" refers to the amount and / or rate of an active pharmaceutical or cosmetic agent required to produce a desired therapeutic or cosmetic result.

[0082] The term "subject" refers to a human or animal that exhibits the onset of a condition (clinical or otherwise) that indicates the need for treatment with any of the active agents described herein. [Example]

[0083] Specific embodiments of the present disclosure will now be illustrated by reference to the following examples, which should be understood as being disclosed solely for the purpose of illustrating the present disclosure and should not be construed as limiting the scope of the present disclosure in any way.

[0084] [Example 1] Comparison of softgel capsule formulations in a non-animal gelling agent capsule shell composition without a water-soluble polymer (control) and a non-animal gelling agent capsule shell composition with a water-soluble polymer. The dissolution is tested in 900 mL of 0.1 N HCl and deionized water at 37°C using a USP Apparatus II with paddles at 75 RPM. The test shell compositions are samples 1.0 inch (25.4 mm) in diameter and 0.7 mm and 1.4 mm thick.

[0085] [Table 1-1]

[0086] [Table 1-2]

[0087] As seen in Table 1, the control non-animal gelator capsule shell composition without a water-soluble polymer had dissolution times in water of 63.25 minutes and 71.05 minutes. In comparison, all of the non-animal gelator capsule shell compositions containing a water-soluble polymer (whether PVA alone, PVA with SLS, or PVA-PEG copolymer) dissolve much faster in both water (less than 20 minutes) and 0.1 N HCl (less than 25 minutes).

[0088] Interestingly, non-animal gelling agent capsule shell compositions containing PVA with SLS exhibited faster dissolution than those containing any of the other water-soluble polymers. Shell compositions containing PVA without SLS exhibited similar dissolution rates to shell compositions containing PVA-PEG copolymer as the water-soluble polymer.

[0089] Although not intended to be limiting, it is believed that the type of water-soluble polymer, as well as the weight ratio of carrageenan to a particular water-soluble polymer, can affect the dissolution time of the shell composition.

[0090] [Example 2] As shown in Table 2 below, the solubility of various softgel shell compositions was evaluated by incorporating natural or synthetic water-soluble polymers.

[0091] [Table 2]

[0092] Softgel shell compositions were prepared for each of the above formulations (F-1 to F-6). Formulations F-1 to F-4 were cast into films. Shell compositions F-1 to F-4 were dried to a moisture content of 6 wt.% to 15 wt.% based on the total weight of the shell composition. The film strength and elasticity of the dried shell compositions were evaluated using a texture analyzer. Table 3 summarizes the strength and elasticity of shell compositions prepared using various water-soluble polymers. This data is generated using dried shell compositions containing moisture contents of 6 wt.% to 15 wt.% based on the total weight of the softgel shell composition.

[0093] The Texture Analyzer test conditions for measuring strength and resilience were as follows: A softgel film having compositions F-1 through F-4 was placed on a platform. A quarter-inch (6.35 mm) ball probe was moved toward the softgel film at 2 mm / sec until the probe penetrated the film. The force measured was the strength of the film. The distance measured was the resilience of the film. The test was performed under ambient conditions.

[0094] [Table 3]

[0095] As seen in Table 3, the control non-animal gelling agent capsule shell composition without a water-soluble polymer had a strength of 4.9 kg and a springiness of 7.5 mm. In comparison, each non-animal gelling agent capsule shell composition containing a water-soluble polymer (whether PVA alone, pullulan, or PVA-PEG copolymer) was stronger, with a strength greater than 5 kg, and more elastic, with a springiness greater than 8 mm.

[0096] [Example 3] Softgel Shell Composition - Dissolution Data Softgel shell compositions prepared with varying concentrations and types of water-soluble polymer were cut into 1 inch by 1 inch squares and their solubilities were evaluated in 0.1 N HCl using a USP Apparatus II with a paddle rotation speed of 75 RPM in 0.1 N HCl with deionized water at 37° C. Table 4 shows the solubility data (also referred to as dissolution data) for shell compositions prepared with various water-soluble polymers.

[0097] The types and concentrations of carrageenan, plasticizer, and buffer used in the samples in Table 4 below were the same as those described in Table 2 for Formulations F-2 through F-6.

[0098] [Table 4]

[0099] Although not intended to be limiting, it is believed that the type of water-soluble polymer, as well as the weight ratio of carrageenan to a particular water-soluble polymer, can affect the dissolution time of the shell composition.

[0100] [Example 4] Softgel Capsule Formulations - Dissolution / Disintegration Data Placebo softgel capsules were prepared using polyvinyl alcohol and pullulan. The softgel capsules contained 900 mg of soybean oil as the fill material. The softgel shell compositions encapsulating the fill material contained carrageenan, plasticizer, and buffering agent in the types and concentrations used in Table 2 for Formulations F-2 to F-6. The types and concentrations of water-soluble polymers in each soybean oil-encapsulating softgel fill material were as listed in Table 5. After drying, the capsules were subjected to dissolution testing to evaluate the capsule rupture time / solubility.

[0101] Elution method: Equipment: USP Equipment II Temperature: 37℃ Medium: 0.1N HCl Paddle rotation speed: 50 and 75 RPM

[0102] [Table 5]

[0103] As can be seen from Table 5, softgel capsules using shell compositions containing a water-soluble polymer (PVA or pullulan) exhibit faster dissolution times in 0.1 N HCl at 75 RPM and 37° C. The shell compositions containing pullulan had faster dissolution times in 0.1 N HCl than the control and the shell compositions containing PVA. The shell compositions containing pullulan maintained similar dissolution times in 0.1 N HCl at 50 RPM and 37° C. and in 0.1 N HCl containing pepsin at 50 RPM and 37° C.

[0104] Disintegration tests were performed using a USP disintegration apparatus on control samples, non-gelatin softgel capsules containing no pullulan, and non-gelatin softgel capsules containing 2 wt.% pullulan. The results are shown in Table 6. The softgel capsules containing 2 wt.% pullulan ruptured much faster than the softgels without pullulan. The addition of pullulan resulted in faster disintegration.

[0105] [Table 6]

[0106] [Example 5] Comparative dissolution of ibuprofen softgel capsules Comparative dissolution tests were conducted using non-gelatin softgel capsules containing 200 mg of ibuprofen manufactured using a standard non-gelatin shell composition and a non-gelatin shell composition according to an embodiment containing 2 wt.% pullulan. The softgel compositions for the standard non-gelatin softgel capsule (CS100A) and the non-gelatin softgel capsule according to an embodiment containing 2 wt.% pullulan are summarized in Table 7 below. Figure 1 summarizes the results of this test. The dissolution tests were conducted in 0.1 N HCl at 37°C using a USP Apparatus II with a paddle rotation speed of 75 RPM.

[0107] [Table 7]

[0108] The results show that the non-gelatin ibuprofen 200 mg softgel capsules according to certain embodiments containing 2 wt.% pullulan ruptured at 18 minutes, faster than the standard non-gelatin ibuprofen 200 mg softgel capsules, which ruptured at 24 minutes. The similarity factor (F2) was calculated to be 40, suggesting that the two dissolution profiles were different. The pullulan softgel capsules had a faster drug release rate than the standard control non-gelatin ibuprofen 200 mg softgel capsules, which may be due to a faster onset of action and a shorter T max may be useful in achieving this.

[0109] The term "similarity factor (f2)" is a quantitative measure that indicates the similarity of the release profiles of two dosage forms. If the f2 value is no less than about 50, the release profiles of the two dosage forms are relative, similar, or bioequivalent (based on the FDA Guidance to Industry published in December 2017 regarding bioequivalence studies for solid oral dosage forms).

[0110] The foregoing description sets forth numerous specific details, such as examples of specific systems, components, methods, etc., to provide a thorough understanding of some embodiments of the present invention. However, it will be apparent to those skilled in the art that at least some embodiments of the present invention may be practiced without these specific details. In other instances, well-known components or methods have not been described in detail to avoid unnecessarily obscuring the present invention. For this reason, the specific details set forth are exemplary. Particular embodiments may vary from these exemplary details and still be considered within the scope of the present invention.

[0111] Although the operations of the methods herein are described in a particular order, the order of the operations of each method may be changed such that certain operations may be performed in the reverse order or such that certain operations may be performed, at least in part, in parallel with other operations. In alternative embodiments, instructions of separate operations or sub-operations may be performed intermittently and / or interleaved.

[0112] It should be understood that the foregoing description is intended to be illustrative, and not limiting. Many other embodiments will become apparent to those skilled in the art upon reading and understanding the above description. The scope of the invention should, therefore, be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. The present invention also includes the following aspects. <1> a shell composition comprising a non-animal derived gelling agent and a water soluble polymer, wherein the shell composition completely dissolves in less than 30 minutes when subjected to dissolution in 900 mL of 0.1 N HCl and deionized water at 37° C. using a USP Apparatus II with paddles at 75 RPM; and a filler material encapsulated within said shell composition; 1. A softgel composition comprising: <2> 2. The softgel composition of claim 1, wherein the non-animal derived gelling agent comprises carrageenan, starch, pregelatinized starch, xanthan gum, agar, pectin, alginate, sugar, high molecular weight polyethylene glycol, sugar-derived alcohol, cellulose derivative, cellulose-based polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, silicon dioxide, curdlan, furcellaran, albumin, soy protein, chitosan, or a combination thereof. <3> 3. The softgel composition of claim 1 or 2, wherein the shell composition further comprises a plasticizer. <4> 4. The softgel composition of any one of claims 1 to 3, wherein the shell composition further comprises a buffering agent. <5> 5. The softgel composition of any one of claims 1 to 4, wherein the water-soluble polymer comprises polyvinyl alcohol, pullulan gum, polylactic acid, polyvinyl alcohol-polyethylene glycol graft copolymer, high molecular weight polyethylene glycol, povidone, a surfactant, or a combination thereof. <6> 6. The softgel composition of claim 5, wherein the surfactant is sodium lauryl sulfate. <7> 7. The softgel composition of any one of claims 1 to 6, wherein the shell composition dissolves in less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes. <8> 8. The softgel composition of any one of claims 1 to 7, wherein the non-animal derived gelling agents include carrageenan and starch. <9> 9. The softgel composition according to any one of 1 to 8 above, wherein the weight ratio of carrageenan to starch in the shell composition is from about 1:1 to about 1:10, from about 1:1 to about 1:8, from about 1:1 to about 1:5, or from about 1:2.5 to about 1:4.5. <10> 10. The softgel composition of claim 9, wherein the carrageenan comprises iota carrageenan, kappa carrageenan, lambda carrageenan, or a combination thereof. <11> 11. The softgel composition of claim 9 or 10, wherein the starch includes native starch, modified starch, potato starch, corn starch, tapioca starch, pea starch, hydroxypropylated starch, hydroxyalkylated starch, acid-treated starch, dextrin, and combinations thereof. <12> 12. The softgel composition of any one of claims 1 to 11, wherein the non-animal gelling agent is in an amount of about 2 wt.% to about 40 wt.%, based on the total weight of the softgel capsule shell composition. <13> 13. The softgel composition of any of claims 1 to 12, comprising less than 10 wt.%, less than 5 wt.%, or less than 1 wt.% animal-derived gelling agent based on the total weight of the softgel capsule shell composition. <14> 14. The softgel composition of any one of claims 1 to 13, wherein the shell composition does not contain an animal-derived gelling agent. <15> 4. The softgel composition of claim 3, wherein the plasticizer comprises glycerin, sorbitol, a solution of sorbitol and sorbitan, triacetin, sodium lauryl sulfate, or a combination thereof. <16> 3. The softgel composition of claim 2, wherein the high molecular weight polyethylene glycol has a number average molecular weight in the range of 600 Da to 2,000,000 Da, or a combination of polyethylene glycols having various number average molecular weights in the range of 600 Da to 2,000,000 Da. <17> 4. The softgel composition according to claim 3, wherein the plasticizer is present in the softgel capsule shell composition in an amount of about 0.5 wt.% to about 40 wt.%, based on the total weight of the softgel capsule shell composition. <18> 5. The softgel composition according to claim 4, wherein the buffering agent is present in the softgel capsule shell composition in an amount of about 0.1 wt.% to about 5 wt.%, based on the total weight of the softgel capsule shell composition. <19> 5. The softgel composition of claim 4, wherein the buffering agent is selected from dibasic sodium phosphate, monobasic sodium phosphate, sodium bicarbonate, sodium citrate, disodium phosphate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, and combinations thereof. <20> 1. A softgel composition comprising a fill material comprising an active pharmaceutical or cosmetic agent, said fill material being encapsulated by a shell composition, said shell composition comprising a non-animal derived gelling agent and a water soluble polymer, wherein said shell composition dissolves completely in less than 30 minutes when subjected to dissolution in 900 mL of 0.1 N HCl and deionized water at 37° C. using a USP Apparatus II with paddles at 75 RPM. <21> 1. A softgel composition comprising a fill material encapsulated by a shell composition, said shell composition comprising: a non-animal derived gelling agent comprising carrageenan, starch, or a combination thereof; and water-soluble polymers including polyvinyl alcohol, pullulan gum, polylactic acid, polyvinyl alcohol-polyethylene glycol graft copolymer, high molecular weight polyethylene glycol, povidone, surfactants, or combinations thereof; The salt gel composition comprising: <22> 22. The softgel composition of claim 20 or 21, wherein the fill material comprises a hydrophilic material, a lipophilic material, an amphiphilic material, or a combination thereof. <23> 23. The softgel composition of any one of claims 20 to 22, wherein the shell composition comprises a surfactant. <24> 24. The softgel composition of any one of claims 20 to 23, wherein the fill material is a solution, suspension, semi-solid, or solid. <25> 25. The softgel composition of any one of claims 21 to 24, wherein the fill material comprises an active pharmaceutical agent or a cosmetic agent. <26> combining a non-animal gelling agent, a water-soluble polymer, and optionally at least one of a buffer, a plasticizer, or water to form a formulation; and encapsulating a filler material in a shell composition comprising said blend; 1. A method for preparing a softgel composition comprising: <27> The composition is mixing a plasticizer with water to form a plasticizer solution; and mixing a water-soluble polymer, a non-animal gelling agent, and a buffer with said plasticizer solution to form a formulation; 27. The method according to claim 26, comprising: <28> The composition is mixing a plasticizer, a non-animal gelling agent, and water to form a plasticizer solution; mixing a water-soluble polymer and a buffer with said plasticizer solution to form a formulation; 27. The method according to claim 26, comprising: <29> 28. The method of claim 26 or 27, further comprising heating the blend to form a molten mass. <30> 30. The method of claim 29, wherein the molten mass is homogeneous. <31> 31. The method of claim 29 or 30, further comprising extruding the molten mass to form a ribbon. <32> 32. The method of claim 31, wherein the ribbon has a thickness in the range of about 0.001 inches to about 0.050 inches (about 0.0254 mm to about 1.27 mm). <33> A method for treating a condition, comprising administering to a subject in need thereof a softgel composition described in any one of 1 to 25 above or a softgel composition prepared according to the method described in any one of 26 to 32 above, wherein the condition is treated, prevented, ameliorated, or alleviated by the administration.

Claims

1. 1. A shell composition comprising a non-animal derived gelling agent and a water soluble polymer, a shell composition that dissolves completely in less than 30 minutes when subjected to dissolution in 900 mL of 0.1 N HCl and deionized water at 37° C. using a USP Apparatus II with paddles at 75 RPM; and a filler material encapsulated within the shell composition; the weight ratio of the water-soluble polymer to the non-animal derived gelling agent is from 3:1 to 1:3; the non-animal derived gelling agent comprises a carrageenan selected from the group consisting of iota carrageenan, kappa carrageenan, lambda carrageenan, and combinations thereof; The softgel composition, wherein the water-soluble polymer comprises polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, or a combination thereof.

2. 10. The softgel composition of claim 1, wherein the shell composition further comprises a plasticizer.

3. 3. The softgel composition of claim 1 or 2, wherein the shell composition further comprises a buffering agent.

4. 4. The softgel composition of claim 1, wherein the shell composition dissolves in less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes.

5. 5. The softgel composition of claim 1, wherein the non-animal derived gelling agent is in an amount of 2 wt. % to 40 wt. % based on the total weight of the softgel composition.

6. 6. The softgel composition of claim 1, comprising less than 10 wt.%, less than 5 wt.%, or less than 1 wt.% of an animal-derived gelling agent, based on the total weight of the softgel composition.

7. 6. The softgel composition of claim 1, wherein the shell composition does not contain an animal-derived gelling agent.

8. 3. The softgel composition of claim 2, wherein the plasticizer comprises glycerin, sorbitol, a solution of sorbitol and sorbitan, triacetin, sodium lauryl sulfate, or a combination thereof.

9. 3. The softgel composition of claim 2, wherein the plasticizer is present in the softgel composition in an amount of 0.5 wt. % to 40 wt. %, based on the total weight of the softgel composition.

10. 4. The softgel composition of claim 3, wherein the buffering agent is present in the softgel composition in an amount of 0.1 wt. % to 5 wt. %, based on the total weight of the softgel composition.

11. 4. The softgel composition of claim 3, wherein the buffering agent is selected from dibasic sodium phosphate, monobasic sodium phosphate, sodium bicarbonate, sodium citrate, disodium phosphate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, and combinations thereof.

12. 1. A softgel composition comprising a fill material comprising an active pharmaceutical agent or a cosmetic agent, the fill material is encapsulated by a shell composition, and the shell composition comprises a non-animal derived gelling agent and a water soluble polymer, and the shell composition completely dissolves in less than 30 minutes when subjected to dissolution in 900 mL of 0.1 N HCl and deionized water at 37° C. using a USP Apparatus II with paddles at 75 RPM; the weight ratio of the water-soluble polymer to the non-animal derived gelling agent is from 3:1 to 1:3; the non-animal derived gelling agent comprises a carrageenan selected from the group consisting of iota carrageenan, kappa carrageenan, lambda carrageenan, and combinations thereof; The softgel composition, wherein the water-soluble polymer comprises polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, or a combination thereof.

13. 1. A softgel composition comprising a fill material encapsulated by a shell composition, a non-animal derived gelling agent, wherein the shell composition comprises a carrageenan selected from the group consisting of iota carrageenan, kappa carrageenan, lambda carrageenan, and combinations thereof; and a water-soluble polymer comprising polyvinyl alcohol, a polyvinyl alcohol-polyethylene glycol graft copolymer, or a combination thereof; The salt gel composition, wherein the weight ratio of the water-soluble polymer to the non-animal derived gelling agent is from 3:1 to 1:

3.

14. 14. The softgel composition of claim 12 or 13, wherein the fill material comprises a hydrophilic material, a lipophilic material, an amphiphilic material, or a combination thereof.

15. 15. The softgel composition of claim 12, wherein the shell composition comprises a surfactant.

16. 16. The softgel composition of claim 12, wherein the fill material is a solution, a suspension, a semi-solid, or a solid.

17. 16. The softgel composition of claim 13, wherein the fill material comprises an active pharmaceutical agent or a cosmetic agent.

18. combining a non-animal derived gelling agent, a water soluble polymer, and optionally at least one of a buffer, a plasticizer, or water to form a formulation; and encapsulating a filler material in a shell composition comprising said blend; 1. A method for preparing a softgel composition comprising: the weight ratio of the water-soluble polymer to the non-animal derived gelling agent is from 3:1 to 1:3; the non-animal derived gelling agent comprises a carrageenan selected from the group consisting of iota carrageenan, kappa carrageenan, lambda carrageenan, and combinations thereof; The method, wherein the water-soluble polymer comprises polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, or a combination thereof.

19. The composition is mixing a plasticizer with water to form a plasticizer solution; and 20. The method of claim 18, comprising mixing a water-soluble polymer, a non-animal derived gelling agent, and a buffer with the plasticizer solution to form a formulation.

20. The composition is mixing a plasticizer, a non-animal derived gelling agent, and water to form a plasticizer solution; 20. The method of claim 18, comprising mixing a water-soluble polymer and a buffer with the plasticizer solution to form a formulation.

21. 21. The method of any one of claims 18 to 20, further comprising heating the blend to form a molten mass.

22. 22. The method of claim 21, wherein the molten mass is homogeneous.

23. 23. The method of claim 21 or 22, further comprising extruding the molten mass to form a ribbon.

24. 24. The method of claim 23, wherein the ribbon has a thickness in the range of 0.001 inch to 0.050 inch (0.0254 mm to 1.27 mm).

Images