Fast-dissolving softgel capsules

Abstract

In certain embodiments, a softgel capsule film comprising a non-gelatin bio-based polymer is disclosed that 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.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 397,554, filed August 12, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to a softgel capsule comprising a softgel capsule film, the softgel capsule film comprising a non-gelatin bio-based polymer, and the softgel capsule also comprising a fill material containing an active agent. [Background technology]

[0003] Softgel capsules are commonly used in both the pharmaceutical and dietary supplement industries. Gelatin is the most commonly used ingredient for softgel shells due to its advantages, including high water solubility, flexibility, and mechanical robustness. Currently, there is a high demand for gelatin, leading to a shortage of supply to meet the growing demand. To reduce this dependency on gelatin, plant-based softgel capsules have been developed that use carrageenan (a seaweed extract) in combination with starch.

[0004] For a compound to be useful as a shell material in softgel applications, the compound must meet two important criteria: (1) the shell must be sufficiently robust and physically stable to retain the fill and maintain its shape, and (2) the shell must be soluble in aqueous media (physiological media) to release its active pharmaceutical ingredient upon ingestion. For immediate-release pharmaceutical dosage forms, it is expected that at least 80% of the contents will be released within 30 minutes.

[0005] Achieving such immediate drug release using starch and carrageenan has proven difficult due to their poor aqueous solubility. One of the disadvantages of this approach is that starch is poorly water-soluble, thereby limiting its use in immediate release dosage forms.

[0006] Therefore, there is a need for improved non-gelatin softgel capsule formulations that have higher aqueous solubility and are amenable to high-speed manufacturing as a reliable and commercially viable alternative to gelatin-based softgel capsules, meeting or exceeding the dissolution specifications of immediate release dosage forms. Summary of the Invention

[0007] According to various embodiments, disclosed herein is a softgel capsule film comprising a non-gelatin bio-based polymer. In certain embodiments, the film completely dissolves in less than 20 minutes when subjected to dissolution in 900 mL of 0.1 N HCl and deionized water at 37° C. using a USP Apparatus II paddle at 75 RPM.

[0008] According to further embodiments, disclosed herein are softgel capsules and methods of making and processing thereof, which include a fill material comprising an active agent, the fill material being encapsulated by a film comprising a non-gelatin bio-based polymer. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 shows representative acetaminophen release profiles in dissolution media containing 2% SDS at each stage according to Example 1 and corresponding photographs. [Figure 2] FIG. 1 shows representative liquid acetaminophen release profiles for 22MC-01 and gelatin capsules according to Example 1. [Figure 3] FIG. 1 shows a representative ibuprofen release profile of 22MC-40 capsules according to Example 1. [Figure 4]FIG. 1 shows representative ibuprofen release profiles for 22MC-02, 22MC-46, and gelatin capsules according to Example 2. [Figure 5] FIG. 1 shows representative ibuprofen release profiles for 21MC-96, 22MC-41, and gelatin capsules according to Example 3. [Figure 6-1] FIG. 6A shows the collected data set for the physical properties and dissolution performance of 22MC-01 after the T12M stability study. [Figure 6-2] FIG. 6B shows the collected data set regarding the physical properties and dissolution performance of 22MC-01 after the T12M stability study. [Figure 6-3] FIG. 6C shows the collected data set regarding the physical properties and dissolution performance of 22MC-01 after the T12M stability study. [Figure 7-1] FIG. 7A shows the collected data set for the physical properties and dissolution performance of 22MC-02, 22MC-46 after T12M stability testing. [Figure 7-2] FIG. 7B shows the collected data set for the physical properties and dissolution performance of 22MC-02, 22MC-46 after T12M stability testing. [Figure 7-3] FIG. 7C shows the collected data set for the physical properties and dissolution performance of 22MC-02, 22MC-46 after T12M stability testing. [Figure 7-4] FIG. 7D shows the collected data set for the physical properties and dissolution performance of 22MC-02, 22MC-46 after T12M stability testing. [Figure 7-5] FIG. 7E shows the collected data set for the physical properties and dissolution performance of 22MC-02, 22MC-46 after T12M stability testing. [Figure 7-6] FIG. 7F shows the collected data set for the physical properties and dissolution performance of 22MC-02, 22MC-46 after T12M stability testing. [Figure 8-1]FIG. 8A shows the collected data set for the physical properties and dissolution performance of 21MC-96 and 22MC-41 after T6M and T12M stability studies. [Figure 8-2] FIG. 8B shows the collected data set regarding the physical properties and dissolution performance of 21MC-96 and 22MC-41 after T6M and T12M stability studies. [Figure 8-3] FIG. 8C shows the collected data set regarding the physical properties and dissolution performance of 21MC-96 and 22MC-41 after T6M and T12M stability studies. [Figure 8-4] FIG. 8D shows the collected data set for the physical properties and dissolution performance of 21MC-96 and 22MC-41 after T6M and T12M stability studies. [Figure 8-5] FIG. 8E shows the collected data set for the physical properties and dissolution performance of 21MC-96 and 22MC-41 after T6M and T12M stability studies. [Figure 8-6] FIG. 8F shows the collected data set for the physical properties and dissolution performance of 21MC-96 and 22MC-41 after T6M and T12M stability studies. DETAILED DESCRIPTION OF THE INVENTION

[0010] Various embodiments of softgel capsule films and formulations and methods of preparing and using the same are described herein. It is to be understood that the invention is not limited to the details of the configuration 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.

[0011] 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," "a particular embodiment," "in one embodiment," or "in an embodiment" in various places throughout this specification do not necessarily refer 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.

[0012] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to a "softgel capsule" includes two or more softgel capsules as well as a single softgel capsule.

[0013] As used herein, "free or substantially free" refers to a composition that contains less than about 1 wt%, less than about 0.5 wt%, less than about 0.25 wt%, less than about 0.1 wt%, less than about 0.05 wt%, less than about 0.01 wt%, or 0 wt% of said component.

[0014] As used herein, "about" refers to any value within a ±10% variance, so that "about 10" would include 9 to 11. As used herein, "a," "an," or "the" refers to one or more unless otherwise specified. Thus, for example, reference to an "additive" includes a single additive as well as a mixture of two or more different additives, and the like.

[0015] 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.

[0016] Any and all examples or the use of exemplary language (e.g., "such as") provided herein are intended only to illuminate particular materials and methods and are not limiting in scope. No language in the specification should be construed as implying that any non-claimed element is essential to the practice of the disclosed materials and methods.

[0017] As used herein, the terms "film," "film composition," "shell," or "shell composition" refer to the shell of a softgel capsule that encapsulates the fill material.

[0018] Although the disclosure herein refers to particular embodiments, 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.

[0019] Disclosed herein is a softgel capsule film comprising a non-gelatin bio-based polymer. In certain embodiments, the film can be completely dissolved in less than 30 minutes when subjected to dissolution in 900 mL of 0.1N HCl and deionized water at 37°C using a USP Apparatus II with a paddle at 75 RPM. The softgel capsule film can dissolve in less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes.

[0020] In certain embodiments of the softgel capsule film, the non-gelatin bio-based polymer comprises stearic acid, maltodextrin, pullulan, or a combination thereof.

[0021] In certain embodiments of the softgel capsule film, the non-gelatin bio-based polymer may be present in an amount of about 1% to about 25% (w / w), about 3% to about 22% (w / w), about 5% to about 20% (w / w), about 7.5% to about 17.5% (w / w), or about 10% to about 15% (w / w), based on the total weight of the film, or any range, subrange, or value therein.

[0022] In certain embodiments of the film, the non-gelatin bio-based polymer can be pullulan. In other embodiments of the film, the non-gelatin bio-based polymer can be stearic acid. In other embodiments of the film, the non-gelatin bio-based polymer can be maltodextrin.

[0023] In certain embodiments of the film, the pullulan in the film may be in an amount of about 1% to about 20%, about 2% to about 18%, about 4% to about 16%, about 5% to about 15%, or about 7.5% to about 12.5% (w / w) of the film, or any range, subrange, or value therein.

[0024] In some embodiments of the film, the stearic acid in the film may be in an amount of about 0.5% to about 5%, about 1% to about 4%, or about 2% to about 3% (w / w) of the film, or any range, subrange, or value therein.

[0025] In certain embodiments of the film, the non-gelatin bio-based polymer may be pullulan and stearic acid in an amount of about 1.5% to about 25%, about 2% to about 20%, about 3% to about 18%, about 5% to about 15%, or about 7.5% to about 12% (w / w) of the film, or any range, subrange, or value therein.

[0026] In certain embodiments, the film may further comprise a synthetic polymer. The synthetic polymer may comprise polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, high molecular weight polyethylene glycol, povidone, a surfactant, a nonionic triblock copolymer, or a combination thereof. In some embodiments, the synthetic polymer may be a nonionic triblock copolymer. The nonionic triblock copolymer may comprise a polyethylene oxide block and a polypropylene oxide block. In some embodiments, the surfactant may comprise sodium lauryl sulfate. In some embodiments of the film, the synthetic polymer in the film may be in an amount of about 4% to about 8% or about 5% (w / w) of the film.

[0027] In certain embodiments, the film may further comprise a non-animal derived gelling agent, which may include carrageenan, starch, pregelatinized starch, xanthan gum, agar, pectin, sugar, 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, egg white powder, lactalbumin, soy protein, chitosan, or a combination thereof.

[0028] In certain embodiments, the non-animal derived gelling agent may comprise carrageenan, starch, or a combination thereof. In some embodiments, the carrageenan may be iota carrageenan, kappa carrageenan, lambda carrageenan, or a combination thereof.

[0029] In some embodiments, the starch may comprise modified starch, potato starch, corn starch, tapioca starch, hydroxypropylated starch, hydroxyalkylated starch, acid treated starch, dextrin, or a combination thereof.

[0030] In certain embodiments, the ratio of carrageenan to starch may be 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.

[0031] In certain embodiments, the non-animal gelling agent does not include starch.

[0032] In certain embodiments, the non-animal gelling agent may comprise about 15% to about 60% (w / w) of the film. In some embodiments, the non-animal gelling agent may comprise about 20% to about 55%, about 25% to about 50%, about 30% to about 45%, or about 35% to about 55% (w / w) of the film. In some embodiments, the film may comprise carrageenan in an amount of about 5% to about 20%, about 8% to about 18%, or about 10% to about 15% (w / w) of the film. In some embodiments, the film may comprise starch in an amount of about 0% to about 45%, about 5% to about 40%, about 10% to about 35%, about 15% to about 30%, or about 20% to about 25% (w / w) of the film.

[0033] In other embodiments, the film may contain less than 10%, less than 5%, or less than 1% (w / w) of a based animal-derived gelling agent. In certain embodiments, the softgel capsule film contains no animal-derived gelling agents.

[0034] In certain embodiments, the softgel capsule film may also include a plasticizer, hi other embodiments, the film may also include a buffering agent.

[0035] In some embodiments, the plasticizer may be glycerol, glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof. In some embodiments, the polysorbate may include polysorbate 20, also known as Tween 20, polysorbate 80, also known as Tween 80, or a combination thereof. In certain embodiments of the film, the plasticizer may be present in an amount of about 15% to about 40%, about 20% to about 35%, or about 25% to about 30% (w / w) of the film.

[0036] In some embodiments, the buffering agent may be 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, or a combination thereof. In some embodiments of the film, the buffering agent may be present in an amount of about 0.1% to about 5% (w / w) of the film. In other embodiments, the buffering agent may be present in an amount of about 0.1% to about 5%, about 0.3% to about 4.5%, about 0.5% to about 4%, about 1% to about 3.5%, or about 1.5% to about 3%, or any value or subrange therein.

[0037] In certain embodiments, the film comprises gelatin in an amount, for example, less than about 50% w / w of the film, less than about 40% w / w of the film, less than about 25% w / w of the film, less than about 10% w / w of the film, less than about 5% w / w of the film, less than about 3% w / w of the film, or less than about 1% w / w of the film.

[0038] Also disclosed in certain embodiments are softgel capsule formulations that include a fill material that includes an active agent, where the fill material is encapsulated by the film compositions disclosed herein.

[0039] In certain embodiments, the softgel capsule comprises a film composition comprising a non-gelatin bio-based polymer, which may include maltodextrin, pullulan, carrageenan, or a combination thereof.

[0040] In certain embodiments of the softgel capsule, the film composition may further comprise a synthetic polymer. The synthetic polymer may be polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, high molecular weight polyethylene glycol, povidone, a surfactant, a nonionic triblock copolymer, or a combination thereof. In some embodiments, the synthetic polymer may be a nonionic triblock copolymer. In some embodiments, the nonionic triblock copolymer may comprise a polyethylene oxide block and a polypropylene oxide block. In some embodiments, the surfactant may be sodium lauryl sulfate.

[0041] In certain embodiments of the softgel capsule, the film composition may further comprise a non-animal derived gelling agent, which may include carrageenan, starch, xanthan gum, agar, pectin, sugar, sugar-derived alcohol, cellulose derivative, cellulose-based polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, silicon dioxide, curdlan, furcellaran, egg white powder, lactalbumin, soy protein, chitosan, or a combination thereof.

[0042] In certain embodiments of the softgel capsule, the film may further comprise a plasticizer. The plasticizer may be glycerol, glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof. In some embodiments, the polysorbate comprises Tween 20, Tween 80, or a combination thereof. In some embodiments, the plasticizer may be present in an amount of about 15% to about 40% (w / w) based on the film. In some embodiments, the plasticizer may be a sorbitol sorbitan solution.

[0043] In certain embodiments of the softgel capsule, the film may further comprise a buffering agent, which may be 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.

[0044] In certain embodiments of the softgel capsule, the film is free of animal-derived gelling agents.

[0045] Also disclosed herein are immediate-release softgel capsules comprising a fill material encapsulated by a film composition, wherein the film composition comprises a non-gelatin bio-based polymer, and the film dissolves in less than about 20 minutes according to a dissolution test using USP Apparatus Paddle II at 75 rpm. In certain embodiments, the fill material may comprise an active agent.

[0046] In certain embodiments, the immediate release softgel capsule comprises a fill material encapsulated by a film composition, wherein at least 80% of the fill material is released within 30 minutes.

[0047] The film composition disclosed herein may further contain at least one of buffering agent, plasticizer, and water.The soft shell capsule formulation described herein can be vegetarian and free of animal-derived materials such as gelatin.The immediate-release soft gel capsule may comprise the film composition described above in the present disclosure.

[0048] In certain embodiments, the films 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 900 mL of 0.1 N HCl and deionized water at 37° C. using USP Apparatus II with paddles at 75 RPM.

[0049] In certain embodiments, the softgel capsule formulation contains water, which may be present 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%, or about 48 wt% of the film.

[0050] In certain embodiments, the shell composition / film of the softgel capsule may optionally include additional agents such as colorants, flavoring agents, sweeteners, fillers, antioxidants, diluents, pH adjusters, or other pharmaceutically acceptable excipients or additives such as synthetic colors and mineral oxides.

[0051] Exemplary suitable colorants may include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, violet, indigo, and brown. In certain embodiments, the color of the dosage form may be indicative of the contents (e.g., one or more active ingredients) contained therein.

[0052] Exemplary suitable flavoring agents may include, but are not limited to, "flavor extracts," which are often obtained by extracting parts of a source, e.g., an animal or plant source, using a solvent such as ethanol or water, natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or whole plants.

[0053] Additional exemplary flavoring agents that may be included in the dosage form include, but are not limited to, breath freshening mixtures such as menthol, spearmint, and cinnamon, other flavors or fragrances such as coffee bean, fruit flavors (e.g., cherry, orange, grape, etc.), particularly those used for oral hygiene, as well as active ingredients used in tooth and mouth rinses such as quaternary ammonium bases. The effect of the flavoring may be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, or the like.

[0054] Exemplary sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof. Artificial sweeteners include, for example, acesulfame and its various salts, such as the 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 the 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; natural enhanced sweeteners such as monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®), stevia (Stevia rebaudiana) (stevioside), monk fruit, and polyhydric alcohols such as sorbitol, mannitol, xylitol, erythritol, and the like.

[0055] The soft shell capsule formulations disclosed herein may further comprise a fill composition. The fill composition may contain at least one of rapeseed oil, medium-chain triglyceride oil, polyethylene glycol, and combinations thereof. Lipophilic and / or hydrophilic fill compositions and / or alcoholic fill compositions may also be incorporated into the soft shell capsule formulations described herein.

[0056] Any pharmaceutically active ingredient, including both water-soluble and poorly water-soluble ones, may be used for the purposes of this disclosure. 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, antiviral agents, anxiolytics, sedatives, hypnotics and neuroleptics, vegetarians, and the like. These include: ATP 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, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and combinations thereof. In certain embodiments, the present invention also relates to methods of treatment utilizing any of the active ingredients disclosed herein to treat a disease or condition that can be treated by the active ingredient.

[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 consisting of, 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 hydrogenated forms thereof, free fatty acids and mono-, di-, and triglycerides having C8-, C10-, C12-, C14-, C16-, C18-, C20-, and C22-fatty acids, and combinations thereof.

[0059] According to certain embodiments, the active agent may include a lipid-lowering agent, 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, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof, and mixtures of any of the foregoing.

[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 myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), 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, malic acid, 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, amino Profen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxypinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprine, azapropazone, benorylate, bronfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, physlamine, 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, antiemetics (e.g., methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, pharmaceutically acceptable salts thereof, and mixtures thereof, toclopramide, methylnaltrexone), antiepileptics (e.g., phenyloin, 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), antihypertensives (e.g., clonidine,methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidal agents, hypnotics, psychotropic agents, 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 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, as well as 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, secobarbital, as well as 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, 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 the active agent include, but are not limited to, benzodiazepines, as well as pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0069] The dosage forms according to the present disclosure contain various active agents and pharmaceutically acceptable salts thereof. 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, 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.; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

[0070] Suitable filling materials include at least one active ingredient and can be prepared according to well-known methods.In addition to at least one active ingredient, suitable filling materials may also include additional filling ingredients such as flavoring agents, sweeteners, coloring agents, and fillers, or other pharmaceutically acceptable excipients or additives such as synthetic coloring agents and mineral oxides.The appropriate amount of pharmaceutically active ingredients and pharmaceutically acceptable excipients can be easily determined by those skilled in the art.

[0071] The disintegration tests disclosed herein were conducted on 1000 mL volumes of liquid at approximately 37° C.±2° C. Disintegration test fluid 1 (also referred to herein as "simulated gastric fluid") was a 2 g / L sodium chloride-hydrochloric acid solution with a pH of 1.2. Disintegration test fluid 2 (also referred to herein as "simulated intestinal fluid") was a 0.2 mol / L potassium dihydrogen phosphate-0.2 mol / L sodium hydroxide solution with a pH of 6.8.

[0072] Disintegration testing with Fluid 1 was conducted for approximately 120 minutes by placing one unit in each of the six tubes of a basket, submerging the basket (and therefore the unit) in Fluid 1, and lifting the basket from the fluid to determine if the unit had disintegrated. Disintegration was defined as the unit breaking or its enteric shell composition rupturing or breaking. If none of the six units disintegrated, the test passed. Similar testing was conducted with Fluid 2 for selected periods of time.

[0073] In some embodiments, the disintegration test may be conducted for about 150 minutes, about 120 minutes, about 105 minutes, about 90 minutes, about 75 minutes, about 60 minutes, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, or about 5 minutes.

[0074] In some embodiments, the softgel capsules may have a burst strength of about 6 kg to about 20 kg, 8 kg to about 15 kg, about 10 kg to about 15 kg, about 8 kg, about 10 kg, about 12 kg, or about 15 kg at 1 month, 3 months, 6 months, or 12 months at 40°C / 75% RH.

[0075] In some embodiments, the softgel capsules may have a burst strength of about 6 kg to about 20 kg, 8 kg to about 15 kg, about 10 kg to about 15 kg, about 8 kg, about 10 kg, about 12 kg, or about 15 kg at 1 month, 3 months, 6 months, or 12 months at 30°C / 65% RH.

[0076] In some embodiments, the softgel capsules may release 80% of the fill material after about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, or about 55 minutes in a dissolution test using, for example, a USP APP II with paddles at 75 RPM in 900 mL of phosphate buffer (50 mM, pH 7.2) at 37° C., or a USP Apparatus II with paddles at 75 RPM in, for example, 900 mL of 0.1 N HCl and deionized water at 37° C. In certain embodiments, the above results for softgel capsules under accelerated stability conditions of 25° C. / 60% RH, 30° C. / 65% RH, or 40° C. / 75% RH may also be obtained at 1 month, 3 months, 6 months, 12 months, 18 months, 22 months, or 24 months. In certain embodiments, after any of the accelerated storage conditions disclosed herein, dissolution does not change by more than 20%, or by more than 10%, or by more than 5% from the zero time point at 1 hour, 4 hour, or 8 hour time points.

[0077] In some embodiments of the softgel capsule, the softgel capsule may have a water activity (Aw) at 1 month, 3 months, 6 months, or 12 months at 40°C / 75% RH that may be about 0.3 to about 1.0, about 0.4 to about 0.9, about 0.5 to about 0.8, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1.0.

[0078] In some embodiments of the softgel capsule, the softgel capsule may have a water activity (Aw) at 1 month, 3 months, 6 months, or 12 months at 30°C / 65% RH that may be about 0.3 to about 1.0, about 0.4 to about 0.9, about 0.5 to about 0.8, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1.0.

[0079] Methods for preparing dosage forms Disclosed herein are methods for preparing the softgel capsule films and capsule formulations disclosed herein, which include combining a non-gelatin bio-based polymer and, optionally, at least one of a synthetic polymer, a non-animal derived gelling agent, a buffer, a plasticizer, and water to form a combination.

[0080] The method may further include transferring the combination to an encapsulation device. In certain embodiments, the method may include encapsulating a fill material into softgel capsules formed from the combination 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 further include packaging the plurality of softgel capsule dosage forms.

[0081] In certain embodiments, the present invention relates to one or more of the items listed below: 1. A softgel capsule film comprising a non-gelatin bio-based polymer, which dissolves in less than 20 minutes according to a dissolution test using USP Apparatus Paddle II at 75 rpm. 2. The softgel capsule film of item 1, wherein the non-gelatin bio-based polymer comprises stearic acid, maltodextrin, pullulan, or a combination thereof. 3. The softgel capsule film according to item 1 or 2, further comprising a synthetic polymer. 4. The softgel capsule according to item 3, wherein the synthetic polymer is polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, high molecular weight polyethylene glycol, povidone, a surfactant, a nonionic triblock copolymer, or a combination thereof. 5. The softgel capsule according to item 3 or 4, wherein the synthetic polymer is a non-ionic triblock copolymer. 6. The softgel capsule of any one of items 3 to 5, wherein the nonionic triblock copolymer comprises polyethylene oxide and polypropylene oxide blocks. 7. The softgel capsule film according to item 3 or 4, wherein the surfactant is sodium lauryl sulfate. 8. The softgel capsule film of any one of the preceding claims, further comprising a non-animal derived gelling agent. 9. The softgel capsule film according to item 8, wherein the non-animal-derived gelling agent comprises carrageenan, starch, pregelatinized starch, xanthan gum, agar, pectin, sugar, 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, egg white powder, lactalbumin, soy protein, chitosan, or a combination thereof. 10. The softgel capsule film of any one of the preceding items, further comprising a plasticizer. 11. The softgel capsule film of any one of the preceding items, further comprising a buffering agent. 12. The softgel capsule film of any one of the preceding items, wherein the film dissolves in less than 15 minutes, less than 10 minutes, or less than 5 minutes. 13. The softgel capsule film of any one of the preceding items, wherein the non-animal derived gelling agent comprises carrageenan, starch, or a combination thereof. 14. The softgel capsule film of any one of the preceding items, wherein the ratio of carrageenan to starch is 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. 15. The softgel capsule film according to item 13, wherein the carrageenan comprises iota carrageenan, kappa carrageenan, lambda carrageenan, or a combination thereof. 16. The softgel capsule film according to item 13, wherein the starch comprises modified starch, potato starch, corn starch, tapioca starch, hydroxypropylated starch, hydroxyalkylated starch, acid-treated starch, dextrin, and combinations thereof. 17. The softgel capsule film according to item 8, wherein the non-animal gelling agent does not include starch. 18. The softgel capsule film according to item 8, wherein the non-animal gelling agent is in an amount of about 15% to about 60% (w / w) of the film. 19. The softgel capsule film according to item 13, wherein the carrageenan is in an amount of about 5 to about 20% (w / w). 20. The softgel capsule film according to item 13, wherein the starch is in an amount of about 0 to about 45% (w / w). 21. A softgel capsule film according to any of the preceding items, containing less than 10%, less than 5%, or less than 1% animal-derived gelling agents. 22. The softgel capsule film of any of the preceding items, wherein the film does not contain animal-derived gelling agents. 23. The softgel capsule film according to item 10, wherein the plasticizer comprises glycerol, glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof. 24. The softgel capsule film according to item 23, wherein the polysorbate comprises Tween 20, Tween 80, or a combination thereof. 25. The softgel capsule film according to item 10, wherein the plasticizer is in an amount of about 15 to about 40% (w / w) of the film. 26. The softgel capsule film according to item 11, wherein the buffering agent is in an amount of about 0.1 to about 5% (w / w) of the film. 27. The softgel capsule film according to item 11, 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. 28. The softgel capsule film of any of the preceding items, wherein the polymer is in an amount of about 1 to about 25% (w / w), about 3 to about 22% (w / w), about 5 to about 20% (w / w), about 7.5 to about 17.5% (w / w), or about 10 to about 15% (w / w) of the film. 29. The softgel capsule film according to item 2, wherein the polymer is pullulan. 30. The softgel capsule film of item 29, wherein the pullulan is in an amount of about 1 to about 20% (w / w), about 2 to about 18% (w / w), about 4 to about 16% (w / w), about 5 to about 15% (w / w), or about 7.5 to about 12.5% (w / w) of the film. 31. The softgel capsule film according to item 2, wherein the polymer is stearic acid. 32. The softgel capsule film according to item 31, wherein the stearic acid is in an amount of about 0.5 to about 5% (w / w), about 1 to about 4% (w / w), or about 2 to about 3% (w / w) of the film. 33. The softgel capsule film according to item 2, wherein the polymer is pullulan and stearic acid. 34. The softgel capsule film of item 33, wherein the polymer is in an amount of about 1.5 to about 25% (w / w), about 2 to about 20% (w / w), about 3 to about 18% (w / w), about 5 to about 15% (w / w), or about 7.5 to about 12.5% (w / w) of the film. 35. The softgel capsule according to item 3, wherein the synthetic polymer is in an amount of about 4 to about 8% (w / w) of the film, or about 5% (w / w). 36. An immediate-release softgel capsule comprising a fill material encapsulated by a film composition, wherein the film composition comprises a non-gelatin bio-based polymer, and wherein the film dissolves in less than 20 minutes according to a dissolution test using USP Apparatus Paddle II at 75 rpm. 37. The immediate-release softgel capsule according to item 36, wherein the fill material comprises an active agent. 38. An immediate-release softgel capsule comprising a fill material encapsulated by a film composition, wherein the film composition comprises a non-gelatin bio-based polymer, and wherein at least 80% of the fill material is released within 30 minutes. 39. The immediate-release softgel capsule according to item 38, wherein the fill material comprises an active agent. [Example]

[0082] [Example 1] Partial replacement of starch with Kolliphor P407 (poloxamer) Starch was partially replaced with Kolliphor P407, a nonionic triblock copolymer consisting of hydrophilic (polyethylene oxide, PEO) and hydrophobic (polypropylene oxide, PPO) blocks. Kolliphor P407 was chosen for its excellent water solubility and thermoreversible gelation behavior. Softgels were prepared using the gel masses shown in Table 1.

[0083] [Table 1]

[0084] Oil-based fillers and polymeric PEG-based fillers were used for encapsulation. Acetaminophen (325 mg per softgel) was suspended in soybean oil, and this suspension was used to encapsulate 900 mg softgels (OET-10291399 Lot#22MC-01). Ibuprofen (200 mg per softgel) was dissolved in a 9:1 mixture of PEG1000 and PEG600, and this mixture was used to encapsulate 360 mg softgels (OET-10291399 Lot#22MC-40).

[0085] After the softgel capsules were dried, they were washed and placed in plastic bags before testing.

[0086] Bursting strength measurements using a fiber optic probe and dissolution tests were performed to evaluate the physical properties and drug release kinetics of the softgels, respectively. The dissolution apparatus was prepared according to the FDA dissolution method with slight modifications. For the 22MC-01 softgel capsules, 2% sodium dodecyl sulfate (SDS) was added to 900 mL of water to release the API entrapped within the oil globules. For the 22MC-40 softgel capsules, 900 mL of 50 mM phosphate buffer at pH 7.2 was used as the dissolution medium. Unless otherwise noted, the dissolution medium was stirred using a paddle apparatus at 100 RPM.

[0087] [Example 2] Partial replacement of starch with stearic acid Stearic acid is a saturated fatty acid with an 18-carbon chain. Stearic acid is known to form lipid-amylose complexes during gelatinization, thus simultaneously retarding the recrystallization / retrogradation process of starch during cooling. Because the aqueous solubility of starch is highly determined by its rate of recrystallization during cooling, starch was partially replaced with stearic acid. Softgels were prepared using the gel masses shown in Table 2.

[0088] [Table 2]

[0089] Ibuprofen (200 mg per capsule) was encapsulated in 360 mg softgels (OET-10291401 Lot#22MC-02 and Lot#22MC-46). The softgel capsules were dried, washed with an ethanol-phosal 53MCT wash, and stored in plastic bags prior to testing.

[0090] Burst strength measurements and fiber optic probes were performed to evaluate the physical properties and drug release kinetics of the softgels disclosed herein, respectively. Dissolution apparatus was prepared according to a slightly modified FDA dissolution method for ibuprofen softgel capsules. Dissolution tests were performed in 900 mL of phosphate buffer (50 mM, pH 7.2) using USP APPII with paddles at 75 RPM.

[0091] An informal stability study was initiated on Lot#22MC-02 capsules to collect data for one month (T1M) at 40°C / 75% RH.

[0092] [Example 3] Complete replacement of starch with maltodextrin and pullulan Maltodextrin is a hydrolyzed starch that exhibits higher water solubility than hydroxypropylated starch. Pullulan is a naturally occurring polysaccharide produced by yeast. Maltodextrin and pullulan were used to completely replace starch, resulting in a robust shell with higher shell solubility. Softgels were produced using the gel mass shown in Table 3.

[0093] [Table 3]

[0094] Ibuprofen (200 mg per capsule) was encapsulated in 360 mg softgels (OET-10291370 Lot#21MC-96 and Lot#22MC-41). After drying, the softgel capsules were washed with an ethanol-Phosal mixture and placed in a plastic bag prior to testing.

[0095] Summary of results [Example 1] Partial replacement of starch with Kolliphor P407 oily filling The softgel burst strength and migration distance of the 22MC-01 capsules are summarized in Table 4. The dried 22MC-01 softgel capsules exhibited a moderate burst strength of 15 kg.

[0096] [Table 4]

[0097] The initial release of the fill occurred after 14 ± 2 minutes of exposure when the capsule tip was opened. The shell dissolved simultaneously as the fill was released into the dissolution medium. However, regardless of whether the shell was fully opened and exposed to the environment, the drug slowly dissolved, as noted in Figure 1. As shown in the photograph in Figure 1, the drug was trapped within the solidified oil globules, which delayed its release into the dissolution medium. Although the majority of the white solidified oil globules were released into the dissolution medium, it took an average of 56 ± 8 minutes for the drug release to reach 80%. This suggested that the delayed release was due to drug solubility and the fill formulation, rather than shell solubility.

[0098] To eliminate the influence of fill formulation on drug solubility and solely evaluate shell solubility, 22MC-01 capsules were filled with liquid acetaminophen and the corresponding release profiles were measured. In parallel, commercially available liquid acetaminophen gelatin softgel capsules were tested, and 22MC-01 was compared with conventional gelatin-based capsules. The resulting release profiles are shown in Figure 2.

[0099] When the effect of drug solubility was isolated, the 22MC-01 release profile was consistent with that of commercially available gelatin-based capsules.

[0100] Informal stability testing continued, with corresponding data collected for 1 month (T1M) at 40°C / 75%RH.

[0101] High molecular weight PEG-based filler Previous studies have shown that all capsules leaked during drying, indicating poor compatibility between PEG and the shell material. It was observed that the shell was susceptible to PEG migration, and that moisture in the shell facilitated migration. Incorporating a higher molecular weight PEG 1000 was expected to mitigate migration, but was not sufficient to completely prevent migration upon drying. Approximately 40% of the capsules remained intact without any leakage.

[0102] Due to PEG migration, the seal integrity was compromised and the resulting softgel burst strength and migration distance of the capsules are reported in Table 5.

[0103] [Table 5]

[0104] For further testing, the intact capsules were packaged and fiber optics was used to collect the ibuprofen release profile shown in Figure 3.

[0105] Unexpectedly, initial release of the fill occurred after 22±4 minutes of exposure, once the capsule tip was opened. The shell dissolved simultaneously as the fill was released into the dissolution medium. Once the capsule crack opened, the fill was released into the dissolution medium, with 80% of the fill released in 33±4 minutes. In any case, this result was better than that of current commercially available capsules, which required 34±16 minutes for initial drug release and 44±21 minutes for 80% of the fill to be released.

[0106] [Example 2] Partial replacement of starch with stearic acid Table 6 summarizes the softgel burst strength and migration distance of capsules from lot 22MC-02 capsules. The dried 22MC-02 softgel capsules exhibited a moderate burst strength of 14 kg.

[0107] [Table 6]

[0108] Ibuprofen release profiles were collected using a fiber optic dissolution tester using USP AppII at 75 rpm and are shown in Figure 4 .

[0109] Figure 4 shows the rupture and dissolution profiles of capsules from 22MC-02 and 22MC-46 when exposed to dissolution media. It took 21 ± 6 minutes for 22MC-02 capsules and 22 ± 1 minute for 22MC-46 capsules to initially release the fill. This is faster than the current commercial product, which requires 34 ± 16 minutes for initial drug release. Despite the delay, 80% of the drug was released in 35 ± 6 minutes and 33 ± 5 minutes for 22MC-02 and 22MC-46 capsules, respectively. This is faster than the typical commercial capsule, which requires 44 ± 21 minutes to release 80% of the drug.

[0110] [Example 3] Partial replacement of starch with stearic acid Table 7 summarizes the softgel burst strength and migration distance of 21MC-96 capsules. The softgel burst strength was extremely low at 5 kg, but this low strength was attributed to improper mold and wedge placement during encapsulation.

[0111] [Table 7]

[0112] It was found that the capsules had air bubbles trapped inside, which was caused by a loose wedge and could also compromise the integrity of the seal. A new minicapsule batch (22MC-41) was produced without any air bubbles.

[0113] The ibuprofen release profile was collected using a fiber optic dissolution tester using USP Apparatus II at 75 RPM and is shown in FIG.

[0114] When exposed to the dissolution medium, 21MC-96 capsules began dissolution immediately, with the first release of the fill occurring after 11 ± 4 minutes. This value was comparable to that of gelatin-based softgel capsules, which required less than 10 minutes for the first release of drug. 80% of the fill was released in 28 ± 8 minutes, which was faster than existing non-animal softgels. Unlike starch-based capsules, which became opaque in the dissolution medium, the starch-free 21MC-96 capsules remained transparent throughout the test and formed a hydrogel.

[0115] A repeat of 22MC-96 (22MC-41) with the appropriate wedge in place exhibited delayed load release compared to 22MC-96, as shown in Figure 5, which was attributed to better sealing quality. Initial load release occurred after 16 ± 6 minutes, with 80% drug release occurring at 32 ± 5 minutes, both of which were faster than existing non-animal softgels.

[0116] Calculation results of elution F2 similarity and Mahalanobis distance An F2 similarity test was conducted to evaluate the difference in drug release profile between the softgels of the present invention and the original non-animal softgels. The amount of drug dissolved (%D) at six different time points (5, 10, 20, 30, 45, and 60 minutes) was collected and the f2 value was calculated using the following equation:

[0117]

number

[0118] Table 8 summarizes the mean %D values at each time point and the f2 values for each lot.

[0119] [Table 8]

[0120] Based on the f2 analysis, the softgels of the present invention exhibited significantly faster dissolution compared to the original non-animal softgels, with an f2 value of <50, which is an indication that the dissolution from the new softgels is dissimilar to the existing ones, consistent with faster and less variability.

[0121] The Mahalanobis distance (MD) is a measure of the distance between a sample point P and a distribution D. This distance represents how far the measurement point is from the distribution mean, specified in terms of the number of standard deviations.

[0122] Early on (5 and 10 minutes), there was no significant difference in the % release between the control and novel softgels, indicating the absence of drug in the dissolution medium. These differences emerged at 20 minutes and became more pronounced at 30 minutes, at which point the % release was a few standard deviations away from the mean control deviation, shown in orange. This difference then became less significant after 45 minutes, at which point the control samples began to burst and release drug.

[0123] MD analysis further supports the faster dissolution of the newly developed softgels compared to the original softgels.

[0124] Release profile after 1 month (T1M) storage at 40℃ / 75%RH Informal stability testing was initiated for 22MC-01, 22MC-02, 21MC-96, 22MC-41, and 22MC-46 capsules at 40°C / 75% RH. Data was collected at 1 month. No leaks were detected and dissolution profiles remained unchanged after 1M accelerated stability testing for all three lots that completed 1M stability testing.

[0125] The data support the use of non-gelatin biobased polymers (stearic acid, maltodextrin, and pullulan) and / or synthetic polymers (Kolliphor P407) for fast-dissolving non-gelatin oral softgels. Compared to current softgel capsules, all newly developed softgel capsules demonstrated superior performance, producing a faster initial drug release within a 20-minute exposure period. For the oil-filled and encapsulated capsules (22MC-01), it took 55 minutes for the drug to reach 80% release, but this slow release was attributed to poor drug solubility and the fill formulation rather than shell dissolution. This conclusion was further substantiated through the dissolution of predissolved drug solutions (using acetaminophen as a model drug) loaded into fabricated air-filled capsules (shell formulation of lot 22MC-01). The encapsulation of higher molecular weight PEG (22MC-40) required a longer initial release time (22 minutes), but 80% of the load was released after 33 minutes. The ibuprofen-loaded capsules (22MC-01 and 21MC-96) demonstrated superior dissolution performance compared to the current softgel capsules. As evidenced by the smaller error bars, the newly developed capsules demonstrated more consistent drug release performance compared to the current softgel capsules.

[0126] Based on this development work, the shell formulations used in lot 21MC-96 / 22MC-41 will be considered for further process development and scale-up because they meet the dissolution criteria required for immediate-release pharmaceutical dosage forms, with at least 80% drug released within 30 minutes. Even if stearic acid capsules demonstrated comparable dissolution, the capsules would be cloudy due to the stearic acid, and thus clear liquid-fill capsules would not be considered. However, they would be scaled up if needed for VMS and, if necessary, cosmetic products in addition to Rx Pharma products.

[0127] Informal stability studies were also conducted for 12 months to determine their physical properties and dissolution performance after T12 months. Informal stability studies were initiated for 21MC-96, 22MC-01, 22MC-02, 22MC-41, and 22MC-46 capsules under storage conditions of 40°C / 75% RH and 30°C / 65% RH. Data were collected during these studies after T3M, T6M, and T12M. Figures 6A-6C show the stability results for lot 22MC-01. Figures 7A-7F show a comparison of the stability results for lots 22MC-02 and 22MC-46. Figures 8A-8F show a comparison of the stability results for lots 22MC-96 and 22MC-41. None of the softgel capsules in this study were detected to have leaked, and their physical properties and dissolution performance were not significantly affected after storage at accelerated conditions. In addition, the results of this study were all within the error bar range and met the criteria for application in immediate release pharmaceutical dosage forms.

[0128] To better understand several embodiments of the present invention, the foregoing description sets forth numerous specific details, such as examples of specific systems, components, methods, and the like. However, it will be apparent to one of ordinary skill in the art that at least some embodiments of the present invention can be practiced without these specific details. In other instances, well-known components and methods have not been described in detail to avoid unnecessarily obscuring the present invention. For this reason, the specific details that are set forth are exemplary. Particular embodiments may vary from these exemplary details and still be within the scope of the present invention.

[0129] Although the operations of the methods are described herein 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 certain operations may be performed, at least in part, concurrently with other operations. In alternative embodiments, instructions of separate operations or sub-operations may be intermittent and / or interleaved.

[0130] It should be understood that the above description is illustrative, and not intended to be 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.

Claims

1. A soft gel capsule film containing a non-gelatin bio-based polymer, which dissolves in less than 20 minutes by dissolution test using a USP apparatus paddle II at 75 rpm.

2. The soft gel capsule film according to claim 1, wherein the non-gelatin bio-based polymer comprises stearic acid, maltodextrin, pullulan, or a combination thereof.

3. The soft gel capsule film according to claim 1, further comprising a synthetic polymer.

4. The soft gel capsule according to claim 3, wherein the synthetic polymer is polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, high molecular weight polyethylene glycol, povidone, surfactant, nonionic triblock copolymer, or a combination thereof.

5. The soft gel capsule according to claim 4, wherein the synthetic polymer is a nonionic triblock copolymer.

6. The soft gel capsule according to claim 5, wherein the nonionic triblock copolymer comprises polyethylene oxide block and polypropylene oxide block.

7. The soft gel capsule film according to claim 4, wherein the surfactant is sodium lauryl sulfate.

8. The soft gel capsule film according to claim 1, further comprising a non-animal derived gelling agent.

9. The soft gel capsule film according to claim 8, wherein the non-animal-derived gelling agent comprises carrageenan, starch, pregelatinized starch, xanthan gum, agar, pectin, sugar, sugar-derived alcohol, cellulose derivative, cellulosic polymer, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, silicon dioxide, curdlan, fercereran, egg white powder, lactalbumin, soy protein, chitosan, or a combination thereof.

10. The soft gel capsule film according to claim 1, further comprising a plasticizer.

11. The soft gel capsule film according to claim 1, further comprising a buffering agent.

12. The soft gel capsule film according to claim 1, wherein the film dissolves in less than 15 minutes, less than 10 minutes, or less than 5 minutes.

13. The soft gel capsule film according to claim 1, wherein the non-animal-derived gelling agent comprises carrageenan, starch, or a combination thereof.

14. The soft gel capsule film according to claim 1, wherein the ratio of carrageenan to starch is approximately 1:1 to approximately 1:10, approximately 1:1 to approximately 1:8, approximately 1:1 to approximately 1:5, or approximately 1:2.5 to approximately 1:4.

5.

15. The soft gel capsule film according to claim 13, wherein the carrageenan comprises iotacarrageenan, kappacarrageenan, lambdacarrageenan, or a combination thereof.

16. The soft gel capsule film according to claim 13, wherein the starch comprises modified starch, potato starch, corn starch, tapioca starch, hydroxypropylated starch, hydroxyalkylated starch, acid-treated starch, dextrin, and combinations thereof.

17. The soft gel capsule film according to claim 8, wherein the non-animal gelling agent does not contain starch.

18. The soft gel capsule film according to claim 8, wherein the non-animal gelling agent is present in an amount of about 15% to about 60% (w / w) of the film.

19. The soft gel capsule film according to claim 13, wherein the amount of carrageenan is about 5 to about 20% (w / w).

20. The soft gel capsule film according to claim 13, wherein the amount of starch is about 0 to about 45% (w / w).

21. A soft gel capsule film according to claim 1, comprising less than 10%, less than 5%, or less than 1% of an animal-derived gelling agent.

22. The soft gel capsule film according to claim 1, wherein the film does not contain an animal-derived gelling agent.

23. The soft gel capsule film according to claim 10, wherein the plasticizer comprises glycerol, glycerin, sorbitol, sorbitol-sorbitan solution, triacetin, polysorbate, or a combination thereof.

24. The soft gel capsule film according to claim 23, wherein the polysorbate comprises Tween 20, Tween 80, or a combination thereof.

25. The soft gel capsule film according to claim 10, wherein the amount of the plasticizer is about 15 to about 40% (w / w) of the film.

26. The soft gel capsule film according to claim 11, wherein the amount of the buffering agent is about 0.1 to about 5% (w / w) of the film.

27. The soft gel capsule film according to claim 11, wherein the buffer is selected from disodium phosphate, monosodium phosphate, sodium bicarbonate, sodium citrate, disodium phosphate, calcium phosphate, dicalcium phosphate, tricalcium phosphate, monopotassium phosphate, dicalococcus phosphate, and combinations thereof.

28. The soft gel capsule film according to claim 1, wherein the polymer is present in an amount of about 1 to about 25% (w / w), about 3 to about 22% (w / w), about 5 to about 20% (w / w), about 7.5 to about 17.5% (w / w), or about 10 to about 15% (w / w) of the film.

29. The soft gel capsule film according to claim 2, wherein the polymer is pullulan.

30. The soft gel capsule film according to claim 29, wherein the amount of pullulan is about 1 to about 20% (w / w), about 2 to about 18% (w / w), about 4 to about 16% (w / w), about 5 to about 15% (w / w), or about 7.5 to about 12.5% ​​(w / w) of the film.

31. The soft gel capsule film according to claim 2, wherein the polymer is stearic acid.

32. The soft gel capsule film according to claim 31, wherein the amount of stearic acid is about 0.5 to about 5% (w / w), about 1 to about 4% (w / w), or about 2 to about 3% (w / w) of the film.

33. The soft gel capsule film according to claim 2, wherein the polymer is pullulan and stearic acid.

34. The soft gel capsule film according to claim 33, wherein the polymer is present in an amount of about 1.5 to about 25% (w / w), about 2 to about 20% (w / w), about 3 to about 18% (w / w), about 5 to about 15% (w / w), or about 7.5 to about 12.5% ​​(w / w) of the film.

35. The soft gel capsule according to claim 3, wherein the synthetic polymer is present in an amount of about 4 to about 8% (w / w) or about 5% (w / w) of the film.

36. An immediate-release softgel capsule comprising a filler material encapsulated by a film composition, wherein the film composition comprises a non-gelatin bio-based polymer, and the film dissolves in less than 20 minutes by dissolution test using a USP apparatus paddle II at 75 rpm.

37. The immediate-release softgel capsule according to claim 36, wherein the filling material contains an active agent.

38. An immediate-release softgel capsule comprising a filler material encapsulated by a film composition, wherein the film composition comprises a non-gelatin bio-based polymer, and at least 80% of the filler material is released within 30 minutes.

39. The immediate-release softgel capsule according to claim 38, wherein the filling material contains an active agent.

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