Fast dissolving soft gel capsule

Abstract

Disclosed in certain embodiments is a soft gel capsule film comprising a non-gelatin bio-based polymer that completely dissolves within less than 30 minutes when dissolved out using a USP device II at a blade of 75 RPM in 900 ml 0.1 N HCL and deionized water at 37 DEG C.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 397,554, filed on August 12, 2022, the entire contents of which are incorporated herein in their entirety. Field of the Invention

[0003] The invention relates to a soft gel capsule, comprising a soft gel capsule film, wherein the soft gel capsule film comprises a non-gelatin bio-based polymer, and the soft gel capsule further comprises a filling material containing an active agent. Background Art

[0004] Soft gel capsules are widely used in the pharmaceutical and nutraceutical industries. Gelatin is the most commonly used ingredient in soft gel capsule shells due to its advantages such as high water solubility, flexibility, and mechanical strength. Today, gelatin is in high demand, which has led to insufficient supply to meet the growing demand. To reduce the dependence on gelatin, plant-based soft gel capsules have been developed using carrageenan (seaweed extract) in combination with starch.

[0005] In order for a compound to function as a shell material in a soft gel capsule application, it must meet two important criteria: (1) the shell must be strong enough to contain the fill and shape, and be physically stable; and (2) the shell needs to be soluble in aqueous media (physiological media) to release the active pharmaceutical ingredient when taken. For an immediate release drug dosage form, at least 80% of the contents are expected to be released within 30 minutes.

[0006] It has been found that immediate release of such drugs is difficult to achieve using starch and carrageenan due to their poor water solubility. One disadvantage of this approach is the poor water solubility of starch, which limits its use in immediate release dosage forms.

[0007] Therefore, there is a need for improved non-gelatin soft gel capsule formulations that have higher water solubility to meet or exceed the dissolution requirements of immediate release dosage forms and are suitable for high-speed manufacturing, which can serve as a reliable and commercially viable alternative to gelatin-based soft gel capsules. SUMMARY OF THE INVENTION

[0009] According to various embodiments, disclosed herein are soft gel capsule films comprising non-gelatin bio-based polymers. In certain embodiments, the film completely dissolves within 20 minutes when dissolved using USP Apparatus II with a paddle at 75 RPM in 900 ml of 0.1N HCL and deionized water at 37 degrees Celsius.

[0010] According to further embodiments, disclosed herein is a soft gel capsule comprising a fill material comprising an active agent encapsulated by a film comprising a non-gelatin bio-based polymer, and methods of making and processing the same. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 1 is a representative release curve of acetaminophen in a dissolution medium containing 2% SDS according to Example 1 and corresponding photos of each stage;

[0012] Figure 2 is a representative liquid acetaminophen release profile of 22MC-01 and gelatin capsule according to Example 1;

[0013] Figure 3 is a representative ibuprofen release profile of 22MC-40 capsules according to Example 1;

[0014] Figure 4 is a representative ibuprofen release profile of 22MC-02, 22MC-46 and gelatin capsules according to Example 2;

[0015] Figure 5 is a representative ibuprofen release profile of 21MC-96, 22MC-41 and gelatin capsules according to Example 3;

[0016] Figures 6A-6C A summary data set of the physical properties and dissolution performance of 22MC-01 after the T12M stability study;

[0017] Figures 7A-7F This is a summary data set of the physical properties and dissolution performance of 22MC-02 and 22MC-46 after the T12M stability study;

[0018] Figures 8A-8F Summary data set of physical properties and dissolution performance of 21MC-96 and 22MC-41 after T6M and T12M stability studies. DETAILED DESCRIPTION OF THE INVENTION

[0020] Various embodiments of soft gel capsule films and formulations and methods of preparation and use thereof are described herein. It should be understood that the present invention is not limited to the construction details or process steps set forth in the following description. The present invention may have other embodiments and may be practiced or executed in a variety of ways.

[0021] References in this specification to "one embodiment," "certain embodiments," "one or more embodiments," or "an embodiment" mean that the particular features, structures, materials, or characteristics described in connection with that embodiment are included in at least one embodiment of the present invention. Thus, phrases such as "in one or more embodiments," "in certain embodiments," "in one embodiment," or "in an embodiment" appearing throughout this specification do not necessarily refer to the same embodiment of the present invention. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0022] As used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a softgel capsule" includes a single softgel capsule as well as two or more softgel capsules.

[0023] As used herein, "free or substantially free" means that the composition contains less than about 1% by weight, less than about 0.5% by weight, less than about 0.25% by weight, less than about 0.1% by weight, less than about 0.05% by weight, less than about 0.01% by weight, or 0% by weight of the component.

[0024] As used herein, "about" refers to any value within a range of ± 10%, for example, "about 10" includes 9 to 11. As used herein, "a", "an" or "the" refers to one or more, unless otherwise indicated. Thus, for example, reference to "an excipient" includes a single excipient as well as a mixture of two or more different excipients, etc.

[0025] Recitation of ranges of values ​​herein are merely intended to serve as a shorthand method of referring individually to each separate value within the range unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0026] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to clarify certain materials and methods and is not intended to limit the scope. No language in the specification should be construed as indicating any non-claimed element is essential to the practice of the disclosed materials and methods.

[0027] As used herein, the terms "film," "film composition," "shell," or "shell composition" refer to the shell of a soft gel capsule encapsulating a fill material.

[0028] Although the disclosure herein is with reference to specific embodiments, it should be understood that these embodiments are only used to illustrate the principles and applications of the present invention. It will be appreciated by those skilled in the art that various modifications and variations may be made to the compositions and methods without departing from the spirit and scope of the present invention. Therefore, the present invention is intended to include modifications and variations within the scope of the appended claims and their equivalents.

[0029] Disclosed herein are soft gel capsule films comprising non-gelatin bio-based polymers. In certain embodiments, the film can be completely dissolved in 30 minutes using a USP apparatus II with a paddle at 75 RPM in 900 ml 0.1N HCL and deionized water at 37 degrees Celsius. The soft gel capsule film can be dissolved in less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes.

[0030] In certain embodiments of the soft gel capsule film, the non-gelatin bio-based polymer includes stearic acid, maltodextrin, pullulan, or a combination thereof.

[0031] In certain embodiments of the soft gel capsule film, the amount of the non-gelatin bio-based polymer may be from about 1% to about 25% (w / w), from about 3% to about 22% (w / w), from about 5% to about 20% (w / w), from about 7.5% to about 17.5% (w / w), or from about 10% to about 15% (w / w), based on the total weight of the film, or any range, sub-range or value therein.

[0032] 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.

[0033] In certain embodiments of the film, the amount of pullulan in the film may be from about 1% to about 20%, from about 2% to about 18%, from about 4% to about 16%, from about 5% to about 15%, or from about 7.5% to about 12.5% ​​(w / w) of the film, or any range, sub-range or value therein.

[0034] In some embodiments of the film, the amount of stearic acid in the film may be from about 0.5% to about 5%, from about 1% to about 4%, or from about 2% to about 3% (w / w) of the film, or any range, sub-range or value therein.

[0035] In certain embodiments of the film, the non-gelatin bio-based polymer can 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, sub-range or value therein.

[0036] In certain embodiments, the film may also include a synthetic polymer. The synthetic polymer may include polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, high molecular weight polyethylene glycol, polyvidone, 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 include polyethylene oxide and polypropylene oxide blocks. In some embodiments, the surfactant may include sodium lauryl sulfate. In some embodiments of the film, the amount of the synthetic polymer in the film may be about 4% to about 8% of the film, or about 5% (w / w).

[0037] In certain embodiments, the film may further comprise a non-animal source gelling agent. The non-animal source gelling agent may include carrageenan, starch, pregelatinized starch, xanthan gum, agar, pectin, sugar, sugar-derived alcohol, cellulose derivatives, cellulose polymers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, silicon dioxide, curdlan, furcellan, protein powder, lactalbumin, soy protein, chitosan, or a combination thereof.

[0038] In certain embodiments, the non-animal source gelling agent may include carrageenan, starch, or a combination thereof. In some embodiments, the carrageenan may be iota carrageenan, kappa carrageenan, lambda carrageenan, or a combination thereof.

[0039] In some embodiments, the starch may include modified starch, potato starch, corn starch, tapioca starch, hydroxypropylated starch, hydroxyalkylated starch, acid-treated starch, dextrin, or a combination thereof.

[0040] 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.

[0041] In certain embodiments, the non-animal gelling agent does not include starch.

[0042] In certain embodiments, the amount of non-animal gelling agent may be about 15% to about 60% (w / w) of the film. In some embodiments, the amount of non-animal gelling agent may be 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 include 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 include 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.

[0043] In other embodiments, the film may contain less than 10%, less than 5%, or less than 1% (w / w) of animal-derived gelling agent.In certain embodiments, the soft gel capsule film does not contain an animal-derived gelling agent.

[0044] In certain embodiments, the soft gel capsule film may further comprise a plasticizer. In other embodiments, the soft gel capsule film may further comprise a buffer.

[0045] In some embodiments, plasticizer can be glycerol (glycerol), glycerin (glycerin), sorbitol, sorbitol sorbitan solution (sorbitol sorbitan solution), triacetin, polysorbate or its combination.In some embodiments, this polysorbate can include polysorbate 20 (also referred to as Tween 20), polysorbate 80 (also referred to as Tween 80) or its combination.In certain embodiments of film, the amount of plasticizer can be about 15% to about 40%, about 20% to about 35% or about 25% to about 30% (w / w) of film.

[0046] In some embodiments, the buffer may be disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, sodium citrate, disodium hydrogen phosphate, calcium phosphate, calcium hydrogen phosphate, tricalcium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, or a combination thereof. In some embodiments of the film, the amount of the buffer may be about 0.1% to about 5% (w / w) of the film. In other embodiments, the amount of the buffer may be 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 herein.

[0047] In certain embodiments, the film includes an amount of gelatin, such as 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.

[0048] Also disclosed in certain embodiments are soft gel capsule formulations comprising a fill material comprising an active agent, wherein the fill material is encapsulated by the film composition disclosed herein.

[0049] In certain embodiments, the soft gel capsule comprises a film composition comprising a non-gelatin bio-based polymer. The non-gelatin bio-based polymer may include maltodextrin, pullulan, carrageenan, or a combination thereof.

[0050] In certain embodiments of soft gel capsules, the film composition may also include a synthetic polymer. The synthetic polymer may be polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, high molecular weight polyethylene glycol, polyvidone, 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 include polyethylene oxide and polypropylene oxide blocks. In some embodiments, the surfactant may be sodium lauryl sulfate.

[0051] In certain embodiments of the soft gel capsule, the film composition may further include a non-animal source gelling agent. The non-animal source gelling agent may include carrageenan, starch, xanthan gum, agar, pectin, sugar, sugar-derived alcohol, cellulose derivatives, cellulose polymers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, silicon dioxide, curdlan, furcellan, protein powder, lactalbumin, soy protein, chitosan or a combination thereof.

[0052] In certain embodiments of soft gel capsules, the film may also include a plasticizer. The plasticizer may be glycerol, glycerol, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate or a combination thereof. In some embodiments, the polysorbate includes Tween 20, Tween 80 or a combination thereof. In some embodiments, the amount of the plasticizer may be about 15% to about 40% (w / w) of the film. In some embodiments, the plasticizer may be sorbitol sorbitan solution.

[0053] In certain embodiments of the soft gel capsule, the film may further comprise a buffer. The buffer may be disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, sodium citrate, disodium hydrogen phosphate, calcium phosphate, calcium hydrogen phosphate, tricalcium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof.

[0054] In certain embodiments of the soft gel capsules, the film is free of animal-derived gelling agents.

[0055] Also disclosed herein is an immediate release soft gel capsule comprising a fill material encapsulated by a film composition, wherein the film composition comprises a non-gelatin bio-based polymer, wherein the film dissolves in less than about 20 minutes according to a dissolution test performed using a USP apparatus paddle II at 75 rpm. In certain embodiments, the fill material may include an active agent.

[0056] In certain embodiments, the immediate release soft gel capsule comprises a fill material encapsulated by a film composition, wherein at least 80% of the fill material is released within 30 minutes.

[0057] The film compositions disclosed herein may further comprise at least one of a buffer, a plasticizer, and water. The soft shell capsule formulations described herein may be vegetarian and free of animal-derived materials, such as gelatin. Immediate release soft gel capsules may comprise the film compositions described above in the present disclosure.

[0058] 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 dissolution is performed using USP Apparatus II with a paddle at 75 RPM in 900 ml of 0.1 NHCl and deionized water at 37 degrees Celsius.

[0059] In certain embodiments, the soft gel capsule formulation contains water. The water may be present in an amount of about 30% to about 60% by weight of the film, or about 35% to about 55% by weight, or about 40% to about 50% by weight, or about 42% by weight, or about 43% by weight, or about 44% by weight, or about 45% by weight, or about 45.5% by weight, or about 46% by weight, or about 47% by weight, or about 48% by weight.

[0060] In one embodiment, the shell composition / film of the soft gel capsule may optionally contain additives such as colorants, flavoring agents, sweeteners, fillers, antioxidants, diluents, pH adjusters or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides.

[0061] Exemplary suitable colorants may include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown. In a specific embodiment, the color of the dosage form may indicate the contents (e.g., one or more active ingredients) contained therein.

[0062] Exemplary suitable flavoring agents may include, but are not limited to, "spice extracts" obtained by extracting a portion of a raw material (e.g., animal or plant material), typically using a solvent such as ethanol or water; natural flavors obtained by extracting essential oils from flowers, fruits, roots, etc. or from whole plants.

[0063] Other exemplary flavoring agents that may be included in the dosage form include, but are not limited to, breath freshening compounds such as menthol, spearmint and cinnamon, coffee beans, other flavoring agents or spices, such as fruit flavoring agents (e.g., cherry, orange, grape, etc.), especially flavoring agents or spices for oral hygiene, and active substances for tooth and oral cleaning, such as quaternary ammonium bases. Flavor enhancers (e.g., tartaric acid, citric acid, vanillin, etc.) can be used to enhance the taste effect.

[0064] Exemplary sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Artificial sweeteners include, for example, acesulfame and various salts thereof, such as potassium salts (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), salts of aspartame-acesulfame (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and various salts thereof, such as sodium salts (available as Sweet'N Low®), stevioside, chlorinated derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizic acid; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); Stevia rebaudiana (Stevioside), natural intense sweeteners such as Lo Han Kuo, polyols such as sorbitol, mannitol, xylitol, erythritol, and the like.

[0065] The soft shell capsule formulation disclosed herein may also include a filling composition. The filling composition may contain at least one of rapeseed oil, medium chain triglyceride oil, polyethylene glycol, and a combination thereof. Lipophilic and / or hydrophilic and / or alcoholic filling compositions may also be encapsulated with the soft shell capsule formulation described herein.

[0066] Any pharmaceutically active ingredient may be used for the purposes of the present disclosure, including water-soluble and poorly water-soluble ingredients. Suitable pharmaceutical active ingredients include, but are not limited to, analgesics and anti-inflammatories, antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigouts, antihypertensives, antimalarials, antimigraines, antimuscarinics, antineoplastics and immunosuppressants, antiprotozoals, antirheumatic drugs, antithyroid drugs, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics, beta blockers, inotropes, corticosteroids, cough suppressants, cytotoxins, decongestants, diuretics, enzymes, antiparkinsonian drugs, gastrointestinal drugs, histamine receptor antagonists, lipid regulators, local anesthetics, neuromuscular drugs, 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 therapeutic methods utilizing any of the active ingredients disclosed herein to treat a disease or condition treatable by the active ingredient.

[0067] In some embodiments, the active pharmaceutical ingredient can be selected from, but is not limited to, dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurine, asimadoline, beclomethasone, apremilast, sapacitabine, linsitinib, abiraterone, vitamin D analogs (e.g., calcifediol, calcitriol, paricalcitol, doxorcalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, pharmaceutically acceptable salts thereof, and combinations thereof.

[0068] In some embodiments, the lipid in the dosage form can be selected from, but is not limited to, almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower seed oil, hydrogenated vegetable oil, walnut oil, and watermelon seed oil. Other oils and fats may include, but are not limited to, fish oil (ω-3), krill oil, animal or vegetable fats (e.g., hydrogenated forms thereof), free fatty acids, and mono-, di-, and triglycerides with C8-, C10-, C12-, C14-, C16-, C18-, C20-, and C22-fatty acids, and combinations thereof.

[0069] 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 and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, mixtures of any of the foregoing, and the like.

[0070] Suitable nutritional actives may include, but are not limited to, 5-hydroxytryptophan, acetyl-L-carnitine, alpha-lipoic acid, alpha-ketoglutaric acid, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), dimethylaminoethanol, fumaric acid, germanium sequioxide, glandular products, glucosamine hydrochloride, glucosamine sulfate, hydroxymethylbutyrate, immunoglobulins, lactic acid, L-carnitine, liver products, malic acid, anhydrous maltose, mannose (d-mannose), methylsulfonylmethane, plant sterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0071] Suitable nutritional supplement actives may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, or combinations thereof.

[0072] Suitable vitamin actives 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.

[0073] Suitable herbal supplement actives may include, but are not limited to, the following: arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginkgo, ginseng, goldenrod, hawthorn, kava, licorice, milk thistle, plantain, rauwolfia, senna, soy, St. John's wort, saw palmetto, turmeric, valerian.

[0074] Mineral actives 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, pyruvic acid, zinc, and other minerals.

[0075] Examples of other possible active agents include, but are not limited to, antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), nonsteroidal anti-inflammatory drugs (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, fluprofen, buclofen, indomethacin, sulindac, zomepirac, tiopine, zidometacin, acemetacin, fentiazine, clodanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenamic acid, piroxicam, sudoxicam, isoxicam, aceclofenac, aloprin, azapropazone, benolate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxybutazone, parecoxib, phenylbutazone, salicyl salicylate), sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, pharmaceutically acceptable salts thereof and mixtures thereof, acetaminophen, antiemetics (e.g. metoclopramide, methylnaltrexone), antiepileptics (e.g. phenyloin, meprobmate and nitrazepam), vasodilators (e.g. nifedipine, papaverine, diltiazem and nicardipine), antitussives and expectorants (e.g. codeine phosphate), antiasthmatics (e.g. theophylline), antacids, antispasmodics (e.g. atropine, scopolamine), Antidiabetic agents (e.g., insulin), diuretics (e.g., ethacrynic acid, bendroflumethiazide), antihypotensives (e.g., propranolol, clonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., salbutamol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidal agents, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine) and cannabinoids, and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof.

[0076] Active agent can also be benzodiazepines, barbiturates, stimulants or their mixture.Term "benzodiazepines" refers to benzodiazepines and derivative drugs of benzodiazepines that can inhibit the central nervous system.Benzodiazepines include but are not limited to alprazolam, bromazepam, clodiazepine, chlordiazepoxide, diazepam, estazolam, flurazepam, halazepam, ketazola, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs and mixtures.The benzodiazepine antagonists that can be used as active agent include but are not limited to flumazenil and its pharmaceutically acceptable salts, hydrates, solvates and mixtures.

[0077] The term "barbiturates" refers to sedative hypnotic drugs derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists that can be used as active agents include, but are not limited to, amphetamine and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0078] The term "stimulant" includes, but is not limited to, amphetamines such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof. Stimulant antagonists that can be used as active agents include, but are not limited to, benzodiazepines and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0079] The dosage form disclosed in the present invention includes various active agents and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include, but are not limited to: inorganic acid salts, such as hydrochlorides, hydrobromides, sulfates, phosphates, etc.; organic acid salts, such as formates, acetates, trifluoroacetates, maleates, tartrates, etc.; sulfonates, such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.; amino acid salts, such as arginine salts, aspartates, glutamates, etc.; and metal salts, such as sodium salts, potassium salts, cesium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; organic amine salts, such as triethylamine salts, pyridine salts, methylpyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.

[0080] Suitable filling materials contain at least one active ingredient and can be prepared according to known methods. In addition to at least one active ingredient, suitable filling materials may also contain other filling components, such as flavoring agents, sweeteners, colorants and fillers or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides. One of ordinary skill in the art can easily determine the appropriate amount of the pharmaceutically active ingredient and the pharmaceutically acceptable excipient.

[0081] The disintegration test disclosed herein is conducted at about 37°C ± 2°C with a fluid volume of 1000 mL. Disintegration test fluid 1 (also referred to herein as "artificial gastric fluid") is a 2 g / L sodium chloride-hydrochloric acid solution with a pH of 1.2. Disintegration test fluid 2 (also referred to herein as "artificial intestinal fluid") is a 0.2 mol / L potassium dihydrogen phosphate-0.2 mol / L sodium hydroxide solution with a pH of 6.8.

[0082] The disintegration test was performed using the first fluid for about 120 minutes by placing a unit in each of the six tubes of the basket, immersing the basket (and the unit) in the first test fluid, then lifting the basket from the fluid and observing whether the unit disintegrates. Disintegration is defined as a state where the unit breaks or the enteric shell composition breaks or breaks. If none of the six units disintegrate, the test is passed. A similar test was performed using the second disintegration test fluid for a selected time.

[0083] In some embodiments, the disintegration test may be performed for about 150 minutes, about 120 minutes, about 105 minutes, about 90 minutes, about 75 minutes, about 60 minutes, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, or about 5 minutes.

[0084] In some embodiments, the soft gel 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 40°C / 75% RH at 1 month, 3 months, 6 months, or 12 months.

[0085] In some embodiments, the soft gel 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 30°C / 65% RH at 1 month, 3 months, 6 months, or 12 months.

[0086] In some embodiments, for example, in 900mL phosphate buffer (50mM, pH7.2), for example, at 37°C, using USP APP II with a paddle of 75RPM for dissolution testing, or in 900ml 0.1N HCL and deionized water, for example, at 37°C, using USP apparatus II with a paddle of 75RPM for dissolution testing, the soft gel capsule can 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 certain embodiments, under the accelerated stability conditions of 25°C / 60%RH, 30°C / 65%RH or 40°C / 75%RH, the soft gel capsule can also obtain the above results at 1 month, 3 months, 6 months, 12 months, 18 months, 22 months, or 24 months. In certain embodiments, following any accelerated storage condition disclosed herein, at 1 hour, 4 hours, or 8 hours, the dissolution rate does not change by more than 20%, by more than 10%, or by more than 5% from time 0.

[0087] In some embodiments of the soft gel capsule, the soft gel capsule may have a water activity (Aw) of 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 at 40°C / 75%RH at 1 month, 3 months, 6 months, or 12 months.

[0088] In some embodiments of the soft gel capsule, the soft gel capsule may have a water activity (Aw) of 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 at 30°C / 65%RH at 1 month, 3 months, 6 months, or 12 months.

[0089] Methods of preparing dosage forms

[0090] Disclosed herein is a method for preparing the soft gel capsule film and capsule formulation disclosed herein. The method comprises mixing a non-gelatin bio-based polymer and optionally at least one synthetic polymer, a non-animal-derived gelling agent, a buffer, a plasticizer, and water to form a combination.

[0091] The method may further include transferring the combination to an encapsulation device. In certain embodiments, the method may include encapsulating a filler material in a soft gel capsule formed by the combination to form a plurality of soft gel capsule dosage forms. The method may further include drying a plurality of soft gel capsule dosage forms in a drum dryer. Certain embodiments also include encapsulating a plurality of soft gel capsule dosage forms.

[0092] In certain embodiments, the present invention relates to one or more of the following lists:

[0093] 1. A soft gel capsule film comprising:

[0094] A non-gelatin bio-based polymer wherein the film dissolves in less than 20 minutes according to a dissolution test performed using a USP apparatus paddle II at 75 rpm.

[0095] 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.

[0096] 3. The soft gel capsule film according to item 1 or 2, further comprising a synthetic polymer.

[0097] 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, a surfactant, a nonionic triblock copolymer or a combination thereof.

[0098] 5. The soft gel capsule according to item 3 or 4, wherein the synthetic polymer is a nonionic triblock copolymer.

[0099] 6. A soft gel capsule according to any one of items 3-5, wherein the nonionic triblock copolymer comprises polyethylene oxide and polypropylene oxide blocks.

[0100] 7. The soft gel capsule film according to item 3 or 4, wherein the surfactant is sodium lauryl sulfate.

[0101] 8. The soft gel capsule film according to any one of the preceding items, further comprising a non-animal-derived gelling agent.

[0102] 9. A soft gel capsule film according to claim 8, wherein the non-animal source gelling agent comprises carrageenan, starch, pregelatinized starch, xanthan gum, agar, pectin, sugar, sugar-derived alcohol, cellulose derivatives, cellulose polymers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, silicon dioxide, curdlan, furcellaran, protein powder, lactalbumin, soy protein, chitosan or a combination thereof.

[0103] 10. The soft gel capsule film according to any one of the preceding items, further comprising a plasticizer.

[0104] 11. The soft gel capsule film according to any one of the preceding items, further comprising a buffer.

[0105] 12. The soft gel capsule film according to any of the preceding items, wherein the film dissolves in less than 15 minutes, less than 10 minutes or less than 5 minutes.

[0106] 13. The soft gel capsule film according to any one of the preceding items, wherein the non-animal source gelling agent comprises carrageenan, starch or a combination thereof.

[0107] 14. The soft gel capsule film according to any of the preceding items, wherein the ratio of carrageenan to starch 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.

[0108] 15. The soft gel capsule film according to item 13, wherein the carrageenan comprises iota carrageenan, kappa carrageenan, lambda carrageenan or a combination thereof.

[0109] 16. The soft gel 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.

[0110] 17. The soft gel capsule film according to claim 8, wherein the non-animal gelling agent does not include starch.

[0111] 18. The soft gel capsule film according to item 8, wherein the amount of the non-animal gelling agent is from about 15% to about 60% (w / w) of the film.

[0112] 19. The soft gel capsule film according to item 13, wherein the amount of carrageenan is about 5% to about 20% (w / w).

[0113] 20. The soft gel capsule film according to item 13, wherein the amount of starch is about 0 to about 45% (w / w).

[0114] 21. The soft gel capsule film according to any of the preceding items, comprising less than 10%, less than 5% or less than 1% of animal-derived gelling agent.

[0115] 22. The soft gel capsule film according to any of the preceding items, wherein the film does not contain gelling agents of animal origin.

[0116] 23. The soft gel capsule film according to item 10, wherein the plasticizer comprises glycerol, glycerol, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate or a combination thereof.

[0117] 24. The soft gel capsule film according to item 23, wherein the polysorbate comprises Tween 20, Tween 80 or a combination thereof.

[0118] 25. The soft gel capsule film according to item 10, wherein the amount of the plasticizer is from about 15% to about 40% (w / w) of the film.

[0119] 26. The soft gel capsule film according to item 11, wherein the amount of the buffer is about 0.1 to about 5% (w / w) of the film.

[0120] 27. The soft gel capsule film according to claim 11, wherein the buffer is selected from disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, sodium citrate, disodium hydrogen phosphate, calcium phosphate, calcium hydrogen phosphate, tricalcium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof.

[0121] 28. A soft gel capsule film according to any of the preceding items, wherein the amount of the polymer is 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.

[0122] 29. The soft gel capsule film according to item 2, wherein the polymer is pullulan.

[0123] 30. A 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.

[0124] 31. The soft gel capsule film according to item 2, wherein the polymer is stearic acid.

[0125] 32. The soft gel capsule film of 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.

[0126] 33. The soft gel capsule film according to item 2, wherein the polymer is pullulan and stearic acid.

[0127] 34. A soft gel capsule film according to claim 33, wherein the amount of the polymer is 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.

[0128] 35. A soft gel capsule according to claim 3, wherein the amount of the synthetic polymer is about 4% to about 8% (w / w), or about 5% (w / w) of the film.

[0129] 36. An immediate release soft gel capsule comprising a fill material encapsulated by a film composition, wherein the film composition comprises a non-gelatin bio-based polymer, wherein the film dissolves in less than 20 minutes according to a dissolution test performed using a USP apparatus paddle II at 75 rpm.

[0130] 37. An immediate release soft gel capsule according to item 36, wherein the fill material comprises an active agent.

[0131] 38. An immediate release soft gel capsule comprising a fill material encapsulated by a film composition, wherein the film composition comprises a non-gelatin bio-based polymer, wherein at least 80% of the fill material is released within 30 minutes.

[0132] 39. An immediate release soft gel capsule according to item 38, wherein the fill material comprises an active agent. Example

[0133] Example 1 - Partial replacement of starch with Kolliphor P407 (Poloxamer)

[0134] The starch was partially replaced by Kolliphor P407, a nonionic triblock copolymer consisting of hydrophilic (polyethylene oxide, PEO) and hydrophobic (polypropylene oxide, PPO) blocks. Kolliphor P407 was chosen because of its excellent water solubility and thermoreversible gelling behavior. Soft gel capsules were prepared using the gel masses shown in Table 1.

[0135] Table 1. Gel formulations containing Kolliphor P407

[0136]

[0137] Oil-based fillers and high molecular weight PEG-based fillers are used for encapsulation. Acetaminophen (325 mg per soft gel capsule) was suspended in soybean oil and the suspension was used to encapsulate 900 mg soft gel capsules (OET-10291399 batch #22MC-01). Ibuprofen (200 mg per soft gel capsule) was dissolved in a mixture of PEG1000 and PEG600 (ratio 9:1) and the mixture was used to encapsulate 360 ​​mg soft gel capsules (OET-10291399 batch #22MC-40).

[0138] The soft gel capsules were dried, washed, and placed in plastic bags before testing.

[0139] Bursting strength measurements and dissolution testing (using a fiber optic probe) were performed to evaluate the physical properties and drug release kinetics of the soft gel capsules, respectively. The dissolution setup was performed according to the FDA dissolution method with slight modifications. 2% sodium dodecyl sulfate (SDS) was added to 900 mL of water to release the API trapped within the oil spheres of 22MC-01 soft gel capsules, and 900 mL of 50 mM phosphate buffer (pH 7.2) was used as the dissolution medium for 22MC-40 soft gel capsules. Unless otherwise stated, the dissolution medium was stirred at 100 RPM using a paddle device.

[0140] Example 2 - Partial replacement of starch with stearic acid

[0141] Stearic acid is a saturated fatty acid with an 18-carbon chain. Stearic acid is known to form lipid-amylose complexes during gelation, thereby simultaneously delaying the recrystallization / retrogradation process of starch during cooling. Since the water solubility of starch depends largely on its recrystallization rate during cooling, part of the starch is replaced by stearic acid. Soft gel capsules were prepared using the gel masses shown in Table 2.

[0142] Table 2. Gel formulations containing stearic acid

[0143]

[0144] Ibuprofen (200 mg per capsule) was encapsulated in 360 mg soft gel capsules (OET-10291401 Batch #22MC-02 and Batch #22MC-46). The soft gel capsules were dried, washed with ethanol-phosal 53 MCT washing solution, and stored in plastic bags before testing.

[0145] The physical properties and drug release kinetics of soft gel capsules disclosed herein were evaluated by burst strength measurement and fiber optic probe, respectively. The dissolution setting was carried out according to the FDA ibuprofen soft gel capsule dissolution method, and slightly modified. Dissolution test was carried out in 900mL phosphate buffer (50mM, pH 7.2) using USP APP II with a paddle of 75RPM.

[0146] An informal stability study was initiated and data was collected for one month at 40°C / 75%RH for batch #22MC-02 capsules.

[0147] Example 3 - Complete replacement of starch with maltodextrin and pullulan

[0148] Maltodextrin is a hydrolyzed starch with higher water solubility than hydroxypropylated starch. Pullulan is a natural polysaccharide produced by yeast. Starch was completely replaced with maltodextrin and pullulan to obtain a strong shell with higher shell solubility. Soft gel capsules were prepared using the gel masses shown in Table 3.

[0149] Table 3. Gel formulations containing maltodextrin and pullulan

[0150]

[0151] Ibuprofen (200 mg per capsule) was encapsulated in 360 mg soft gel capsules (OET-10291370 Batch #21MC-96 and Batch #22MC-41). After drying, the soft gel capsules were washed with an ethanol-Phosal mixture and placed in a plastic bag before testing.

[0152] Summary of results

[0153] Example 1 - Partial replacement of starch with Kolliphor P407

[0154] Oil-based fillers

[0155] The soft gel capsule burst strength and travel distance of 22MC-01 capsules are summarized in Table 4. The dried 22MC-01 soft gel capsules showed a moderate burst strength of 15 kg.

[0156] Table 4. Soft gel rupture strength and travel distance of dried 22MC-01 capsules

[0157]

[0158] After 14 ± 2 minutes of exposure, the capsule tip opens and initial fill release occurs. The shell dissolves simultaneously as the fill is released into the dissolution medium. However, drug dissolves slowly, whether or not the shell is fully opened and exposed to the surrounding environment, e.g. Figure 1 As shown. Figure 1 As shown in the photo in , the drug was trapped inside the solidified oil globules, which delayed the release into the dissolution medium. Although most of the white solidified oil globules were released into the dissolution medium, it took an average of 56 ± 8 minutes to achieve 80% drug release. This suggests that the delayed release is not due to the solubility of the shell, but rather to the solubility of the drug and the fill formulation.

[0159] To eliminate the effect of fill formulation on drug solubility and evaluate only shell solubility, 22MC-01 capsules were filled with liquid acetaminophen and the corresponding release profiles were measured. Commercially available liquid acetaminophen gelatin soft gel capsules were tested in parallel to compare 22MC-01 with conventional gelatin-based capsules. Figure 2 shown.

[0160] When drug solubility effects were eliminated, the release profile of 22MC-01 matched that of commercially available gelatin-based capsules.

[0161] Informal stability testing is ongoing and corresponding 1 month (Tl M) data are being collected at 40°C / 75% RH.

[0162] High molecular weight PEG-based fillers

[0163] Previous studies have shown poor compatibility between PEG and shell materials, as all capsules leaked during drying. The shell was observed to be susceptible to PEG migration, while water in the shell aided transport. Addition of higher molecular weight PEG1000 was expected to mitigate migration, but was not sufficient to completely stop migration during drying. Approximately 40% of the capsules remained intact without any leakage.

[0164] Due to PEG migration, the seal integrity was compromised and the resulting soft gel rupture strength and capsule migration distance are shown in Table 5.

[0165] Table 5. Soft gel rupture strength and travel distance of dried 22MC-40 capsules

[0166]

[0167] The complete capsules were packaged for further testing, and the release profile of ibuprofen was collected using optical fiber, e.g. Figure 3 shown.

[0168] Unexpectedly, initial fill release occurred after 22 ± 4 minutes of exposure as the capsule tip opened. The shell dissolved simultaneously as the fill was released into the dissolution medium. Once the capsule was cracked, the fill was released into the dissolution medium, and 80% of the fill was released within 33 ± 4 minutes. Regardless, the results are better than the currently available capsules, which require 34 ± 16 minutes for initial drug release and 44 ± 21 minutes to reach 80% fill release.

[0169] Example 2 - Partial replacement of starch with stearic acid

[0170] The soft gel rupture strength and travel distance of 22MC-02 capsules are summarized in Table 6. The dried 22MC-02 soft gel capsules showed a moderate rupture strength of 14 kg.

[0171] Table 6. Soft gel rupture strength and travel distance of dried 22MC-02 capsules

[0172]

[0173] The ibuprofen release profile was collected using a fiber optic dissolution apparatus with USP App II at 75 rpm. Figure 4 shown.

[0174] Figure 4 The rupture and dissolution profiles of 22MC-02 and 22MC-46 capsules when exposed to the dissolution medium are shown. It took 21 ± 6 minutes for the 22MC-02 capsules and 22 ± 1 minutes for the 22MC-46 capsules to begin releasing the filler. This value is faster than the current commercially available products, which take 34 ± 16 minutes to begin releasing the drug. Despite the delay, 22MC-02 and 22MC-46 capsules released 80% of the drug in 35 ± 6 minutes and 33 ± 5 minutes, respectively. This is faster than conventional commercially available capsules, which take 44 ± 21 minutes to release 80% of the drug.

[0175] Example 3 - Partial replacement of starch with stearic acid

[0176] The soft gel burst strength and travel distance of 21MC-96 capsules are summarized in Table 7. The soft gel capsule burst strength was very low, only 5 kg; however, this low strength was due to improper die and wedge settings during the encapsulation process.

[0177] Table 7. Soft gel rupture strength and travel distance of dried 21MC-96 capsules

[0178]

[0179] It was found that there were bubbles inside the capsules, which were caused by the wedges not being fixed and could also compromise the seal integrity. A new batch of mini capsules (22MC-41) was prepared, which had no bubbles.

[0180] The ibuprofen release profiles were collected using a fiber optic dissolution apparatus equipped with USP Apparatus II at 75 RPM. Figure 5 shown.

[0181] The 21MC-96 capsules began to dissolve immediately after exposure to the dissolution medium and began to release the fill after 11±4 minutes. This value is comparable to gelatin-based soft gel capsules, which begin to release the drug in less than 10 minutes. 80% of the fill was released in 28±8 minutes, which is faster than existing non-animal soft gel capsules. Unlike starch-based capsules that become opaque in the dissolution medium, the starch-free 21MC-96 capsules remained transparent and formed a hydrogel throughout the run.

[0182] like Figure 5 The 22MC-96 shown repeated with the proper wedge setting (22MC-41) showed delayed fill release compared to 22MC-96 due to better seal quality. Initial fill release occurred after 16 ± 6 minutes and 80% of drug release occurred after 32 ± 5 minutes. Both values ​​are faster than existing non-animal soft gel capsules.

[0183] Dissolution F2 similarity and Mahalanobis distance calculation results

[0184] The F2 similarity test was performed to evaluate the difference in drug release curves between the soft gel of the present invention and the original non-animal soft gel. The drug dissolution amount (%D) at 6 different time points (5, 10, 20, 30, 45, 60 minutes) was collected, and the f2 value was calculated using the following formula:

[0185]

[0186] R(t) = % drug dissolved in the reference product at time tD

[0187] T(t) = %D of the test product dissolved at time point t

[0188] n = number of time points

[0189] Table 8 summarizes the average %D and f2 values ​​of each batch at each time.

[0190] Table 8. %D and corresponding f2 values ​​of each newly prepared soft gel at different time points

[0191]

[0192] According to the f2 analysis, the soft gel capsules of the present invention showed faster dissolution compared to the original non-animal soft gel, so the f2 value <50 indicates that the dissolution of the new soft gel is different from the existing soft gel and is faster, more consistent and less variable.

[0193] The Mahalanobis distance (MD) is a measure of the distance between a sample point P and a distribution D. This distance expresses the distance of a measured point from the mean of the distribution by specifying the number of standard deviations.

[0194] There is no significant difference in the % release between the control and new soft gels during the initial phase (5 and 10 minutes), indicating that no drug was present in the dissolution medium. Differences emerge at 20 minutes and become more pronounced at 30 minutes, where the % release deviates by several standard deviations from the mean control, shown in orange. Differences become less pronounced after 45 minutes, as the control sample begins to rupture and release drug at this time.

[0195] MD analysis further demonstrated that the newly developed soft gels dissolve faster compared with the original soft gels.

[0196] Release profile after 1 month storage at 40°C / 75% RH (T1M)

[0197] An informal stability study was conducted at 40°C / 75%RH for 22MC-01, 22MC-02, 21MC-96, 22MC-41, and 22MC-46 capsules. Data were collected after 1 month. For all three batches that completed 1M stability, no leakage was detected and there was no change in the dissolution profile after the 1M accelerated stability study.

[0198] Data support the use of non-gelatin bio-based polymers (stearic acid, maltodextrin, and pullulan) and / or synthetic polymers (Kolliphor P407) for fast dissolving non-gelatin oral soft gels. All of the newly developed soft gel capsules showed relatively superior performance compared to current soft gel capsules, with faster initial drug release within 20 minutes after exposure. For oil-filled encapsulated capsules (22MC-01), 55 minutes were required to achieve 80% drug release; however, such slow release was due to poor drug solubility and fill formulation, rather than shell dissolution. This conclusion was further demonstrated by filling pre-dissolved drug solutions (acetaminophen as a model drug) into prepared air-filled capsules (shell formulation of batch 22MC-01). When encapsulating a higher molecular weight PEG (22MC-40), initial release took longer (22 minutes); however, 80% of the fill was released after 33 minutes. The dissolution performance of the ibuprofen capsules (22MC-01 and 21MC-96) was superior to that of the current soft gel capsules. The newly developed capsules showed more consistent drug release performance compared to the current soft gel capsules, as evidenced by the smaller error bars.

[0199] Based on this development work, the shell formulations used in batches 21MC-96 / 22MC-41 will be considered for further process development and scale-up as they meet the dissolution specification of no less than 80% drug release in 30 minutes required for an immediate release drug dosage form. Although the stearic acid capsules showed comparable dissolution, the capsules were turbid due to the presence of stearic acid and therefore would not be considered clear liquid filled capsules. However, they will be scaled up for use in Rx Pharma products as well as VMS and cosmetics as needed if required.

[0200] An informal stability study was also conducted for 12 months to determine the physical properties and dissolution performance after T12 months. Informal stability studies were conducted on 21MC-96, 22MC-01, 22MC-02, 22MC-41, and 22MC-46 capsules at 40°C / 75%RH and 30°C / 65%RH storage conditions. During this study, data were collected after T3M, T6M, and T12M. Figures 6A-6C Represents the stability study results of batch number 22MC-01. Figures 7A-7FA comparison of stability studies of batches 22MC-02 and 22MC-46 is shown. Figures 8A-8F Comparison of stability studies of batches 22MC-96 and 22MC-41 is shown. It was found that no leakage was detected in any of the soft gel capsules studied, and that the physical properties and dissolution performance were not significantly affected after storage under accelerated conditions. In addition, the results of this study were within the error range and met the application criteria for immediate release pharmaceutical dosage forms.

[0201] The foregoing description sets forth many specific details, such as examples of specific systems, components, methods, etc., in order to provide a good understanding of several embodiments of the present invention. However, it will be appreciated by those skilled in the art that at least some embodiments of the present invention may be implemented without these specific details. In other cases, well-known components or methods are not described in detail to avoid unnecessarily obscuring the present invention. Therefore, the specific details set forth are exemplary. Specific embodiments may differ from these exemplary details, but are still considered to be within the scope of the present invention.

[0202] Although the operation of the method is described in a particular order herein, the order of operation of each method can be changed so that certain operations can be performed in reverse order, or certain operations can be performed at least partially simultaneously with other operations. In another embodiment, the instructions or sub-operations of different operations can be adopted in an intermittent and / or alternating manner.

[0203] It should be understood that the above description is intended to be illustrative, not restrictive. Those skilled in the art will appreciate many other embodiments after reading and understanding the above description. Therefore, the scope of the present invention should be determined with reference to the appended claims and the full scope of equivalents enjoyed by such claims.

Claims

1. A soft gel capsule film comprising: A non-gelatin bio-based polymer wherein the film dissolves in less than 20 minutes according to a dissolution test performed using a USP apparatus paddle II at 75 rpm.

2. The soft gel capsule film of 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, a surfactant, a 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 of claim 5, wherein the nonionic triblock copolymer comprises polyethylene oxide and polypropylene oxide blocks.

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 source gelling agent comprises carrageenan, starch, pregelatinized starch, xanthan gum, agar, pectin, sugar, sugar-derived alcohol, cellulose derivatives, cellulose polymers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, silicon dioxide, curdlan, furcellaran, protein 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 buffer.

12. The soft gel capsule film of 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 of claim 1, wherein the non-animal source gelling agent comprises carrageenan, starch, or a combination thereof.

14. The soft gel capsule film of claim 1, wherein the ratio of carrageenan to starch 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.

15. The soft gel capsule film of claim 13, wherein the carrageenan comprises iota carrageenan, kappa carrageenan, lambda carrageenan, 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 of claim 8, wherein the non-animal gelling agent does not include starch.

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

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

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

21. The soft gel capsule film of 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 of claim 1, wherein the film is free of animal-derived gelling agents.

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

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

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

26. The soft gel capsule film of claim 11, wherein the amount of the buffer is from 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 the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, sodium citrate, disodium hydrogen phosphate, calcium phosphate, calcium hydrogen phosphate, tricalcium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof.

28. The soft gel capsule film of claim 1, wherein the amount of the polymer is 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 of claim 2, wherein the polymer is pullulan.

30. The soft gel capsule film of 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 of claim 2, wherein the polymer is stearic acid.

32. The soft gel capsule film of 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 of claim 2, wherein the polymer is pullulan and stearic acid.

34. The soft gel capsule film of claim 33, wherein the amount of the polymer is 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 of claim 3, wherein the amount of the synthetic polymer is from about 4% to about 8% (w / w), or about 5% (w / w) of the film.

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

37. The immediate release soft gel capsule of claim 36, wherein the fill material comprises an active agent.

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

39. The immediate release soft gel capsule of claim 38, wherein the fill material comprises an active agent.

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