Coated enteric softgel capsules

Abstract

Disclosed herein are softgel capsules comprising a fill material, a shell composition, and a coating having an enteric polymer, the coating providing a mass increase of about 1% to about 10% of the capsule mass, improving enteric robustness and minimizing moisture absorption during dissolution of the softgel capsule.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 397,558, filed August 12, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to a softgel capsule comprising a fill composition and a shell composition, the shell composition comprising pectin. The softgel capsule of the present invention further comprises a coating comprising an enteric polymer. [Background technology]

[0003] Soft capsules, particularly soft gelatin capsules (or soft gel capsules), provide a dosage form that is more readily accepted by patients because the capsules are easy to swallow and do not require flavoring to mask the unpleasant taste of the active agent. Soft gel encapsulation of drugs also offers the potential for improving the bioavailability of pharmaceuticals. For example, the active ingredient can be easily released in a liquid state as soon as the gelatin shell ruptures.

[0004] Efforts have been made to create enteric-coated dosage forms. Enteric-coated dosage forms are designed to protect the contents of the dosage form from gastric conditions. For example, enteric-coated dosage forms have been developed in which conventional enteric polymers (i.e., acid-insoluble polymers) are added to the capsule shell. However, the addition of conventional enteric polymers can lead to leaky capsules due to poor sealing. Furthermore, it has been found that the addition of enteric polymers to the capsule shell can cause the shell to absorb large amounts of water, which can weaken the mechanical strength and affect the chemical stability of the drug substance.

[0005] Therefore, there is currently a need for softgel capsules that minimize water uptake and maintain mechanical strength. Summary of the Invention

[0006] The present invention relates to a softgel capsule comprising a lightweight enteric polymer coating. The softgel capsule of the present disclosure comprises a fill composition and a shell composition, the shell composition comprising pectin. The softgel capsule further comprises a coating comprising an enteric polymer. It has been found that including a lightweight coating in the softgel capsule improves enteric robustness. It has also been found that the use of a lightweight coating achieves a more uniform coating of the softgel capsule, resulting in more consistent performance of the dosage form. Furthermore, the coating also increases the pH threshold of the capsule so that the capsule can be further delivered to the digestive system (e.g., colonic delivery).

[0007] The present invention also relates to a method of making an enteric coated softgel capsule.

[0008] The present disclosure is illustrated by way of example, and not limitation, in the figures of the accompanying drawings, in which like references indicate similar elements. It should be noted that the different references to "an" or "one" embodiment in this disclosure do not necessarily refer to the same embodiment, and such references do mean at least one. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 shows capsule moisture absorption results for coated softgel capsules according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present disclosure advances the state of the art by developing an enteric-coated oral dosage form, particularly an enteric-coated softgel capsule, that improves the enteric properties of softgel capsules. The enteric-coated softgel capsules of the present invention do not dissolve in the stomach environment, but dissolve further into the digestive system, e.g., in the intestine or colon. Such a mechanism is beneficial for the delivery of active ingredients that may cause stomach irritation or are sensitive to the acidic stomach environment.

[0011] As used herein, the term "enteric" refers to the resistance of a material to dissolution or disintegration, such that dissolution or disintegration does not occur in the gastric environment. For example, embodiments described herein include enteric shell compositions that dissolve in natural, artificial, or simulated intestinal fluids, but not in natural, artificial, or simulated gastric fluids. Embodiments described herein also include coatings having enteric polymers.

[0012] As used herein, "active pharmaceutical ingredient" refers to a drug or compound that can be used in the diagnosis, cure, mitigation, treatment, or prevention of a condition. The term "condition" or "conditions" refers to a medical condition that can be treated or prevented by administering an effective amount of an active agent to a subject. Non-limiting exemplary conditions that may benefit from enteric-coated softgel capsules include, but are not limited to, capsules containing lactic acid bacteria, fish oil capsules, proton pump inhibitors, aspirin, and similar products.

[0013] As used herein, the term "active ingredient" refers to any material intended to produce a therapeutic, prophylactic, or other desired effect, whether or not it has been approved by a governmental agency for that purpose. This term, with reference to a particular drug, includes the pharmaceutically active agent and all of its pharmaceutically acceptable salts, solvates, and crystalline forms that possess pharmaceutically activity.

[0014] Any pharmaceutically active ingredient can be used for the purposes of the present invention, including both water-soluble and poorly water-soluble ones. Suitable pharmaceutically active ingredients include, but are not limited to, analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarials, antimigraine agents, antimuscarinics, antineoplastic and immunosuppressive agents, antiprotozoal agents, antirheumatic agents, antithyroid agents, antiviral agents, anxiolytics, sedatives, hypnotics, and neuroleptic agents. , beta-blockers, cardiac inotropes, corticosteroids, antitussives, cytotoxins, 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.

[0015] 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.

[0016] 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, 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, 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 include, but are not limited to, fish oil (omega-3), krill oil, animal or vegetable fats, such as their hydrogenated forms, free fatty acids having C8-, C10-, C12-, C14-, C16-, C18-, C20-, and C22-fatty acids, monoglycerides, diglycerides, and triglycerides, and combinations thereof.

[0017] According to certain embodiments, the active agent includes 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.

[0018] Suitable functional active agents include, but are not limited to, 5-hydroxytryptophan, acetyl L-carnitine, alpha lipoic acid, alpha-ketoglutarate, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin 812), dimethylaminoethanol, fumaric acid, germanium sesquioxide, glandular products, glucosamine hydrochloride, glucosamine sulfate, hydroxymethyl butyrate, 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.

[0019] Suitable nutritional supplements include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, or combinations thereof.

[0020] Suitable vitamin active agents include, but are not limited to, 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.

[0021] Suitable herbal supplement active agents include, but are not limited to, 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, japonicus, senna, soybean, St. John's wort, saw palmetto, turmeric, and valerian.

[0022] Mineral activators include, but are not limited to, boron, calcium, chelated minerals, chloride, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malate, pyruvate, zinc, and other minerals.

[0023] Examples of other possible active agents include 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, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, fluprofen, bucloxic acid,acid), indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxepinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprine, azapropazone, benorylate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, pharmaceutically acceptable salts thereof, and mixtures thereof), and acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., phenytoin, meprobamate, and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem, and nicardipine), antitussives and expectorants (e.g., codeine phosphate), antiasthmatics (e.g., theophylline), antacids, antispasmodics (e.g., atropine, scopolamine), antidiabetic drugs (e.g., insulin), diuretics (e.g., ethacrynic acid, bendroflumethiazide), antihypertensives (e.g., propranolol, clonidine), antihypertensives (e.g., For example, clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), anti-hemorrhoids, hypnotics, psychotropic drugs, 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.

[0024] The active agent may be a benzodiazepine, a barbiturate, a stimulant, or a mixture thereof. The term "benzodiazepine" refers to benzodiazepines and benzodiazepine derivatives that can depress the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures. Benzodiazepine antagonists that can be used as the active agent include, but are not limited to, flumazenil, and its pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0025] The term "barbiturates" refers to sedative-hypnotic drugs (2,4,6-trioxohexahydropyrimidines) derived from barbituric acid. Barbiturates include, but are not limited to, amobarbital, aprobarbital, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures. Barbiturate antagonists that can be used as active agents include, but are not limited to, amphetamine, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0026] The term "stimulant" includes, but is not limited to, amphetamines, such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.The stimulant antagonists that can be used as active agents include, but are not limited to, benzodiazepines, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0027] The dosage forms of the present disclosure include various active agents and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; amino acid salts such as alginate, aspartate, glutamate, etc., and 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.

[0028] As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount of an active agent, or the rate at which it is administered, needed to bring about the desired therapeutic result.

[0029] As used herein, the term "shell" or "shell composition" refers to the shell of a softgel capsule that encapsulates the fill material.

[0030] As used herein, "conventional enteric polymer" refers to, but is not limited to, acrylic acid and methacrylic acid polymers available under the trade name EUDRAGIT®, as well as other conventional acid-insoluble polymers, such as methyl acrylate-methacrylic acid copolymers. Other conventional acid-insoluble polymers include, but are not limited to, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), alginates, such as sodium alginate and potassium alginate, stearic acid, and shellac. In some embodiments, the enteric shell composition of the present invention does not contain an acid-insoluble polymer. In other words, the enteric shell composition and the enteric softgel capsule are "free or substantially free of conventional enteric polymers."

[0031] 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 the element in question.

[0032] Throughout the specification and claims, all references to wt% refer to the weight of the element relative to the weight of the total composition, sometimes expressed as w / w.

[0033] As used herein, "fill material" or "fill" refers to a composition containing at least one pharmaceutically active ingredient that is encapsulated by an enteric capsule shell.

[0034] As used herein, "delayed release" refers to the release of an active agent after passing through the stomach.

[0035] As used herein, "about" refers to any value within a ±10% variance; for example, "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, a reference to an "excipient" includes not only a single excipient but also a mixture of two or more different excipients.

[0036] Recitation of ranges of numerical values herein is merely intended as a shorthand method of referring individually to each separate value falling within the range, unless otherwise stated herein, and all separate values are incorporated herein as if each were individually set forth herein. All methods described herein can be performed in any suitable order unless otherwise stated herein or otherwise clearly contradicted by context.

[0037] The use of any examples or exemplary language (e.g., "such as") presented herein is intended merely to highlight certain materials and methods and is not intended to limit the scope. Nothing in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods.

[0038] According to one embodiment, the delayed-release softgel capsule comprises a fill material comprising an active agent, a shell composition comprising pectin, and a coating comprising an enteric polymer.

[0039] In some capsule embodiments, the coating of the softgel capsule may result in a mass increase of about 0.1% to about 10%, about 0.5% to about 5%, about 1% to about 10%, about 1% to about 5%, about 1% to about 3%, or about 2% to about 5% of the capsule.

[0040] Suitable filler materials include at least one pharmaceutically active ingredient and can be prepared by known methods. In addition to at least one pharmaceutically active ingredient, suitable filler materials may also include additional filler elements, such as flavoring agents, sweeteners, coloring agents, and fillers, or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides. The appropriate amount of pharmaceutically active ingredients and pharmaceutically acceptable excipients can be easily determined by those skilled in the art.

[0041] In some embodiments, the pectin in the shell composition may be low-methoxy pectin. In certain embodiments, the low-methoxy pectin may be LM pectin (P-25), LM pectin (445C), LM pectin (100C), or a combination thereof. In other embodiments, the pectin may be amidated or non-amidated pectin. The addition of pectin contributes to the enteric properties of the dosage form. However, excessive pectin in the dosage form may reduce the gel strength of the softgel capsule, which may adversely affect the sealing ability of the softgel capsule. Therefore, pectin can be added to the dosage form at a concentration high enough to form an enteric dosage form, while at a concentration low enough to mitigate the loss of gel strength. In some embodiments, the amount of pectin in the enteric shell composition is about 2 wt% to about 30 wt%, about 2 wt% to about 25 wt%, about 2 wt% to about 20 wt%, about 3 wt% to about 15 wt%, about 3 wt% to about 5.5 wt%, about 5 wt% to about 10 wt%, about 2.5 wt% to about 20 wt%, about 5 wt% to about 18 wt%, 7.5 wt% to about 15 wt%, or about 10 wt% to about 12 wt%, based on the total weight of the shell composition. The degree of esterification of the pectin incorporated in the shell composition may be less than about 50%, or may range from about 10% to about 50%, from about 20% to about 40%, or from about 25% to about 35%.

[0042] In some embodiments of the capsule, the shell composition may further include a plasticizer. The plasticizer may include glycerol, glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof. In one embodiment, the plasticizer may include glycerin and sorbitol sorbitan solution. 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. Other suitable plasticizers include, but are not limited to, sugar alcohol plasticizers, such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers, such as diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine; and mixtures thereof.Other exemplary plasticizers include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyl groups, ester-based plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single-block polymers, citrate ester-based plasticizers, and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0043] In some embodiments, the amount of plasticizer may be from about 5 wt% to about 75 wt%, from about 2 wt% to about 40 wt%, from about 2 wt% to about 15 wt%, from about 4 wt% to about 12 wt%, from about 5 wt% to about 60 wt%, from about 10 wt% to about 55 wt%, from about 15 wt% to about 50 wt%, from about 20 wt% to about 45 wt%, or from about 25 wt% to about 35 wt%, based on the total weight of the shell composition.

[0044] In some embodiments, the plasticizer may be glycerin, which may be present in an amount of about 5 wt% to about 30 wt%, about 8 wt% to about 26 wt%, about 12 wt% to about 22 wt%, or about 15 wt% to about 22 wt%, based on the total weight of the shell composition.

[0045] In some embodiments, the plasticizer can be a sorbitol sorbitan solution, which can be present in an amount of about 2 wt% to about 40 wt%, about 5 wt% to about 36 wt%, about 8 wt% to about 30 wt%, about 10 wt% to about 27 wt%, or about 15 wt% to about 22 wt%, based on the total weight of the shell composition.

[0046] In some embodiments of the softgel capsule, the shell composition may further comprise gelatin. The gelatin may include type A gelatin, type B gelatin, skin gelatin, and / or bone gelatin, used alone or in combination. In one embodiment, the gelatin is 250 Bloom gelatin. In another embodiment, only one type of gelatin is present. In yet another embodiment, the gelatin is a combination of at least two types of gelatin. In certain embodiments, the amount of gelatin in the enteric shell composition is about 10 wt% to about 80 wt%, about 15 wt% to about 60 wt%, about 20 wt% to about 55 wt%, about 25 wt% to about 50 wt%, about 30 wt% to about 45 wt%, or about 35 wt% to about 40 wt%, based on the total weight of the shell composition.

[0047] In some embodiments, the shell composition of the softgel capsule may include a cellulose derivative, such as hydroxypropylmethylcellulose (HPMC). In certain embodiments, the amount of cellulose derivative (e.g., HPMC) in the shell composition is about 0.15 wt% to about 4.0 wt%, more preferably about 0.20 wt% to about 2.0 wt%, and most preferably about 0.25 wt% to about 1.4 wt%. In some embodiments, the enteric capsule shell composition may include HPMC, methylcellulose (MC), hydroxypropylcellulose (HPC), or a combination thereof. The cellulose derivative may be added to the shell composition to reduce the possibility of a decrease in gel strength. The concentration of the cellulose derivative in the enteric shell composition may be an amount effective to improve gel strength, but not so high as to prevent sealing.

[0048] In some embodiments, the shell composition of the softgel capsule may also include gellan gum, dextrose, water, or a combination thereof. In some embodiments, the amount of dextrose may be about 0.001 wt% to about 10 wt%, about 0.001 wt% to about 5 wt%, about 0.01 wt% to about 4.5 wt%, about 0.01 wt% to about 4 wt%, about 0.1 wt% to about 3 wt%, or about 1 wt% to about 2.5 wt%, based on the total weight of the shell composition.

[0049] In certain embodiments, the shell composition 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 dyes and mineral oxides.

[0050] Exemplary suitable colorants include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown, etc. In certain embodiments, the color of a dosage form can represent the contents (e.g., one or more active ingredients) contained in the dosage form.

[0051] Exemplary suitable flavoring agents include, but are not limited to, "flavor extracts," which are obtained by extracting raw materials, e.g., parts of animal or plant material, often with a solvent, e.g., ethanol or water; natural extracts obtained by extracting essential oils from flowers, fruits, roots, etc., or from whole plants.

[0052] Further 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 bean, other flavors or aromas such as fruit flavors (e.g., cherry, orange, grape, etc.), particularly those used for oral hygiene, and actives used in tooth and mouthwashes, such as quaternary ammonium bases. The flavor effect can be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

[0053] Exemplary sweeteners 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 potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salt (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trademark MagnaSweet®); Stevia rebaudiana (stevioside), natural high-intensity sweeteners such as monk fruit, polyols such as sorbitol, mannitol, xylitol, erythritol, and the like.

[0054] In some embodiments, the enteric polymer of the coating may be an acrylic polymer, a methacrylic acid polymer, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), alginates such as sodium alginate, potassium alginate, stearic acid, shellac, or a combination thereof. In some embodiments, the enteric polymer may be an acrylic polymer, a methacrylic acid polymer, or a combination thereof. In some embodiments, the enteric polymer may be an aqueous dispersion of an anionic copolymer based on methyl acrylate, methyl methacrylate, and methacrylic acid.

[0055] In some embodiments of the delayed-release softgel capsule, the coating may further comprise a plasticizer, which may be a glyceride, triethyl citrate, or a combination thereof.

[0056] In some embodiments, the enteric polymer in the coating is in an amount of about 10 wt% to about 60 wt%, about 15 wt% to about 50 wt%, about 20 wt% to about 40 wt%, about 25 wt% to about 35 wt%, or about 30 wt% based on the total weight of the coating. In some embodiments, the amount of plasticizer in the coating may be in an amount of about 2 wt% to about 10 wt%, about 3 wt% to about 9 wt%, about 4 wt% to about 8 wt%, or about 5 wt% based on the total weight of the coating.

[0057] In some embodiments, the softgel capsules can provide omega-3 in an amount of about 100 mg to about 1000 mg, about 150 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 350 mg to about 600 mg, or about 400 mg to about 500 mg per serving.

[0058] In some embodiments, the delayed-release softgel capsules can be tested in a disintegration test (described in more detail below) conducted in a 1000 mL beaker in an NT-40H apparatus with a basket and rack assembly at about 37°C ± 2°C. Enteric-coated softgel capsules according to this embodiment can remain intact in an acidic medium for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, or at least about 6 hours, or from about 1 hour to about 6 hours, from about 1 hour to about 4 hours, or from about 1 hour to about 2 hours. In some embodiments, the softgel capsules can disintegrate in intestinal fluid in less than about 30 minutes, less than about 20 minutes, less than about 10 minutes, or less than about 5 minutes. In certain embodiments, the above results may also be achieved for softgel capsules under accelerated stability conditions of 25°C / 60% RH, 30°C / 65% RH, or 40°C / 75% RH at 1 month, 3 months, 6 months, 12 months, 18 months, 22 months, or 24 months.

[0059] The disintegration tests performed herein are consistent with the European Pharmacopoeia and the United States Pharmacopoeia for enteric-coated formulations. The apparatus used for the disintegration test is the NT-40H model (manufactured by Toyama Sangyo Co., Ltd.). The apparatus consists of a basket-rack assembly, a 1000-mL low-profile beaker with a height of 138-160 mm and an internal diameter of 97-115 mm for the immersion liquid, a thermostat for heating the liquid to 35-39°C, and a device for raising and lowering the basket in the immersion liquid at a constant repetition rate of 29-32 cycles per minute over a distance of 53-57 mm. The volume of liquid in the container is such that at the highest point of the upward stroke, the wire mesh remains at least 15 mm below the liquid surface, and on the downward stroke, it does not descend below 25 mm from the bottom of the container. The top of the basket-rack assembly should never be submerged. The time required for the upward stroke is equal to the time required for the downward stroke, and changes in stroke direction are smooth transitions rather than abrupt reversals. The basket rack assembly moves vertically along its axis, with no apparent horizontal movement or motion of the axis from the vertical.

[0060] The disintegration tests disclosed herein were carried out with a liquid volume of 1000 mL at approximately 37°C ± 2°C. Disintegration test fluid 1 (also referred to herein as "artificial gastric fluid") was a 2 g / L sodium chloride-hydrochloric acid solution (pH 1.2). Disintegration test fluid 2 (also referred to herein as "artificial intestinal fluid") was a 0.2 mol / L potassium dihydrogen phosphate-0.2 mol / L sodium hydroxide solution (pH 6.8).

[0061] Disintegration testing with the first fluid was performed for approximately 120 minutes by placing one unit in each of the six tubes of the basket, immersing the basket (and thus the units) in the first test fluid, and then removing the basket from the fluid to observe whether the units had disintegrated. Disintegration is defined as the unit breaking or the enteric shell composition rupturing or breaking. The test is passed if none of the six units disintegrated. A similar test is performed for a selected duration using the second disintegration test fluid.

[0062] 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.

[0063] In certain embodiments, a two-stage disintegration test may be performed on the softgel capsules of the present disclosure. In the two-stage disintegration test, the softgel capsules are exposed to an acidic medium (pH=1.2) and then a buffered medium (pH=6.8). Upon exposure to both the acidic and buffered media, the softgel capsules may remain intact for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, or for about 1 hour to about 6 hours, about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, or about 1 hour to about 2 hours. In certain embodiments, the above results may also be achieved for softgel capsules under accelerated storage conditions of 25°C / 60% RH, 30°C / 65% RH, or 40°C / 75% RH 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, the intact time does not change by more than 20%, more than 10%, or more than 5% from time 0 at 1 hour, 4 hour, or 8 hour time points.

[0064] In certain embodiments, a two-stage disintegration test may be performed on the softgel capsules of the present disclosure. In the two-stage disintegration test, the softgel capsules are exposed to an acidic medium (pH=1.2) and then a buffered medium (pH=7.5). Upon exposure to the acidic and buffered media, the softgel capsules may remain intact for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, or for about 1 hour to about 6 hours, about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, or about 1 hour to about 2 hours. In certain embodiments, the above results may also be achieved for softgel capsules under accelerated storage conditions of 25°C / 60% RH, 30°C / 65% RH, or 40°C / 75% RH 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, the intact time does not change by more than 20%, more than 10%, or more than 5% from time 0 at 1 hour, 4 hour, or 8 hour time points.

[0065] In some embodiments, disintegration tests may be performed using a buffer solution having a pH of 7.5. Under these conditions, the softgel capsule may disintegrate in less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, or less than about 5 minutes. In some embodiments, disintegration tests may be performed at 1 month, 3 months, 6 months, 12 months, 18 months, 22 months, or 24 months using a buffer solution having a pH of 7.5 and under accelerated storage conditions of 5°C / 60% RH, 30°C / 65% RH, or 40°C / 75% RH. Under these conditions, the softgel capsule may disintegrate in less than about 45 minutes, less than about 40 minutes, less than about 35 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, or less than about 5 minutes.

[0066] In some embodiments, the softgel capsules can be tested under moisture absorption tests by exposing the softgel capsules to an aqueous medium. The softgel capsules may have a moisture absorption rate of less than 2%, less than 1.5%, less than 1%, less than 0.8%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, or less than 0.05% after 5, 10, 15, 30, 45, 60, or 120 minutes of exposure. In certain embodiments, the above results can also be achieved for softgel capsules under accelerated storage conditions of 25°C / 60% RH, 30°C / 65% RH, or 40°C / 75% RH at 1 month, 3 months, 6 months, 12 months, 18 months, 22 months, or 24 months.

[0067] Encapsulation of the fill material can be accomplished in any conventional manner, for example, rotary die encapsulation can be utilized.

[0068] According to one embodiment, the enteric coated softgel capsule is prepared by a method comprising preparing a fill material comprising an active agent, encapsulating the fill material in a shell composition comprising pectin, thereby forming a softgel capsule, and then coating the capsule with a coating composition comprising an enteric polymer such that the capsule gains about 1% to about 10% in mass.

[0069] A method of preparing a softgel capsule includes preparing a shell composition, which may include pectin, a plasticizer, gelatin, gellan gum, dextrose, water, or a combination thereof, as described herein.

[0070] The coating composition is then prepared by preparing a coating suspension comprising an enteric polymer, a plasticizer, water, or a combination thereof. In certain embodiments, the enteric polymer may comprise an anionic copolymer based on methyl acrylate.

[0071] In certain embodiments, the present invention relates to one or more of the items in the following list: 1. The delayed-release softgel capsule may comprise a fill material comprising an active agent, a shell composition comprising pectin, and a coating comprising an enteric polymer. 2. The delayed-release softgel capsule according to item 1, wherein the coating provides a mass increase of about 1% to about 10 wt %, or about 2% to about 5% of the capsule. 3. The delayed-release softgel capsule of item 1 or 2, wherein the shell composition further comprises a plasticizer. 4. The delayed-release softgel capsule of item 3, wherein the plasticizer comprises glycerol, glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof. 5. The delayed-release softgel capsule according to any one of items 3 to 4, wherein the plasticizer comprises glycerin and sorbitol sorbitan solution. 6. The delayed-release softgel capsule according to item 4, wherein the polysorbate comprises Tween 20, Tween 80, or a combination thereof. 7. The delayed-release softgel capsule of any one of items 1 to 6, wherein the shell composition further comprises gelatin. 8. The delayed-release softgel capsule according to item 7, wherein the gelatin is selected from the group consisting of type A gelatin, type B gelatin, and mixtures thereof. 9. The delayed-release softgel capsule according to item 7, wherein the gelatin is selected from the group consisting of fish gelatin, skin gelatin, bone gelatin, and mixtures thereof. 10. The delayed-release softgel capsule of any one of items 1 to 9, wherein the shell composition further comprises gellan gum. 11. The delayed-release softgel capsule of any one of items 1 to 10, wherein the shell composition further comprises dextrose. 12. The delayed-release softgel capsule of any one of items 1 to 11, wherein the shell composition further comprises water. 13. The delayed-release softgel capsule of any one of items 1 to 12, wherein the pectin is a low methoxy pectin. 14. The delayed-release softgel capsule of any one of items 1 to 13, wherein the enteric polymer is an acrylic polymer, a methacrylic acid polymer, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), alginate, stearic acid, shellac, or a combination thereof. 15. The delayed-release softgel capsule according to item 14, wherein the alginate is sodium alginate, potassium alginate, or a combination thereof. 16. The delayed-release softgel capsule according to item 14, wherein the enteric polymer is an acrylic polymer, a methacrylic acid polymer, or a combination thereof. 17. The delayed-release softgel capsule of any one of items 1 to 16, wherein the coating further comprises a plasticizer. 18. The delayed-release softgel capsule of item 17, wherein the plasticizer comprises a glyceride, triethyl citrate, or a combination thereof. 19. The delayed-release softgel capsule according to any one of items 1 to 18, wherein the pectin is in an amount of about 2.5 wt% to about 20 wt%, 5 wt% to about 18 wt%, 7.5 wt% to about 15 wt%, or about 10 wt% to about 12 wt%, based on the total weight of the shell composition. 20. The delayed-release softgel capsule according to any one of items 7 to 9, wherein the gelatin is in an amount of about 15 wt% to about 60 wt%, about 20 wt% to about 55 wt%, about 25 wt% to about 50 wt%, about 30 wt% to about 45 wt%, or about 35 wt% to about 40 wt%, based on the total weight of the shell composition. 21. The delayed-release softgel capsule according to item 11, wherein the dextrose is in an amount of about 0.001 wt% to about 5 wt%, about 0.01 wt% to about 4.5 wt%, about 0.01 wt% to about 4 wt%, about 0.1 wt% to about 3 wt%, or about 1 wt% to about 2.5 wt%, based on the total weight of the shell composition. 22. The delayed-release softgel capsule according to any one of items 4 to 6, wherein the plasticizer is in an amount of about 5 wt% to about 60 wt%, about 10 wt% to about 55 wt%, about 15 wt% to about 50 wt%, about 20 wt% to about 45 wt%, or about 25 wt% to about 35 wt%, based on the total weight of the shell composition. 23. The delayed-release softgel capsule according to any one of items 1 to 22, wherein the enteric polymer is in an amount of about 20 wt% to about 40 wt%, about 25 wt% to about 35 wt%, or about 30 wt%, based on the total weight of the coating. 24. The delayed-release softgel capsule according to item 17, wherein the plasticizer is present in an amount of about 2 wt% to about 10 wt%, about 3 wt% to about 9 wt%, about 4 wt% to about 8 wt%, or about 5 wt%, based on the total weight of the coating. 25. The delayed-release softgel capsule of any one of paragraphs 1 to 24, wherein the shell composition does not burst at 15 minutes, 30 minutes, 45 minutes, or 60 minutes at pH 1.2 when measured using a USP Apparatus II equipped with a paddle at 50 RPM in 750 ml 0.1 N HCl acidic medium, pH adjusted with phosphate buffer. 26. The delayed-release softgel capsule of any one of paragraphs 1 to 25, wherein the shell composition does not burst at 15 minutes, 30 minutes, 45 minutes, or 60 minutes at a pH of 6 to 7 when measured using a USP Apparatus II equipped with a paddle at 50 RPM in 750 ml 0.1 N HCl acidic medium, pH adjusted with phosphate buffer. 27. A method for preparing a delayed-release softgel capsule according to any one of items 1 to 26, comprising: preparing a filler material including an active agent; encapsulating the fill material with a shell composition comprising pectin to form a capsule; coating the capsule with a coating composition comprising an enteric polymer; A method comprising: [Example]

[0072] Specific embodiments of the present invention will now be described with reference to the following examples, which should be understood to be merely illustrative of the invention and should not be construed as limiting the scope of the invention in any way.

[0073] Coating of delayed-release softgel capsules A batch of coated delayed-release softgel capsules was produced in accordance with the present disclosure. A batch of 1000 mg delayed-release softgel capsules was utilized for the coating experiment. The fill material was purified fish oil containing 300 mg of omega-3. The shell composition of the delayed-release softgel capsules is summarized in Table 1.

[0074] [Table 1]

[0075] A coating composition containing EUDRAGIT® FS30D, an aqueous dispersion of an anionic copolymer based on methyl acrylate, methyl methacrylate, and methacrylic acid, was prepared and used to coat the polymer. The coating composition also contained PlasACRYL® T20 as a plasticizer. PlasACRYL® T20 is understood to include a 20% aqueous suspension containing an antiblocking agent, a plasticizer, and a stabilizer. The coating composition was prepared as a coating suspension. This is summarized in Table 2.

[0076] [Table 2]

[0077] 1000 mg delayed-release fish oil softgel capsules were coated to achieve a 2% mass gain. The coated softgel capsules were subjected to various tests to evaluate enteric coating robustness. The coated capsules were also packaged in induction-sealed HDPE bottles and placed in accelerated development stability conditions according to stability protocol ISS-21-047.

[0078] Coated immediate-release softgel capsule comparison A batch of coated fish oil softgel capsules was produced for comparative purposes. A batch of 1000 mg immediate release fish oil softgel capsules was utilized for coating testing. The fill material was fish oil containing 300 mg of omega-3. The shell formulation of the immediate release softgel capsules is summarized in Table 3.

[0079] [Table 3]

[0080] 1000 mg immediate-release fish oil softgel capsules were coated using the same coating suspension described in Table 2 to achieve a mass gain of 2% (Sublot 21SC-12A) and 3.6% (Sublot 21SC-12B), respectively. The coated capsules were subjected to various tests to evaluate enteric coating robustness. The coated immediate-release capsules were also packaged in induction-sealed HDPE bottles and subjected to accelerated development stability conditions according to stability protocols ISS-22-027 and ISS-22-028.

[0081] Disintegration and Burst Tests 1000 mg of coated delayed-release fish oil softgel capsules and 1000 mg of coated immediate-release fish oil softgels were subjected to a two-stage disintegration test and a two-stage burst test.

[0082] Disintegration tests were carried out using a disintegration apparatus B, ERWEKA, type: ZT 224. In the acidic stage, 0.1 N HCl was used, and in the buffer stage, pH 6.8 and pH 7.5 phosphate buffers were used.

[0083] A two-stage burst test was performed using a Dissolution Apparatus II, Distek, Model 2500. The acidic stage used the biorelevant medium FaSSGF containing the enzyme (pepsin) at pH 1.6, and the buffer stage used phosphate buffer containing the enzyme (pancreatin) at pH 7.5.

[0084] 1000 mg of coated delayed-release fish oil softgel capsules, 1000 mg of coated immediate-release fish oil softgel capsules, and 1000 mg of uncoated delayed-release fish oil softgel capsules were also subjected to moisture absorption testing to compare the mass gain of the capsules after various exposure times. The immersion medium utilized in this test was the same acidic medium used in the disintegration test, 0.1 N HCl.

[0085] Capsule disintegration test results Table 4 summarizes the burst strength data for the uncoated and 2% mass gain coated delayed-release fish oil softgel capsules. The burst strength data was similar before and after the coating step. Therefore, the coating did not appear to affect the physical robustness of the delayed-release softgel capsules.

[0086] [Table 4]

[0087] Table 5 summarizes the two-stage disintegration test results at time zero immediately after coating the softgel capsules.

[0088] [Table 5]

[0089] The above results demonstrate that a 2% mass increase resulted in softgel capsules with robust enteric coating. It should be noted that the coated softgel capsules produced intact softgels in both pH 1.2 HCl acidic medium and pH 6.8 phosphate buffer. However, the 2% mass increase coated softgel capsules still ruptured in pH 7.5 buffer within an average of 24 minutes. The increased threshold pH of the coated softgel capsules allows for colonic delivery of the dosage form.

[0090] Table 6 summarizes the two-stage decay results under accelerated stability conditions (40°C / 75% RH) at 1 month and 3 months, respectively.

[0091] [Table 6]

[0092] For coated delayed-release softgel capsules (21SC-09A) with a 2% mass gain at T=1 month, the softgel capsules remained intact in both pH 1.2 and pH 6.8 media and burst in 34 minutes in pH 7.5 buffer. At T=3 months, the coated delayed-release softgel capsules remained intact in pH 1.2 HCl media and burst in 43 minutes in pH 7.5 phosphate buffer.

[0093] Table 7 summarizes the two-stage disintegration test results at 6 and 12 months under long-term stability conditions (25°C / 60% RH), at 18 months under intermediate stability conditions (30°C / 65% RH), at 6 months under accelerated stability conditions (40°C / 75% RH), and at 22 months under room temperature holding conditions.

[0094] [Table 7]

[0095] For coated delayed-release softgel capsules (21SC-09A) with a 2% mass gain at T = 6 months (25°C / 60% RH), the softgel capsules remained intact at pH 1.2 and burst in 11 minutes in pH 7.5 phosphate buffer. At T = 12 months (25°C / 60% RH), the softgel capsules remained intact at pH 1.2 and burst in 15 minutes in pH 7.5 phosphate buffer. At T = 6 months (40°C / 75% RH), the delayed-release softgel capsules remained intact in pH 1.2 HCl medium and burst in 17 minutes in pH 7.5 phosphate buffer. At T = 18 months (30°C / 65% RH), the delayed-release softgel capsules remained intact in pH 1.2 HCl medium and burst in 15 minutes in pH 7.5 phosphate buffer. For T=22 months (RT retention), the delayed-release softgel capsules remained intact in pH 1.2 HCl medium and burst in 11 minutes in pH 7.5 phosphate buffer.

[0096] Results for coated immediate-release fish oil softgel capsules are also presented herein. Table 8 summarizes the two-stage disintegration data for coated immediate-release softgel capsules with a 2% mass gain and a 3.6% mass gain, respectively.

[0097] The coated immediate-release softgel capsules (21SC-12A) with a 2% mass gain burst in pH 1.2 HCl medium, failing to meet the requirements for enteric-coated dosage forms. The coated immediate-release softgel capsules (21SC-12B) with a 3.6% mass gain did not burst completely in pH 1.2 acidic medium. However, all softgel capsules released small amounts of fill material, indicating insufficient enteric coating.

[0098] [Table 8]

[0099] Two-stage burst test Table 9 summarizes the two-stage burst data for both the coated delayed-release softgel capsules with a 2% mass gain (21SC-09A) and the coated immediate-release softgel capsules with a 2% mass gain (21SC-12A) and a 3.6% mass gain (21SC-12B), respectively.

[0100] For the coated delayed-release softgel capsules (21SC-09A) with a 2% mass gain, the capsules remained intact in FaSSGF containing the enzyme and burst in an average of 15 minutes in pH 7.5 phosphate buffer containing the enzyme. Small oil droplets were observed in four of six containers during the initial acidic phase, but the capsules remained intact and no further release was observed.

[0101] Coated immediate-release softgel capsules with a 2% mass gain (21SC-12A) and a 3.6% mass gain (21SC-12B) released small amounts of fill material (more than 10%) in pH FaSSGF media containing enzymes, indicating poor enteric coating.

[0102] [Table 9]

[0103] Moisture absorption test Table 10 summarizes moisture absorption data for the 2% mass gain coated delayed-release capsules, the coated immediate-release softgels with 2% mass gain and 3.6% mass gain, and the uncoated delayed-release softgel capsules, respectively. Figure 1 illustrates the capsule moisture absorption rate for the coated capsules. Moisture absorption tests were performed by placing the softgel capsules in an aqueous medium.

[0104] [Table 10]

[0105] The coated delayed-release softgel capsules showed limited mass gain during the 120-minute immersion period, significantly demonstrating the strong moisture barrier provided by the combination of the 2% mass gain coating and pectin shell. Meanwhile, the coated immediate-release softgel capsules with both 2% and 3.6% mass gains began to lose mass after 60 minutes, indicating that the aqueous medium had penetrated the coating layer and dissolved the non-pectin shell. The uncoated delayed-release softgel capsules showed a mass gain of over 92% after 120 minutes, demonstrating strong moisture absorption.

[0106] Thus, the data indicate that coating delayed-release softgel capsules with a relatively low mass gain (2%) significantly improves enteric robustness and minimizes moisture absorption during dissolution. Also, a low mass gain coating may achieve more consistent coating uniformity, resulting in more consistent performance of the dosage form. Furthermore, coating delayed-release softgel capsules with an appropriate enteric polymer system may broaden their application by raising the pH threshold for delivery of the dosage form further into the digestive system (e.g., colonic delivery).

[0107] The foregoing description sets forth numerous specific details, such as examples of specific systems, components, methods, etc., to provide a thorough understanding of some embodiments of the present invention. However, it will be apparent to those skilled in the art that at least some embodiments of the present invention can be practiced without these specific details. In other instances, well-known components or methods have not been described in detail to avoid unnecessarily obscuring the present invention. Thus, the specific details described are exemplary. It may be contemplated that particular embodiments may vary from these example details and still be within the scope of the present invention.

[0108] Although the operations of the methods herein are described in a particular order, the order of the operations of each method may be changed so that certain operations can be performed in reverse order or certain operations can 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.

[0109] It should be understood that the above description is intended to be illustrative, and not limiting. Many other embodiments will be 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 filler material containing an activator, A shell composition containing pectin, Coating containing enteric-coated polymer and A delayed-release softgel capsule containing, The amount of pectin is 2.5 wt% to 20 wt% of the total mass of the shell composition. The enteric-coated polymer comprises a combination of methyl acrylate, methyl methacrylate, and methacrylic acid. The coating results in a mass increase of 0.5% to 3 wt% of the capsule. The delayed-release softgel capsule, which, when measured using a USP Apparatus II equipped with a paddle in 750 ml of 0.1N HCl acidic medium pH-adjusted with phosphate buffer at 50 RPM, does not rupture at a pH of 1.2 at 15 minutes.

2. The delayed-release softgel capsule according to claim 1, wherein the shell composition further comprises a plasticizer.

3. The delayed-release softgel capsule according to claim 2, wherein the plasticizer comprises glycerol, glycerin, sorbitol, sorbitol-sorbitan solution, triacetin, polysorbate, or a combination thereof.

4. The delayed-release softgel capsule according to claim 3, wherein the plasticizer comprises a glycerin and sorbitol sorbitan solution.

5. The delayed-release softgel capsule according to claim 3, wherein the polysorbate comprises polysorbate 20, polysorbate 80, or a combination thereof.

6. The delayed-release softgel capsule according to claim 1, wherein the shell composition further comprises gelatin.

7. The delayed-release softgel capsule according to claim 6, wherein the gelatin is selected from the group consisting of type A gelatin, type B gelatin, and mixtures thereof.

8. The delayed-release softgel capsule according to claim 6, wherein the gelatin is selected from the group consisting of fish gelatin, skin gelatin, bone gelatin, and mixtures thereof.

9. The delayed-release softgel capsule according to claim 1, further comprising gellan gum in the shell composition.

10. The delayed-release softgel capsule according to claim 1, further comprising dextrose in the shell composition.

11. The delayed-release softgel capsule according to claim 1, wherein the shell composition further comprises water.

12. The delayed-release softgel capsule according to claim 1, wherein the pectin is low-methoxypectin.

13. The delayed-release softgel capsule according to claim 1, wherein the enteric-coated polymer further comprises an acrylic polymer, cellulose succinate acetate, cellulose phthalate acetate, cellulose butyrate acetate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate acetate (hypromellose succinate acetate), polyvinyl acetate phthalate (PVAP), alginate, stearic acid, shellac, or a combination thereof.

14. The delayed-release softgel capsule according to claim 13, wherein the alginate is sodium alginate, potassium alginate, or a combination thereof.

15. The delayed-release softgel capsule according to claim 13, wherein the enteric-coated polymer is an acrylic polymer, a methacrylic polymer, or a combination thereof.

16. The delayed-release softgel capsule according to claim 1, wherein the coating further comprises a plasticizer.

17. The delayed-release softgel capsule according to claim 16, wherein the plasticizer comprises a glyceride, triethyl citrate, or a combination thereof.

18. The delayed-release softgel capsule according to claim 6, wherein the amount of gelatin is 15 wt% to 60 wt% of the total mass of the shell composition.

19. The delayed-release softgel capsule according to claim 10, wherein the amount of dextrose is 0.001 wt% to 5 wt% of the total mass of the shell composition.

20. The delayed-release softgel capsule according to claim 3, wherein the amount of the plasticizer is 5 wt% to 60 wt% of the total mass of the shell composition.

21. The delayed-release softgel capsule according to claim 1, wherein, when measured using a USP Apparatus II equipped with a paddle in 750 ml of 0.1 N HCl acidic medium pH-adjusted with phosphate buffer at 50 RPM, the shell composition does not rupture at a pH of 6-7 at 15 minutes.

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