Softgel capsules and methods for preparing softgel capsules

Abstract

Disclosed herein is a method for preparing a softgel capsule comprising a fill material and a shell composition comprising pectin, comprising treating the softgel capsule with a solution comprising a calcium salt.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 432,445, filed December 14, 2022, the entire contents of which are incorporated herein in their entirety.

[0002] The present invention relates to a method for preparing softgel capsules, comprising treating the softgel capsules with a solution containing a calcium salt, e.g., calcium chloride. Also provided is a softgel capsule comprising a fill material and a shell composition, wherein the shell composition comprises calcium ions. [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 they are easy to swallow and do not require flavoring to mask the unpleasant taste of the active ingredient. Soft gel encapsulation of drugs also offers the potential for improving the bioavailability of pharmaceuticals. For example, the active ingredient can be rapidly released in liquid form as soon as the gelatin shell ruptures.

[0004] Efforts have been made to create enteric dosage forms. Enteric dosage forms are designed to protect the contents of the dosage form from gastric conditions. For example, enteric dosage forms have been developed in which a conventional enteric polymer (i.e., an acid-insoluble polymer) is added to the capsule shell. It has been found that electrostatic attraction can occur in such capsule shells, allowing complex coacervates to form in the shell, which are insoluble at acidic pH but soluble at neutral and basic pH.

[0005] Therefore, there is currently a need to improve the methods for preparing softgel capsules to improve the pH tolerance in intestinal dissolution and disintegration and robustness of the shell. Summary of the Invention

[0006] The present invention is directed to a method for preparing a softgel capsule. The method includes treating the softgel capsule with a solution including a calcium salt, such as calcium chloride, where the softgel capsule includes a fill material and a shell composition. In some embodiments, the solution may further include hydrochloric acid. In some embodiments, the solution may further include water. In some embodiments, the solution may further include a sugar. The sugar may be dextrose.

[0007] In some embodiments of the method, the calcium salt may be present in an amount of about 1 wt % to about 25 wt %, about 2 wt % to about 22 wt %, about 3 wt % to about 20 wt %, about 4 wt % to about 18 wt %, about 5 wt % to about 16 wt %, about 6 wt % to about 14 wt %, or about 7 wt % to about 12 wt %, based on the total weight of the solution.

[0008] In some embodiments, the solution may have a pH of less than about 3.

[0009] In some embodiments, dextrose may be present in an amount of about 0.1 wt% to about 20 wt%, about 1 wt% to about 19 wt%, about 2 wt% to about 18 wt%, about 3 wt% to about 16 wt%, about 4 wt% to about 14 wt%, about 5 wt% to about 12 wt%, or about 6 wt% to about 10 wt%, based on the total weight of the solution.

[0010] In some embodiments, the shell composition can include a plasticizer, pectin, gellan gum, dextrose, gelatin, or a combination thereof. In some embodiments of the shell composition, the plasticizer can include glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof. In other embodiments, the plasticizer can include glycerin, sorbitol sorbitan solution, or a combination thereof. In yet other embodiments, the plasticizer can be a sorbitol sorbitan solution.

[0011] In some embodiments, the method may further include drying the capsules after capsule processing. In some embodiments, drying may be performed by tumble drying the capsules. Drying may be performed for about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, or about 4 hours. In some embodiments, drying may be performed in a drying chamber or drying tunnel.

[0012] In some embodiments of the method, treating can include using a washing / cooling treatment device for a predetermined time. The washing / cooling treatment device can be fully automated. In some embodiments, the predetermined time is about 2.5 seconds, about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes.

[0013] In another embodiment of the present disclosure, a softgel capsule is provided, comprising a fill material comprising an active ingredient and a shell composition, the shell composition comprising calcium ions.

[0014] In some embodiments, the shell composition can include pectin. The pectin can be a low-methoxy pectin. In some embodiments, the pectin can be present in an amount of about 1 wt% to about 25 wt%, about 2 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.

[0015] In some embodiments, the shell composition may include a plasticizer. In some embodiments, the plasticizer may include glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof. In other embodiments, the plasticizer may include glycerin and sorbitol sorbitan solution. In some embodiments, the polysorbate may include Tween 20, Tween 80, or a combination thereof.

[0016] In some embodiments, the plasticizer may be present 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.

[0017] In some embodiments, the shell composition may include gelatin. In some embodiments, the gelatin may be selected from the group consisting of type A gelatin, type B gelatin, and mixtures thereof. In some embodiments, the gelatin may be selected from the group consisting of fish gelatin, hide gelatin, bone gelatin, and mixtures thereof. In some embodiments, the gelatin may be present 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.

[0018] In some embodiments, the shell composition can include gellan gum in an amount of about 0.001 wt% to about 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 wt%, based on the total weight of the shell composition.

[0019] In some embodiments, the shell composition can include dextrose in an amount of about 0.001 wt% to about 5 wt%, about 0.01 wt% to about 4.5 wt%, about 0.05 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.

[0020] In some embodiments, the softgel capsules may be treated with a treatment solution containing a calcium salt. The calcium salt may be calcium chloride, calcium citrate, calcium gluconate, calcium lactate, or any other soluble calcium salt. The calcium salt may be present in an amount of about 1 wt% to about 25 wt%, about 2 wt% to about 22 wt%, about 3 wt% to about 20 wt%, about 4 wt% to about 18 wt%, about 5 wt% to about 16 wt%, about 6 wt% to about 14 wt%, or about 7 wt% to about 12 wt%, based on the total weight of the treatment solution.

[0021] In some embodiments, the treatment solution may further comprise water. In some embodiments, the treatment solution may further comprise a sugar. The sugar may comprise dextrose. The dextrose may be present in an amount of about 0.1 wt% to about 20 wt%, about 2 wt% to about 18 wt%, about 3 wt% to about 16 wt%, about 4 wt% to about 14 wt%, about 5 wt% to about 12 wt%, or about 6 wt% to about 10 wt%, based on the total weight of the treatment solution.

[0022] In some embodiments, the treatment solution may further comprise hydrochloric acid.

[0023] In some embodiments, the treatment may result in a weight gain of about 1% to about 10% for the capsules, and in some embodiments, the capsules may have improved burst strength when compared to capsules without calcium treatment.

[0024] In some embodiments, the capsules do not burst at a pH of 1.2 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, or 120 minutes when measured in a USP Apparatus II with paddles at 50 RPM or 100 RPM in 0.1 N hydrochloric acid (HCl) medium.

[0025] In some embodiments, the capsules do not burst at a pH of 3.0, a pH of 4.0, or a pH of 5.0 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, or 90 minutes when measured in a USP Apparatus II with paddles at 50 RPM or 100 RPM in an acid medium.

[0026] In some embodiments, the capsules burst at a pH of 6-8 in 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes when measured in a USP Apparatus II with paddles at 50 RPM, 100 RPM, 150 RPM, or 200 RPM in phosphate buffer.

[0027] The present disclosure is illustrated by way of example and not limitation in the accompanying figures. [Brief explanation of the drawings]

[0028] [Figure 1] This figure shows a comparison of capsule moisture absorption between capsules tested according to embodiments of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0029] The present disclosure advances the state of the art by developing a processing method for preparing softgel capsules. The disclosed method rapidly initiates ionotropic gelation and initiates a specific degree of gelatin and pectin cross-linking by dextrose to enhance the enteric function and physical robustness of the capsules. Treatment of softgel capsules with a calcium-containing solution has been found to initiate ionotropic gelation (the calcium cross-linking effect). Thus, the inventors believe that calcium ions cross-link the shell composition to form a larger, stronger, enhanced network.

[0030] As used herein, the term "enteric" refers to the property of resisting dissolution or disintegration of a material 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, simulated, or simulated intestinal fluids, but not in natural, simulated, or simulated gastric fluids. Embodiments described herein may include a coating having an enteric polymer.

[0031] 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(s)" refers to a medical condition that can be treated or prevented by administration of an effective amount of an active ingredient to a subject. Representative non-limiting conditions that can benefit from enteric coated softgel capsules can include, but are not limited to, capsules containing lactic acid bacteria, fish oil capsules, proton pump inhibitors, aspirin, and similar products.

[0032] As used herein, the term "active ingredient" refers to any material intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose. In the context of a specific pharmaceutical agent, this term includes the active pharmaceutical ingredient and all pharmaceutically acceptable salts, solvates, and crystalline forms thereof, which salts, solvates, and crystalline forms are pharmaceutically active.

[0033] Any pharmaceutically active ingredient, including both water-soluble and poorly soluble in water, may be used for the purposes of the present invention. Suitable pharmaceutically active ingredients include analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarials, antimigraine drugs, antimuscarinic agents, antineoplastic and immunosuppressive agents, antiprotozoal agents, antirheumatic agents, antithyroid agents, antiviral agents, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, cardiotonic agents, etc. These include, but are not limited to, drugs, corticosteroids, antitussives, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian drugs, gastrointestinal drugs, histamine receptor antagonists, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and antianginal drugs, nutritional supplements, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants and combinations thereof.

[0034] 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.

[0035] In some embodiments, the lipid in the dosage form may be selected from the group consisting of, 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, colza oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp seed oil, hydrogenated 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 oil, hydrogenated vegetable oil, walnut oil, and watermelon seed oil. Other oils and fats may include, but are not limited to, fish oil (omega-3), krill oil, animal or vegetable fats, such as hydrogenated forms thereof, free fatty acids and mono-, di- and triglycerides with C8-, C10-, C12-, C14-, C16-, C18-, C20- and C22-fatty acids and combinations thereof.

[0036] According to certain embodiments, the active agent may comprise 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.

[0037] Suitable nutritional supplement active ingredients include 5-hydroxytryptophan, acetyl L-carnitine, alpha lipoic acid, alpha-ketoglutaric acid, bee-derived products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), dimethylaminoethanol, fumaric acid, germanium sequioxide, glandular products. These may include, but are not limited to, glutamic acid, glutamic acid, glutamic acid, glutamic acid salts, glutamic acid derivatives, glutamic acid ester ...

[0038] Suitable nutritional active agents may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements or combinations thereof.

[0039] Suitable vitamin active agents may 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.

[0040] Suitable herbal supplement active agents may 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, psyllium, rauwolfia, senna, soybean, St. John's wort, saw palmetto, turmeric, and valerian.

[0041] Mineral activators may 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, malic acid, pyruvate, zinc, and other minerals.

[0042] 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, pyroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen), and the like. , aminoprofen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprine, azapropazone, benorilate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etoposide Dolac, 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, salicylsalicylic acid, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, pharmaceutically acceptable and their salts and mixtures thereof) and 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, anticonvulsants (e.g., atropine, scopolamine), antidiabetic drugs (e.g., insulin), diuretics (e.g., ethacrynic acid,bendrofluthiazide), antihypotensives (e.g., propranolol, clonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, 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.

[0043] The active agent can also be a benzodiazepine, a barbiturate, a stimulant, or a mixture thereof. The term "benzodiazepine" refers to benzodiazepines and drugs that are derivatives of benzodiazepines and can depress the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate, 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 their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0044] The term "barbiturate" refers to hypnotic sedatives derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists that may be used as the active agent include, but are not limited to, amphetamine, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0045] 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 may be used as the active agent include, but are not limited to, benzodiazepines, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0046] The dosage forms according to 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.; sulfonate salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; amino acid salts such as alginate, aspartate, glutamate, etc.; metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

[0047] As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount of the active ingredient, or the rate at which it is administered, needed to produce the desired therapeutic result.

[0048] As used herein, "shell" or "shell composition" refers to the shell of a softgel capsule that encapsulates the fill material.

[0049] As used herein, "conventional enteric polymer" refers to, but is not limited to, acrylic acid and methacrylic acid polymers and other conventional acid-insoluble polymers, such as methyl acrylate-methacrylic acid copolymers, which may be available under the EUDRAGIT® trade name. 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), algenic acid salts, such as sodium alginate and potassium alginate, stearic acid, and shellac. In some embodiments, the enteric shell compositions of the present invention are free of acid-insoluble polymers. In other words, the enteric shell compositions and enteric-coated softgel capsules are "free of or substantially free of conventional enteric polymers."

[0050] All references to wt % throughout the specification and claims refer to the weight of the component relative to the weight of the total composition, which may also be stated as w / w.

[0051] As used herein, "fill material" or "fill" refers to the composition that is encapsulated by the enteric capsule shell and that contains at least one active pharmaceutical ingredient.

[0052] As used herein, "delayed release" refers to the release of an active ingredient after it has passed through the stomach.

[0053] As used herein, "about" refers to any value within ±10% variance, whereby "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 mixtures of two or more different excipients, and the like.

[0054] Recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by content.

[0055] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to clarify certain materials and methods and does not pose a limitation on scope. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods.

[0056] According to one embodiment, a method for preparing a softgel capsule includes treating the softgel capsule with a solution containing a calcium salt, the softgel capsule including a fill material and a shell composition. The calcium salt can be calcium chloride, calcium citrate, calcium gluconate, calcium lactate, or any other soluble calcium salt.

[0057] In some embodiments of the method, the solution may further comprise hydrochloric acid. In some embodiments, the solution may further comprise water. In other embodiments, the solution may further comprise a sugar. The sugar may comprise dextrose.

[0058] In some embodiments of the method, calcium chloride may be present in an amount of about 1 wt % to about 25 wt %, about 2 wt % to about 22 wt %, about 3 wt % to about 20 wt %, about 4 wt % to about 18 wt %, about 5 wt % to about 16 wt %, about 6 wt % to about 14 wt %, or about 7 wt % to about 12 wt %, based on the total weight of the solution.

[0059] In certain embodiments of the present invention, hydrochloric acid may be included to obtain a solution having a pH of less than 3.

[0060] In some embodiments, dextrose may be included in the solution in an amount of about 0.1 wt% to about 20 wt%, about 1 wt% to about 19 wt%, about 2 wt% to about 18 wt%, about 3 wt% to about 16 wt%, about 4 wt% to about 14 wt%, about 5 wt% to about 12 wt%, or about 6 wt% to about 10 wt%, based on the total weight of the solution.

[0061] In some embodiments of the method, the shell composition may include a plasticizer, pectin, gellan gum, dextrose, gelatin, or a combination thereof.

[0062] In certain embodiments, the plasticizer may include glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof. In some embodiments, the plasticizer may include glycerin, sorbitol sorbitan solution, or a combination thereof. In yet other embodiments, the plasticizer may be a sorbitol sorbitan solution.

[0063] In some embodiments, the method may further include drying the softgel capsule. In some embodiments, drying may be performed by tumble drying the capsule. In some embodiments, drying is performed for about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, or about 4 hours. In other embodiments, the method may include drying the capsule in a drying chamber or drying tunnel.

[0064] In some embodiments of the method, the treating may include utilizing a softgel capsule washing / cooling treatment device, wherein the softgel capsules are treated with the solution for a predetermined period of time. The softgel capsule washing / cooling treatment device may be fully automated.

[0065] In certain embodiments, the predetermined time for treatment can be about 2.5 seconds, about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes.

[0066] In another embodiment of the present invention, a softgel capsule is provided. The softgel capsule may include a fill material comprising an active ingredient and a shell composition, the shell composition including calcium ions.

[0067] Suitable fill materials contain at least one pharmaceutically active ingredient and can be prepared according to known methods. In addition to at least one pharmaceutically active ingredient, suitable fill materials can contain additional fill ingredients, 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 amounts of pharmaceutically active ingredients and pharmaceutically acceptable excipients can be easily determined by those skilled in the art.

[0068] In some embodiments, the shell composition may include pectin. The pectin in the shell composition may be low-methoxy pectin. In one embodiment, the low-methoxy pectin may be LM pectin (P-25), LM pectin (445C), LM pectin (100C), or a combination thereof. In another embodiment, the pectin may be amidated pectin 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 in turn may adversely affect the sealability of the softgel capsule. Therefore, pectin may be added to the dosage form at a concentration high enough to form an enteric-coated dosage form, yet low enough to mitigate the loss of gel strength. In one embodiment, the amount of pectin in the enteric shell composition is about 1 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 can be less than about 50%, or can range from about 10% to about 50%, from about 20% to about 40%, or from about 25% to about 35%.

[0069] In some capsule embodiments, the shell composition may further comprise a plasticizer. The plasticizer may include 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 Tween 20, Tween 80, or a combination thereof. Other suitable plasticizers may include, but are not limited to, sugar alcohol plasticizers such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers such as diglycerin, dipropylene glycol, polyethylene glycols of 10,000 MW or less, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine, and the like; and mixtures thereof. Other representative plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyl groups, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single-block polymers, citrate ester-type plasticizers, and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0070] In some embodiments, the amount of plasticizer can be 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.

[0071] In some embodiments of the softgel capsule, the shell composition may further comprise gelatin. The gelatin may include type A gelatin, type B gelatin, hide gelatin, and / or bone gelatin, used alone or in combination. In one embodiment, the gelatin is 250 Bloom gelatin. In another embodiment, there is only one type of gelatin. In yet another embodiment, the gelatin is a combination of at least two types of gelatin. In one embodiment, 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.

[0072] 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 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.

[0073] In some embodiments, the amount of gellan gum may be present in an amount of about 0.001 wt% to about 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 wt%, based on the total weight of the shell composition.

[0074] In some embodiments, the softgel capsules may be treated with a treatment solution. The treatment solution may include a calcium salt. The calcium salt may be calcium chloride, calcium citrate, calcium gluconate, calcium lactate, or any other soluble calcium salt. In one embodiment, the calcium salt may be calcium chloride.

[0075] In some embodiments, the calcium salt may be present in an amount of about 1 wt% to about 25 wt%, about 2 wt% to about 22 wt%, about 3 wt% to about 20 wt%, about 4 wt% to about 18 wt%, about 5 wt% to about 16 wt%, about 6 wt% to about 14 wt%, or about 7 wt% to about 12 wt%, based on the total weight of the treatment solution.

[0076] In some embodiments, the treatment solution may further comprise water. In other embodiments, the treatment solution may further comprise a sugar. The sugar may be dextrose. The sugar or dextrose may be present in an amount of about 0.1 wt% to about 20 wt%, about 2 wt% to about 18 wt%, about 3 wt% to about 16 wt%, about 4 wt% to about 14 wt%, about 5 wt% to about 12 wt%, or about 6 wt% to about 10 wt%, based on the total weight of the treatment solution.

[0077] In some embodiments, the softgel capsules may be treated with a calcium treatment solution, which may result in a weight gain of about 1% to about 10%, about 2% to about 8%, or about 3% to about 5% of the capsule.

[0078] In some embodiments, after treatment, the capsules may have improved burst strength when compared to capsules without the treatment of the present invention.

[0079] In one embodiment, the shell composition of the softgel capsule may optionally include additional materials such as colorants, flavorants, sweeteners, fillers, antioxidants, diluents, pH modifiers, or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides.

[0080] Exemplary suitable colorants may include, but are not limited to, pigments such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown, etc. In certain embodiments, the color of the dosage form may be indicative of the ingredients contained therein (e.g., one or more active ingredients).

[0081] Representative suitable flavoring agents may include, but are not limited to, "flavor extracts" obtained by extracting parts of raw materials, such as animal or plant materials, often using solvents such as ethanol or water; natural essences obtained by extracting essential oils from flowers, fruits, roots, etc. or from whole plants.

[0082] Additional representative flavoring agents that may be present in the dosage form include, but are not limited to, breath freshening compounds such as menthol, spearmint, and cinnamon, coffee bean, other flavors or fragrances, such as fruit flavors (e.g., cherry, orange, grape, etc.), particularly those used for oral hygiene, and actives used in dental and oral cleaning, such as quaternary ammonium bases, etc. The effect of the flavoring may be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

[0083] Representative sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Artificial sweeteners may include, for example, acesulfame and its various salts, such as the potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salt (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as the sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); Stevia rebaudiana (stevioside); natural high-intensity sweeteners such as Lo Han Kuo; and polyols such as sorbitol, mannitol, xylitol, and erythritol.

[0084] In some embodiments, the softgel capsule does not rupture at a rupture at 15, 30, 45, 60, 75, 90, 105, or 120 minutes when measured in a USP Apparatus II with paddles at 50 RPM or 100 RPM in 0.1 N hydrochloric acid (HCl) acid medium at a pH of 1.2.

[0085] In some embodiments, the softgel capsule does not burst at a pH of 3.0, a pH of 4.0, or a pH of 5.0 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, or 90 minutes when measured in a USP Apparatus II with paddles at 50 RPM or 100 RPM in an acid medium.

[0086] In some embodiments, the capsules burst at a pH of 6-8 in 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes when measured in a USP Apparatus II with paddles at 50 RPM, 100 RPM, 150 RPM, or 200 RPM in phosphate buffer.

[0087] Encapsulation of the fill material can be accomplished in any conventional manner. For example, rotary die encapsulation can be used.

[0088] According to one embodiment, enteric-coated softgel capsules are prepared by a process including preparing a fill material containing an active ingredient; and encapsulating the fill material in a shell composition to form a softgel capsule. The capsules are then treated with a treatment solution containing a calcium source, such as calcium chloride, calcium chloride dihydrate (CaCl:2H0), calcium citrate, calcium gluconate, or calcium lactate. The treatment includes utilizing a fully automated softgel capsule washing / cooling treatment device. The softgel capsules are further dried after treatment using a tumble dryer in a drying chamber or tunnel.

[0089] List of Items 1. A method for preparing a softgel capsule comprising treating the softgel capsule with a solution comprising a calcium salt, said softgel capsule comprising a fill material and a shell composition. 2. The method according to item 1, wherein the calcium salt comprises calcium chloride, calcium citrate, calcium gluconate, calcium lactate, or a combination thereof. 3. The method according to item 1, wherein the solution further comprises hydrochloric acid. 4. The method according to item 1, wherein the solution further comprises water. 5. The method according to any one of items 1 to 4, wherein the solution further contains a sugar. 6. The method according to item 5, wherein the sugar comprises dextrose. 7. The method according to any one of items 1 to 6, wherein the calcium salt is contained in an amount of about 1 wt % to about 25 wt %, about 2 wt % to about 22 wt %, about 3 wt % to about 20 wt %, about 4 wt % to about 18 wt %, about 5 wt % to about 16 wt %, about 6 wt % to about 14 wt %, or about 7 wt % to about 12 wt %, based on the total weight of the solution. 8. The method according to item 3, wherein the pH of the solution is less than 3. 9. The method according to Item 6, wherein the dextrose is contained in an amount of about 0.1 wt% to about 20 wt%, about 1 wt% to about 19 wt%, about 2 wt% to about 18 wt%, about 3 wt% to about 16 wt%, about 4 wt% to about 14 wt%, about 5 wt% to about 12 wt%, or about 6 wt% to about 10 wt%, based on the total weight of the solution. 10. The method of any one of claims 1 to 9, wherein the shell composition comprises a plasticizer, pectin, gellan gum, dextrose, gelatin, or a combination thereof. 11. The method of claim 10, wherein the plasticizer comprises glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof. 12. The method of claim 10, wherein the plasticizer comprises glycerin, sorbitol sorbitan solution, or a combination thereof. 13. The method according to item 10, wherein the plasticizer is a sorbitol sorbitan solution. 14. The method of any one of claims 1 to 13, further comprising drying the capsules after treating the capsules. 15. The method according to item 14, wherein the drying is carried out by tumble drying the capsules. 16. The method according to item 14, wherein the drying occurs for about 5 minutes to about 6 hours, 15 minutes to about 5 hours, 30 minutes to about 4 hours, 45 minutes to about 3 hours, about 1 hour to about 2.5 hours, or about 1.5 hours to about 2 hours. 17. The method according to item 14, wherein the drying is carried out in a drying chamber or drying tunnel. 18. The method of any one of claims 1 to 17, wherein said treating comprises using a cleaning / cooling treatment device for a predetermined period of time. 19. The method according to item 18, wherein the washing / cooling treatment device is fully or partially automated. 20. The method of claim 18, wherein the cleaning / cooling treatment device is jacked and can be cooled or cooled using an external cooler. 21. The method according to item 18, wherein the time is about 2.5 seconds, about 5 seconds to about 10 minutes, about 10 seconds to about 9 minutes, about 15 seconds to about 8 minutes, about 20 seconds to about 7 minutes, about 25 seconds to about 6 minutes, about 30 seconds to about 5 minutes, about 35 seconds to about 4 minutes, about 40 seconds to about 3 minutes, about 45 seconds to about 2 minutes, or about 50 seconds to about 1 minute. 22. A filler material containing an active ingredient; shell composition, wherein the shell composition comprises calcium ions. 23. The softgel capsule of item 22, wherein the shell composition comprises pectin. 24. The softgel capsule according to item 23, wherein the pectin is a low methoxy pectin. 25. The softgel capsule according to item 23, wherein the pectin is present in an amount of about 1 wt% to about 25 wt%, about 2 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. 26. The softgel capsule according to item 22, wherein the shell composition comprises a plasticizer. 27. The softgel capsule according to item 26, wherein the plasticizer comprises glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof. 28. The softgel capsule according to item 26, wherein the plasticizer comprises glycerin and sorbitol sorbitan solution. 29. The softgel capsule according to item 27, wherein the polysorbate comprises Tween 20, Tween 80, or a combination thereof. 30. The softgel capsule according to item 26, wherein the plasticizer is present 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. 31. The softgel capsule of item 22, wherein the shell composition comprises gelatin. 32. The softgel capsule according to item 31, wherein the gelatin is selected from the group consisting of type A gelatin, type B gelatin, and mixtures thereof. 33. The softgel capsule according to item 31, wherein the gelatin is selected from the group consisting of fish gelatin, hide gelatin, bone gelatin, and mixtures thereof. 34. The softgel capsule according to item 31, wherein the gelatin is present 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. 35. The softgel capsule of item 22, wherein the shell composition comprises gellan gum. 36. The softgel capsule according to item 35, wherein the gellan gum is present in an amount of about 0.001 wt% to about 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 wt%, based on the total weight of the shell composition. 37. The softgel capsule of item 22, wherein the shell composition comprises dextrose. 38. The softgel capsule according to item 37, wherein the dextrose is present in an amount of about 0.001 wt% to about 5 wt%, about 0.01 wt% to about 4.5 wt%, about 0.05 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. 39. The softgel capsule according to item 22, wherein the softgel capsule is treated with a treatment solution containing calcium chloride. 40. The softgel capsule according to item 39, wherein the calcium chloride is contained in an amount of about 1 wt% to about 25 wt%, about 2 wt% to about 22 wt%, about 3 wt% to about 20 wt%, about 4 wt% to about 18 wt%, about 5 wt% to about 16 wt%, about 6 wt% to about 14 wt%, or about 7 wt% to about 12 wt%, based on the total weight of the treatment solution. 41. The softgel capsule according to item 39, wherein the treatment solution further comprises water. 42. The softgel capsule according to item 39 or 41, wherein the treatment solution further comprises a sugar. 43. The softgel capsule of item 42, wherein the sugar comprises dextrose. 44. The softgel capsule according to item 43, wherein the dextrose is contained in an amount of about 0.1 wt% to about 20 wt%, about 2 wt% to about 18 wt%, about 3 wt% to about 16 wt%, about 4 wt% to about 14 wt%, about 5 wt% to about 12 wt%, or about 6 wt% to about 10 wt%, based on the total weight of the treatment solution. 45. The softgel capsule of any one of items 39, 41, or 42, wherein the treatment solution further comprises hydrochloric acid. 46. ​​The softgel capsule according to any one of items 39 to 45, wherein the treatment results in a weight gain of about 1% to about 10% of the capsule. 47. The softgel capsule of any one of items 22 to 46, wherein the capsule has improved burst strength when compared to a capsule without calcium. 48. The softgel capsule according to any one of items 22 to 47, wherein the capsule does not burst at a pH of 1.2 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, or 120 minutes when measured in a USP Apparatus II with paddles at 50 RPM or 100 RPM in 0.1 N hydrochloric acid (HCl) acid medium. 49. The softgel capsule according to any one of items 22 to 47, wherein the capsule does not burst at a pH of 3.0, a pH of 4.0, or a pH of 5.0 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, or 90 minutes when measured in a USP Apparatus II with paddles at 50 RPM or 100 RPM in an acid medium at a pH of 3.0, a pH of 4.0, or a pH of 5.0. 50. The softgel capsule according to any one of items 22 to 47, wherein the capsule ruptures in less than 5 minutes, less than 10 minutes, less than 15 minutes, less than 20 minutes, less than 25 minutes, less than 30 minutes, less than 35 minutes, less than 40 minutes, less than 45 minutes, less than 50 minutes, less than 55 minutes, or less than 60 minutes at a pH of 6 to 8 when measured in a USP Apparatus II with paddles at 50 RPM, 100 RPM, 150 RPM, or 200 RPM in phosphate buffer.

[0090] Example Specific embodiments of the present invention will now be elucidated by reference to the following examples, it being understood that these examples are disclosed merely by way of illustration of the present invention and should not be construed as limiting the scope of the present invention.

[0091] Experimental Procedures and Methods calcium chloride solution Among all available types of calcium ion resources for initiating the calcium cross-linking effect, calcium chloride was considered the preferred choice due to its low cost and higher solubility. To simplify the procedure, weight percentages were used for all different concentrations of calcium chloride solution. Examples of 5% and 10% calcium chloride basic formulations are listed in Table 1.

[0092] The ionotropic gelation of pectin is pH dependent. The gel network is more stable at lower pH (below 5) than at higher pH (above 7) environments. The pH value of the calcium chloride solution was intentionally adjusted from pH > 8 to pH < 3 with 0.1 N hydrochloric acid solution, which is a key finding of this study. [Table 1]

[0093] Calcium chloride and dextrose solution Reducing sugars such as dextrose contain free aldehyde or ketone groups and can be classified as typical cross-linking agents for inducing covalent cross-linking. By adding dextrose as a reducing sugar to calcium chloride solution, it can promote enteric function on the surface of softgel capsules. Examples of basic formulations of 10% calcium chloride and 5% or 10% dextrose solutions are listed in Table 2. The pH value of the calcium chloride / dextrose solution was also intentionally adjusted to pH<3 with 0.1N hydrochloric acid solution. [Table 2]

[0094] Softgel capsules Softgel capsules from different manufacturing batches (Samples 1-5) were utilized to evaluate calcium treatment. The gel mass formulations used to manufacture these three lots are shown in Table 3. [Table 3]

[0095] After the capsules were tumble dried in a normal encapsulation process, they were collected and treated by immersing them in a stainless steel container with a filtering basket containing 3 liters of calcium chloride solution for various times (5 seconds, 10 seconds, and 20 seconds, respectively). Approximately 500 capsules were manually treated at each time point. After calcium treatment, the capsules were tumble dried in a tumble dryer for 1 hour to remove excess water on the shell introduced by the calcium treatment. The treated capsules were then dried in a drying chamber as in a standard softgel tunnel drying process.

[0096] Some of the finished capsules were also treated with calcium chloride and dextrose solution or calcium chloride solution for longer treatment times to evaluate the upper limit of treatment time and the effect of adding dextrose.

[0097] To be fully integrated into the current encapsulation process, a calcium processing or calcium and dextrose processing step can be added to the process chain just prior to tumble drying in a conventional softgel manufacturing process using fully automated equipment.

[0098] The fully automated device consists of a jacked rectangular container or calcium treatment solution reservoir with an integrated conveyor. Treatment time can be controlled by adjusting the speed of the conveyor belt. The temperature of the calcium solution can be maintained by an external cooler connected to the jacked container.

[0099] Summary of test results Weight gain after calcium treatment After calcium treatment, a small weight gain was expected for the treated capsules. Table 4 summarizes the weight gain data from untreated and immediately treated capsules and from dried finished capsules. [Table 4]

[0100] Compared to untreated wet capsules, the weight gain immediately after calcium treatment varied from 35 mg to 59 mg per capsule or 6.4% to 11.1% of the shell weight, depending on the contact time. The weight gain of the dried calcium-treated products was 13 to 16 mg per capsule or 3.7 to 4.6% of the shell weight.

[0101] Weight gain with calcium and dextrose treatment Table 5 summarizes the weight gain data from untreated and treated finished dry capsules at 1 minute, 2 minutes, and 5 minutes of contact time. [Table 5]

[0102] Compared to untreated dried finished capsules, the weight gain of the calcium and dextrose treated products ranged from 55 to 115 mg per capsule or 10.8 to 22.6% of the shell weight. The concentration of the solution did not affect capsule weight gain; treatment time was the only factor.

[0103] Low methyl amidated (LMA) pectin is more sensitive to the presence of calcium ions and more tolerant to calcium content than high methyl (HM) and low methyl (LM) pectins. LMA gels over a wider range of calcium concentrations, but the gel strength of pectin is below 40 mg Ca. 2+ The gel strength reaches its maximum level at around 10 ...

[0104] Capsule moisture absorption test Capsule moisture absorption testing was performed by exposing capsules to a 0.1 N HCl solution for a specified time and recording the weight gain of the capsules. Table 6 summarizes the moisture absorption data for untreated and treated finished dry capsules at contact times of 1 minute, 2 minutes, and 5 minutes, respectively. Figure 1 shows a capsule moisture absorption comparison between the capsules tested. [Table 6]

[0105] The untreated softgel capsules had a weight gain of over 15.4% after 5 minutes and a weight gain of 22.6% after 10 minutes, indicating stronger moisture absorption. Both the calcium + dextrose treated softgel capsules had very similar weight gains after 5 and 10 minutes of exposure to acid medium, with less weight gain compared to the untreated capsules. This suggests better moisture protection provided by the calcium and dextrose treatment.

[0106] Appearance of the capsule The fresh softgel capsules treated with 5% calcium chloride aqueous solution were clear and transparent, with slightly improved shape. No obvious differences were identified when compared to the untreated capsules. The softgel capsules treated with 10% calcium chloride aqueous solution for 20 seconds exhibited a slightly cloudy appearance. Therefore, the treatment time is preferably within about 10 seconds when a 10% calcium chloride solution is used. The dried finished softgel capsules treated with calcium chloride and dextrose solution were clear and transparent. No obvious differences were identified when compared to the untreated capsules.

[0107] Capsule burst strength The bursting strength of softgel capsules is an indicator of capsule seal quality. It is an important quality attribute for softgel capsules and indicates how tightly the softgel seals or how fragile the capsule is. Using a Texture Analyzer TA HD Plus, bursting strength data for all 47 samples was collected and is summarized in Table 7.

[0108] The results showed that the burst strength of the calcium-treated capsules for lot sample 3 was significantly higher than that of the untreated capsules. The burst strength of the capsules treated with 10% CaCl for both 5 and 20 seconds was significantly higher than that of the capsules treated with 5% CaCl for both 5 and 20 seconds for lot sample 1. Therefore, it was believed that the calcium treatment introduced a calcium bridging effect, which resulted in stronger complex gelation. Thus, the robustness of the softgel capsules was improved. [Table 7]

[0109] Capsule disintegration test This disintegration test is considered the standard enteric functionality test in both USP and EP. It is extremely important that the finished product pass the required disintegration test described in the finished product specifications. To evaluate the quality of the untreated finished softgel capsules and the calcium-treated capsules, a two-stage disintegration test was conducted on both treated and untreated capsules according to EP and USP specifications. In this test, an acid stage disintegration test of up to 2 hours was conducted, and a wide range buffer stage disintegration test was conducted only on selected calcium-treated and untreated softgels.

[0110] Table 8 summarizes the test results of fresh calcium chloride treated finished capsules from different batches. [Table 8]

[0111] The disintegration time of calcium-treated capsules in acid medium was significantly longer than that of untreated capsules. Preliminary results indicate that the calcium cross-linking effect enhanced the enteric function of softgel capsules. Capsules treated with 5% calcium chloride solution for 20 seconds showed better enteric function in acid medium than those treated for shorter periods.

[0112] Selected finished dry softgel capsules from Lot Sample 2 were treated with two different concentrations of calcium chloride and dextrose solutions for 1 minute, 2 minutes, and 5 minutes, respectively. Table 9 summarizes the test results for the dry finished capsules treated with the calcium and dextrose solutions. Again, only the acid stage disintegration test was performed for up to 2 hours. Capsules from the same batch were also treated with a 5% calcium chloride solution for 15 minutes to address contact time limitations. [Table 9]

[0113] Capsules treated for 5 minutes did not perform as well as the 1 and 2 minute treatments, confirming that an overload of calcium ions reduces gel enteric function. Adding dextrose to the calcium treatment has not shown any significant benefit in improving enteric properties so far.

[0114] Table 10 summarizes the results of the two-stage disintegration test of calcium chloride treated and untreated finished capsules from Samples 4 and 5. [Table 10]

[0115] The disintegration time of calcium-treated capsules in acid medium remained intact for 2 hours and was significantly longer than that of untreated capsules in buffer medium. This result indicates that the calcium cross-linking effect enhanced the enteric function of the softgel capsules. The enhanced enteric function induced by calcium treatment was stable and consistent.

[0116] Two-stage capsule dissolution test The two-stage dissolution test is also considered a standard enteric coating functionality test in both the USP and EP methods. It is extremely important that the enteric coated product also pass the required two-stage dissolution test described in the product specifications. To evaluate the quality of the finished softgel capsules and calcium-treated capsules, the two-stage dissolution test was performed on both treated and untreated capsules in selected batches.

[0117] From previous development studies, the inventors have found that a hardening step is necessary for pectin-gelatin polyelectrolyte complex systems to achieve and provide the required enteric functionality. To achieve the formation of the interaction complex, hardening time can require a minimum of 1 to 4 weeks at ambient conditions. If the finished capsules are tested before hardening is complete, premature release can be observed in the first 5 to 15 minutes of the two-stage dissolution test. To shorten or eliminate hardening time and make the softgel capsule more efficient, calcium treatment can shorten or even eliminate hardening time. Table 11 summarizes the data on the test results of capsules from different batches. [Table 11]

[0118] The test data clearly showed that even within one week of production, all calcium-treated capsules passed the two-stage burst test without any observed premature release, while two of six untreated capsules from the same batch still had premature release. Also, all treated capsules burst in the buffer stage within 10 minutes, confirming that the ionotropic gelation of pectin initiated by calcium ions is pH-dependent.

[0119] High pH tolerance The pH value of human gastric juice can fluctuate over time. The normal volume of gastric juice is 20 to 100 mL, and the pH is acidic (1.5 to 3.5). However, the pH of gastric juice can rise during food digestion. To ensure that the enteric coating functions over the entire pH range, it is important that the capsules be able to withstand higher pH environments for a certain period of time. Previous testing of capsules made with pectin and gelatin gels showed that the capsules could only remain intact in a pH 5 medium for approximately 30 minutes before bursting. Table 12 summarizes the data on the test results of capsules from different batches after calcium treatment in a pH 5 medium. [Table 12]

[0120] The rupture time of calcium-treated capsules in a pH 5 medium was significantly longer than that of untreated capsules, indicating that calcium treatment enhanced the high pH tolerance of the softgel capsules. The longer the calcium treatment time, the higher the pH tolerance of the capsules.

[0121] Summary and Conclusion The data compiled in this study demonstrated the benefits of calcium treatment of softgels. Calcium treatment provided multiple benefits over softgel capsules, including but not limited to: 1. Minimal changes to current gel formulations or processes by incorporating an in-line calcium treatment step after encapsulation. 2. Same appearance and slightly improved shape. 3. No cure time is required before conducting the two-stage burst or disintegration test. 4. Improved moisture resistance in acid media. 5. Improved enteric performance: Passed two-stage burst test and two-stage disintegration test (both USP and EP). 6. Improved high pH tolerance. Remains intact in pH 5.0 medium for 1 hour. 7. The addition of dextrose to calcium has not shown any advantage in short-term storage, however, because dextrose cross-linking takes time, ongoing long-term stability studies are expected to show further enhanced enteric functionality.

[0122] Calcium treatment or calcium and dextrose treatment has an optimal treatment time that allows pectin gelation to reach its maximum gel strength and enteric functionality. Calcium and dextrose treatment does not show significant differences compared to calcium treatment alone at short times. The effectiveness of dextrose addition will be further evaluated.

[0123] Also, for enhanced enteric function and performance, the target ribbon thickness of the capsules could possibly be reduced by calcium treatment, resulting in lower raw material costs.

[0124] The foregoing description sets forth numerous specific details, such as examples of specific systems, components, methods, etc., to provide a thorough understanding of some embodiments of the present invention. However, it will be apparent to those skilled in the art that at least some embodiments of the present invention may be practiced without these specific details. In other instances, well-known components or methods have not been described in detail to avoid unnecessarily obscuring the present invention. Thus, the specific details shown are exemplary. It is contemplated that particular embodiments may deviate from these illustrative details and still be within the scope of the present invention.

[0125] Although the operations of the methods herein are described in a particular order, the order of the operations of each method may be changed, such that certain operations may be performed in reverse order, or such that certain operations may be performed, at least in part, concurrently with other operations. In alternative embodiments, instructions or sub-operations of distinct operations may be performed intermittently and / or alternately.

[0126] It should be understood that the above description is illustrative, and not limiting. Many other embodiments will become apparent to those skilled in the art upon reading and understanding the above description. The scope of the invention should, therefore, be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. treating a softgel capsule with a solution comprising a calcium salt, wherein the softgel capsule comprises a fill material and a shell composition; A method for preparing a softgel capsule.

2. 10. The method of claim 1, wherein the calcium salt comprises calcium chloride, calcium citrate, calcium gluconate, calcium lactate, or a combination thereof.

3. The method of claim 1 , wherein the solution further comprises hydrochloric acid.

4. The method of claim 1 , wherein the solution further comprises water.

5. The method of claim 1 , wherein the solution further comprises a sugar.

6. 6. The method of claim 5, wherein the sugar comprises dextrose.

7. 10. The method of claim 1, wherein the calcium salt is present in an amount of about 1 wt % to about 25 wt %, about 2 wt % to about 22 wt %, about 3 wt % to about 20 wt %, about 4 wt % to about 18 wt %, about 5 wt % to about 16 wt %, about 6 wt % to about 14 wt %, or about 7 wt % to about 12 wt %, based on the total weight of the solution.

8. 4. The method of claim 3, wherein the pH of the solution is less than 3.

9. 7. The method of claim 6, wherein the dextrose is present in an amount of about 0.1 wt % to about 20 wt %, about 1 wt % to about 19 wt %, about 2 wt % to about 18 wt %, about 3 wt % to about 16 wt %, about 4 wt % to about 14 wt %, about 5 wt % to about 12 wt %, or about 6 wt % to about 10 wt %, based on the total weight of the solution.

10. The method of claim 1 , wherein the shell composition comprises a plasticizer, pectin, gellan gum, dextrose, gelatin, or a combination thereof.

11. 11. The method of claim 10, wherein the plasticizer comprises glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof.

12. 11. The method of claim 10, wherein the plasticizer comprises glycerin, sorbitol sorbitan solution, or a combination thereof.

13. 11. The method of claim 10, wherein the plasticizer is a sorbitol sorbitan solution.

14. 10. The method of claim 1, further comprising drying the capsules after treating the capsules.

15. 15. The method of claim 14, wherein said drying is performed by tumble drying said capsules.

16. 15. The method of claim 14, wherein the drying occurs for about 5 minutes to about 6 hours, 15 minutes to about 5 hours, 30 minutes to about 4 hours, 45 minutes to about 3 hours, about 1 hour to about 2.5 hours, or about 1.5 hours to about 2 hours.

17. 15. The method of claim 14, wherein the drying is carried out in a drying chamber or drying tunnel.

18. The method of claim 1 , wherein said treating comprises using a cleaning / cooling treatment device for a predetermined period of time.

19. 20. The method of claim 18, wherein the cleaning / cooling treatment device is fully or partially automated.

20. 20. The method of claim 18, wherein the cleaning / cooling treatment device is jacked and can be cooled or chilled using an external cooler.

21. 19. The method of claim 18, wherein the time period is about 2.5 seconds, about 5 seconds to about 10 minutes, about 10 seconds to about 9 minutes, about 15 seconds to about 8 minutes, about 20 seconds to about 7 minutes, about 25 seconds to about 6 minutes, about 30 seconds to about 5 minutes, about 35 seconds to about 4 minutes, about 40 seconds to about 3 minutes, about 45 seconds to about 2 minutes, or about 50 seconds to about 1 minute.

22. a fill material comprising an active agent; shell composition, wherein the shell composition comprises calcium ions. Soft gel capsule.

23. 23. The softgel capsule of claim 22, wherein the shell composition comprises pectin.

24. 24. The softgel capsule of claim 23, wherein the pectin is a low methoxy pectin.

25. 24. The softgel capsule of claim 23, wherein the pectin is present in an amount of about 1 wt % to about 25 wt %, about 2 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.

26. 23. The softgel capsule of claim 22, wherein the shell composition comprises a plasticizer.

27. 27. The softgel capsule of claim 26, wherein the plasticizer comprises glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof.

28. 27. The softgel capsule of claim 26, wherein the plasticizer comprises glycerin and sorbitol sorbitan solution.

29. 28. The softgel capsule of claim 27, wherein the polysorbate comprises Tween 20, Tween 80, or a combination thereof.

30. 27. The softgel capsule of claim 26, wherein the plasticizer is present 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.

31. 23. The softgel capsule of claim 22, wherein the shell composition comprises gelatin.

32. 32. The softgel capsule of claim 31, wherein the gelatin is selected from the group consisting of type A gelatin, type B gelatin, and mixtures thereof.

33. 32. The softgel capsule of claim 31, wherein the gelatin is selected from the group consisting of fish gelatin, hide gelatin, bone gelatin, and mixtures thereof.

34. 32. The softgel capsule of claim 31, wherein the gelatin is present 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.

35. 23. The softgel capsule of claim 22, wherein the shell composition comprises gellan gum.

36. 36. The softgel capsule of claim 35, wherein the gellan gum is present in an amount of about 0.001 wt % to about 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 wt %, based on the total weight of the shell composition.

37. 23. The softgel capsule of claim 22, wherein the shell composition comprises dextrose.

38. 38. The softgel capsule of claim 37, wherein the dextrose is present in an amount of about 0.001 wt% to about 5 wt%, about 0.01 wt% to about 4.5 wt%, about 0.05 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.

39. 23. The softgel capsule of claim 22, treated with a treatment solution comprising calcium chloride.

40. 40. The softgel capsule of claim 39, wherein the calcium chloride is present in an amount of about 1 wt % to about 25 wt %, about 2 wt % to about 22 wt %, about 3 wt % to about 20 wt %, about 4 wt % to about 18 wt %, about 5 wt % to about 16 wt %, about 6 wt % to about 14 wt %, or about 7 wt % to about 12 wt %, based on the total weight of the treatment solution.

41. 40. The softgel capsule of claim 39, wherein the treatment solution further comprises water.

42. 42. The softgel capsule of claim 39 or 41, wherein the treatment solution further comprises a sugar.

43. 43. The softgel capsule of claim 42, wherein the sugar comprises dextrose.

44. 44. The softgel capsule of claim 43, wherein the dextrose is present in an amount of about 0.1 wt % to about 20 wt %, about 2 wt % to about 18 wt %, about 3 wt % to about 16 wt %, about 4 wt % to about 14 wt %, about 5 wt % to about 12 wt %, or about 6 wt % to about 10 wt %, based on the total weight of the processing solution.

45. 40. The softgel capsule of claim 39, wherein the treatment solution further comprises hydrochloric acid.

46. 40. The softgel capsule of claim 39, wherein the treatment results in a weight gain of about 1% to about 10% of the capsule.

47. 23. The softgel capsule of claim 22, having improved burst strength when compared to a capsule without calcium.

48. 23. The softgel capsule of claim 22, which does not burst at a pH of 1.2 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, or 120 minutes when measured in a 0.1 N hydrochloric acid (HCl) acidic medium with a USP Apparatus II with paddles at 50 RPM or 100 RPM.

49. 23. The softgel capsule of claim 22, which does not burst at a pH of 3.0, a pH of 4.0, or a pH of 5.0 in 15, 30, 45, 60, 75, or 90 minutes when measured with a USP Apparatus II with paddles at 50 RPM or 100 RPM in an acidic medium having a pH of 3.0, a pH of 4.0, or a pH of 5.

0.

50. 23. The softgel capsule of claim 22, which ruptures at a pH of 6 to 8 in less than 5 minutes, less than 10 minutes, less than 15 minutes, less than 20 minutes, less than 25 minutes, less than 30 minutes, less than 35 minutes, less than 40 minutes, less than 45 minutes, less than 50 minutes, less than 55 minutes, or less than 60 minutes when measured in a USP Apparatus II with paddles at 50 RPM, 100 RPM, 150 RPM, or 200 RPM in phosphate buffer.

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