Soft gel capsule and method for preparing soft gel capsule

Abstract

Disclosed herein is a method of making a soft gel capsule comprising treating a soft gel capsule with a solution comprising a calcium salt wherein the soft gel capsule comprises a filler material and a shell composition comprising pectin.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 432,445, filed on December 14, 2022, the entire content of which is incorporated herein by reference in its entirety. Field of the Invention

[0003] The present invention relates to a method of preparing soft gel capsules, which comprises treating the soft gel capsules with a solution comprising a calcium salt (e.g., calcium chloride). Also provided are soft gel capsules comprising a filling material and a shell composition, wherein the shell composition comprises calcium ions. Background of the Invention

[0004] Soft capsules, especially soft gelatin capsules (or soft gel capsules), provide a dosage form that is more readily acceptable to patients because the capsules are easy to swallow and do not require flavoring to mask any unpleasant taste of the active agent. The soft gel capsule encapsulation of a drug further provides the potential to improve the bioavailability of the pharmaceutical agent. For example, once the gelatin shell ruptures, the active ingredient can be rapidly released in liquid form.

[0005] Efforts have been made to manufacture 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, such that a coacervate layer can form in the shell, which is insoluble at acidic pH but soluble at neutral and alkaline pH.

[0006] Accordingly, there is a current need to improve methods of preparing soft gel capsules to improve pH tolerance in enteric coating and disintegration and the robustness of the shell. Summary of the Invention

[0007] The present invention relates to a method for preparing soft gel capsules. The method comprises treating the soft gel capsules with a solution comprising a calcium salt (e.g., calcium chloride), wherein the soft gel capsules comprise a filling material and a shell composition. In some embodiments, the solution may further comprise hydrochloric acid. In some embodiments, the solution may further comprise water. In some embodiments, the solution may further comprise sugar. The sugar may be dextrose.

[0008] In some embodiments of the method, the calcium salt may be included 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.

[0009] In some embodiments, the solution can have a pH of less than about 3.

[0010] In some embodiments, dextrose can be included 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.

[0011] 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 glycerol, sorbitol, sorbitan solution, triacetin, polysorbate, or a combination thereof. In other embodiments, the plasticizer can include glycerol, sorbitan solution, or a combination thereof. In yet another embodiment, the plasticizer can be sorbitan solution.

[0012] In some embodiments, the method can further include drying the capsules after treating the capsules. In some embodiments, the drying can be performed by drum drying the capsules. The drying can occur for about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, or about 4 hours. In some embodiments, the drying can be performed in a drying chamber or a drying tunnel.

[0013] In some embodiments of the method, the treating can include using a wash / cool treatment device for a predetermined period of time. The wash / cool treatment device can be fully automated. In some embodiments, the predetermined period of 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.

[0014] In another embodiment of the present disclosure, a soft gel capsule is provided. The soft gel capsule includes a filling material and a shell composition, the filling material includes an active agent, wherein the shell composition includes calcium ions.

[0015] In some embodiments, the shell composition can include pectin. The pectin can be low-methoxyl pectin. In some embodiments, pectin can be included 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.

[0016] In some embodiments, the shell composition may comprise a plasticizer. In some embodiments, the plasticizer may comprise glycerol, sorbitol, sorbitan solution, triacetin, polysorbate, or a combination thereof. In another embodiment, the plasticizer may comprise glycerol and sorbitan solution. In some embodiments, the polysorbate may comprise Tween 20, Tween 80, or a combination thereof.

[0017] In some embodiments, the plasticizer may be included 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.

[0018] In some embodiments, the shell composition may comprise 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 included 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.

[0019] In some embodiments, the shell composition may comprise gellan gum. The gellan gum may be included 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.

[0020] In some embodiments, the shell composition may comprise dextrose. The dextrose may be included 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.

[0021] In some embodiments, the soft gel capsule may be treated with a treatment solution comprising 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 included 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.

[0022] In some embodiments, the treatment solution may further comprise water. In some embodiments, the treatment solution may further comprise sugar. The sugar may comprise dextrose. The dextrose may be included 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.

[0023] In some embodiments, the treatment solution may further comprise hydrochloric acid.

[0024] In some embodiments, the treatment may provide a weight gain of about 1% to about 10% of the capsule. In some embodiments, the capsule may have improved breaking strength when compared to capsules that are not treated with calcium.

[0025] In some embodiments, at pH 1.2, when measured in 0.1N hydrochloric acid (HCl) acidic medium with a USP apparatus II with paddles at 50 RPM or 100 RPM, the capsule does not rupture at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes or 120 minutes.

[0026] In some embodiments, at pH 3.0, pH 4.0, pH 5.0, when measured in an acidic medium with the above pH with a USP apparatus II with paddles at 50 RPM or 100 RPM, the capsule does not rupture at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes or 90 minutes.

[0027] In some embodiments, at a pH between 6 and 8, when measured in phosphate buffer with a USP apparatus II with paddles at 50 RPM, 100 RPM, 150 RPM or 200 RPM, the capsule ruptures at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes or 60 minutes. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In the figures of the drawings, the present disclosure is illustrated by way of example and not limitation.

[0029] The figure shows a comparison of the capsule hygroscopicity between test capsules according to an example of the present disclosure. DETAILED DESCRIPTION

[0030] The present disclosure improves the state of the art by developing a processing method for preparing soft gel capsules. The method of the present disclosure rapidly initiates ionic gelation and a certain degree of crosslinking of gelatin and pectin with dextran to enhance the enteric function and physical robustness of the capsules. By treating the soft gel capsules with a calcium-containing solution, ionic gelation (calcium bridging effect) was found to be initiated. Thus, the inventors believe that calcium ions bridge the shell composition to form a larger and stronger reinforcing network.

[0031] As used herein, the term "enteric" is used to refer to the anti-dissolution or disintegration property of a substance such that dissolution or disintegration does not occur in the gastric environment. By way of example, the embodiments described herein include enteric shell compositions that dissolve in biological, artificial, or simulated intestinal fluid but not in biological, artificial, or simulated gastric fluid. The embodiments described herein may include a coating having an enteric polymer.

[0032] As used herein, a "pharmaceutically active ingredient" refers to a drug or compound that can be used for diagnosing, curing, alleviating, treating, or preventing a disease. The term "condition" or "conditions" refers to those medical conditions that can be treated or prevented by administering an effective amount of an active agent to a subject. Exemplary non-limiting conditions that can benefit from enteric soft gel capsules can include, but are not limited to, capsules containing lactic acid bacteria, fish oil capsules, proton pump inhibitors, aspirin (acetylsalicylic acid), and similar products.

[0033] As used herein, the term "active ingredient" refers to any material intended to produce a therapeutic, prophylactic, or other desired effect, whether or not approved by a government agency for such purpose. This term with respect to a particular reagent includes a pharmaceutically active agent and all of its pharmaceutically acceptable salts, solvates, and crystalline forms, where the salts, solvates, and crystalline forms are pharmaceutically active.

[0034] Any pharmaceutically active ingredient can be used for the purposes of the present invention, including those that are water-soluble and those that are poorly soluble in water. Suitable pharmaceutically active ingredients include, but are not limited to, analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterial agents, anticoagulants, antidepressants, antidiabetic agents, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarials, antimigraine agents, antimuscarinics, antineoplastic and immunosuppressive agents, antiprotozoals, antirheumatics, antithyroid agents, antivirals, anxiolytics, sedatives, hypnotics, and neuroleptics, β-blockers, inotropes, corticosteroids, cough suppressants, cytotoxics, decongestants, diuretics, enzymes, antiparkinson agents, gastrointestinal agents, histamine receptor antagonists, lipid regulators, local anesthetics, neuromuscular agents, nitrates, and antianginal agents, nutraceuticals, opioid analgesics, oral vaccines, proteins, peptides, and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and combinations thereof.

[0035] In some embodiments, the active pharmaceutical ingredient can be selected from, but not limited to, the group consisting of: dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurine, 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, its pharmaceutically acceptable salts, and combinations thereof.

[0036] In some embodiments, the lipids in the dosage form can be selected from, but not limited to, the group consisting of: almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew nut oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia nut oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, walnut 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 can include, but are not limited to, fish oil (ω-3), krill oil, animal or vegetable fats (e.g., in their hydrogenated form), free fatty acids, and monoglycerides, diglycerides, and triglycerides having C8-, C10-, C12-, C14-, C16-, C18-, C20-, and C22-fatty acids, and combinations thereof.

[0037] According to certain embodiments, the active agent can include lipid-lowering agents, including but not limited to statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), fibrates (e.g., clofibrate, ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil), niacin, bile acid sequestrants, ezetimibe, lomitapide, plant sterols, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof, mixtures of any of the foregoing, and the like.

[0038] Suitable nutraceutical active agents can include but are not limited to 5-hydroxytryptophan, acetyl-L-carnitine, alpha-lipoic acid, alpha-ketoglutarate, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetylenic acid esters, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), dimethylaminoethanol, fumaric acid, germanium sesquioxide, glandular products, glucosamine HCl, glucosamine sulfate, hydroxy-methylbutyrate, immunoglobulins, lactic acid, L-carnitine, liver products, malic acid, anhydrous maltose, mannose (d-mannose), methylsulfonylmethane, plant sterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0039] Suitable nutritional supplement active agents can include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, or combinations thereof.

[0040] Suitable vitamin active agents can include but are not limited to the following: ascorbic acid (vitamin C), B vitamins, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbates, mixed tocopherols, niacin (vitamin B3), orotic acid, para-aminobenzoic acid, pantothenates, 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.

[0041] Suitable herbal supplement active agents can include but are not limited to the following: arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginkgo, ginseng, goldenrod, hawthorn, kava-kava, licorice, milk thistle, plantain, rauwolfia, senna, soy, St. John's wort, saw palmetto, turmeric, valerian.

[0042] Mineral active agents can include but are not limited to the following: boron, calcium, chelated minerals, chloride, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvate, zinc and other minerals.

[0043] Examples of other possible active agents include, but are not limited to, antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), non-steroidal anti-inflammatory agents (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, suprofen, aminoprofen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tofenamicacid), diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprin, azapropazone, benorilate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicylic acid salicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, their pharmaceutically acceptable salts and mixtures thereof) and acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptic drugs (e.g., phenyloin, meprobmate and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardipine), antitussives and expectorants (e.g., codeine phosphate), antiasthmatic drugs (e.g., theophylline), antacids, antispasmodics (e.g., atropine, scopolamine), antidiabetic drugs (e.g., insulin), diuretics (e.g., ethacrynicacid), bendrofluthiazide), antihypotensive agents (e.g., propranolol, clonidine), antihypertensive agents (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidal agents, hypnotics, psychotropic drugs, antidiarrheal agents, mucolytics, sedatives, decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants, e.g., phenylpropanolamine), and cannabinoids, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof.

[0044] The active agent can also be a benzodiazepine, barbiturate, stimulant, or a mixture thereof. The term "benzodiazepine" refers to benzodiazepines and drugs that are derivatives of benzodiazepines capable of inhibiting 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 pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Benzodiazepine antagonists that can be used as active agents include, but are not limited to, flumazenil, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0045] The term "barbiturate" refers to sedative-hypnotic drugs 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 can be used as active agents include, but are not limited to, amphetamine, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0046] The term "stimulant" includes, but is not limited to, amphetamine, such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof. Stimulant antagonists that can be used as active agents include, but are not limited to, benzodiazepines, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0047] Formulations according to the present disclosure include various active agents and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonate salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; amino acid salts such as arginine salt, aspartate salt, glutamate salt, etc.; and metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metals such as calcium salt, magnesium salt, etc.; organic amine salts such as triethylamine salt, pyridine salt, methylpyridine salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

[0048] As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount of an active agent or the rate of its administration required to produce the desired therapeutic result.

[0049] As used herein, "shell" or "shell composition" refers to the shell of a soft gel capsule encapsulating a filling material.

[0050] As used herein, "conventional enteric polymers" refers to, but is not limited to, acrylic and methacrylic acid polymers, which are available under the trade name EUDRAGIT®, and other conventional acid-insoluble polymers, such as methyl acrylate-methacrylic acid copolymer. 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 (e.g., sodium alginate and potassium alginate), stearic acid, and shellac. In some embodiments, the enteric shell composition of the present invention does not contain acid-insoluble polymers. In other words, the enteric shell composition and the enteric soft gel capsule "do not contain or substantially do not contain conventional enteric polymers".

[0051] All references to wt% throughout the specification and claims refer to the weight of the component relative to the weight of the entire composition and may also be designated as w / w.

[0052] As used herein, "fill material" or "fill" refers to a composition that is encapsulated by an enteric capsule shell and contains at least one pharmaceutically active ingredient.

[0053] As used herein, "delayed release" means the release of the active agent after passing through the stomach.

[0054] As used herein, "about" refers to any value within a variation of ± 10%, such that "about 10" would include 9 to 11. As used herein, unless otherwise specified, "a", "an", or "the" refers to one or more. Thus, for example, a reference to "excipient" includes a single excipient and mixtures of two or more different excipients, etc.

[0055] Unless otherwise indicated herein, the recitation of a range of values herein is merely intended to be a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein may be performed in any suitable order.

[0056] The use of any and all examples or exemplary language (e.g., "such as") provided herein is merely intended to illustrate particular materials and methods and does not limit the scope. The language in the specification should not be construed as indicating that any unclaimed element is essential for the practice of the disclosed materials and methods.

[0057] According to one embodiment, a method of preparing soft gel capsules comprises treating the soft gel capsules with a solution comprising a calcium salt, wherein the soft gel capsules comprise a filling material and a shell composition. The calcium salt can be calcium chloride, calcium citrate, calcium gluconate, calcium lactate, or any other soluble calcium salt.

[0058] In some embodiments of the method, the solution can further comprise hydrochloric acid. In some embodiments, the solution can further comprise water. In other embodiments, the solution can further comprise sugar. The sugar can comprise dextrose.

[0059] In some embodiments of the method, calcium chloride can be included 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.

[0060] In certain embodiments of the method, hydrochloric acid can be included to produce a solution having a pH less than 3.

[0061] In some embodiments, dextrose can 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.

[0062] In some embodiments of the method, the shell composition can comprise a plasticizer, pectin, gellan gum, dextrose, gelatin, or a combination thereof.

[0063] In certain embodiments, the plasticizer can comprise glycerol, sorbitol, sorbitan solution, triacetin, polysorbate, or a combination thereof. In some embodiments, the plasticizer can comprise glycerol, sorbitan solution, or a combination thereof. In yet another embodiment, the plasticizer can be sorbitan solution.

[0064] In some embodiments, the method can further comprise drying the soft gel capsules. In some embodiments, the drying can be performed by tumbling the capsules. In some embodiments, the drying occurs for about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, or about 4 hours. In other embodiments, the method can comprise drying the capsules in a drying chamber or a drying tunnel.

[0065] In some embodiments of the method, the processing may include using a soft gel capsule washing / cooling processing device, wherein the soft gel capsules are treated with a solution for a predetermined period of time. The soft gel capsule washing / cooling processing device may be fully automated.

[0066] In certain embodiments, the predetermined period of time for processing may 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.

[0067] In other embodiments of the present invention, a soft gel capsule is provided. The soft gel capsule may include a filling material and a shell composition, the filling material including an active agent, wherein the shell composition includes calcium ions.

[0068] Suitable filling materials include at least one pharmaceutically active ingredient and may be prepared according to known methods. In addition to the at least one pharmaceutically active ingredient, suitable filling materials may include additional filling components such as flavoring agents, sweetening agents, coloring agents, and fillers or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides. Those of ordinary skill in the art can readily determine the appropriate amounts of pharmaceutically active ingredients and pharmaceutically acceptable excipients.

[0069] In some embodiments, the shell composition may include pectin. The pectin in the shell composition may be low-methoxyl pectin. In one embodiment, the low-methoxyl 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 soft gel capsule, which may in turn adversely affect the sealability of the soft gel capsule. Therefore, pectin may be added to the dosage form at a concentration high enough to form an enteric dosage form and yet low enough to mitigate the reduction in gel strength. In one embodiment, based on the total weight of the shell composition, 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%. The degree of esterification of the pectin incorporated into the shell composition may be less than about 50%, or may be in the range of about 10% to about 50%, about 20% to about 40%, or about 25% to about 35%.

[0070] In some embodiments of the capsule, the shell composition may further comprise a plasticizer. The plasticizer may comprise glycerol, sorbitol, sorbitan solution, triacetin, polysorbate, or a combination thereof. In one embodiment, the plasticizer may comprise glycerol and sorbitan solution. In some embodiments, the polysorbate may comprise Tween 20, Tween 80, or a combination thereof. Other suitable plasticizers may include, but are not limited to, sugar alcohol plasticizers such as isomaltulose, maltitol, xylitol, erythritol, adonitol, galactitol, pentaerythritol, or mannitol; or polyol plasticizers such as diglycerol, dipropylene glycol, polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3 - propanediol, 2 - methyl - 1,3 - propanediol, trimethylolpropane, polyether polyol, ethanolamine; and mixtures thereof. Other exemplary plasticizers may also 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, ethylene glycol ethers, poly(propylene glycol), multi - block polymers, single - block polymers, citrate - type plasticizers, and triacetin. Such plasticizers may include 1,2 - butanediol, 2,3 - butanediol, styrene glycol, monopropyl 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, tributyl acetylcitrate, triethyl citrate, glyceryl monostearate, polysorbate 80, triethyl acetylcitrate, tributyl citrate, and allyl glycolate and mixtures thereof.

[0071] In some embodiments, the amount of the plasticizer may be 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.

[0072] In some embodiments of the soft - gel capsule, the shell composition may further comprise gelatin. The gelatin may comprise 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, only one type of gelatin is present. In yet another embodiment, the gelatin is a combination of at least two types of gelatin. In one embodiment, based on the total weight of the enteric - coated shell composition, the amount of gelatin 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%.

[0073] In some embodiments, the shell composition of the soft gel capsule may further comprise gellan gum, dextrose, water, or a combination thereof. In some embodiments, based on the total weight of the shell composition, the amount of dextrose may be from about 0.001 wt% to about 5 wt%, from about 0.01 wt% to about 4.5 wt%, from about 0.01 wt% to about 4 wt%, from about 0.1 wt% to about 3 wt%, or from about 1 wt% to about 2.5 wt%.

[0074] In some embodiments, based on the total weight of the shell composition, the amount of gellan gum may be included in an amount of from about 0.001 wt% to about 5 wt%, from about 0.01 wt% to about 4 wt%, from about 0.1 wt% to about 3 wt%, or from about 1 wt% to about 2 wt%.

[0075] In some embodiments, the soft gel capsule may be treated with a treatment solution. The treatment solution may comprise 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.

[0076] In some embodiments, based on the total weight of the treatment solution, the calcium salt may be included in an amount of from about 1 wt% to about 25 wt%, from about 2 wt% to about 22 wt%, from about 3 wt% to about 20 wt%, from about 4 wt% to about 18 wt%, from about 5 wt% to about 16 wt%, from about 6 wt% to about 14 wt%, or from about 7 wt% to about 12 wt%.

[0077] In some embodiments, the treatment solution may further comprise water. In other embodiments, the treatment solution may further comprise sugar. The sugar may be dextrose. Based on the total weight of the treatment solution, the sugar or dextrose may be included in an amount of from about 0.1 wt% to about 20 wt%, from about 2 wt% to about 18 wt%, from about 3 wt% to about 16 wt%, from about 4 wt% to about 14 wt%, from about 5 wt% to about 12 wt%, or from about 6 wt% to about 10 wt%.

[0078] In some embodiments, the soft gel capsule may be treated with a calcium treatment solution. The treatment may provide a weight gain of about 1% to about 10%, about 2% to about 8%, or about 3% to about 5% of the capsule.

[0079] In some embodiments, when compared to capsules without the treatment of the present invention, after treatment, the capsules may have improved breaking strength.

[0080] In one embodiment, the shell composition of the soft gel capsule may optionally include additional reagents such as colorants, flavoring agents, sweeteners, fillers, antioxidants, diluents, pH regulators, or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides.

[0081] Exemplary suitable colorants can include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown. In certain embodiments, the color of the dosage form may indicate the contents therein (e.g., one or more active ingredients).

[0082] Exemplary suitable flavoring agents can include, but are not limited to, "flavor extracts" obtained by extracting a portion of a raw material (e.g., animal or plant material), typically by using a solvent such as ethanol or water; natural flavorings obtained by extracting essential oils from flowers, fruits, roots, etc. or from the whole plant.

[0083] Additional exemplary flavoring agents that can be in the dosage form can include, but are not limited to, breath freshening compounds such as menthol, spearmint, and cinnamon; coffee beans; other flavors or fragrances such as fruit flavors (e.g., cherry, orange, grape, etc.), especially those for oral hygiene, and active agents for tooth and oral cleaning such as quaternary ammonium bases. The effect of the flavor can be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

[0084] Exemplary sweeteners can include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Artificial sweeteners include, for example: acesulfame and its various salts such as the potassium salt (available as Sunett®); alitame; aspartame (available as NutraSweet® and Equal®); the salt of aspartame - acesulfame (available as Twinsweet®); neohesperidin dihydrochalcone; naringin dihydrochalcone; dihydrochalcone compounds; neotame; cyclamate; saccharin and its various salts such as the sodium salt (available as Sweet'N Low®); stevia; chlorinated derivatives of sucrose such as sucralose (available as Kaltame® and Splenda®); and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; ammonium glycyrrhizinate (sold under the trade name MagnaSweet®); stevia (stevioside), natural high - potency sweeteners (e.g., monk fruit), polyols (e.g., sorbitol, mannitol, xylitol, erythritol, etc.).

[0085] In some embodiments, at pH 1.2, when measured in 0.1N hydrochloric acid (HCl) acidic medium using a USP Apparatus II with paddles at 50 RPM or 100 RPM, the soft gelatin capsules do not rupture within 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, or 120 minutes.

[0086] In some embodiments, at pH 3.0, pH 4.0, or pH 5.0, when measured in an acidic medium using a USP Apparatus II with paddles at 50 RPM or 100 RPM, the soft gelatin capsules do not rupture within 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, or 90 minutes.

[0087] In some embodiments, at a pH between 6 and 8, when measured in phosphate buffer using a USP Apparatus II with paddles at 50 RPM, 100 RPM, 150 RPM, or 200 RPM, the capsules rupture within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or 60 minutes.

[0088] Encapsulation of the filling material can be done in any conventional manner. As an example, rotary die encapsulation can be used.

[0089] According to one embodiment, an enteric soft gelatin capsule is prepared by a process comprising: preparing a filling material comprising an active agent; encapsulating the filling material in a shell composition to form a soft gelatin capsule. The capsule is then treated with a treatment solution comprising a calcium source such as calcium chloride, calcium chloride dihydrate (CaCl2:2H2O), calcium citrate, calcium gluconate, or calcium lactate. The treatment involves using a fully automatic soft gelatin capsule washing / cooling treatment device. The soft gelatin capsules are further dried after treatment using a drum dryer in a drying chamber or drying tunnel.

[0090] List of items

[0091] 1. A method for preparing soft gelatin capsules, comprising:

[0092] Treating the soft gelatin capsules with a solution comprising a calcium salt, wherein the soft gelatin capsules comprise a filling material and a shell composition.

[0093] 2. The method according to item 1, wherein the calcium salt comprises calcium chloride, calcium citrate, calcium gluconate, calcium lactate, or a combination thereof.

[0094] 3. The method according to item 1, wherein the solution further comprises hydrochloric acid.

[0095] 4. The method according to item 1, wherein the solution further comprises water.

[0096] 5. The method according to any one of items 1 to 4, wherein the solution further comprises sugar.

[0097] 6. The method according to item 5, wherein the sugar comprises dextrose.

[0098] 7. The method according to any one of the preceding items, wherein the calcium salt is included 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.

[0099] 8. The method according to item 3, wherein the pH of the solution is less than 3.

[0100] 9. The method according to item 6, wherein the dextrose is included 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.

[0101] 10. The method according to any one of the preceding items, wherein the shell composition comprises a plasticizer, pectin, gellan gum, dextrose, gelatin, or a combination thereof.

[0102] 11. The method according to item 10, wherein the plasticizer comprises glycerol, sorbitol, sorbitan solution, triacetin, polysorbate, or a combination thereof.

[0103] 12. The method according to item 10, wherein the plasticizer comprises glycerol, sorbitan solution, or a combination thereof.

[0104] 13. The method according to item 10, wherein the plasticizer is a sorbitan solution.

[0105] 14. The method according to any one of the preceding items, further comprising drying the capsule after treating the capsule.

[0106] 15. The method according to item 14, wherein the drying is performed by drum drying the capsule.

[0107] 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.

[0108] 17. The method according to item 14, wherein the drying is carried out in a drying chamber or a drying tunnel.

[0109] 18. The method according to any one of the preceding items, wherein the treatment comprises using a washing / cooling treatment device for a predetermined period of time.

[0110] 19. The method according to item 18, wherein the washing / cooling treatment device is fully or partially automated.

[0111] 20. The method according to item 18, wherein the washing / cooling treatment device is covered and can be frozen or cooled using an external cooler.

[0112] 21. The method according to item 18, wherein the period of 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.

[0113] 22. A soft gel capsule, comprising:

[0114] a filling material comprising an active ingredient; and

[0115] a shell composition, wherein the shell composition contains calcium ions.

[0116] 23. The soft gel capsule according to item 22, wherein the shell composition comprises pectin.

[0117] 24. The soft gel capsule according to item 23, wherein the pectin is low-methoxyl pectin.

[0118] 25. The soft gel capsule according to item 23, wherein the pectin is included 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.

[0119] 26. The soft gel capsule according to item 22, wherein the shell composition comprises a plasticizer.

[0120] 27. The soft gelatin capsule according to item 26, wherein the plasticizer comprises glycerol, sorbitol, sorbitan solution, triacetin, polysorbate or a combination thereof.

[0121] 28. The soft gelatin capsule according to item 26, wherein the plasticizer comprises glycerol and sorbitan solution.

[0122] 29. The soft gelatin capsule according to item 27, wherein the polysorbate comprises Tween 20, Tween 80 or a combination thereof.

[0123] 30. The soft gelatin capsule according to item 26, wherein the plasticizer is included 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.

[0124] 31. The soft gelatin capsule according to item 22, wherein the shell composition comprises gelatin.

[0125] 32. The soft gelatin capsule according to item 31, wherein the gelatin is selected from the group consisting of Type A gelatin, Type B gelatin and mixtures thereof.

[0126] 33. The soft gelatin capsule according to item 31, wherein the gelatin is selected from the group consisting of fish gelatin, hide gelatin, bone gelatin and mixtures thereof.

[0127] 34. The soft gelatin capsule according to item 31, wherein the gelatin is included 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.

[0128] 35. The soft gelatin capsule according to item 22, wherein the shell composition comprises gellan gum.

[0129] 36. The soft gelatin capsule according to item 35, wherein the gellan gum is included 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.

[0130] 37. The soft gelatin capsule according to item 22, wherein the shell composition comprises dextrose.

[0131] 38. The soft gel capsule according to item 37, wherein the dextrose is included 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.

[0132] 39. The soft gel capsule according to item 22, wherein the soft gel capsule is treated with a treatment solution including calcium chloride.

[0133] 40. The soft gel capsule according to item 39, wherein the calcium chloride is included 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.

[0134] 41. The soft gel capsule according to item 39, wherein the treatment solution further includes water.

[0135] 42. The soft gel capsule according to item 39 or 41, wherein the treatment solution further includes sugar.

[0136] 43. The soft gel capsule according to item 42, wherein the sugar includes dextrose.

[0137] 44. The soft gel capsule according to item 43, wherein the dextrose is included 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.

[0138] 45. The soft gel capsule according to any one of items 39, 41 or 42, wherein the treatment solution further includes hydrochloric acid.

[0139] 46. The soft gel capsule according to any one of items 39 to 45, wherein the treatment provides a weight increase of about 1% to about 10% of the capsule.

[0140] 47. The soft gel capsule according to any one of items 22 to 46, wherein the capsule has improved breaking strength as compared to a calcium-free capsule.

[0141] 48. The soft gel capsule according to any one of items 22 to 47, wherein at pH 1.2, when measured in 0.1N hydrochloric acid (HCl) acidic medium with a USP apparatus II having a paddle at 50 RPM or 100 RPM, the capsule does not rupture at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes or 120 minutes.

[0142] 49. The soft gel capsule according to any one of items 22 to 47, wherein at pH 3.0, pH 4.0, pH 5.0, when measured in an acidic medium having the above pH with a USP apparatus II having a paddle at 50 RPM or 100 RPM, the capsule does not rupture at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes or 90 minutes.

[0143] 50. The soft gel capsule according to any one of items 22 to 47, wherein at a pH between 6 and 8, when measured in phosphate buffer with a USP apparatus II having a paddle at 50 RPM, 100 RPM, 150 RPM or 200 RPM, the capsule ruptures at 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.

[0144] Examples

[0145] Specific embodiments of the present invention will now be illustrated by reference to the following examples. It should be understood that these examples are disclosed only by way of illustration of the present invention and should not limit the scope of the present invention in any way.

[0146] Experimental procedures and methods

[0147] Calcium chloride solution

[0148] Among all available types of calcium ion resources for initiating the calcium bridging effect, calcium chloride is considered a preferred choice due to its low cost and higher solubility. To simplify the procedure, weight percentages are used for all different concentrations of calcium chloride solution. Examples of 5% and 10% calcium chloride base formulations are listed in Table 1.

[0149] Pectin ionic gelation is pH-dependent. The gel network is more stable at lower pH (less than 5) than in a higher pH (above 7) environment. It is an important finding of this study that the pH value of the calcium chloride solution was intentionally adjusted from pH > 8 to pH < 3 with 0.1N hydrochloride solution.

[0150] Table 1. Aqueous calcium chloride solution

[0151]

[0152] Calcium chloride and hydrochloric acid solution

[0153]

[0154] Calcium chloride and dextrose solution

[0155] Reducing sugars (e.g., dextrose) contain free aldehyde or ketone groups and can be classified as typical crosslinking agents that induce covalent crosslinking. By adding dextrose as a reducing sugar to a calcium chloride solution, it can enhance the enteric function on the surface of soft gel capsules. Examples of the basic formulation of 10% calcium chloride and 5% or 10% dextrose solution are listed in Table 2. The pH value of the calcium chloride / dextrose solution was intentionally adjusted to pH < 3 with 0.1N hydrochloride solution.

[0156] Table 2. Aqueous solution of calcium chloride and dextrose

[0157]

[0158] Soft gel capsules

[0159] Soft gel capsules from different manufacturing batches (Samples 1 to 5) were used to evaluate the calcium treatment. The gel substance formulations used to manufacture these three batches are shown in Table 3.

[0160] Table 3. Qualitative shell formulation

[0161]

[0162] After drum drying the capsules during the conventional encapsulation process, the capsules were collected and treated by immersing them in a stainless-steel container with a filter basket containing 3 liters of calcium chloride solution for different periods of time (5 seconds, 10 seconds, and 20 seconds respectively). Approximately 500 capsules were manually processed at each time point. After the calcium treatment, the capsules were drum dried in a drum dryer for 1 hour to remove the excess water introduced by the calcium treatment on the shell. The treated capsules were later dried in a drying chamber according to the standard soft gel tunnel drying process.

[0163] 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 the treatment time and the effectiveness of dextrose addition.

[0164] To be fully integrated into the current encapsulation process, the calcium treatment or calcium and dextrose treatment step can be added to the process chain just before drum drying with fully automated equipment during the conventional soft gel manufacturing process.

[0165] The fully automated equipment consists of a jacked rectangular container or a calcium treatment solution reservoir with a built-in conveyor. The treatment time can be adjusted by regulating the speed of the conveyor belt. The temperature of the calcium solution can be maintained by an external cooler hooked to the jacked container.

[0166] Overview of test results

[0167] Weight gain during calcium treatment

[0168] After calcium treatment, it is expected that the treated capsules gain a small amount of weight. Table 4 summarizes the weight gain data from untreated and treated fresh capsules as well as dried finished capsules.

[0169] Table 4. Summary of weight gain (Sample 1)

[0170]

[0171] Compared with untreated wet capsules, the weight gain just after calcium treatment varies in the range 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 product is between 13 to 16 mg per capsule or 3.7 to 4.6% of the shell weight.

[0172] Weight gain during calcium and dextrose treatment

[0173] Table 5 summarizes the weight gain data from untreated and treated finished dried capsules with contact times of 1 minute, 2 minutes, and 5 minutes.

[0174] Table 5. Summary of weight gain (Sample 2, 20 oblong)

[0175]

[0176] Compared with untreated finished dried capsules, the weight gain of the calcium and dextrose-treated product is between 55 to 115 mg per capsule or 10.8 to 22.6% of the shell weight. The concentration of the solution does not affect the capsule weight gain, and the treatment time is the only factor.

[0177] Low methoxylated (LMA) pectin is sensitive to the presence of calcium ions and is more tolerant of calcium content compared to high methoxyl (HM) pectin and low methoxyl (LM) pectin. LMA will gel over a wide range of calcium concentrations. However, the pectin gel strength will reach its maximum level at approximately 40 mg Ca per gram of pectin 2+ , and then the gel strength will decrease as the calcium ion concentration increases. The weight gain should be carefully controlled by limiting the treatment time.

[0178] Capsule hygroscopicity test

[0179] The hygroscopicity test of the capsules was carried out by exposing the capsules to 0.1N HCl solution for a certain time and recording the weight increase of the capsules. Table 6 summarizes the hygroscopicity data of the untreated and treated finished dry capsules with contact times of 1 minute, 2 minutes, and 5 minutes respectively. Figure 1 Show the comparison of capsule hygroscopicity between the test capsules.

[0180] Table 6. Capsule hygroscopicity results (per capsule) of selected soft gel capsules

[0181]

[0182] The untreated soft gel capsules had a weight increase of more than 15.4% after 5 minutes and 22.6% after 10 minutes, indicating stronger hygroscopicity. The calcium plus dextrose-treated soft gel capsules had very similar weight increases after 5 minutes and 10 minutes of exposure to the acidic medium and had less weight increase when compared to the untreated capsules. This indicates that the calcium and dextrose treatment provides a better moisture barrier.

[0183] Capsule appearance

[0184] The fresh soft gel capsules treated with 5% calcium chloride aqueous solution were clear and transparent with a slightly improved shape. No obvious differences were identified when compared to the untreated capsules. The soft gel capsules treated with 10% calcium chloride aqueous solution for 20 seconds showed a slightly turbid appearance. Therefore, if a 10% calcium chloride solution is used, the treatment time is preferably within about 10 seconds. The dry finished soft gel capsules treated with calcium chloride and dextrose solution were clear and transparent. No obvious differences were identified when compared to the untreated capsules.

[0185] Capsule breaking strength

[0186] The breaking strength of the soft gel capsules is an indicator of the capsule sealing quality. This is a key quality attribute of the soft gel capsules and indicates how strong the soft gel seal is or how brittle the capsules are. The breaking strength data of all 47 samples were collected by using a physical property analyzer TA. HD plus is summarized in Table 7.

[0187] From the results, the breaking strength of the calcium-treated capsules of batch sample 3 was significantly higher than that of the untreated capsules. For batch sample 1, the breaking strength of the capsules treated with 10% CaCl2 for 5 seconds and 20 seconds was significantly higher than that of the capsules treated with 5% CaCl2 for 5 seconds and 20 seconds. Therefore, it is considered that the calcium treatment introduced a calcium bridging effect, which produced stronger complex gelation. Therefore, the robustness of the soft gel capsules was improved.

[0188] Table 7. Fracture strength of dried soft gel capsules

[0189]

[0190] Capsule disintegration test

[0191] The disintegration test is considered a standard enteric coating function test in both USP and EP. It is important that the finished product passes the required disintegration test described in the finished product specifications. To evaluate the quality of untreated finished soft gel capsules and calcium-treated capsules, a two-stage disintegration test was performed on both treated and untreated capsules according to EP and USP standards. In this study, an acidic phase disintegration test of up to 2 hours was performed, and an extended buffer phase disintegration test was only performed on selected calcium-treated soft gels and untreated soft gels.

[0192] Table 8 summarizes the test results of freshly calcium chloride-treated finished capsules from different batches.

[0193] Table 8. Summary of the 2-hour disintegration test of selected finished capsules (USP APP B in 0.1N HCl (pH = 1.2 ± 0.2) for up to 2 hours)

[0194]

[0195] * Misalignment of the capsule led to premature rupture of 1 capsule

[0196] The disintegration time of calcium-treated capsules in acidic medium was significantly longer than that of untreated capsules. Preliminary results indicate that the calcium bridging effect enhances the enteric coating function of soft gel capsules. Capsules treated with 5% calcium chloride solution for 20 seconds showed better enteric coating performance in acidic medium than capsules treated for shorter times.

[0197] Finished dried soft gel capsules from batch sample 2 were selected and treated with two different concentrations of calcium chloride and dextran solutions for 1 minute, 2 minutes, and 5 minutes respectively. Table 9 summarizes the test results of dried finished capsules treated with calcium and dextran solutions. Similarly, only an acidic phase disintegration test of up to 2 hours was performed. In addition, capsules from the same batch were treated with 5% calcium chloride solution for 15 minutes to challenge the contact time limit.

[0198] Table 9. Summary of the 2-hour disintegration test of sample 2 finished capsules (USP APP B in 0.1N HCl (pH = 1.2 ± 0.2) for up to 2 hours)

[0199]

[0200] The capsules treated for 5 minutes did not perform as well as those treated for 1 minute and 2 minutes, which confirmed that the excessive calcium ion loading reduced the enteric coating function of the gel. Adding dextran to the calcium treatment has not shown a significant benefit in improving the enteric properties.

[0201] Table 10 summarizes the two-stage disintegration test results of the calcium chloride-treated and untreated finished capsules from Samples 4 and 5.

[0202] Table 10. Summary of the two-stage disintegration test of selected finished capsules (USP APP B in 0.1N HCl (pH = 1.2 ± 0.2) for up to 2 hours and in phosphate buffer (pH = 6.8 ± 0.2) for an extended test time)

[0203]

[0204] The disintegration time of the calcium-treated capsules remained intact for two hours in the acidic medium, and the disintegration time in the buffer medium was significantly longer than that of the untreated capsules. The results indicate that the calcium bridging effect enhanced the enteric coating function of the soft gel capsules. The enhancement of the enteric coating function caused by the calcium treatment was stable and consistent.

[0205] Two-stage dissolution test of capsules

[0206] The two-stage dissolution test is also regarded as the standard enteric coating function test in both the USP and EP methods. Importantly, enteric products also pass the required two-stage dissolution test described in the product specifications. To evaluate the quality of the finished soft gel capsules and the calcium-treated capsules, the two-stage dissolution test was performed on both the treated and untreated capsules of the selected batches.

[0207] Based on previous development work, we found that the curing process is necessary for the pectin-gelatin polyelectrolyte complex system to be completed and able to provide the required enteric coating function. To complete the formation of the interaction complex, the curing time may require at least one to four weeks under ambient conditions. If the finished capsules are tested before the curing is completed, premature release may be observed within the first 5 to 15 minutes of the two-stage dissolution test. To shorten or eliminate the curing time and make the soft gel capsules more effective, calcium treatment can reduce or even eliminate the curing time. Table 11 summarizes the data on the test results for capsules from different batches.

[0208] Table 11. Summary of the two-stage dissolution test of Sample 1 (USP APP II in 0.1N HCl (pH = 1.2 ± 0.2) for 2 hours, followed by testing in converted phosphate buffer pH 6.8 ± 0.2)

[0209]

[0210] *Manufacturing date

[0211] The test data clearly show that even within one week after manufacturing, all calcium-treated capsules passed the two-stage rupture test without any premature release being observed, while 2 out of 6 untreated capsules from the same batch still had premature release. In addition, all treated capsules ruptured within 10 minutes during the buffering phase, which confirmed that calcium-ion-induced pectin ionic gelation is pH-dependent.

[0212] High pH tolerance

[0213] The pH value of human gastric juice can vary 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 may increase during food digestion. To ensure enteric function delivery across all pH ranges, it is important that the capsules can tolerate a higher pH environment for a certain period of time. According to previous studies on capsules prepared with pectin and gelatin gels, the capsules may only remain intact in a pH 5 medium for approximately 30 minutes before rupturing. Table 12 outlines the data on the test results of capsules from different batches after calcium treatment in a pH 5 medium.

[0214] Table 12. Overview of higher pH tolerance tests

[0215]

[0216] The rupture time of calcium-treated capsules in a pH 5 medium was significantly longer than that of untreated capsules. This indicates that calcium treatment enhances the high pH tolerance of soft gel capsules. The longer the calcium treatment time, the higher the pH tolerance of the capsules.

[0217] Overview and conclusions

[0218] The data outlined in this study demonstrate the benefits of calcium treatment of soft gels. Calcium treatment provides multiple benefits to soft gel capsules, including but not limited to:

[0219] 1. Minimal changes to the current gel formulation or process by incorporating an in-line calcium treatment step after encapsulation.

[0220] 2. The same appearance and a slightly improved shape.

[0221] 3. No curing time is required before performing the two-stage rupture or disintegration tests.

[0222] 4. An improved moisture barrier in acidic media.

[0223] 5. Improved enteric performance: passing both the two-stage rupture test and the two-stage disintegration test (both USP and EP).

[0224] 6. Improved high pH tolerance. Remains intact for one hour in a pH 5.0 medium.

[0225] 7. Adding dextrose to calcium showed no advantage in short-term storage. However, due to the time taken for dextrose cross-linking, ongoing long-term stability studies are expected to show further enhanced enteric coating functionality.

[0226] Calcium treatment or calcium and dextrose treatment has an optimal treatment time for gelling pectin to its maximum gel strength and enteric coating functionality. In the short term, there was no significant difference between calcium and dextrose treatment compared to calcium treatment alone. The effectiveness of adding dextrose will be further evaluated.

[0227] Furthermore, due to the enhanced enteric coating functionality and performance, the target strip thickness of the capsule can potentially be reduced by calcium treatment, thus reducing raw material costs.

[0228] The foregoing description sets forth numerous specific details, such as examples of particular systems, components, methods, etc., in order to provide a good understanding of several 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 are not described in detail in order to avoid unnecessarily obscuring the present invention. Accordingly, the specific details set forth are illustrative. Specific embodiments may vary from these illustrative details and still be contemplated as being within the scope of the present invention.

[0229] Although the operations of the methods herein are described in a particular order, the order of operations of each method may be changed such that some operations may be performed in reverse order, or such that some operations may be performed at least partially concurrently with other operations. In another embodiment, the instructions or sub-operations of different operations may be carried out in an intermittent and / or alternating manner.

[0230] It should be understood that the above description is intended to be illustrative and not restrictive. After reading and understanding the above description, many other embodiments will be apparent to those skilled in the art. Accordingly, the scope of the present invention should be determined by reference to the appended claims and the full scope of equivalents thereto.

Claims

1. A method for preparing soft gel capsules, which comprises: Treating the soft gel capsules with a solution comprising a calcium salt, wherein the soft gel capsules comprise a filling material and a shell composition.

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

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

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

5. The method according to claim 1, wherein the solution further comprises sugar.

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

7. The method according to claim 1, wherein the calcium salt is included 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 claim 3, wherein the pH of the solution is less than 3.

9. The method according to claim 6, wherein the dextrose is included 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 according to claim 1, wherein the shell composition comprises a plasticizer, pectin, gellan gum, dextrose, gelatin, or a combination thereof.

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

12. The method according to claim 10, wherein the plasticizer comprises glycerol, sorbitan solution, or a combination thereof.

13. The method according to claim 10, wherein the plasticizer is sorbitan solution.

14. The method according to claim 1, which further comprises drying the capsules after treating the capsules.

15. The method according to claim 14, wherein the drying is performed by drum drying the capsules.

16. The method according to 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. The method according to claim 14, wherein the drying is performed in a drying chamber or a drying tunnel.

18. The method according to claim 1, wherein the treatment comprises using a washing / cooling treatment device for a predetermined period of time.

19. The method according to claim 18, wherein the washing / cooling treatment device is fully or partially automated.

20. The method according to claim 18, wherein the washing / cooling treatment device is topped and capable of being frozen or cooled using an external cooler.

21. The method according to 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 soft gel capsule, comprising: a filling material comprising an active agent; and a shell composition, wherein the shell composition contains calcium ions.

23. The soft gel capsule according to claim 22, wherein the shell composition comprises pectin.

24. The soft gel capsule according to claim 23, wherein the pectin is low-methoxyl pectin.

25. The soft gel capsule according to claim 23, wherein the pectin is included 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 soft gel capsule according to claim 22, wherein the shell composition comprises a plasticizer.

27. The soft gel capsule according to claim 26, wherein the plasticizer comprises glycerol, sorbitol, sorbitan solution, triacetin, polysorbate or a combination thereof.

28. The soft gel capsule according to claim 26, wherein the plasticizer comprises glycerol and sorbitan solution.

29. The soft gel capsule according to claim 27, wherein the polysorbate comprises Tween 20, Tween 80 or a combination thereof.

30. The soft gel capsule according to claim 26, wherein the plasticizer is included 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 soft gel capsule according to claim 22, wherein the shell composition comprises gelatin.

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

33. The soft gel capsule according to claim 31, wherein the gelatin is selected from the group consisting of fish gelatin, hide gelatin, bone gelatin and mixtures thereof.

34. The soft gel capsule according to claim 31, wherein the gelatin is included 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 soft gelatin capsule according to claim 22, wherein the shell composition comprises gellan gum.

36. The soft gelatin capsule according to claim 35, wherein the gellan gum is included 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 soft gelatin capsule according to claim 22, wherein the shell composition comprises dextrose.

38. The soft gelatin capsule according to claim 37, wherein the dextrose is included 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 soft gelatin capsule according to claim 22, wherein the soft gelatin capsule is treated with a treatment solution comprising calcium chloride.

40. The soft gelatin capsule according to claim 39, wherein the calcium chloride is included 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 soft gelatin capsule according to claim 39, wherein the treatment solution further comprises water.

42. The soft gelatin capsule according to claim 39 or 41, wherein the treatment solution further comprises sugar.

43. The soft gelatin capsule according to claim 42, wherein the sugar comprises dextrose.

44. The soft gelatin capsule according to claim 43, wherein the dextrose is included 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 soft gelatin capsule according to claim 39, wherein the treatment solution further comprises hydrochloric acid.

46. The soft gelatin capsule according to claim 39, wherein the treatment provides a weight increase of about 1% to about 10% of the capsule.

47. The soft gelatin capsule according to claim 22, wherein the capsule has improved breaking strength compared to a calcium-free capsule.

48. The soft gelatin capsule according to claim 22, wherein at pH 1.2, when measured in 0.1N hydrochloric acid (HCl) acidic medium using a USP apparatus II with a paddle at 50 RPM or 100 RPM, the capsule does not rupture at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes or 120 minutes.

49. The soft gelatin capsule according to claim 22, wherein at pH 3.0, pH 4.0, pH 5.0, when measured in an acidic medium having the above pH using a USP apparatus II with a paddle at 50 RPM or 100 RPM, the capsule does not rupture at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes or 90 minutes.

50. The soft gelatin capsule according to claim 22, wherein at a pH between 6 and 8, when measured in phosphate buffer using a USP apparatus II with a paddle at 50 RPM, 100 RPM, 150 RPM or 200 RPM, 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.

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