Softgel capsules and methods for manufacturing softgel capsules

Abstract

The present invention discloses a method for manufacturing a softgel capsule comprising the step of treating the softgel capsule with a solution containing a calcium salt, wherein the softgel capsule comprises a filler and a shell composition containing pectin.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims priority to U.S. provisional patent application No. 63 / 432,445 filed on December 14, 2022, the entire contents of which are incorporated herein in their entirety.

[0003] Field of invention

[0004] The present invention relates to a method for manufacturing a softgel capsule, comprising the step of treating the softgel capsule with a solution containing a calcium salt, such as calcium chloride. Additionally, a softgel capsule comprising a filler and a shell composition is provided, wherein the shell composition contains calcium ions. Background Technology

[0005] Soft capsules, particularly soft gelatin capsules (or softgel capsules), provide a formulation that is more easily accepted by patients because they are easy to swallow and do not require flavoring to mask any unpleasant taste of the active ingredient. When a drug is encapsulated in a softgel, it offers the additional potential to improve the bioavailability of the pharmaceutical formulation. For example, the active ingredient can be rapidly released in liquid form as soon as the gelatin shell ruptures.

[0006] Efforts have been devoted to developing enteric formulations. Enteric formulations are designed to protect the contents of the formulation from gastric conditions. For example, enteric formulations have been developed by adding conventional enteric polymers (i.e., acid-insoluble polymers) to the capsule shell. Within these capsule shells, electrostatic attraction can occur, allowing complex coacervates to form; these have been found to be insoluble at acidic pH but soluble at neutral and basic pH.

[0007] Therefore, there is currently a need to improve the manufacturing method of softgel capsules to improve pH tolerance and shell rigidity during intestinal dissolution and disintegration. Prior art literature

[65535] International Publication WO2022 / 104338

[0008] Summary of the Invention

[0009] The present invention relates to a method for manufacturing a softgel capsule. The method comprises the step of treating a softgel capsule with a solution containing a calcium salt, such as calcium chloride, wherein the softgel capsule comprises a filler and a shell composition. In some embodiments, the solution may further contain hydrochloric acid. In some embodiments, the solution may further contain water. In some embodiments, the solution may further contain a sugar. The sugar may be dextrose.

[0010] 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.

[0011] In some embodiments, the pH of the solution may be less than about 3.

[0012] In some embodiments, dextrose may 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.

[0013] In some embodiments, the shell composition may comprise a plasticizer, pectin, gellan gum, dextrose, gelatin, or a combination thereof. In some embodiments of the shell composition, the plasticizer may comprise glycerin, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate, or a combination thereof. In other embodiments, the plasticizer may comprise glycerin, sorbitol sorbitan solution, or a combination thereof. In yet another embodiment, the plasticizer may be a sorbitol sorbitan solution.

[0014] In some embodiments, the method may further include a step of drying the capsule after processing the capsule. In some embodiments, the drying step may be carried out by rotary drying of the capsule. The drying step may be carried out for about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, or about 4 hours. In some embodiments, the drying step may be carried out in a drying chamber or a drying tunnel.

[0015] In some embodiments of the method, the processing step may include the step of using a washing / quenching processing equipment for a predetermined period. The washing / quenching processing equipment may be fully automated. In some embodiments, the predetermined period 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.

[0016] In another embodiment of the present disclosure, a softgel capsule is provided. The softgel capsule comprises a filler comprising an active agent and a shell composition, wherein the shell composition comprises calcium ions.

[0017] In some embodiments, the shell composition may include pectin. The pectin may be low methoxy pectin. In some embodiments, the pectin may 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.

[0018] In some embodiments, the shell composition may include a plasticizer. In some embodiments, the plasticizer may include glycerin, sorbitol, a sorbitol-sorbitan solution, triacetin, polysorbate, or a combination thereof. In another embodiment, the plasticizer may include glycerin and a sorbitol-sorbitan solution. In some embodiments, the polysorbate may include Tween 20, Tween 80, or a combination thereof.

[0019] In some embodiments, the plasticizer may be included in an amount of about 5% to about 60% by weight, about 10% to about 55% by weight, about 15% to about 50% by weight, about 20% to about 45% by weight, or about 25% to about 35% by weight based on the total weight of the shell composition.

[0020] 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, bovine gelatin, bone gelatin, and mixtures thereof. In some embodiments, the gelatin may be included in an amount of about 15% to about 60% by weight, about 20% to about 55% by weight, about 25% to about 50% by weight, about 30% to about 45% by weight, or about 35% to about 40% by weight, based on the total weight of the shell composition.

[0021] In some embodiments, the shell composition may include gellan gum. 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.

[0022] In some embodiments, the shell composition may include 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.

[0023] In some embodiments, the softgel capsule 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 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.

[0024] In some embodiments, the treatment solution may additionally contain water. In some embodiments, the treatment solution may additionally contain sugar. The sugar may include dextrose. 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.

[0025] In some embodiments, the treatment solution may additionally contain hydrochloric acid.

[0026] In some embodiments, the treatment may provide a weight increase of about 1% to about 10% of the capsule. In some embodiments, the capsule may have improved burst strength compared to a capsule without calcium treatment.

[0027] In some embodiments, the capsule does not rupture at pH 1.2 at 15, 30, 45, 60, 75, 90, 105, or 120 minutes when measured with a USP device II with a paddle at 50 RPM or 100 RPM in a 0.1N hydrochloric acid (HCl) acidic medium.

[0028] In some embodiments, the capsule does not rupture at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, or 90 minutes at the pH when measured with a USP device II with a paddle at 50 RPM or 100 RPM in an acidic medium having pH 3.0, pH 4.0, or pH 5.0.

[0029] In some embodiments, the capsule ruptures at pH 6 to 8 in phosphate buffer at 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes when measured with a USP device II with a paddle at 50 RPM, 100 RPM, 150 RPM, or 200 RPM. Brief explanation of the drawing

[0030] The present disclosure is not intended to be limiting but is illustrated by the accompanying drawings. The drawing shows a comparison of capsule moisture absorption rates between capsules tested according to an embodiment of the present disclosure. Specific details for implementing the invention

[0031] The present disclosure advances state-of-the-art technology by developing a processing method for manufacturing softgel capsules. The method of the present disclosure rapidly initiates ionic gelation and initiates cross-linking of gelatin and pectin by dextrose to a certain level in order to improve the enteric function and physical rigidity of the capsule. It has been found that ionic gelation (calcium cross-linking effect) is initiated by treating the softgel capsule with a calcium-containing solution. Accordingly, the inventors determine that calcium ions cross-link the shell composition to form a larger and stronger enhanced network.

[0032] As used herein, the term “enteric” is used to refer to the dissolution or disintegration resistance property of a substance that prevents dissolution or disintegration from occurring in the gastric environment. For example, embodiments described herein include an enteric shell composition that dissolves in biological, artificial, or simulated intestinal fluid rather than in biological, artificial, or simulated gastric fluid. Embodiments described herein may include a coating having an enteric polymer.

[0033] As used herein, "pharmaceutical active ingredient" refers to a drug or compound that may be used for the diagnosis, cure, alleviation, treatment, or prevention of a pathological condition. The terms "pathological condition" or "pathological conditions" refer to medical conditions that may be treated or prevented by administering an effective amount of an active preparation to a subject. Exemplary non-limiting conditions for which benefits may be derived from enteric softgel capsules may include, but are not limited to, capsules containing probiotics, fish oil capsules, proton pump inhibitors, aspirin, and similar products.

[0034] As used herein, the term "active ingredient" refers to any substance intended to produce a therapeutic, prophylactic, or other intended effect, regardless of whether it has been approved for such purpose by a government agency. With respect to specific formulations, this term includes pharmaceutically active formulations and all pharmaceutically acceptable salts, solvates, and crystalline forms thereof, wherein the salts, solvates, and crystalline forms are pharmaceutically active.

[0035] Any pharmaceutical active ingredient, including both water-soluble and water-insoluble pharmaceutical active ingredients, may be used for the purposes of the present invention. Suitable pharmaceutical active ingredients include analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterial agents, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarials, antimigraine agents, antimuscarinic agents, antitumor agents and immunosuppressants, protozoal agents, antirheumatic agents, antithyroid agents, antivirals, anxiolytics, sedatives, hypnotics and antineuroblockers, beta-blockers, cardiac anticholinergics, corticosteroids, cough suppressants, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agonists, histamine receptor antagonists, lipid regulators, local anesthetics, neuromuscular agents, nitrates and anti-anginal agents, nutritional supplements, narcotic analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives. Spermicides, stimulants, and combinations thereof are included, but not limited to.

[0036] In some embodiments, the active pharmaceutical ingredient may be selected, without limitation, from the group consisting of dabigatran, dronedarone, ticagrelo, iloperidone, ivacaptor, midostaurine, shimadolin, beclomethasone, apremilast, safacitabine, lincitinib, abiraterone, vitamin D analogs (e.g., calcipediol, calcitriol, paricalcitol, doxercalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, rubiprostone, pharmaceutically acceptable salts thereof, and combinations thereof.

[0037] In some embodiments, the lipid in the dosage form may be selected, but not limited to, from the group consisting of almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, flaxseed oil, macadamia oil, mango butter, Manila oil, mongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, walnut oil, and watermelon seed oil. Other oils and fats include, but are not limited to, fish oil (omega-3), krill oil, hydrogenated forms of animal or vegetable fats, free fatty acids, and mono-, di-, and tri-glycerides with C8-, C10-, C12-, C14-, C16-, C18-, C20-, and C22 fatty acids, and combinations thereof.

[0038] According to a specific embodiment, the active agent may include, but is not limited to, lipid-lowering agents including statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), fibrates (e.g., clofibrate, ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil), niacin, bile acid adsorbents, ezetimibe, romitafid, phytosterols, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof, and any mixture of the foregoing.

[0039] Suitable nutraceutical active ingredients include 5-hydroxytryptophan, acetyl L-carnitine, alpha-lipoic acid, alpha-ketoglutarate, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin 812), dimethylaminoethanol, fumaric acid, germanium sequoiac oxide, glandular products, glucosamine HCl, glucosamine sulfate, hydroxyl methyl butyrate, immunoglobulin, lactic acid, L-carnitine, liver products, malic acid, maltose anhydride, mannose (d-mannose), methylsulfonylmethane, phytosterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast. Shark cartilage, theobromine, vanadyl sulfate, and yeast may be included, but not limited to.

[0040] Suitable nutritional supplement active preparations may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, or combinations thereof.

[0041] Suitable vitamin active preparations may include, but are not limited to: ascorbic acid (vitamin C), vitamin B, 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), tocopherols, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oils, and fat-soluble vitamins.

[0042] Suitable herbal supplement active preparations may include, but are not limited to: amica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginkgo biloba, ginseng, golden bellflower, hawthorn, kawa, licorice, burdock, milk thistle, psyllium husk, rauowolfia, senna, soybean, St. John's wort, saw palmetto, turmeric, valerian.

[0043] Mineral active preparations may include, but are not limited to: boron, calcium, chelated minerals, chlorides, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malate, pyruvate, zinc, and other minerals.

[0044] Examples of other possible active agents include antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), non-steroidal anti-inflammatory drugs (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, pyroprofen, carprofen, oxaprozine, pramodofen, murodofen, trioxaprofen, suprofen, aminoprofen, fluprofen, bucloxate, indomethacin, sulindac, zomepirac, thiopinacrox, zidomethacin, acemethacin, pentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, Isoxicam, Aceclofenac, Alloxiprine, Azapropazone, Benorylate, Bromfenac, Carprofen, Choline Magnesium Salicylate, Diflunisal, Etodolac, Etoricoxib, Physulamine, Fenbufen, Fenoprofen, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Romoxicam, Loxoprofen, Meloxicam, Mefenamic Acid, Metamizole, Methyl Salicylate, Magnesium Salicylate, Nabumetone, Naproxen, Nimesulide, Oxyfenbutazone, Parecoxib, Phenylbutazone, Salicyl Salicylate, Sulindac, Sulfinpyrazone, Tenoxicam, Tiaprofenic Acid, Tolmetin.Pharmaceutically acceptable salts of these and mixtures thereof) and acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), anticonvulsants (e.g., phenyltoin, meprobemate, and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem, and nicardipine), antitussives and expectorants (e.g., codeine phosphate), antiasthmatics (e.g., theophylline), antacids, antispasmodics (e.g., atropine, scopolamine), antidiabetic agents (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluthiazide), antihypotension 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), antihemorrhoids, Hypnotics, psychotropic drugs, antidiarrheals, mucolytics, sedatives, decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine), and cannabinoids, as well as their pharmaceutically acceptable salts, hydrates, solvates, and prodrugs, are included but not limited thereto.

[0045] Additionally, the active agent may be a benzodiazepine, a barbiturate, a stimulant, or a mixture thereof. The term “benzodiazepine” refers to benzodiazepines and drugs that are benzodiazepine derivatives capable of depressing the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, chlorazefate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, kwazepam, temazepam, triazolam, and methylphenidate, as well as their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures. Benzodiazepine antagonists that may be used as active agents include, but are not limited to, flumazenil, as well as its pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0046] The term "barbiturate" refers to sedative hypnotics derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metabarbital, pentobarbital, phenobarbital, and secobarbital, as well as their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures. Barbiturate antagonists that may be used as active agents include, but are not limited to, amphetamines, as well as their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0047] The term “stimulant” includes, but is not limited to, amphetamines such as dextroamphetamine resin complexes, dextroamphetamine, methamphetamine, and methylphenidate, as well as their pharmaceutically acceptable salts, hydrates, solvates, and mixtures. Stimulant antagonists that may be used as activators include, but are not limited to, benzodiazepines, as well as their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0048] The dosage forms according to the present disclosure include various active agents and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include, but are not limited to, inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic salts such as formate, acetate, trifluoride acetate, maleate, tartrate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; amino acid salts such as arginate, aspartate, glutamate, 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, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N.N'-dibenzylethylenediamine salt, etc.

[0049] As used herein, the terms "therapeutically effective" and "effective dose" refer to the amount of active agent or the rate at which the active agent is administered required to produce a desired treatment result.

[0050] As used herein, "shell" or "shell composition" refers to the shell of a softgel capsule that encapsulates a filler.

[0051] As used herein, “conventional enteric polymers” refers to, but is not limited to, acrylic acid and methacrylic acid polymers available for sale under the trade name EUDRAGIT® and other conventional acid-insoluble polymers, e.g., methyl acrylate-methacrylic acid copolymers. Other conventional acid-insoluble polymers include, but are not limited to, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypermellose acetate succinate), polyvinyl acetate phthalate (PVAP), alginates such as sodium alginate and potassium alginate, stearic acid, and shellac. In some embodiments, the enteric shell composition of the present invention does not contain acid-insoluble polymers. That is, the enteric shell composition and the enteric softgel capsules are “without or substantially without conventional enteric polymers.”

[0052] All weight % mentioned throughout the specification and claims refer to the weight of a component based on the weight of the total composition and may be specified as w / w.

[0053] As used herein, "filler" or "filler" refers to a composition encapsulated by an enteric capsule shell and containing at least one pharmaceutically active ingredient.

[0054] As used herein, "delayed release" refers to the release of the active agent after passing through the stomach.

[0055] As used herein, "about" refers to any value within a variation range of ±10%, and "about 10" will include 9 to 11. As used herein, "singular" refers to one or more unless otherwise specified. Thus, for example, the expression "excipient" includes not only a single excipient but also a mixture of two or more different adjuvants.

[0056] References to value ranges herein are intended to be a simple way of individually referring to each distinct value within such range unless otherwise specified in this specification, and each distinct value is incorporated into this specification as if individually referred to herein. All methods described herein may be carried out in any appropriate order unless otherwise specified herein or if the context clearly contradicts them.

[0057] Any use of any examples or exemplary phrases provided herein (e.g., "e.g., for example") is merely intended to illustrate specific materials and methods and is not to limit the scope. No phrase in this specification should be interpreted as indicating that non-claimed elements are essential for the practice of the disclosed materials and methods.

[0058] According to one embodiment, a method for manufacturing a softgel capsule comprises the step of treating a softgel capsule with a solution containing a calcium salt, wherein the softgel capsule comprises a filler and a shell composition. The calcium salt may be calcium chloride, calcium citrate, calcium gluconate, calcium lactate, or any other soluble calcium salt.

[0059] In some embodiments of the method, the solution may additionally contain hydrochloric acid. In some embodiments, the solution may additionally contain water. In other embodiments, the solution may additionally contain sugar. The sugar may include dextrose.

[0060] In some embodiments of the method, calcium chloride 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.

[0061] In a specific embodiment of the present method, hydrochloric acid may be included to produce a solution having a pH of less than 3.

[0062] 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.

[0063] In some embodiments of the present method, the shell composition may include a plasticizer, pectin, gellan gum, dextrose, gelatin, or a combination thereof.

[0064] In certain embodiments, the plasticizer may include glycerin, sorbitol, a sorbitol-sorbitan solution, triacetin, polysorbate, or a combination thereof. In some embodiments, the plasticizer may include glycerin, a sorbitol-sorbitan solution, or a combination thereof. In another embodiment, the plasticizer may be a sorbitol-sorbitan solution.

[0065] In some embodiments, the method may further include a step of drying the softgel capsule. In some embodiments, the drying step may be carried out by rotary drying of the capsule. In some embodiments, the drying step 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 a step of drying the capsule in a drying chamber or a drying tunnel.

[0066] In some embodiments of the method, the processing step may include a step of using a softgel capsule washing / quenching processing equipment, wherein the softgel capsule is treated with a solution for a predetermined period. The softgel capsule washing / quenching processing equipment may be fully automated.

[0067] In a specific embodiment, the predetermined period 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.

[0068] In another embodiment of the present invention, a softgel capsule is provided. The softgel capsule may comprise a filler comprising an active agent and a shell composition, wherein the shell composition comprises calcium ions.

[0069] Suitable fillers may comprise at least one pharmaceutically active ingredient and may be prepared according to known methods. In addition to at least one pharmaceutically active ingredient, suitable fillers may comprise additional filler components such as flavorings, sweeteners, coloring agents and fillers, or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides. Appropriate amounts of the pharmaceutically active ingredient and pharmaceutically acceptable excipients can be easily determined by a person skilled in the art.

[0070] 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 formulation. However, if there is too much pectin in the formulation, it may reduce the gel strength of the softgel capsule, which can have a negative effect on the sealability of the softgel capsule. Therefore, pectin may be added to the formulation at a concentration high enough to form an enteric formulation while being low enough to mitigate the reduction in 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 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%.

[0071] In some embodiments of the capsule, 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 include sugar alcohol plasticizers such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers such as diglycerin, dipropylene glycol, polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, and ethanolamine; and mixtures thereof may be included, but are not limited thereto. In addition, other exemplary plasticizers may include, without limitation, low molecular weight polymers, oligomers, copolymers, oils, small molecular weight organics, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, homoblock polymers, citric acid ester-type plasticizers, and triacetin. These 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.

[0072] In some embodiments, the amount of plasticizer may be about 5% to about 60% by weight, about 10% to about 55% by weight, about 15% to about 50% by weight, about 20% to about 45% by weight, or about 25% to about 35% by weight based on the total weight of the shell composition.

[0073] In some embodiments of the softgel capsule, the shell composition may further comprise gelatin. The gelatin may include type A gelatin, type B gelatin, bovine 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 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% to about 80% by weight, about 15% to about 60% by weight, about 20% to about 55% by weight, about 25% to about 50% by weight, about 30% to about 45% by weight, or about 35% to about 40% by weight, based on the total weight of the shell composition.

[0074] 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.

[0075] In some embodiments, the amount of 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.

[0076] In some embodiments, the softgel capsule may be treated with a treatment solution. The treatment solution may contain a calcium salt. The calcium salt may be calcium chloride, calcium citrate, calcium gluconate, calcium lactate, or other soluble calcium salts. In one embodiment, the calcium salt may be calcium chloride.

[0077] In some embodiments, 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.

[0078] In some embodiments, the treatment solution may additionally contain water. In other embodiments, the treatment solution may additionally contain sugar. The sugar may be dextrose. The sugar or 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.

[0079] In some embodiments, the softgel capsule may be treated with a calcium treatment solution. Through treatment, a weight increase of about 1% to about 10%, about 2% to about 8%, or about 3% to about 5% of the capsule may be achieved.

[0080] In some embodiments, the capsule after treatment may have improved burst strength compared to the capsule not treated by the present invention.

[0081] In one embodiment, the shell composition of the softgel capsule may optionally include additional agents such as coloring agents, flavoring agents, sweeteners, fillers, antioxidants, diluents, pH adjusters, or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides.

[0082] Exemplary suitable coloring agents may include, but are not limited to, colors such as, for example, white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown. In specific embodiments, the color of the formulation may indicate the contents contained therein (e.g., one or more active ingredients).

[0083] Exemplary suitable flavoring agents often include, but are not limited to, "flavor extracts" obtained by extracting a part of the raw material, e.g., animal or plant material, using a solvent such as ethanol or water; and natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from whole plants.

[0084] Additional exemplary flavoring agents that may be included in the formulation may include, but are not limited to, odor-removing compounds such as menthol, spearmint, and cinnamon, other flavoring agents or flavorings such as coffee beans, fruit flavorings (e.g., cherry, orange, grape, etc.), and active agents used in dental and oral rinses such as quaternary ammonium bases, as well as those used particularly in oral hygiene. The effect of the flavoring agent may be enhanced by using flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

[0085] Exemplary sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Artificial sweeteners include, for example, acesulfame and various salts thereof, such as potassium salt (marketed as Sunett®), alitam, aspartame (marketed as NutraSweet® and Equal®), aspartame-acesulfame salt (marketed as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and various salts thereof, such as sodium salt (marketed as Sweet'N Low®), stevia, chloro derivatives of sucrose, such as sucralose (Kaltame® and Splenda®), and mogroside. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; Monoammonium glycyrrhizinate (marketed under the brand name MagnaSweet®); natural high-intensity sweeteners such as Stevia rebaudiana (Stevioside) and monk fruit, and polyols such as sorbitol, mannitol, xylitol, and erythritol are included.

[0086] In some embodiments, the softgel capsule does not rupture at pH 1.2 at 15, 30, 45, 60, 75, 90, 105, or 120 minutes when measured with a USP device II with a paddle at 50 RPM or 100 RPM in a 0.1N hydrochloric acid (HCl) acidic medium.

[0087] In some embodiments, the softgel capsule does not rupture at 15, 30, 45, 60, 75, or 90 minutes at pH 3.0, pH 4.0, or pH 5.0 when measured with a USP device II with a paddle at 50 RPM or 100 RPM in an acidic medium.

[0088] In some embodiments, the capsule ruptures at pH 6 to 8 in phosphate buffer at 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes when measured with a USP device II with a paddle at 50 RPM, 100 RPM, 150 RPM, or 200 RPM.

[0089] The encapsulation of the filler can be achieved by any conventional method. For example, rotary die encapsulation can be used.

[0090] According to one embodiment, an enteric softgel capsule is manufactured by a process comprising the following steps: preparing a filler containing an active agent; and encapsulating the filler in a shell composition forming a softgel capsule. The capsule is then treated with a treatment solution containing a calcium source such as calcium chloride, calcium chloride dihydrate (CaCl2:2H2O), calcium citrate, calcium gluconate, or calcium lactate. The treatment involves the use of a fully automated softgel capsule washing / quenching treatment equipment. After treatment, the softgel capsule is further dried using a rotary dryer in a drying room or drying tunnel.

[0091] List of items

[0092] 1. A method for manufacturing a softgel capsule,

[0093] The step of treating a softgel capsule with a solution containing a calcium salt, wherein

[0094] The above softgel capsule comprises a filler and a shell composition, a method.

[0095] 2. The method according to the first item, wherein the calcium salt comprises calcium chloride, calcium citrate, calcium gluconate, calcium lactate, or a combination thereof.

[0096] 3. The method according to the first item, wherein the solution further comprises hydrochloric acid.

[0097] 4. A method according to the first item, wherein the solution further comprises water.

[0098] 5. A method in which, in any one of items 1 to 4, the solution further comprises sugar.

[0099] 6. In the fifth item, the method wherein the sugar comprises dextrose.

[0100] 7. A method wherein, in any one of the above items, 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.

[0101] 8. In the third item, the pH of the solution is less than 3.

[0102] 9. The method of 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.

[0103] 10. A method wherein, in any one of the above items, the shell composition comprises a plasticizer, pectin, gellan gum, dextrose, gelatin, or a combination thereof.

[0104] 11. A method in which, in any one of the above items, the plasticizer comprises glycerin, sorbitol, sorbitol-sorbitan solution, triacetin, polysorbate, or a combination thereof.

[0105] 12. The method of item 10, wherein the plasticizer comprises glycerin, a sorbitol sorbitan solution, or a combination thereof.

[0106] 13. In the 10th item, the plasticizer is a sorbitol sorbitan solution, method.

[0107] 14. A method comprising, in any one of the above items, an additional step of drying the capsule after processing the capsule.

[0108] 15. A method according to item 14, wherein the drying step is carried out by rotary drying of the capsule.

[0109] 16. The method of item 14, wherein the drying step is performed 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.

[0110] 17. In the 14th item, the drying step is carried out in a drying room or a drying tunnel.

[0111] 18. A method wherein, in any one of the above items, the processing step comprises using a washing / quenching treatment equipment for a predetermined period.

[0112] 19. In item 18, the washing / quick cooling treatment equipment is a method that is fully or partially automated.

[0113] 20. In item 18, the washing / quick cooling treatment equipment is of the jacket type and can be cooled or quick-cooled using an external quiver.

[0114] 21. In the 18th item, the above 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.

[0115] 22. As a softgel capsule,

[0116] A filler comprising an active agent; and

[0117] A softgel capsule comprising a shell composition containing calcium ions.

[0118] 23. In item 22, the shell composition is a softgel capsule comprising pectin.

[0119] 24. In item 23, the pectin is low methoxy pectin, a softgel capsule.

[0120] 25. A softgel capsule according to item 23, wherein the pectin is included in an amount of about 1% to about 25% by weight, about 2% to about 20% by weight, 5% to about 18% by weight, 7.5% to about 15% by weight, or about 10% to about 12% by weight based on the total weight of the shell composition.

[0121] 26. In item 22, the shell composition is a softgel capsule comprising a plasticizer.

[0122] 27. In item 26, the plasticizer comprises glycerin, sorbitol, sorbitol-sorbitan solution, triacetin, polysorbate, or a combination thereof, a softgel capsule.

[0123] 28. In item 26, the plasticizer comprises a softgel capsule comprising glycerin and a sorbitol sorbitan solution.

[0124] 29. In item 27, the polysorbate is a softgel capsule comprising Tween 20, Tween 80, or a combination thereof.

[0125] 30. A softgel capsule according to item 26, wherein the plasticizer is included in an amount of about 5% to about 60% by weight, about 10% to about 55% by weight, about 15% to about 50% by weight, about 20% to about 45% by weight, or about 25% to about 35% by weight, based on the total weight of the shell composition.

[0126] 31. In item 22, the shell composition is a softgel capsule comprising gelatin.

[0127] 32. In item 31, the gelatin is selected from the group consisting of type A gelatin, type B gelatin, and mixtures thereof, in a softgel capsule.

[0128] 33. In item 31, the gelatin is selected from the group consisting of fish gelatin, bovine gelatin, bone gelatin, and mixtures thereof, in a softgel capsule.

[0129] 34. A softgel capsule according to item 31, wherein the gelatin is included in an amount of about 15% to about 60% by weight, about 20% to about 55% by weight, about 25% to about 50% by weight, about 30% to about 45% by weight, or about 35% to about 40% by weight, based on the total weight of the shell composition.

[0130] 35. In item 22, the shell composition is a softgel capsule comprising gellan gum.

[0131] 36. A softgel capsule according to item 35, wherein the gellan gum is included in an amount of about 0.001% to about 5% by weight, about 0.01% to about 4% by weight, about 0.1% to about 3% by weight, or about 1% to about 2% by weight based on the total weight of the shell composition.

[0132] 37. In item 22, the shell composition is a softgel capsule comprising dextrose.

[0133] 38. A softgel 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.

[0134] 39. In item 22, the softgel capsule is treated with a treatment solution containing calcium chloride.

[0135] 40. A softgel capsule according to item 39, wherein the calcium chloride is included in an amount of about 1% to about 25% by weight, about 2% to about 22% by weight, about 3% to about 20% by weight, about 4% to about 18% by weight, about 5% to about 16% by weight, about 6% to about 14% by weight, or about 7% to about 12% by weight, based on the total weight of the treatment solution.

[0136] 41. In item 39, the treatment solution further comprises water, a softgel capsule.

[0137] 42. In item 39 or 41, the treatment solution further comprises a sugar, a softgel capsule.

[0138] 43. In item 42, the sugar is a softgel capsule containing dextrose.

[0139] 44. A softgel capsule according to item 43, wherein the dextrose is included in an amount of about 0.1% to about 20% by weight, about 2% to about 18% by weight, about 3% to about 16% by weight, about 4% to about 14% by weight, about 5% to about 12% by weight, or about 6% to about 10% by weight, based on the total weight of the treatment solution.

[0140] 45. A softgel capsule, wherein the treatment solution further comprises hydrochloric acid in any one of Item 39, Item 41, or Item 42.

[0141] 46. ​​A softgel capsule, wherein in any one of items 39 to 45, the treatment provides a weight increase of about 1% to about 10% of the capsule.

[0142] 47. In any one of items 22 to 46, the capsule is a softgel capsule having improved burst strength compared to a capsule without calcium.

[0143] 48. In any one of items 22 through 47, the capsule is a softgel capsule that does not rupture at pH 1.2 for 15, 30, 45, 60, 75, 90, 105, or 120 minutes when measured using a USP device II with a paddle at 50 RPM or 100 RPM in a 0.1N hydrochloric acid (HCl) acidic medium.

[0144] 49. A softgel capsule according to any one of items 22 through 47, wherein the capsule does not rupture at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, or 90 minutes at the pH when measured using a USP device II with a paddle at 50 RPM or 100 RPM in an acidic medium having a pH of 3.0, 4.0, or 5.0.

[0145] 50. Any one of items 22 through 47, wherein the capsule is a softgel capsule that ruptures within 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 phosphate buffer using a USP device II with a paddle at 50 RPM, 100 RPM, 150 RPM, or 200 RPM at a pH of 6 to 8.

[0146] Examples

[0147] Specific embodiments of the present invention are described below through the following examples. These examples are disclosed merely to illustrate the invention and should not be construed as limiting the scope of the invention in any way.

[0148] Experimental Procedure and Method

[0149] calcium chloride solution

[0150] Among all available types of calcium ion sources to initiate the calcium crosslinking effect, calcium chloride was considered a preferred choice because it is inexpensive and has higher solubility. To simplify the procedure, weight percentages were used for all various concentrations of calcium chloride solutions. Examples of 5% and 10% calcium chloride basic formulations are shown in Table 1.

[0151] Pectin ionic gelation depends on pH. The gel network is more stable in a low pH (less than 5) environment than in a high pH (greater than 7) environment. The pH value of the calcium chloride solution was intentionally adjusted from pH > 8 to pH < 3 using a 0.1N hydrochloride solution, which is a key finding of this study.

[0152] Table 1. Aqueous calcium chloride solution

[0153]

[0154] Calcium chloride and hydrochloric acid solution

[0155]

[0156] Calcium chloride and dextrose solution

[0157] Reducing sugars such as dextrose contain free aldehyde or ketone groups and can be classified as typical crosslinking agents that induce covalent crosslinking. The enteric function on the surface of softgel capsules can be enhanced by adding dextrose as a reducing sugar to a calcium chloride solution. Examples of basic formulations of 10% calcium chloride and 5% or 10% dextrose solutions are shown in Table 2. The pH value of the calcium chloride / dextrose solution was also intentionally adjusted to pH <3 using a 0.1N hydrochloric acid solution.

[0158] Table 2. Aqueous solutions of calcium chloride and dextrose

[0159]

[0160] softgel capsules

[0161] To evaluate calcium treatment, softgel capsules of various manufactured batches (Samples 1 to 5) were utilized. The gel high-volume formulations used to manufacture these three lots are shown in Table 3.

[0162] Table 3. Qualitative shell formulations

[0163]

[0164] After the capsules were rotary-dried using a standard encapsulation process, they were collected and treated by immersing them in a stainless steel container with a filter basket containing 3 liters of sodium chloride solution for several periods (5, 10, and 20 seconds, respectively). Approximately 500 capsules were manually treated at each time point. After calcium treatment, the capsules were rotary-dried in a rotary dryer for 1 hour to remove excess water introduced into the shell due to the calcium treatment. Subsequently, the treated capsules were dried in a drying chamber according to a standard softgel tunnel drying process.

[0165] In addition, some of the final capsules were treated with a calcium chloride and dextrose solution or a calcium chloride solution for an extended period to evaluate the upper limit of the treatment time and the effectiveness of dextrose addition.

[0166] To ensure full integration into the current encapsulation process, the calcium treatment or calcium and dextrose treatment step can be added into the process chain immediately prior to rotary drying in a typical softgel manufacturing process with fully automated equipment.

[0167] The fully automated equipment consists of a jacketed rectangular container with an integrated conveyor or a calcium treatment solution reservoir. The processing time can be regulated by adjusting the speed of the conveyor belt. The temperature of the calcium solution can be maintained by an external quencher connected to the jacketed container.

[0168] Summary of test results

[0169] Weight increase due to calcium treatment

[0170] After calcium treatment, a slight increase in weight was expected for the treated capsules. Table 4 summarizes the weight increase data for the untreated capsules, the capsules immediately after treatment, and the dried final capsules.

[0171] Table 4. Summary of Weight Increase (Sample 1)

[0172]

[0173] 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 calcium-treated and dried product was 13 to 16 mg per capsule or 3.7% to 4.6% of the shell weight.

[0174] Weight increase due to calcium and dextrose treatment

[0175] Table 5 summarizes the weight gain data of untreated capsules and final dried capsules treated with contact times of 1 minute, 2 minutes, and 5 minutes.

[0176] Table 5. Summary of weight increase (Sample 2, 20 rectangles)

[0177]

[0178] Compared to the untreated and dried final capsule, the weight increase of the calcium and dextrose-treated product was 55 to 115 mg per capsule or 10.8 to 22.6% of the shell weight. The concentration of the solution did not affect the weight increase of the capsule, and the treatment time was the only factor.

[0179] Low methylamide (LMA) pectin is sensitive to the presence of calcium ions and is more tolerant to calcium content compared to high methyl (HM) and low methyl (LM) pectins. Although LMA gels over a wider range of calcium concentrations, the pectin gel strength is based on Ca per gram of pectin. 2+ It reaches a maximum level at about 40 mg, and thereafter, gel strength decreases with increasing calcium ion concentration. Weight gain must be closely controlled by limiting processing time.

[0180] Capsule moisture absorption test

[0181] The capsule moisture absorption test was performed by exposing capsules to a 0.1N HCl solution for a set period of time and recording the increase in capsule weight. Table 6 summarizes the moisture absorption data of untreated and treated final dried capsules at contact times of 1 minute, 2 minutes, and 5 minutes, respectively. Figure 1 shows a comparison of capsule moisture absorption rates between the tested capsules.

[0182] Table 6. Capsule moisture absorption results of selected softgel capsules (per capsule)

[0183]

[0184] Untreated softgel capsules showed a weight increase of over 15.4% after 5 minutes and 22.6% after 10 minutes, indicating stronger moisture absorption. Both calcium and dextrose-treated softgel capsules showed very similar weight increases after 5 and 10 minutes of exposure to an acidic medium, with less weight increase compared to untreated capsules. This demonstrated the superior moisture barrier provided by calcium and dextrose treatment.

[0185] Capsule exterior

[0186] The softgel capsules immediately after treatment with a 5% aqueous calcium chloride solution were clear and transparent and had a slightly improved shape. No obvious difference was found compared to the untreated capsules. The softgel capsules treated with a 10% aqueous calcium chloride solution for 20 seconds showed a slightly cloudy appearance. Therefore, when using a 10% calcium chloride solution, it is desirable to keep the treatment time within approximately 10 seconds. The final softgel capsules treated with calcium chloride and dextrose solutions and dried were clear and transparent. No obvious difference was found compared to the untreated capsules.

[0187] Capsule rupture strength

[0188] The burst strength of softgel capsules is an indicator of capsule sealing quality. It is a key quality attribute of softgel capsules and indicates how strongly the softgel is sealed or how easily the capsule breaks. Burst strength data for all 47 samples were collected using Texture Analyzer TA. HD Plus and are summarized in Table 7.

[0189] According to the results, the rupture strength of the calcium-treated capsules of Lot Sample 3 was significantly higher than that of the untreated capsules. For Lot Sample 1, the rupture strength of all capsules treated with 10% CaCl2 for 5 and 20 seconds was significantly higher than that of all capsules treated with 5% CaCl2 for 5 and 20 seconds. Therefore, it was determined that calcium treatment introduces a calcium cross-linking effect to form a stronger complex gel. Consequently, the rigidity of the softgel capsules was improved.

[0190] Table 7. Burst strength of dried softgel capsules

[0191]

[0192] Capsule disintegration test

[0193] Disintegration testing is considered a standard enteric function test in both USP and EP. It is important that the final product passes the required disintegration tests described in the final product specifications. To evaluate the quality of untreated final softgel capsules and calcium-treated capsules, a two-phase disintegration test was performed on both treated and untreated capsules in accordance with EP and USP standards. In this study, an acid phase disintegration test of up to 2 hours was performed, and an extended buffered phase disintegration test was performed only on selected calcium-treated and untreated softgels.

[0194] Table 8 summarizes the test results of the final capsules immediately after treatment with calcium chloride, manufactured from several batches.

[0195] Table 8. Summary of 2-hour disintegration tests of selected final capsules (in 0.1N HCl (pH = 1.2±0.2) for up to 2 hours in USP APP B)

[0196]

[0197] The disintegration time of calcium-treated capsules in an acidic medium was significantly longer than that of untreated capsules. Preliminary results demonstrate that the calcium cross-linking effect improved the enteric function of softgel capsules. Capsules treated with a 5% calcium chloride solution for 20 seconds exhibited superior enteric performance in an acidic medium compared to capsules treated for a shorter period.

[0198] The final dried softgel capsules of Lot Sample 2 were selected to be treated with two concentrations of calcium chloride and dextrose solutions for 1, 2, and 5 minutes, respectively. Table 9 summarizes the test results of the final capsules treated with calcium and dextrose solutions and dried. Once again, only acid disintegration tests of up to 2 hours were performed. Additionally, capsules from the same batch were treated with a 5% calcium chloride solution for 15 minutes to challenge the contact time limit.

[0199] Table 9. Summary of the 2-hour disintegration test of the final capsule of Sample 2 (in 0.1N HCl (pH = 1.2±0.2) for up to 2 hours in USP APP B)

[0200]

[0201] Capsules treated for 5 minutes did not show as good an effect as capsules treated for 1 or 2 minutes, confirming that an excessive calcium ion load reduced gel enteric function. Adding dextrose to the calcium treatment has not yet shown a significant benefit in improving enteric properties.

[0202] Table 10 summarizes the results of the two-stage disintegration test of the calcium chloride-treated and untreated final capsules of samples 4 and 5.

[0203] Table 10. Summary of the two-stage disintegration test of selected final capsules (in 0.1N HCl (pH = 1.2±0.2) for up to 2 hours in USP APP B and in phosphate buffer (pH = 6.8±0.2) during the long-term test time)

[0204]

[0205] The disintegration time of calcium-treated capsules in an acidic medium was 2 hours, which was significantly longer than that of untreated capsules in a buffer medium. The results demonstrated that the calcium cross-linking effect improved the enteric function of softgel capsules. The improvement in enteric function induced by calcium treatment is stable and consistent.

[0206] Capsule 2-stage disintegration test

[0207] The two-step disintegration test is considered a standard enteric function test in both USP and EP methods. It is important for enteric products to pass the mandatory two-step disintegration test described in the product specifications. To evaluate the quality of the final softgel capsules and calcium-treated capsules, the two-step disintegration test was performed on both treated and untreated capsules in selected batches.

[0208] Previous development work revealed that a curing process is required for the pectin-gelatin polyelectrolyte composite system to be completed and provide the necessary enteric function. To complete the formation of the interacting complex, the curing time may require at least 1 to 4 weeks under ambient conditions. If the final capsule is tested before curing is complete, premature release may be observed during the first 5 to 15 minutes of the two-stage dissolution test. To shorten or eliminate curing time and increase the efficiency of softgel capsules, calcium treatment may reduce or eliminate curing time. Table 11 summarizes the data on test results for capsules from various batches.

[0209] Table 11. Summary of the two-step dissolution test of Sample 1 (tested in phosphate buffer pH 6.8±0.2 followed by 0.1N HCl (pH=1.2±0.2) for 2 hours in USP APP II)

[0210]

[0211] Test data clearly showed that all calcium-treated capsules passed the two-stage rupture test without any release due to premature rupture observed even within one week of manufacturing, whereas premature release occurred in 2 out of 6 untreated capsules from the same batch. Additionally, all treated capsules ruptured within 10 minutes in the buffering stage, confirming that pectin ionic gelation initiated by calcium ions varies with pH.

[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 can increase during the digestion of food. To ensure that enteric function is reliably provided across the entire pH range, it is important that the capsule can withstand a higher pH environment for a certain period. According to previous studies on capsules made of pectin and gelatin gel, the capsules could remain intact for only about 30 minutes in a pH 5 medium before rupture. Table 12 summarizes test result data for capsules from various batches after calcium treatment in a pH 5 medium.

[0214] Table 12. Summary of High-Concentration pH Tolerance Tests

[0215]

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

[0217] Summary and Conclusion

[0218] The data summarized in this study demonstrated the benefits of calcium treatment for softgels. Calcium treatment provided numerous benefits to softgel capsules, including, but not limited to:

[0219] 1. Minimizes changes to current gel formulations or processes by incorporating an inline calcium processing step after encapsulation.

[0220] 2. Identical appearance and slightly improved shape.

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

[0222] 4. Moisture barrier improved in acidic media.

[0223] 5. Improved enteric performance: Passed Phase 2 rupture test and Phase 2 disintegration test (both USP and EP)

[0224] 6. Improved high pH tolerance. Remains intact for 1 hour in a pH 5.0 medium.

[0225] 7. The addition of dextrose to calcium did not show any benefit in short-term storage. However, since dextrose crosslinking takes time, it is expected that further enhanced enteric function will be demonstrated in continuous long-term stability studies.

[0226] Calcium treatment or calcium and dextrose treatment has an optimal treatment time that allows pectin gelation to reach maximum gel strength and enteric function. Calcium and dextrose treatment does not show a significant difference compared to short-term calcium treatment alone. The efficacy of adding dextrose will be evaluated further.

[0227] In addition, since calcium treatment improves enteric function and performance, the target ribbon thickness of the capsule can potentially be reduced, which can consequently lower raw material costs.

[0228] The foregoing description provides many specific details, such as examples of specific systems, components, methods, etc., so that various embodiments of the present invention may be well understood. However, it will be obvious to those skilled in the art that at least some embodiments of the present invention may be practiced without these specific details. In other cases, well-known components or methods are not described in detail to avoid unnecessarily obscuring the present invention. Accordingly, the specific details presented are illustrative. Specific embodiments may differ from these exemplary details and may still be considered to be within the scope of the present invention.

[0229] Although the operations of the method of the present invention are described in a specific order, the order of the operations of each method may be changed so that specific operations may be performed in reverse order or specific operations may be performed at least partially simultaneously with other operations. In another embodiment, instructions or sub-operations of different operations may be in a discontinuous and / or alternating manner.

[0230] It should be understood that the above description is for illustrative purposes only and is not limiting. Those skilled in the art will find many other embodiments apparent upon reading and understanding the above description. Accordingly, the scope of the invention should be determined by referring to the appended claims and the entire scope of equivalents provided by such claims.

Claims

Claim 1 A method for processing a softgel capsule, comprising the step of applying a processing solution to a softgel capsule, wherein the processing solution comprises a calcium salt and a sugar, and the softgel capsule comprises a filler and a shell composition. Claim 2 A method according to claim 1, wherein the calcium salt comprises calcium chloride, calcium citrate, calcium gluconate, calcium lactate, or a combination thereof. Claim 3 A method according to claim 1, wherein the solution further comprises hydrochloric acid. Claim 4 A method according to claim 1, wherein the solution further comprises water. Claim 5 A method according to claim 1, wherein the sugar comprises dextrose. Claim 6 A method according to claim 1, wherein the calcium salt is included in an amount of about 1% by weight to about 25% by weight based on the total weight of the solution. Claim 7 In paragraph 3, the method wherein the pH of the solution is less than 3. Claim 8 A method according to claim 5, wherein the dextrose is included in an amount of about 0.1% by weight to about 20% by weight based on the total weight of the solution. Claim 9 The method according to claim 1, wherein the shell composition comprises a plasticizer, pectin, gellan gum, dextrose, gelatin, or a combination thereof. Claim 10 In claim 9, the method comprises the plasticizer comprising glycerin, sorbitol, sorbitol-sorbitan solution, triacetin, polysorbate, or a combination thereof. Claim 11 In claim 9, the method comprises the plasticizer comprising glycerin, a sorbitol sorbitan solution, or a combination thereof. Claim 12 In claim 9, the method wherein the plasticizer is a sorbitol sorbitan solution. Claim 13 A method according to claim 1, further comprising the step of drying the capsule after processing the capsule. Claim 14 In paragraph 13, the drying step is carried out by rotary drying of the capsule. Claim 15 In paragraph 13, the drying step is performed for about 5 minutes to about 6 hours. Claim 16 In paragraph 13, the drying step is carried out in a drying room or a drying tunnel. Claim 17 A method according to claim 1, further comprising the steps of adding the softgel capsule to a washing treatment device and applying the treatment solution for a time of about 5 minutes to about 10 minutes. Claim 18 In paragraph 17, the above-mentioned washing treatment equipment is a fully automated method. Claim 19 In paragraph 17, the above-mentioned washing treatment equipment is of the jacket type, and the washing equipment is cooled or quenched using an external quencher, method. Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete Claim 43 delete Claim 44 delete Claim 45 delete Claim 46 delete Claim 47 delete Claim 48 delete Claim 49 delete Claim 50 delete

Images