Enteric coated soft gel capsule

Abstract

A soft gel capsule includes a filler material, a shell composition, and a coating having an enteric polymer wherein the coating provides a weight gain of the capsule from about 1% to about 10%. The coating improves the robustness of the enteric solubility of the soft gel capsule and maximally reduces the hygroscopicity of the soft gel capsule in the dissolving process.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 397,558, filed on August 12, 2022, the entire contents of which are incorporated herein in their entirety. Field of the Invention

[0003] The present invention relates to a soft gel capsule, which comprises a filling composition and a shell composition, wherein the shell composition comprises pectin. The soft gel capsule of the present invention further comprises a coating comprising an enteric polymer. Background of the Invention

[0005] Since the capsule is easy to swallow and does not need to be flavored to mask the unpleasant taste of the active drug, soft capsules, especially soft gelatin capsules (or soft gel capsules), provide a dosage form that is more easily accepted by patients. Soft gel encapsulation of drugs provides a potential for further improving the bioavailability of drugs. For example, once the gelatin shell is broken, the active ingredient will be quickly released in liquid form.

[0006] Efforts have been made to create enteric dosage forms. Enteric dosage forms are designed to protect the dosage form ingredients from the effects of gastric conditions. For example, enteric dosage forms have been developed in which conventional enteric polymers (i.e., polymers that are insoluble in acid) are added to the capsule shell. However, the addition of conventional enteric polymers can cause the capsule to leak easily due to inadequate sealing. In addition, it has been found that the addition of enteric polymers to the capsule shell can cause the shell to absorb a large amount of water, thereby weakening the mechanical strength and potentially affecting the chemical stability of the drug substance.

[0007] Therefore, there is a need for a soft gel capsule that can minimize water absorption and maintain mechanical strength. Summary of the invention

[0008] The present invention relates to soft gel capsules comprising a lightweight enteric polymer coating. The soft gel capsules of the present disclosure include a fill composition and a shell composition, wherein the shell composition includes pectin. The soft gel capsules also have a coating including an enteric polymer. It has been found that the addition of a lightweight coating to the soft gel capsules can improve the robustness of enteric solubility. It has also been found that the use of a lightweight coating can achieve a more uniform coating on the soft gel capsules, thereby making the performance of the dosage form more consistent. In addition, the coating also increases the pH threshold of the capsule, allowing it to be further delivered in the digestive system, such as colon delivery.

[0009] The invention also relates to a method for preparing the enteric soft gel capsule. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The present disclosure is illustrated in the accompanying drawings by way of example and not limitation, in which like reference numerals represent like elements. It should be noted that different references to "one" or "an" embodiment in the present disclosure do not necessarily refer to the same embodiment, and such references represent at least one.

[0011] Figure 1 Capsule moisture absorption results of coated soft gel capsules according to an embodiment of the present invention are shown. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present disclosure improves the enteric solubility of soft gel capsules by developing enteric oral dosage forms, particularly enteric soft gel capsules, thereby promoting the development of the prior art. The enteric soft gel capsules of the present invention will not dissolve in the gastric environment of the stomach, but further dissolve in the digestive system (e.g., intestines or colon). This mechanism is conducive to delivering active ingredients that may cause gastric irritation or be sensitive to the acidic environment of the stomach.

[0014] As used herein, the term "enteric" is used to refer to the dissolution or disintegration resistance of a substance such that dissolution or disintegration does not occur in the gastric environment. For example, embodiments described herein include enteric shell compositions that dissolve in biological, artificial or simulated intestinal fluids, but not in biological, artificial or simulated gastric fluids. Embodiments described herein also include coatings containing enteric polymers.

[0015] As used herein, "pharmaceutically active ingredient" refers to a drug or compound that can be used to diagnose, cure, alleviate, treat or prevent a condition. The term "condition" 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 may benefit from enteric soft gel capsules may include, but are not limited to, capsules containing lactic acid bacteria, fish oil capsules, proton pump inhibitors, aspirin and similar products.

[0016] 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 governmental agency for that purpose. For specific pharmaceutical agents, the term includes the pharmaceutically active agent and all pharmaceutically acceptable salts, solvates, and crystalline forms thereof, wherein the salts, solvates, and crystalline forms are pharmaceutically active.

[0017] Any pharmaceutically active ingredient may be used for the purpose of the present invention, including water-soluble and poorly water-soluble ingredients. Suitable pharmaceutical active ingredients include, but are not limited to, analgesics and anti-inflammatories, antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigouts, antihypertensives, antimalarials, antimigraines, antimuscarinics, antineoplastics and immunosuppressants, antiprotozoals, antirheumatic drugs, antithyroid drugs, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics, beta blockers, inotropes, corticosteroids, cough suppressants, cytotoxins, decongestants, diuretics, enzymes, antiparkinsonian drugs, gastrointestinal drugs, histamine receptor antagonists, lipid regulators, local anesthetics, neuromuscular drugs, nitrates and antianginal agents, nutritional agents, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants and combinations thereof. In certain embodiments, the present invention also relates to therapeutic methods utilizing any of the active ingredients disclosed herein to treat a disease or condition treatable by the active ingredient.

[0018] In some embodiments, the active pharmaceutical ingredient can be selected from, but is not limited to, dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurine, asimadoline, beclomethasone, apremilast, sapacitabine, linsitinib, abiraterone, vitamin D analogs (e.g., calcifediol, calcitriol, paricalcitol, doxorcalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, pharmaceutically acceptable salts thereof, and combinations thereof.

[0019] In some embodiments, the lipid in the dosage form can be selected from, but is not limited to, almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower seed oil, hydrogenated vegetable oil, walnut oil, and watermelon seed oil. Other oils and fats may include, but are not limited to, fish oil (ω-3), krill oil, animal or vegetable fats (e.g., hydrogenated forms thereof), free fatty acids, and mono-, di-, and triglycerides with C8-, C10-, C12-, C14-, C16-, C18-, C20-, and C22-fatty acids, and combinations thereof.

[0020] According to certain embodiments, the active agent may include a lipid-lowering agent, including but not limited to statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin), fibrates (e.g., clofibrate, ciprofibrate, bezafibrate, fenofibrate and gemfibrozil), niacin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, mixtures of any of the foregoing, and the like.

[0021] Suitable nutritional actives may include, but are not limited to, 5-hydroxytryptophan, acetyl-L-carnitine, alpha-lipoic acid, alpha-ketoglutaric acid, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), dimethylaminoethanol, fumaric acid, germanium sequioxide, glandular products, glucosamine hydrochloride, glucosamine sulfate, hydroxymethylbutyrate, immunoglobulins, lactic acid, L-carnitine, liver products, malic acid, anhydrous maltose, mannose (d-mannose), methylsulfonylmethane, plant sterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0022] Suitable nutritional supplement actives may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, or combinations thereof.

[0023] Suitable vitamin actives may include, but are not limited to, the following: ascorbic acid (vitamin C), B vitamins, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbates, mixed tocopherols, niacin (vitamin B3), orotic acid, para-aminobenzoic acid, pantothenate, pantothenic acid (vitamin B5), pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamine (vitamin B1), tocotrienols, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oils, and oil-soluble vitamins.

[0024] Suitable herbal supplement actives may include, but are not limited to, the following: arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginkgo, ginseng, goldenrod, hawthorn, kava, licorice, milk thistle, plantain, rauwolfia, senna, soy, St. John's wort, saw palmetto, turmeric, valerian.

[0025] Mineral actives may include, but are not limited to, the following: boron, calcium, chelated minerals, chloride, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvic acid, zinc, and other minerals.

[0026] Examples of other possible active agents include, but are not limited to, antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), nonsteroidal anti-inflammatory drugs (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, fluprofen, buclofen, indomethacin, sulindac, zomeprofen, Acid, thiopinic acid, zidometacin, acemetacin, fentiac, clorinac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenamic acid, piroxicam, sudoxicam, isoxicam, aceclofenac, aloprin, azapropazone, benolate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, Nabumetone, naproxen, nimesulide, oxybutazone, parecoxib, phenylbutazone, salicylsalicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, pharmaceutically acceptable salts thereof and mixtures thereof) and acetaminophen, antiemetics (e.g. metoclopramide, methylnaltrexone), antiepileptics (e.g. phenyloin, meprobmate and nitrazepam), vasodilators (e.g. nifedipine, papaverine, diltiazem and nicardipine), cough suppressants and expectorants (e.g. codeine phosphate), antiasthmatics (e.g. theophylline), Antacids, antispasmodics (e.g., atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, bendroflumethiazide), antihypotensives (e.g., propranolol, clonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., salbutamol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidal drugs, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine) and cannabinoids, and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof.

[0027] Active agent can also be benzodiazepines, barbiturates, stimulants or their mixture.Term "benzodiazepines" refers to benzodiazepines and derivative drugs of benzodiazepines that can inhibit the central nervous system.Benzodiazepines include but are not limited to alprazolam, bromazepam, clodiazepine, chlordiazepoxide, diazepam, estazolam, flurazepam, halazepam, ketazola, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs and mixtures.The benzodiazepine antagonists that can be used as active agent include but are not limited to flumazenil and its pharmaceutically acceptable salts, hydrates, solvates and mixtures.

[0028] The term "barbiturates" refers to sedative hypnotic drugs derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists that can be used as active agents include, but are not limited to, amphetamine and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0029] The term "stimulant" includes, but is not limited to, amphetamines such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof. Stimulant antagonists that can be used as active agents include, but are not limited to, benzodiazepines and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0030] The dosage form disclosed in the present invention includes various active agents and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include, but are not limited to: inorganic acid salts, such as hydrochlorides, hydrobromides, sulfates, phosphates, etc.; organic acid salts, such as formates, acetates, trifluoroacetates, maleates, tartrates, etc.; sulfonates, such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.; amino acid salts, such as arginine salts, aspartates, glutamates, etc.; and metal salts, such as sodium salts, potassium salts, cesium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; organic amine salts, such as triethylamine salts, pyridine salts, methylpyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.

[0031] As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount of active agent or the rate of administration required to produce the desired therapeutic effect.

[0032] As used herein, "shell" or "shell composition" refers to the shell of a soft gel capsule encapsulating a fill material.

[0033] As used herein, "conventional enteric polymers" refer to, but are not limited to, acrylic acid and methacrylic acid polymers, which are available under the trade names The enteric shell compositions of the present invention 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 compositions of the present invention do not include acid-insoluble polymers. In other words, the enteric shell compositions and enteric soft gel capsules "do not contain or substantially do not contain conventional enteric polymers".

[0034] As used herein, "free or substantially free" means that the composition contains less than about 1% by weight, less than about 0.5% by weight, less than about 0.25% by weight, less than about 0.1% by weight, less than about 0.05% by weight, less than about 0.01% by weight, or 0% by weight of the component.

[0035] All references to weight % in the specification and claims refer to the weight of the component relative to the weight of the entire composition, which may also be expressed as w / w.

[0036] As used herein, "fill material" or "fill" refers to a composition containing at least one pharmaceutically active ingredient that is enclosed by an enteric-coated capsule shell.

[0037] As used herein, "delayed release" means that the active agent is released after it passes through the stomach.

[0038] As used herein, "about" refers to any value that varies within a range of ±10%, so "about 10" includes 9 to 11. As used herein, "a", "an" or "the" refers to one or more, unless otherwise indicated. Thus, for example, "an excipient" includes a single excipient as well as a mixture of two or more different excipients, etc.

[0039] Recitation of ranges of values ​​herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0040] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to illustrate certain materials and methods and does not limit the scope. No language in the specification should be construed as indicating any non-claimed element is essential to the practice of the disclosed materials and methods.

[0041] According to one embodiment, a delayed-release soft gel capsule comprises: a fill material comprising an active agent, a shell composition comprising pectin, and a coating comprising an enteric polymer.

[0042] In some embodiments of the capsule, the coating of the soft gel capsule can provide a weight gain of the capsule of about 0.1% to about 10%, about 0.5% to about 5%, about 1% to about 10%, about 1% to about 5%, about 1% to about 3%, or about 2% to about 5%.

[0043] Suitable filling materials contain at least one pharmaceutically active ingredient and can be prepared according to known methods. In addition to at least one pharmaceutically active ingredient, suitable filling materials may also contain other filling components, such as flavoring agents, sweeteners, colorants and fillers or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides. Those of ordinary skill in the art can easily determine the appropriate amount of the pharmaceutically active ingredient and the pharmaceutically acceptable excipient.

[0044] In some embodiments, the pectin in the shell composition can be low methoxyl pectin. In one embodiment, low methoxyl pectin can be LM pectin (P-25), LM pectin (445C), LM pectin (100C) or a combination thereof. In another embodiment, pectin can be amidated pectin or non-amidated pectin. The addition of pectin contributes to the enteric solubility of the dosage form. However, too much pectin in the dosage form may reduce the gel strength of the soft gel capsule, which in turn may have an adverse effect on the sealing of the soft gel capsule. Therefore, pectin can be added to the dosage form at a sufficiently high concentration to form an enteric-coated dosage form, while being sufficiently low to mitigate the reduction in gel strength. In one embodiment, the amount of pectin in the enteric shell composition is about 2% to about 30%, about 2% to about 25%, about 2% to about 20%, about 3% to about 15%, about 3% to about 5.5%, about 5% to about 10%, about 2.5% to about 20%, about 5% to about 18%, 7.5% to about 15%, or about 10% to about 12% by weight, 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 range from about 10% to about 50%, from about 20% to about 40%, or from about 25% to about 35%.

[0045] In some embodiments of capsule, shell composition can also include plasticizer.Plasticizer can include glycerol (glycerol), glycerin (glycerin), sorbitol, sorbitol sorbitan solution (sorbitolsorbitansolution), triacetin, polysorbate or its combination.In one embodiment, plasticizer can include glycerol and sorbitol sorbitan solution.In some embodiments, polysorbate can include polysorbate 20 (also referred to as Tween 20), polysorbate 80 (also referred to as Tween 80) or its combination. Other suitable plasticizers may include, but are not limited to, sugar alcohol plasticizers, such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol or mannitol; or polyol plasticizers, such as diglycerol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propylene glycol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, 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 with aliphatic hydroxyl groups, ester plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single-block polymers, citrate plasticizers, and triacetin. Such plasticizers may include 1,2-butanediol, 2,3-butanediol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitan lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.

[0046] In some embodiments, the amount of plasticizer can be about 5 wt % to about 75 wt %, about 2 wt % to about 40 wt %, about 2 wt % to about 15 wt %, about 4 wt % to about 12 wt %, 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.

[0047] In some embodiments, the plasticizer may be glycerol. The content of glycerol may be about 5 wt % to about 30 wt %, about 8 wt % to about 26 wt %, about 12 wt % to about 22 wt %, or about 15 wt % to about 22 wt %, based on the total weight of the shell composition.

[0048] In some embodiments, the plasticizer can be a sorbitol sorbitan solution. The content of the sorbitol sorbitan solution can be about 2 wt % to about 40 wt %, about 5 wt % to about 36 wt %, about 8 wt % to about 30 wt %, about 10 wt % to about 27 wt % or about 15 wt % to about 22 wt % based on the total weight of the shell composition.

[0049] In some embodiments of soft gel capsules, the shell composition can also include gelatin. Gelatin can include type A gelatin, type B gelatin, skin gelatin and / or bone gelatin used alone or in combination. In one embodiment, the gelatin is 250 bloom gelatin. In another embodiment, there is only one type of gelatin. In another embodiment, 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% by weight to about 80% by weight, about 15% by weight to about 60% by weight, about 20% by weight to about 55% by weight, about 25% by weight to about 50% by weight, about 30% by weight to about 45% by weight, or about 35% by weight to about 40% by weight based on the total weight of the shell composition.

[0050] In some embodiments, the shell composition of the soft gel capsule can include a cellulose derivative, such as hydroxypropyl methylcellulose (HPMC). In one embodiment, the amount of the cellulose derivative (e.g., HPMC) in the shell composition is about 0.15 wt % to about 4.0 wt %, more preferably about 0.20 wt % to about 2.0 wt %, most preferably about 0.25 wt % to about 1.4 wt %. In some embodiments, the enteric capsule shell composition can include HPMC, methylcellulose (MC), hydroxypropyl cellulose (HPC) or a combination thereof. Cellulose derivatives can be added to the shell composition to alleviate the potential reduction of gel strength. The concentration of the cellulose derivative in the enteric shell composition can be an effective amount to improve gel strength, but it cannot be too high to interfere with sealing.

[0051] In some embodiments, the shell composition of the soft gel capsule may further include gellan gum, dextrose, water or a combination thereof. In some embodiments, the amount of dextrose may be about 0.001 wt % to about 10 wt %, about 0.001 wt % to about 5 wt %, about 0.01 wt % to about 4.5 wt %, about 0.01 wt % to about 4 wt %, about 0.1 wt % to about 3 wt % or about 1 wt % to about 2.5 wt % based on the total weight of the shell composition.

[0052] In one embodiment, the shell composition of the soft gel capsule may optionally contain additional agents such as colorants, flavoring agents, sweeteners, fillers, antioxidants, diluents, pH adjusters or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides.

[0053] Exemplary suitable colorants can include, but are not limited to, pigments such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown. In a specific embodiment, the color of the dosage form can indicate the contents (e.g., one or more active ingredients) contained therein.

[0054] Exemplary suitable flavoring agents may include, but are not limited to, "spice extracts" typically obtained by extracting a portion of a raw material (e.g., animal or plant material) using a solvent (e.g., ethanol or water); natural flavors obtained by extracting essential oils from flowers, fruits, roots, etc., or from whole plants.

[0055] Additional exemplary flavoring agents that may be in the dosage form may include, but are not limited to, breath freshening compounds such as menthol, spearmint and cinnamon, coffee beans, other flavoring agents or spices such as fruit flavors (e.g., cherry, orange, grape, etc.), particularly those used for oral hygiene, and actives for tooth and oral cleaning, such as quaternary ammonium bases. Flavor enhancers such as tartaric acid, citric acid, vanillin, etc. may be used to enhance the effect of flavor.

[0056] 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 its various salts, such as potassium salts (available as obtain), alitame, aspartame (available as and Aspartame-acesulfame salt (available as obtained), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as sodium salt (available as Sweet'N Obtained from stevioside, chlorinated derivatives of sucrose, such as sucralose (available as and Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizic acid glycosides; monoammonium glycyrrhizinate (trade name sold); Stevia rebaudiana (Stevioside), natural strong sweeteners such as monk fruit (Lo Han Kuo), polyols such as sorbitol, mannitol, xylitol, erythritol, etc.

[0057] In some embodiments, the enteric polymer of the coating can be an acrylic acid polymer, a methacrylic acid polymer, 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, potassium alginate, stearic acid, shellac, or a combination thereof. In some embodiments, the enteric polymer can be an acrylic acid polymer, a methacrylic acid polymer, or a combination thereof. In some embodiments, the enteric polymer can be an aqueous dispersion of an anionic copolymer based on methyl acrylate, methyl methacrylate, and methacrylic acid.

[0058] In some embodiments of the delayed release soft gel capsule, the coating may further comprise a plasticizer. The plasticizer may be glyceride, triethyl citrate or a combination thereof.

[0059] In some embodiments, the amount of enteric polymer in the coating is about 10% to about 60% by weight, about 15% to about 50% by weight, about 20% to about 40% by weight, about 25% to about 35% by weight, or about 30% by weight based on the total weight of the coating. In some embodiments, the amount of plasticizer in the coating can be about 2% to about 10% by weight, about 3% to about 9% by weight, about 4% to about 8% by weight, or about 5% by weight based on the total weight of the coating.

[0060] In some embodiments, the dosage of omega-3 in a soft gel capsule can be about 100 mg to about 1000 mg, about 150 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 350 mg to about 600 mg, or about 400 mg to about 500 mg per dose.

[0061] In some embodiments, the delayed release soft gel capsule can be tested by disintegration test in a basket assembly NT-40H model device in a 1000 mL beaker at about 37°C ± 2°C (described in more detail below). The enteric soft gel capsule according to this embodiment can remain intact in an acidic medium for about one hour, about two hours, about three hours, about four hours, about five hours, or at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, or at least about 6 hours, or about 1 hour to about 6 hours, about 1 hour to about 4 hours, or about 1 hour to about 2 hours. In some embodiments, the soft gel capsule can disintegrate in intestinal fluid in about 30 minutes or less, about 20 minutes or less, about 10 minutes or less, about 5 minutes or less. In certain embodiments, the above results can also be achieved for soft gel capsules at 1 month, 3 months, 6 months, 12 months, 18 months, 22 months or 24 months under accelerated stability conditions of 25°C / 60%RH, 30°C / 65%RH or 40°C / 75%RH.

[0062] The disintegration test conducted herein is consistent with the provisions of the European Pharmacopoeia and the United States Pharmacopoeia for enteric coated preparations. The apparatus used for the disintegration test is the NT-40H model (manufactured by Toyama Sangyo Co., Ltd.). The apparatus is a basket assembly, a 1000-mL low-profile beaker (138 to 160 mm in height and 97 to 115 mm in inner diameter) for immersion in the liquid, a thermostatic device for heating the liquid to between 35°C and 39°C, and a device for raising and lowering the basket in the immersion liquid at a constant frequency of 29 to 32 times per minute by a distance of not less than 53 mm and not more than 57 mm. The volume of liquid in the container is such that the wire mesh remains at least 15 mm below the surface of the liquid at the highest point of the upward stroke and is lowered to not less than 25 mm from the bottom of the container during the downward stroke. The top of the basket assembly should not be submerged at any time. The time required for the upward stroke is equal to the time required for the downward stroke, and the change in stroke direction is a smooth transition without a sudden reversal of motion. The basket assembly moves vertically along its axis. There is no noticeable horizontal motion or movement of the axis away from the vertical.

[0063] The disintegration test disclosed herein is conducted at about 37°C ± 2°C with a fluid volume of 1000 mL. Disintegration test fluid 1 (also referred to herein as "artificial gastric fluid") is a 2 g / L sodium chloride-hydrochloric acid solution with a pH of 1.2. Disintegration test fluid 2 (also referred to herein as "artificial intestinal fluid") is a 0.2 mol / L potassium dihydrogen phosphate-0.2 mol / L sodium hydroxide solution with a pH of 6.8.

[0064] The disintegration test was performed using the first fluid for about 120 minutes by placing a unit in each of the six tubes of the basket, immersing the basket (and the unit) in the first test fluid, then lifting the basket from the fluid and observing whether the unit disintegrates. Disintegration is defined as a state where the unit breaks or the enteric shell composition breaks or breaks. If none of the six units disintegrate, the test is passed. A similar test was performed using the second disintegration test fluid for a selected time.

[0065] In some embodiments, the disintegration test may be performed for about 150 minutes, about 120 minutes, about 105 minutes, about 90 minutes, about 75 minutes, about 60 minutes, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, or about 5 minutes.

[0066] In certain embodiments, a two-stage disintegration test can be performed on the soft gel capsule of the present disclosure. Under the two-stage disintegration test, the soft gel capsule is first subjected to an acidic medium (pH=1.2), and then subjected to a buffer medium (pH=6.8). When exposed to acidic and buffered media, the soft gel capsule can remain intact for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, or about 1 hour to 6 hours, about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, or about 1 hour to about 2 hours. In certain embodiments, under the accelerated storage conditions of 25°C / 60%RH, 30°C / 65%RH or 40°C / 75%RH, the soft gel capsule can also obtain the above results at 1 month, 3 months, 6 months, 12 months, 18 months, 22 months or 24 months. In certain embodiments, at 1 hour, 4 hours, or 8 hours, the intact time varies by no more than 20%, no more than 10%, or no more than 5% from time 0 following any accelerated storage condition disclosed herein.

[0067] In certain embodiments, a two-stage disintegration test can be performed on the soft gel capsule of the present disclosure. Under the two-stage disintegration test, the soft gel capsule is first subjected to an acidic medium (pH=1.2), and then subjected to a buffer medium (pH=7.5). When exposed to acidic and buffered media, the soft gel capsule can remain intact for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, or about 1 hour to 6 hours, about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, or about 1 hour to about 2 hours. In certain embodiments, under the accelerated storage conditions of 25°C / 60%RH, 30°C / 65%RH or 40°C / 75%RH, the soft gel capsule can also obtain the above results at 1 month, 3 months, 6 months, 12 months, 18 months, 22 months or 24 months. In certain embodiments, at 1 hour, 4 hours, or 8 hours, the intact time varies by no more than 20%, no more than 10%, or no more than 5% from time 0 following any accelerated storage condition disclosed herein.

[0068] In some embodiments, the disintegration test can be carried out using a buffer having a pH of 7.5. Under these conditions, the soft gel capsule can disintegrate in about 30 minutes or less, about 25 minutes or less, about 20 minutes or less, about 15 minutes, about 10 minutes or less, or about 5 minutes or less. In some embodiments, the disintegration test can be carried out in 1 month, 3 months, 6 months, 12 months, 18 months, 22 months, or 24 months using a buffer having a pH of 7.5 under accelerated storage conditions of 5°C / 60%RH, 30°C / 65%RH, or 40°C / 75%RH. Under these conditions, the soft gel capsule can disintegrate in about 45 minutes or less, about 40 minutes or less, about 35 minutes or less, about 30 minutes or less, about 25 minutes or less, about 20 minutes or less, about 15 minutes or less, about 10 minutes or less, or about 5 minutes or less.

[0069] In some embodiments, the soft gel capsule can be exposed to an aqueous medium to test the hygroscopicity of the soft gel capsule. After the soft gel capsule is exposed for 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes or 120 minutes, the moisture absorption rate of the soft gel capsule can be less than 2%, less than 1.5%, less than 1%, less than 0.8%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1% or less than 0.05%. In certain embodiments, under the accelerated storage conditions of 25°C / 60%RH, 30°C / 65%RH or 40°C / 75%RH, the soft gel capsule can also obtain the above results at 1 month, 3 months, 6 months, 12 months, 18 months, 22 months or 24 months.

[0070] The encapsulation of the filler material may be accomplished in any conventional manner. For example, a rotary mold encapsulation may be used.

[0071] According to one embodiment, the enteric soft gel capsule is prepared by a method comprising the following steps: preparing a fill material, the fill material comprising an active agent; encapsulating the fill material in a shell composition, wherein the shell composition comprises pectin, thereby forming a soft gel capsule. The capsule is then coated with a coating composition comprising an enteric polymer so that the weight of the capsule increases by about 1% to about 10%.

[0072] The method of preparing a soft gel capsule includes preparing a shell composition, wherein the shell composition may include pectin, a plasticizer, gelatin, gellan gum, dextrose, water, or a combination thereof as described herein.

[0073] The coating composition is then prepared by preparing a coating suspension containing an enteric polymer, a plasticizer, water, or a combination thereof. In certain embodiments, the enteric polymer may comprise an anionic copolymer based on methyl acrylate.

[0074] In certain embodiments, the invention relates to one or more of the following:

[0075] 1. A delayed-release soft gel capsule may include: a fill material, wherein the fill material comprises an active agent; a shell composition, wherein the shell composition comprises pectin; and a coating comprising an enteric polymer.

[0076] 2. The sustained-release soft gel capsule according to item 1, wherein the coating provides a weight gain of the capsule of about 1% to about 10% by weight, or about 2% to about 5%.

[0077] 3. The sustained-release soft gel capsule according to item 1 or 2, wherein the shell composition further comprises a plasticizer.

[0078] 4. The sustained-release soft gel capsule according to item 3, wherein the plasticizer comprises glycerol, glycerol, sorbitol, sorbitol sorbitan solution, triacetin, polysorbate or a combination thereof.

[0079] 5. The sustained-release soft gel capsule according to any one of items 3-4, wherein the plasticizer comprises glycerin and sorbitol sorbitan solution.

[0080] 6. The sustained-release soft gel capsule according to item 4, wherein the polysorbate comprises Tween 20, Tween 80 or a combination thereof.

[0081] 7. The sustained-release soft gel capsule according to any one of the preceding items, wherein the shell composition further comprises gelatin.

[0082] 8. The sustained-release soft gel capsule according to item 7, wherein the gelatin is selected from type A gelatin, type B gelatin and a mixture thereof.

[0083] 9. The sustained-release soft gel capsule according to item 7, wherein the gelatin is selected from fish gelatin, skin gelatin, bone gelatin and mixtures thereof.

[0084] 10. The sustained-release soft gel capsule according to any one of the preceding items, wherein the shell composition further comprises gellan gum.

[0085] 11. The sustained-release soft gel capsule according to any one of the preceding items, wherein the shell composition further comprises glucose.

[0086] 12. The sustained-release soft gel capsule according to any one of the preceding items, wherein the shell composition further comprises water.

[0087] 13. The sustained-release soft gel capsule according to any one of the preceding items, wherein the pectin is low-methoxyl pectin.

[0088] 14. A sustained-release soft gel capsule according to any one of the preceding items, wherein the enteric polymer is an acrylic acid polymer, a methacrylic acid polymer, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate (PVAP), alginate, stearic acid, shellac or a combination thereof.

[0089] 15. The sustained-release soft gel capsule according to item 14, wherein the alginate is sodium alginate, potassium alginate or a combination thereof.

[0090] 16. The sustained-release soft gel capsule according to item 14, wherein the enteric polymer is an acrylic acid polymer, a methacrylic acid polymer or a combination thereof.

[0091] 17. The sustained-release soft gel capsule according to any one of the preceding items, wherein the coating further comprises a plasticizer.

[0092] 18. The sustained-release soft gel capsule according to item 17, wherein the plasticizer comprises glyceride, triethyl citrate or a combination thereof.

[0093] 19. The sustained-release soft gel capsule according to any of the preceding items, wherein the amount of pectin is about 2.5 wt % to about 20 wt %, 5 wt % to about 18 wt %, 7.5 wt % to about 15 wt %, or about 10 wt % to about 12 wt % based on the total weight of the shell composition.

[0094] 20. A sustained-release soft gel capsule according to any one of items 7-9, wherein the amount of gelatin is 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.

[0095] 21. A sustained-release soft gel capsule according to claim 11, wherein the amount of glucose is 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.

[0096] 22. A sustained-release soft gel capsule according to any one of items 4-6, wherein the amount of the plasticizer is 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.

[0097] 23. The sustained-release soft gel capsule according to any one of the preceding items, wherein the amount of the enteric polymer is about 20 wt % to about 40 wt %, about 25 wt % to about 35 wt %, or about 30 wt % based on the total weight of the coating.

[0098] 24. A sustained-release soft gel capsule according to claim 17, wherein the amount of the plasticizer is about 2 wt % to about 10 wt %, about 3 wt % to about 9 wt %, about 4 wt % to about 8 wt %, or about 5 wt % based on the total weight of the coating.

[0099] 25. A sustained release soft gel capsule according to any one of the preceding items, wherein the shell composition does not rupture at 15 minutes, 30 minutes, 45 minutes or 60 minutes in 750 ml of 0.1 N HCL acidic medium adjusted with phosphate buffer at pH 1.2 when measured with USP Apparatus II with paddles at 50 RPM.

[0100] 26. A sustained release soft gel capsule according to any one of the preceding items, wherein the shell composition does not rupture at 15 minutes, 30 minutes, 45 minutes or 60 minutes in 750 ml of 0.1 N HCL acidic medium adjusted with phosphate buffer at a pH between 6 and 7 when measured with USP Apparatus II with paddles at 50 RPM.

[0101] 27. A method for preparing a sustained-release soft gel capsule according to any one of the preceding items, the method comprising:

[0102] preparing a fill material comprising an active agent;

[0103] encapsulating a fill material with a shell composition comprising pectin to form a capsule; and

[0104] The capsules are coated with a coating composition comprising an enteric polymer. Example

[0105] The specific embodiments of the present invention will now be described with reference to the following examples. It should be understood that these examples are disclosed only to illustrate the present invention and should not limit the scope of the present invention in any way.

[0106] Delayed release soft gel capsule coating

[0107] A batch of coated delayed release soft gel capsules was manufactured according to the present disclosure. A batch of 1000 mg delayed release soft gel capsules was used for coating experiments. The fill material was refined fish oil containing 300 mg of omega 3. The shell composition of the delayed release soft gel capsules is summarized in Table 1.

[0108] Table 1. Soft gel capsule shell composition

[0109] Project Description %(weight%) Pectin 5.0–18.0 gelatin 25.0–48.0 Dextrose 0.01–2.20 glycerin 8.0–22.0 Sorbitol sorbitan solution 4.0–36.0 Purified water 5.0–18.0 total 100.00

[0110] Prepared containing FS30D (an aqueous dispersion based on an anionic copolymer of methyl acrylate, methyl methacrylate and methacrylic acid) is used as the coating polymer. The coating composition also comprises T20 is used as a plasticizer, T20 is understood to include a 20% aqueous suspension containing an anti-adherent, a plasticizer and a stabilizer. The coating compositions were prepared as coating suspensions, which are summarized in Table 2.

[0111] Table 2. Coating suspension composition

[0112]

[0113] 1000 mg delayed release fish oil soft gel capsules were coated to a 2% weight gain. The coated soft gel capsules were subjected to various tests to evaluate the robustness of enteric solubility. The coated capsules were also packaged into induction sealed HDPE bottles and subjected to developmental stability testing under accelerated conditions according to stability protocol ISS-21-047.

[0114] Comparison of coated immediate release soft gel capsules

[0115] For comparison, we manufactured a batch of coated fish oil soft gel capsules. A batch of 1000 mg immediate release fish oil soft gel capsules was used for coating trials. The fill material was fish oil containing 300 mg ω3. The shell formulations of the immediate release soft gel capsules are summarized in Table 3.

[0116] Table 3. Soft gel shell formulation

[0117] Project Description %(weight%) gelatin 28.0–56.0 glycerin 12.0–35.0 Purified water 5.0–18.0 total 100.00

[0118] 1000 mg immediate release fish oil soft gel capsules were coated using the same coating suspension described in Table 2 to achieve 2% (Sub-batch 21SC-12A) and 3.6% (Sub-batch 21SC-12B) weight gains, respectively. The coated capsules were subjected to various tests to evaluate the robustness of enteric solubility. The coated immediate release capsules were also packaged into induction sealed HDPE bottles and subjected to developmental stability testing under accelerated conditions according to stability protocols ISS-22-027 and ISS-22-028.

[0119] Disintegration and rupture testing

[0120] The 1000 mg coated delayed-release fish oil soft gel capsules and the 1000 mg coated immediate-release fish oil soft gel capsules were subjected to a two-stage disintegration test and a two-stage rupture test.

[0121] The disintegration test was conducted using a disintegration apparatus B (ERWEKA, model: ZT 224). In the acidic stage, 0.1 N HCl was used; in the buffer stage, pH 6.8 and pH 7.5 phosphate buffer solutions were used.

[0122] A two-stage burst test was performed using a Dissolution Apparatus II, Distek, Model: 2500. In the acidic stage, a biorelevant medium FaSSGF containing an enzyme (pepsin) was used at pH 1.6; in the buffered stage, a phosphate buffer solution containing an enzyme (pancreatin) was used at pH 7.5.

[0123] The 1000 mg coated delayed release fish oil soft gel capsules, 1000 mg coated immediate release fish oil soft gel capsules and 1000 mg uncoated delayed release fish oil soft gel capsules were also subjected to hygroscopicity testing to compare the weight gain of the capsules after exposure to different times. The immersion medium used in this study was the same acidic medium used in the disintegration test, 0.1 N HCl.

[0124] Capsule disintegration test results

[0125] Table 4 summarizes the bursting strength data for uncoated and 2% weight gain coated delayed release fish oil soft gel capsules. The bursting strength data before and after the coating step were similar. Therefore, coating does not appear to affect the physical robustness of the delayed release soft gel capsules.

[0126] Table 4. Bursting strength of 1000 mg coated delayed release fish oil soft gel capsules

[0127] sample Bursting strength(kg) Moving distance(mm) Batch 4701394 (uncoated) 99.4 4.91 21SC-09A(2% weight gain) 110.7 4.74

[0128] Table 5 summarizes the results of the two-stage disintegration test at time zero for the soft gel capsules after coating.

[0129] Table 5. Disintegration results of 1000 mg coated delayed release soft gel capsules at T0

[0130]

[0131] The above results indicate that a 2% weight gain gives the soft gel capsules robust enteric properties. Notably, the coated soft gel capsules resulted in intact soft gel capsules in both pH 1.2 HCl acidic media and pH 6.8 phosphate buffer. However, the 2% weight gain coated soft gel capsules still ruptured within an average of 24 minutes in pH 7.5 buffer. The increase in the threshold pH value of the coated soft gel capsules enables colonic delivery of the dosage form.

[0132] Table 6 summarizes the two-stage disintegration results at 1 month and 3 months under accelerated stability conditions (40°C / 75% RH).

[0133] Table 6. Disintegration results of 1000 mg coated delayed-release soft gel capsules at T1 and T3

[0134]

[0135] For the coated delayed-release soft gel capsule (21SC-09A) with 2% weight gain, at T = 1 month, the soft gel capsule remained intact in pH 1.2 and pH 6.8 media, and ruptured at 34 minutes in pH 7.5 buffer. At T = 3 months, the coated delayed-release soft gel capsule remained intact in pH 1.2 HCl media, and ruptured at 43 minutes in pH 7.5 phosphate buffer.

[0136] Table 7 summarizes the two-stage disintegration test results at 6 and 12 months under long-term stability conditions (25°C / 60% RH), 18 months under medium-term stability conditions (30°C / 65% RH), 6 months under accelerated stability conditions (40°C / 75% RH), and 22 months under room temperature holding conditions.

[0137] Table 7. Disintegration results of 1000 mg coated delayed-release soft gel capsules at T6, T12, T18 and T22 (discs in buffer stage)

[0138]

[0139]

[0140] For the coated delayed-release soft gel capsule (21SC-09A) with 2% weight gain, at T = 6 months (25°C / 60%RH), the soft gel capsule remained intact in pH 1.2 and ruptured at 11 minutes in pH 7.5 phosphate buffer; and at T = 12 months (25°C / 60%RH), the soft gel capsule remained intact in pH 1.2 and ruptured at 15 minutes in pH 7.5 phosphate buffer. For T = 6 months (40°C / 75%RH), the delayed-release soft gel capsule remained intact in the HCl medium of pH 1.2 and ruptured at 17 minutes in pH 7.5 phosphate buffer. For T = 18 months (30°C / 65%RH), the delayed-release soft gel capsule remained intact in the HCl medium of pH 1.2 and ruptured at 15 minutes in pH 7.5 phosphate buffer. For T=22 months (RT retention), the delayed release soft gel capsules remained intact in pH 1.2 HCl medium and ruptured at 11 minutes in pH 7.5 phosphate buffer.

[0141] Results for coated immediate release fish oil soft gel capsules are also presented. Table 8 summarizes the two-stage disintegration data for coated immediate release soft gel capsules with 2% and 3.6% weight gain, respectively.

[0142] The coated immediate release soft gel capsules (21SC-12A) with 2% weight gain ruptured in HCl medium at pH 1.2, which did not meet the requirements of enteric dosage forms. The coated immediate release soft gel capsules (21SC-12B) with 3.6% weight gain did not completely rupture in acidic medium at pH 1.2. However, all soft gel capsules released a small amount of fill material, indicating insufficient enteric solubility.

[0143] Table 8. Disintegration results of 1000 mg coated immediate release soft gel capsules with 2% weight gain and 3.6% weight gain

[0144]

[0145] Two-stage burst test

[0146] Table 9 summarizes the two-stage rupture data for coated delayed release soft gel capsules with 2% weight gain (21SC-09A) and coated immediate release soft gel capsules with 2% weight gain (21SC-12A) and 3.6% weight gain (21SC-12B), respectively.

[0147] For the coated delayed release soft gel capsules (21SC-09A) with 2% weight gain, the capsules remained intact in the enzyme-containing FaSSGF and ruptured in an average of 15 minutes in the enzyme-containing pH 7.5 phosphate buffer. During the first acidification stage, tiny oil droplets were observed in 4 of 6 containers, but the capsules remained intact and no further release was observed.

[0148] Coated immediate release softgel capsules with 2% WG (21SC-12A) and 3.6% WG (21SC-12B) released small amounts of fill material (more than 10%) in pH FaSSGF medium containing enzymes, indicating insufficient enteric solubility.

[0149] Table 9. Two-stage burst test results for coated delayed-release soft gel capsules with 2% weight gain and coated immediate-release soft gel capsules with 2% weight gain and 3.6% weight gain

[0150]

[0151] ＊ Observe tiny droplets

[0152] Hygroscopicity test

[0153] Table 10 summarizes the moisture absorption data for the 2% weight gain coated delayed release capsules, the coated immediate release soft gel capsules with 2% weight gain and 3.6% weight gain, and the uncoated delayed release soft gel capsules, respectively. Figure 1 Capsule moisture absorption of coated capsules is shown. The moisture absorption test was performed on soft gel capsules placed in aqueous medium.

[0154] Table 10. Capsule moisture absorption results of selected soft gel capsules (per capsule)

[0155]

[0156] The coated delayed-release soft gel capsules had limited weight gain during the 120-minute soaking period, which clearly indicated that the 2% weight gain coating and pectin shell combination provided a strong moisture barrier. Meanwhile, the coated immediate-release soft gel capsules with 2% weight gain and 3.6% weight gain began to lose weight after 60 minutes, indicating that the aqueous medium penetrated the coating layer and dissolved the non-pectin shell. The uncoated delayed-release soft gel capsules gained more than 92% weight after 120 minutes, indicating strong hygroscopicity.

[0157] Thus, the data suggest that coating delayed-release softgel capsules with a relatively low weight gain (2%) can significantly improve enteric robustness and minimize hygroscopicity during dissolution. In addition, low weight gain coatings can achieve more consistent coating uniformity, resulting in more stable performance of the dosage form. In addition, coating delayed-release softgel capsules with appropriate enteric polymer systems may expand the scope of application, as the increase in pH threshold allows for deeper delivery of the dosage form into the digestive system, such as colon delivery.

[0158] The foregoing description sets forth many specific details, such as examples of specific systems, components, methods, etc., in order to provide a good understanding of several embodiments of the present invention. However, it will be appreciated by those skilled in the art that at least some embodiments of the present invention may be implemented without these specific details. In other cases, well-known components or methods are not described in detail to avoid unnecessarily obscuring the present invention. Therefore, the specific details set forth are exemplary. Specific embodiments may differ from these exemplary details, but are still considered to be within the scope of the present invention.

[0159] Although the operation of the method is described in a particular order herein, the order of operation of each method can be changed so that certain operations can be performed in reverse order, or certain operations can be performed at least partially simultaneously with other operations. In another embodiment, the instructions or sub-operations of different operations can be adopted in an intermittent and / or alternating manner.

[0160] It should be understood that the above description is intended to be illustrative, not restrictive. Those skilled in the art will appreciate many other embodiments after reading and understanding the above description. Therefore, the scope of the present invention should be determined with reference to the appended claims and the full scope of equivalents enjoyed by such claims.

Claims

1. A delayed-release soft gel capsule comprising: a fill material, wherein the fill material comprises an active agent; a shell composition, wherein the shell composition comprises pectin; and A coating comprising an enteric polymer.

2. The delayed-release soft gel capsule according to claim 1, wherein the coating provides a weight gain of the capsule of about 1% to about 10% by weight, or about 2% to about 5%.

3. The delayed-release soft gel capsule according to claim 1, wherein the shell composition further comprises a plasticizer.

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

5. The delayed release soft gel capsule according to claim 4, wherein the plasticizer comprises glycerol and sorbitol sorbitan solution.

6. The delayed-release soft gel capsule according to claim 4, wherein the polysorbate comprises Tween 20, Tween 80 or a combination thereof.

7. The delayed release soft gel capsule according to claim 1, wherein the shell composition further comprises gelatin.

8. The delayed release soft gel capsule according to claim 7, wherein the gelatin is selected from the group consisting of Type A gelatin, Type B gelatin and mixtures thereof.

9. The delayed release soft gel capsule according to claim 7, wherein the gelatin is selected from the group consisting of fish gelatin, skin gelatin, bone gelatin and mixtures thereof.

10. The delayed release soft gel capsule according to claim 1, wherein the shell composition further comprises gellan gum.

11. The delayed release soft gel capsule according to claim 1, wherein the shell composition further comprises dextrose.

12. The delayed-release soft gel capsule according to claim 1, wherein the shell composition further comprises water.

13. The delayed release soft gel capsule according to claim 1, wherein the pectin is low methoxyl pectin.

14. The delayed-release soft gel capsule according to claim 1, wherein the enteric polymer is an acrylic acid polymer, a methacrylic acid polymer, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate (PVAP), alginate, stearic acid, shellac or a combination thereof.

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

16. The delayed-release soft gel capsule according to claim 14, wherein the enteric polymer is an acrylic acid polymer, a methacrylic acid polymer or a combination thereof.

17. The delayed release soft gel capsule according to claim 1, wherein the coating further comprises a plasticizer.

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

19. The delayed-release soft gel capsule according to claim 1, wherein the amount of pectin is about 2.5 wt% to about 20 wt%, 5 wt% to about 18 wt%, 7.5 wt% to about 15 wt%, or about 10 wt% to about 12 wt% based on the total weight of the shell composition.

20. The delayed-release soft gel capsule according to claim 7, wherein the amount of gelatin is about 15 wt % to about 60 wt %, about 20 wt % to about 55 wt %, about 25 wt % to about 50 wt %, about 30 wt % to about 45 wt % or about 35 wt % to about 40 wt % based on the total weight of the shell composition.

21. The delayed-release soft gel capsule according to claim 11, wherein the amount of dextrose is about 0.001 wt % to about 5 wt %, about 0.01 wt % to about 4.5 wt %, about 0.01 wt % to about 4 wt %, about 0.1 wt % to about 3 wt % or about 1 wt % to about 2.5 wt % based on the total weight of the shell composition.

22. The delayed-release soft gel capsule according to claim 4, wherein the amount of the plasticizer is from about 5 wt % to about 60 wt %, from about 10 wt % to about 55 wt %, from about 15 wt % to about 50 wt %, from about 20 wt % to about 45 wt % or from about 25 wt % to about 35 wt % based on the total weight of the shell composition.

23. The delayed-release soft gel capsule according to claim 1, wherein the amount of the enteric polymer is about 20 wt% to about 40 wt%, about 25 wt% to about 35 wt%, or about 30 wt% based on the total weight of the coating.

24. The delayed-release soft gel capsule according to claim 17, wherein the amount of the plasticizer is about 2 wt% to about 10 wt%, about 3 wt% to about 9 wt%, about 4 wt% to about 8 wt%, or about 5 wt% based on the total weight of the coating.

25. The delayed release soft gel capsule according to claim 1, wherein the shell composition does not rupture at 15 minutes, 30 minutes, 45 minutes or 60 minutes in 750 ml of 0.1 N HCL acidic medium adjusted in pH with phosphate buffer at pH 1.2 when measured with USP Apparatus II with paddles at 50 RPM.

26. The delayed release soft gel capsule according to claim 1, wherein the shell composition does not rupture at 15 minutes, 30 minutes, 45 minutes or 60 minutes in 750 ml of 0.1 N HCL acidic medium adjusted with phosphate buffer at pH between 6 and 7 when measured with USP Apparatus II with paddles at 50 RPM.

27. A method for preparing the delayed-release soft gel capsule of claim 1, the method comprising: preparing a fill material comprising an active agent; encapsulating a fill material with a shell composition comprising pectin to form a capsule; and The capsules are coated with a coating composition comprising an enteric polymer.

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