Delayed-release softgel capsules

Abstract

The present invention provides a delayed-release softgel capsule and a method for preparing it. [Solution] A delayed-release softgel capsule comprising a filling material and a pH-dependent shell composition. In one embodiment, the pH-dependent shell composition comprises gelatin, pectin, dextrose, and a combination of glycerin and sorbitol or sorbitol-sorbitan solution. The delayed-release properties of the capsule meet the intestinal disintegration criteria and / or inhibit the premature release of the filling material at acidic pH (such as any pH from about 1.2 to about 6).

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 112,456, filed on November 11, 2020, the content of which is incorporated herein in its entirety.

[0002] The present invention relates to delayed - release soft - gel capsules in which a gelatin - based shell composition has delayed - release properties by including a combination of plasticizers.

Background Art

[0003] Soft capsules, particularly soft gelatin capsules (or soft - gel capsules), are easy to swallow and do not require flavoring to mask any unpleasant taste of the active agent, providing a dosage form that is more readily acceptable to patients. Encapsulation of a drug in a soft - gel can further provide the potential to improve the bioavailability of the pharmaceutical. For example, the active ingredient can be rapidly released in liquid form as soon as the gelatin shell breaks. Efforts have been made to create delayed - release dosage forms. Delayed - release dosage forms are designed to protect the contents of the dosage form from gastric conditions. For example, a delayed - release dosage form can be produced by adding a pH - dependent coating to the surface of a manufactured dosage form such as a tablet or a capsule. Such a coating can be applied by spraying the dosage form and then drying the dosage form, usually at a high temperature. This method of coating a capsule with a pH - dependent coating can result in drawbacks regarding performance and appearance. For example, the capsule may look rough, the coating may be unevenly applied, and / or the coating may crack.

[0004]

[0004] ​​​The formulation may be prone to peeling off. In addition, a pH-dependent coating is applied. The process is extremely inefficient.

[0005] Conventional pH-dependent polymers (i.e., acid-insoluble polymers) were added to the capsule shell. Other delayed-release formulations have been developed. However, the addition of conventional pH-dependent polymers is insufficiently dense. Because it is sealed, it is prone to leakage, or because it contains a large amount of polymer, it is fragile (i.e., like an eggshell). It can produce capsules like these.

[0006] Improving the pH-dependent shell composition of softgel capsules is an ongoing effort. [Overview of the project]

[0007] This invention relates to delayed-release softgel capsules. Delayed-release softgel capsules are (a) Filling material and (2) pH-dependent shell composition. Delayed release soft according to the present invention. Gel capsules do not require pH-dependent coating. By eliminating the need to add to the gel capsule during the coating process, The risk of damaging the lug is also minimized.

[0008] In a particular embodiment, the pH-dependent shell composition is (a) gelatin, (b) dextrin (c) Pectin such as low methoxyl pectin, (d) Glycerin, (e) Sorbate Contains sorbitol or sorbitol sorbitan solution. In certain embodiments, pH-dependent The shell composition is approximately 0.5 wt% to 8 wt% of the total weight of the dry pH-dependent shell composition. Alternatively, it contains approximately 5 wt% to 40 wt% glycerin in the pH-dependent shell composition. The w:w ratio of reserpine to sorbitol or sorbitol sorbitan solution is about 1:1 .5 to about 1:7.

[0009] In certain embodiments, the pH-dependent shell composition comprises (a) a film-forming agent, (b) reserpine, and (c) a sorbitol or sorbitol sorbitan solution. In certain embodiments, the pH-dependent shell composition comprises glycerin in an amount of about 0.5 wt% to about 8 wt% or about 5 wt% to about 40 wt% based on the total weight of the dry pH-dependent shell composition and the w:w ratio of glycerin to sorbitol or sorbitol sorbitan solution in the pH-dependent shell composition is in the range of about 1:1.5 to about 1:7.

[0010] The present disclosure also encompasses processes for making any of the delayed-release soft gel capsules described herein.

[0011] In certain embodiments, the present disclosure also encompasses methods of treating a condition by administering to a subject in need thereof any of the delayed-release soft gel compositions described herein.

[0012] The soft gel capsules described herein, the pH-dependent shell compositions described herein, and their preparation processes can be adjusted / regulated / modified to achieve target pH dissolution / disintegration profiles (e.g., break-up / dissolution / disintegration times in acidic media and buffer media) of the shell composition in various pH environments.

[0013] In certain embodiments, the present disclosure encompasses methods of inhibiting early release of the filling material (and correspondingly, the active agent present in the filling material) in the early stages of the gastrointestinal tract.

[0014] In certain embodiments, the present disclosure is directed to a method of inhibiting belching by early release of a filling material (and correspondingly , an active agent present in the filling material) in the early gastrointestinal tract.

BRIEF DESCRIPTION OF THE INVENTION

[0015] The present invention advances the state of the art by developing a delayed-release oral dosage form, particularly a delayed-release soft gel capsule, that achieves the associated advantages of conventional delayed-release dosage forms without the need to apply a pH-dependent coating. The delayed-release soft gel capsules of the present invention do not dissolve / disintegrate in the gastric environment of the stomach, but rather dissolve at a target pH, such as above about 1.2, above about 2, above about 3, above about 3.5, above about 4, above about 5, above about 6, or above about 6.8. The dissolution profile of the delayed-release soft gel capsules described herein can be adjusted by modifying the shell composition of the soft gel capsules. Such a mechanism is beneficial for the delivery of active ingredients that can cause gastric irritation or are sensitive to the acidic environment of the stomach. Such a mechanism is also beneficial for reducing belching after ingestion of a capsule encapsulating a filling material that tends to contribute to belching. For example, belching often occurs when taking pharmaceutical products formulated in dosage forms that exhibit some leakage (even very small amounts) in the stomach before reaching the intestine. Leakage can be particularly problematic when belching is associated with substances having an unpleasant odor perception, such as fish oil and garlic, which are commonly delivered in soft gels. As described herein

[0016] ​​​​​​​​​​​​Delayed-release softgel capsules prevent premature leakage in the gastric environment (resulting in the capsule It can be formulated in a manner that minimizes and / or eliminates premature release of the filler.

[0017] definition As used herein, the term "pH-dependent" means, for example, at least about 15 minutes, less than At least 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, less than For a period of at least 4 hours, or at least 5 hours, it dissolves or breaks down in the gastric environment. To refer to the resistance of a substance to dissolution or decay, such that it does not occur or substantially does not occur. It is used. In certain embodiments, the gastric environment of the stomach is here phosphate buffer solution, hydroxide In a buffer solution such as sodium solution or potassium hydroxide solution, 1, 2, 2, 3, 4, 5 Alternatively, this can be simulated by adding 0.1N HCl adjusted to pH 6 and, if necessary, pepsin. It is possible. Pharmacopoeial methods do not include pepsin, but they better simulate / mimic in vivo conditions. Therefore, pepsin was added in the specific dissolution / disintegration tests described herein. It should be noted that, therefore, it should not be interpreted as being limited to a certain particular In embodiments, the compositions described herein contain pepsin in a 0.1N HCl environment (pepsin Even in the above situation (which is estimated to be a more aggressive environment than 0.1N HCl without synth), It is resistant to dissolution / disintegration.

[0018] For example, the embodiments described herein provide approximately 3.5% of the benefits compared to biological, artificial, or simulated gastric juice. At pH levels of 5 or higher, 4 or higher, 5 or higher, or 6 or higher (for example, in living organisms, artificial or simulated organisms) Contains a pH-dependent shell composition that preferentially dissolves in the duodenal environment and / or intestinal fluid. Hmm. In certain embodiments, the intestinal environment may or may not contain pancreatin. This can be simulated with pH 6.8 phosphate buffer. For example, the pH-dependent shell composition described herein. The items are: less than approximately 60 minutes, less than approximately 45 minutes, less than approximately 30 minutes, less than approximately 20 minutes, less than approximately 10 minutes, and In less than 5 minutes, the pH level rises to approximately 3.5 or higher, 4 or higher, 5 or higher, or 6 or higher (for example) If necessary, a bio-, artificial, or imitation pancreatin solution such as pH 6.8 phosphate buffer containing pancreatin. Dissolves in the pseudoduodenal environment and / or intestinal fluid. The pharmacopoeial method is pancreatin Although it does not contain pancreatin, pancreatin is included in this specification to better simulate / mimic in vivo conditions. It should be noted that it was added in the specific dissolution / disintegration tests described in the document. Therefore, without being construed as limiting, in certain embodiments described herein The composition described contains pancreatin and has a pH of approximately 3.5 or higher, 4 or higher, 5 or higher, 6 or higher, and This is a buffered environment of 6.8 (a more aggressive environment than a buffered environment of pH 6.8 without pancreatin). It exhibits a similar dissolution / disintegration profile in (presumably) the following locations.

[0019] As used herein, "pharmaceutical active ingredient" and "activator" refer to the diagnosis, treatment, and Refers to a drug or compound that may be used in mitigation, treatment, or prevention. A particular practice In terms of form, appropriate "activators" are vitamins, minerals, and supplements (VMS). Any dietary supplements include: Exemplary delayed-release softgel capsules contain, without limitation, lactic acid bacteria, Probiotics, fish oil capsules, valproic acid, garlic, peppermint oil, polyethylene Recall, ibuprofen solution or suspension, proton pump inhibitors, aspirin and This may include capsules containing similar products.

[0020] The term "condition" or "conditions" refers to the target of an effective amount of activator. This refers to medical conditions that can be treated or prevented by the administration of [medicine name].

[0021] As used herein, the term “active ingredient” means “active ingredient” as used by government agencies for that purpose. Whether approved or not, if it produces a therapeutic, preventative, or other intended effect It refers to any substance that is intended to be used. In the context of a specific drug, this term refers to the pharmaceutical activator, This includes all pharmaceutically acceptable salts, solvates, and crystalline forms thereof, and salts, solvates The crystalline form is pharmaceutically active.

[0022] Any pharmaceutically active ingredient, including both water-soluble and poorly water-soluble substances, is included in this It may be used for the purposes of the invention. Suitable pharmaceutically active ingredients include, without limitation, analgesics and anti- Inflammatory drugs (e.g., ibuprofen, naproxen sodium, aspirin), antacids, antacids Insecticides, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetic drugs, antidiarrheals, antiepileptic drugs, anti Antifungal agents, antigout agents, antihypertensive agents, antimalarial drugs, antimigraine agents, antimuscarinic agents, antineoplasms Drugs and immunosuppressants, antiparasitic drugs, antirheumatic drugs, antithyroid drugs, antiviral drugs, anxiolytics, Sedatives, hypnotics and nerve relaxants, beta-blockers, cardiac inotropes, corticosteroids, cough Antidotes, cytotoxic drugs, decongestants, diuretics, enzymes, antiparkinson's disease drugs, gastrointestinal drugs, hista Min receptor antagonists, lipid regulators, local anesthetics, neuromuscular agents, nitrates, and anti-stenotics. Cardiac drugs, nutritional supplements, opioid analgesics, anticonvulsants (e.g., valproic acid), oral vaccines, Proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, etc. This includes combinations of those.

[0023] In some embodiments, the active pharmaceutical ingredient is not limited to dabigatran, doronedarone, or tica. Grelor, Iloperidone, Ibakhtol, Midostaurin, Asimadrine, Beclomet Zon, apremilast, sapacitabine, lincitinib, abiraterone, vitamin D analog (For example, calcifediol, calcitriol, paricalcitol, doxelcalci Ferrol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib) Sibuprofen, tacrolimus, testosterone, lubiprostone, and their pharmaceutically acceptable The group can be selected from salts and combinations thereof.

[0024] In some embodiments, the lipids in the dosage form are not limited to almond oil, argan oil, avocado oil. Cocoa oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter Coconut oil, rapeseed oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, cannabis Oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, Manila oil, mon Gongonut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil Oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, peppermint oil, rice bran Oils, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, walnut oil, and The group may be selected from melon seed oil. Other oils and fats may be used, but are not limited to these. However, fish oil (omega-3), krill oil, for example, animal or vegetable fats in their hardened forms, Free fatty acids as well as C8-, C10-, C12-, C14-, C16-, C18-, C2 Monoglycerides, diglycerides, and triglycerides containing O- and C22- fatty acids This may include fatty acid esters such as EPA and DHA3, as well as combinations thereof.

[0025] According to certain embodiments, the activator is a statin (for example, , lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin (Rosuvastatin and pitavastatin), fibrates (e.g., clofibrate) , cyprofibrate, bezafibrate, fenofibrate, and gemfibrog (Lu), niacin, bile acid blockers, ezetimibe, lomitapide, phytosterols, and to the pharmaceutically acceptable salts, hydrates, solvates and prodrugs of the aforementioned It may contain a lipid-lowering agent that includes any mixture of these agents.

[0026] Appropriate dietary supplement activators include, but are not limited to, 5-hydroxytryptopha N, acetyl L-carnitine, alpha-lipoic acid, alpha-ketoglutaric acid, honeybee raw Ingredients: Betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan Choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, Cyanocobalamin (Vitamin 812), Dimethylaminoethanol, Fumaric Acid, 32% Germanium, glandular product, glucosamine HCl, glucosamine sulfate, hydroxymethyl Rubylate, immunoglobulin, lactic acid, L-carnitine, liver products, malic acid, anhydrous malic acid Lutose, mannose (d-mannose), methylsulfonylmethane, phytosterols picolinic acid, pyruvic acid, red yeast extract, S-adenosylmethionine, selenium yeast, It may contain shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0027] Appropriate nutritional supplements and activators include vitamins, minerals, fiber, fatty acids, amino acids, and May include steroid supplements or combinations thereof.

[0028] Appropriate vitamin activators may include, but are not limited to, ascorbic acid ( Vitamin C, Vitamin B, Biotin, Fat-soluble vitamins, Folic acid, Hydroxycitric acid, I Nositol, mineral ascorbate, mixed tocopherols, niacin (vitamin B 3) Orotic acid, para-aminobenzoic acid, pantothenate, pantothenic acid (vitamin B5) Pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins Thiamine (vitamin B1), tocotrienol, vitamin A, vitamin D, vitamin E Vitamin F, vitamin K, vitamin oil, and fat-soluble vitamins.

[0029] Appropriate herbal supplement activators may include, but are not limited to, the following: Arni Bilberry, black cohosh, cat's claw, chamomile, echinacea, pine Evening primrose oil, fenugreek, flaxseed, feverfew, garlic oil, ginger root, ginkgo ( Ginkgo biloba, Korean ginseng, goldenrod, hawthorn, birch, can Elephant, milk thistle, plantain, Indian jasmine, senna, soybean, St. John's wort Saw palmetto, turmeric, valerian.

[0030] Mineral activators may include, but are not limited to, boron, calcium, and cyanoacrylate. Rated minerals, chlorides, chromium, coated minerals, cobalt, copper, mud Mite, iodine, iron, magnesium, manganese, mineral premix, mineral products, Molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvic acid Salt, zinc, and other minerals.

[0031] Other possible activators include, but are not limited to, antihistamines (e.g., Ranicin). Zin, dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlor Lupheniramine maleate), nonsteroidal anti-inflammatory drugs (e.g., aspirin, celecoxib) Sibu, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, Fenoprofen, flubufen, indoprofen, pyroprofen, Luprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen Fruprofen, Suprofen, Aminoprofen, Fluprofen, Bucloxic Acid, Indometasis N, sulindac, zomepirac, thiopinac, zidomethacin, acemetacin, fenthiaz C, Clidanac, Oxypinac, Meclofenamic acid, Flufenamic acid, Diflumic acid, Tol Fenamic acid, diflulysal, fluphenisal, piroxicam, sudoxicam, isoxy Cam, aceclofenac, alloxipyrine, azapropazon, benolilate, bromfe Nak, carprofen, choline magnesium salicylate, diflunisal, etodolac, E Tricoxib, Faislamine, Fenbufen, Fenoprofen, F Lurbiprofen, ibuprofen, indomethacin, ketoprofen, ketrolac, ro Lunoxicam, loxoprofen, meloxicam, mefenamic acid, metamisole, salicy Methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimeslide, oxy Fenbutazone, parecoxib, phenylbutazone, salicylate salicylate, sulindac, Sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, and their pharmacological properties (acceptable salts and mixtures thereof) as well as acetaminophen, antiemetics (e.g., me Toclopramide, methylnaltrexone), antiepileptic drugs (e.g., pheniloin, mephthong) (Lobmate and nitrazepam), vasodilators (e.g., nifedipine, papaverine, di) Lutiazem and nicardipine), antitussives and expectorants (e.g., codeine phosphate), anti Asthma medications (e.g., theophylline), antacids, antispasmodics (e.g., atropine, scopolamine) Antidiabetic drugs (e.g., insulin), diuretics (e.g., ethacrine, bendroflutia) Zide), antihypertensive drugs (e.g., propranolol, clonidine), antihypertensive drugs (e.g., Clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g.) For example, hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetrasulfamethoxazole) Ikurin), anti-hemorrhoid drugs, sleeping pills, psychotropic drugs, antidiarrheals, mucolytics, sedatives, decongestants (examples) (e.g., pseudoephedrine), laxatives, vitamins, stimulants (phenylpropanolamine) (including appetite suppressants such as) and cannabinoids, as well as their pharmaceutically acceptable This includes salts, hydrates, solvates, and prodrugs.

[0032] The activators may be benzodiazepines, barbiturates, stimulants, or mixtures thereof. To obtain. The term "benzodiazepine" refers to a substance that can suppress the central nervous system. This refers to drugs that are derivatives of benzodiazepines and benzodiazepines. Benzodiazepines are these. Not limited to, but include alprazolam, bromazepam, chlordiazepoxide, and chlorazepate. , diazepam, estazolam, flurazepam, harazepam, ketazolam, lorazepam, ni Trazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, This includes pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Benzodiazepine antagonists that can be used as activators are not limited to these. However, flumazenil and its pharmaceutically acceptable salts, hydrates, solvates and mixtures Includes.

[0033] The term "barbiturate" refers to barbituric acid (2,4,6,-trioxohexahydro This refers to sedatives and hypnotics derived from pyrimidines. Barbiturates are not limited to these. However, amobarbital, aprobarbital, butabarbital, butarbital Methehexital, Mehobarbital, Metalbital, Pentobarbital, Phenoba Rubital, secobarbital, and their pharmaceutically acceptable salts, hydrates, and solvates Includes substances, prodrugs, and mixtures. Barbiturate compounds that can be used as activators. Tagonists include, but are not limited to, amphetamines and their pharmaceutically acceptable substances. This includes salts, hydrates, solvates, and mixtures.

[0034] The term "stimulant" is not limited to these, but includes amphetamines, for example, dextromethorphan. Amphetamine resin complex, dextroamphetamine, methamphetamine, methylphen Dates, as well as their pharmaceutically acceptable salts, hydrates, and solvates and mixtures. This includes, but is not limited to, stimulant antagonists that can be used as activators. Benzodiazepines, as well as their pharmaceutically acceptable salts, hydrates, solvates, and mixtures. Includes.

[0035] The dosage forms described herein include various activators and their pharmaceutically acceptable salts. Acceptable salts are not limited to these, but include inorganic salts, such as hydrochloride salts and hydrobromic acid salts. Salts, sulfates, phosphates, etc.; organic acid salts, e.g., formate, acetate, trifluoroacetate, Maleates, tartrates, etc.; sulfonates, e.g., methanesulfonates, benzenesulfonates Alginates, p-toluenesulfonates, etc.; amino acid salts, e.g., alginates, as Paramethyl salts, glutamate salts, and metal salts, such as sodium salts and potassium salts. cesium salts, etc.; alkaline earth metals, for example, calcium salts, magnesium salts, etc.; Amine salts, for example, triethylamine salt, pyridine salt, picoline salt, ethanolamine Salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzyl ethyl Includes diamine salts, etc.

[0036] As used herein, the terms “therapeutically effective” and “effective dose” mean “the desired treatment.” This refers to the amount or percentage of an active agent that is necessary to produce a result.

[0037] As used herein, “shell” or “shell composition” refers to a shell that encloses a filling material. It refers to the shell of a softgel capsule.

[0038] As used herein, “does not contain or substantially does not contain” means less than approximately 1 wt%. , less than approximately 0.5 wt%, less than approximately 0.25 wt%, less than approximately 0.1 wt%, approximately 0.05 wt% This refers to a composition containing less than, approximately less than 0.01 wt%, or 0 wt% of the aforementioned component.

[0039] All references to wt% throughout this specification and claims refer to the weight of the entire composition in question. This refers to the weight of a component in terms of quantity, and can also be expressed as w / w.

[0040] As used herein, “filling material” or “filling” refers to pH-dependent capsules. This refers to a composition encapsulated by a seal and containing at least one pharmaceutically active ingredient.

[0041] As used herein, the term "delayed-release capsule" or "delayed-release softgel capsule" is used. "Softgel capsules" or "pH-dependent capsules" or "pH-dependent softgel capsules" are filled with a filling material. Encased in a shell, the capsule exhibits delayed or pH-dependent properties once the capsule is dried. This refers to... In certain embodiments, these terms refer to capsules that have also been cured after drying. Obtain. In certain embodiments, no further processing steps after drying are required. In this embodiment, no further processing steps are required after curing.

[0042] Where used herein, "approximately" refers to any value within a range of ±10%. Therefore, "approximately 10" includes 9-11. When used herein, "one (a)" "An" or "the" refers to one or more unless otherwise specified. This refers to, for example, "one excipient," and "two or more excipients." This includes mixtures of different excipients, etc.

[0043] Unless otherwise specified herein, the enumeration of value ranges herein is within the range of It is intended to function merely as a simplified method for referring to each separate value individually. Each of these separate values ​​is incorporated herein as if they were individually listed herein. Unless otherwise specifically indicated herein or clearly refuted by the context, All methods described herein may be carried out in any suitable order.

[0044] Any use of any example or illustrative word (e.g., "etc.") provided herein The purpose is simply to reveal certain materials and methods, and is not limited in scope. No such restrictions are imposed. The terms used herein refer to any non-claimed elements disclosed in the materials and It should not be interpreted as indicating that the method is essential for its practical application.

[0045] Soft gel capsule dosage form According to the first embodiment, the pH-dependent softgel capsule comprises (a) a filling material and (b) The shell composition is pH-dependent, and the filling material contains at least one activator, and the shell composition is pH-dependent. The composition consists of gelatin, dextrose, pH-dependent material (e.g., low-methoxyl pectin), Furthermore, it includes a combination of glycerin and sorbitol or sorbitol-sorbitan solution. Preferably, glycerin is added in an amount of about 0.5 wt relative to the total weight of the dry pH-dependent shell composition. Present in pH-dependent shell compositions in amounts of t% to approximately 8 wt% or approximately 5 wt% to approximately 40 wt%. Furthermore, sorbitol or sorbitol sorbitan in glycerin in pH-dependent shell compositions The w:w ratio in the solution is in the range of approximately 1:1.5 to 1:7.

[0046] According to a particular embodiment, the pH-dependent softgel is (a) a filler material and (b) pH The shell composition is pH-dependent, and the filler material contains at least one activator, and the shell composition is pH-dependent. The product consists of (a) a film-forming agent, (b) glycerin, and (c) sorbitol or sorbitol. Contains a bitolsorbitan solution. In certain embodiments, the pH-dependent shell composition is dry Approximately 0.5 wt% to approximately 8 wt% or approximately 5 wt% relative to the total weight of the dry pH-dependent shell composition Contains approximately 40 wt% glycerin, and sorbitan glycerin in pH-dependent shell composition The w:w ratio for sorbitol or sorbitol / sorbitan solution is approximately 1:1.5 to 1:7. It is within the range.

[0047] A suitable filler material contains at least one pharmaceutically active ingredient and is prepared according to known methods. It is possible that, in addition to at least one pharmaceutically active ingredient, a suitable filler material may be added as an additional filler. For example, flavoring agents, sweeteners, coloring agents and fillers or other pharmaceutically acceptable excipients. Alternatively, it may contain additives, such as synthetic dyes and mineral oxides. Pharmaceutical active ingredients and The appropriate amount of pharmaceutically acceptable excipients can be easily determined by those skilled in the art.

[0048] In one embodiment, gelatin in a pH-dependent shell composition is used alone or in combination. The gelatin used is either type A gelatin, type B gelatin, or animal hide or skin gelatin (for example, calf). May contain animal skin (pig skin) and / or bone gelatin (e.g., cow bone, pig bone). In one embodiment, the gelatin is 250 bloom gelatin. In another embodiment, one There is only one type of gelatin. In yet another embodiment, the gelatin is at least two This is a combination of types of gelatin. In one embodiment, gelatin in a pH-dependent shell composition The amount of chin is approximately 30 wt% to 85 wt% relative to the total weight of the dried capsule shell composition. Approx. 30wt%~Approx. 75wt%, Approx. 30wt%~Approx. 65wt%, Approx. 30wt%~Approx. 55wt %, approximately 30 wt% to 40 wt%, approximately 40 wt% to 80 wt%, approximately 45 wt% to 65 wt%, approximately 45 wt% to approximately 75 wt%, or approximately 50 wt% to approximately 70 wt%, or so It is any single value or subrange within that range.

[0049] In certain embodiments, the pH-dependent shell composition is gelatin, pectin, or dextrin. A non-animal-derived gelling agent in place of or in addition to at least one of the strouss. It may contain a film-forming agent. Suitable non-animal gelling agents include, without limitation, carrageenan. Starch, pregelatinized starch, xanthan gum, agar, pectin, alginate, sugar , high molecular weight polyethylene glycol, sugar-derived alcohol, cellulose derivative, cellulose Spolymer, hydroxyethylcellulose, hydroxypropylcellulose, hydroxy Propylmethylcellulose, carboxymethylcellulose, microcrystalline cellulose, Atapal Jite, bentonite, dextrin, alginate, kaolin, lecithin, silicate Aluminum magnesium, carbomer, carbopole, silicon dioxide, curdlan, f - Contains celeran, albumin, soy protein, chitosan, or a combination thereof.

[0050] Carrageenan includes iotacarrageenan, kappacarrageenan, and lambdacarrageenan. It could be at least one of the following.

[0051] Starch includes modified starch or natural starch, sweet potato starch, potato starch Pun, corn starch, tapioca starch, pea starch, hydroxypropyl Hydroxyalkylated starch, acid-treated starch, dextrin, high ammonium compounds Raw unprocessed corn starch, processed waxy corn starch, non-granular starch Pun, processed high-amylose corn starch, pregelatinized rice flour, and combinations thereof It is possible. As used herein and in the claims, the term “modified starch” means Contains starches such as hydroxypropylated starch and acid-diluted starch. Generally, processed Starch is a product prepared by the chemical treatment of starch, for example, acid-treated starch. Starch, enzyme-treated starch, oxidized starch, cross-linked starch, and other starch derivatives It is preferable that the modified starch is derivatized, in which case the side chains are hydrophilic or hydrophobic. Modified with hydrate groups, this creates a more complex structure with strong interactions between side chains.

[0052] In certain embodiments, the non-animal gelling agent is, for example, about 2 wt.% to about 20 wt.%. %, about 2wt.%~about 15wt.%, about 2wt.%~about 40wt.%, about 10wt.%~ Approximately 80 wt.%, or approximately 15 wt.% to approximately 75 wt.%, or approximately 20 wt.% Approximately 70 wt.%, or approximately 25 wt.% to approximately 60 wt.%, or approximately 25 wt.% Approximately 45 wt.%, or approximately 20 wt.% to approximately 35 wt.%, or approximately 30 wt.% Approximately 40 wt.%, or approximately 32 wt.%, or approximately 35 wt.%, or approximately 38 wt. In the shell composition, in an amount of t.%, or any sub-range or single concentration value therewith, Yes, all wt.% are based on the total weight of the shell composition. In one embodiment, a non-animal gel The additive contains carrageenan and does not contain starch (or modified starch). One embodiment Therefore, the soft gel shell composition is substantially free of starch (or modified starch). Or not included.

[0053] In one embodiment, the pH-dependent capsule shell composition contains dextrose. In terms of form, the amount of dextrose in the pH-dependent capsule shell composition is the amount of dextrose in the dry capsule shell. Approximately 0.001 wt% to approximately 1.0 wt%, approximately 0.002 wt% of the total weight of the composition. Approximately 0.008 wt%, approximately 0.005 wt%, or approximately 0.01 wt% to approximately 4 wt%, approximately 0 0.1 wt% or approximately 0.15 wt% to approximately 3 wt%, approximately 0.1 wt% to approximately 1 wt%, approximately 0 0.1 or approximately 0.15 wt% or approximately 0.2 wt% or approximately 0.25 wt% ~ approximately 2 wt%, approximately 0.1wt% to approximately 0.2wt%, approximately 0.1wt% to approximately 0.4wt%, or so It is any single value or subrange within that range. Dextrose is a potential factor in gel strength. It may be added to the delayed-release capsule shell to mitigate the decrease. (To be interpreted as limited.) Instead, dextrose interacts with gelatin in the shell composition, causing cross-linking of the gelatin. It is thought that the concentration of dextrose in the pH-dependent shell composition improves gel strength. It may be an effective amount, but it should not be so high as to interfere with capsule sealing, manufacturability, or product performance. It's fine.

[0054] In some embodiments, the pH-dependent shell composition is pectin, for example, low-methoxyl pectin It may contain . In one embodiment, pectin is a low methyl having a degree of esterification of less than 50. It is a luester (LM) pectin. In some embodiments, the pectin is amidated pectin. In certain embodiments, the amidated pectin is less than 25, 5-25, 10 It may have a degree of amidation of ~20, or 15~25. In other embodiments, low methoxyl ( LM) Pectin is a non-amidated pectin. In certain embodiments, pectin is amidated. It is a combination of amidated and unamidated pectin. The addition of pectin affects the pH of the dosage form. It contributes to addiction.

[0055] Excessive pectin in the dosage form may reduce the gel strength of softgel capsules. This can then negatively affect the sealing properties of the softgel capsule. pH-dependent shell composition Too much pectin inside can also increase the viscosity of the shell composition, from a manufacturing standpoint. To make processing difficult or impossible. Therefore, pectin is necessary to form a delayed-release dosage form. The dosage form should be at a sufficiently high concentration, while simultaneously mitigating the decrease in gel strength and the increase in viscosity. It can be added to it.

[0056] In one embodiment, the amount of pectin in the pH-dependent shell composition is the amount of pectin in the dried capsule shell. Approximately 2 wt% to 20 wt%, approximately 3 wt% to 15 wt%, and approximately 3 wt% relative to the total weight of the composition. t% ~ approx. 5.5wt%, approx. 4wt% ~ approx. 11wt%, approx. 7wt% ~ approx. 12wt%, approx. 8w t% to approximately 13 wt%, or approximately 5 wt% to approximately 10 wt%, or any single within that range It is a value or a subrange.

[0057] The degree of esterification of pectin incorporated into pH-dependent shell compositions is less than approximately 50%. It is possible, or approximately 10% to 50%, approximately 20% to 40%, or approximately 25% to 35% It can be in the range of %. Also, pectin can be amidated or unamidated.

[0058] In certain embodiments, the pH-dependent shell composition includes a stabilizer containing gellan gum and / or includes a binder. In certain embodiments, stabilizers in the pH-dependent shell composition and The amount of the and / or binder (e.g., gellan gum) is equal to the total weight of the dry capsule shell composition. For comparison, approximately 0.05 wt% to 5 wt%, approximately 0.1 wt% to 3 wt%, or approximately 0. 2 wt% to approximately 2 wt% of stabilizers and / or binders (e.g., gellan gum), or It is any single value or a subrange within that range. In a particular embodiment, pH-dependent The amount of gellan gum in the gel composition is approximately 0.5% of the total weight of the dry capsule shell composition. 4wt% to approximately 5wt%, approximately 0.4wt% to approximately 3wt%, approximately 0.4wt% to approximately 2wt%, The amount is approximately 0.4 to approximately 1 wt%. In other embodiments, gelatin in the pH-dependent shell composition The amount of gum is approximately 0.4 wt% to 0.5 wt% relative to the total weight of the dry capsule shell composition. t%, approximately 0.4 wt% to approximately 0.6 wt%, approximately 0.4 wt% to approximately 0.7 wt%, or approximately 0 It is approximately 0.4 to 0.8 wt%. In further embodiments, gelatin in pH-dependent shell compositions The amount of gum is approximately 0.5 wt% to 0.6 wt% relative to the total weight of the dry capsule shell composition. t%, is approximately 0.5 wt% to 0.7 wt%, or approximately 0.5 to 0.8 wt%.

[0059] In a particular embodiment, the pH-dependent shell composition is approximately 20,000 cPs, approximately 30,0 00 cPs, approximately 40,000 cPs, approximately 50,000 cPs, approximately 60,000 cPs, and more. Or, from approximately 70,000 cPs to approximately 80,000 cPs, or approximately 90,000 cPs. Ps, approx. 100,000cPs, approx. 110,000cPs, approx. 120,000cPs, approx. 130,000 cPs, approximately 140,000 cPs, or approximately 150,000 cPs It may have viscosity within any range, any subrange within that range, or a single value. In terms of application, the pH-dependent shell composition is approximately 100,000 cPs to approximately 130,000 cPs. s, or in the range of approximately 110,000 cPs to approximately 125,000 cPs, or approximately 115, It has a viscosity of 000 cPs, or approximately 120,000 cPs. Viscosity is measured using a rheometer. The measurement is performed using a gel mass sample (e.g., pH-dependent shell as described herein). Place one of the compositions on the sample stage of a rheometer maintained at 60°C. It rotates at a specific speed, resulting in a constant shear rate. Viscosity affects shear stress and shear rate. It is obtained by measuring the degree.

[0060] In a particular embodiment, the pH-dependent shell composition lasts for a maximum of approximately 24 hours, and a maximum of approximately 48 hours. Even after heat aging for up to approximately 72 hours, up to approximately 96 hours, or up to approximately one week, the manufacturability remains. Suitable viscosity can be maintained. In certain embodiments, the viscosity of the pH-dependent shell composition is controlled by heat. After aging (up to approximately 24 hours, up to approximately 48 hours, up to approximately 72 hours, up to approximately 96 hours, or the most Approximately 1 week, (from the viscosity value of the composition before aging) up to approximately 80%, up to approximately 70%, up to approximately 6 It can decrease by 0%, up to approximately 50%, up to approximately 40%, up to approximately 35%, or up to approximately 30%.

[0061] In one embodiment, the plasticizers in the pH-dependent shell composition are glycerin and sorbite Includes a combination of sorbitol or sorbitol sorbitan solution. pH-dependent as intended herein. The shell composition contains both glycerin and sorbitol or sorbitol-sorbitan solution. Including this method improves the robustness of softgel capsules and their enteric coating properties. Identified. Glycerin and The presence of both sorbitol and sorbitol-sorbitan solution is a filler material or This is thought to minimize moisture absorption of the pH-dependent shell composition from the external environment. , the physical and mechanical strength of the softgel capsules described herein and the It is thought that this enhances the enteric coating properties of the listed softgel capsules (for example, in a two-step dissolution test). (As proven by the two-stage collapse test).

[0062] In the pH-dependent shell compositions described herein, glycerin is used in the amounts and ratios described herein. A combination of phosphorus and sorbitol solution or glycerin and sorbitol sorbitan solution Using a combination of liquids helps inhibit the premature release of softgel capsules. Furthermore, it was discovered that softgel capsules have a non-pH-dependent shell composition. This was also present when amidated pectin was included. This benefit also applies to softgel capsules. It existed even when it was not compounded. In contrast, glycerol plasticizer alone (that is, (i.e., sorbitol or sorbitol sorbitan solution is not available) or as described herein. pH-dependent shell compositions containing amounts and ratios other than those mentioned above are, in certain embodiments, soft It was observed that some of the gel capsules experienced premature release. Similarly, glycerin plasticizer It contains only (i.e., sorbitol or sorbitol-sorbitan solution), A pH-dependent shell composition containing amounts and ratios other than those specified herein is a certain In some embodiments, failure of the two-stage collapse test described herein was observed.

[0063] In certain embodiments, the above benefits (e.g., moisture absorption, physical and mechanical strength, Disintegration test results, flexibility of using non-amidated pectin, including or (Regarding the flexibility of exclusion) pH-dependent system including at least two of (a) to (c) Observed in the shell composition: (a) Dry pH-dependent, approximately Choose from 0.5 wt%, approximately 1 wt%, approximately 2 wt%, or approximately 3 wt%, and then select approximately 4 wt%. A quantity in the range of %, approximately 5 wt%, approximately 6 wt%, approximately 7 wt%, or approximately 8 wt%, (b) Glycerin in any subrange or single concentration within that range; (b) Dry pH dependent Approximately 10 wt%, 11 wt%, 12 wt%, and 13 wt% of the total weight of the shell composition. From either t%, or approximately 14 wt%, to approximately 15 wt%, approximately 16 wt%, or approximately 17 wt%. %, an amount in the range of approximately 18 wt%, approximately 19 wt%, or approximately 20 wt%, or Any sub-range or single concentration value of sorbitol or sorbitol sorbitol within that range Thanh solution; or (c) from any of approximately 1:1.5, 1:2, or 1:3 A range of approximately 1:4, 1:5, 1:6, or 1:7, or within that range. A partial range or a single w:w ratio of glycerin sorbitol or sorbitol sorbitol w:w ratio for rubitan solution.

[0064] In certain embodiments, glycerin is added to the total weight of the dry pH-dependent shell composition. Approximately 5 wt% to 40 wt%, approximately 10 wt% to 25 wt%, or approximately 15 wt% to 2 A pH-dependent amount in the range of 0 wt%, or any subrange within that range, or a single concentration value. It may be included in the gel composition.

[0065] In addition to glycerin and sorbitol or sorbitol-sorbitan solution, pH-dependent Other suitable plasticizers that may be included in the shell composition include, but are not limited to, sugar alcohols Plasticizers, for example, isomalt, maltitol, xylitol, erythritol, adonito Calcium, dulciitol, pentaerythritol, or mannitol; or polyols are acceptable. Plasticizers, such as diglycerin, dipropylene glycol, up to 10,000 MW of polyethylene Teylene glycol, neopentyl glycol, propylene glycol, 1,3-propane Diol, 2-methyl-1,3-propanediol, trimethylolpropane, poly- May include terpolyols, ethanolamines; and mixtures thereof. Other examples may be included. Plasticizers include, without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, and fats. Low molecular weight polyols having a hydroxyl group, ester-based plasticizers, glycol ethers, Poly(propylene glycol), multiblock polymer, singleblock polymer, Citrate ester plasticizers and triacetin may also be included. Such plasticizers include 1, 2-Butylene glycol, 2,3-Butylene glycol, Styrene glycol, Monopro Pyrene 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, Resorbate 80, acetyl triethyl citrate, tributyl citrate, and glycol It may contain allyl acids, as well as mixtures thereof.

[0066] In a particular embodiment, the total amount of all plasticizers in the pH-dependent shell composition is dry cap. Approximately 10 wt% to 50 wt% and approximately 15 wt% to 45 wt% relative to the total weight of the cell shell composition. wt%, about 15wt% to about 40wt%, about 18wt% to about 45wt%, about 18wt% to about 42 wt%, approximately 20 wt% to approximately 35 wt%, approximately 25 wt% to approximately 30 wt%, or within that range. It can be any single value or a subrange of .

[0067] In certain embodiments, any of the pH-dependent shell compositions described herein are synthesized It may further contain polymers. Suitable synthetic polymers are, without limitation, under the trademark name EUDRAGIT. Acrylic and methacrylic polymers, available under the registered trademark Kol A methacrylate-ethyl acrylate copolymer that may be available from licoat (registered trademark) Mer and other conventional acid-insoluble polymers, such as methyl acrylate-methacrylate copolymers. Contains mer. Other suitable acid-insoluble polymers include, without limitation, cellulose succinate acetate, acetic acid. Cellulose phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate Hydroxypropyl methylcellulose acetate succinate (hypromellose Cete succinate, polyvinyl acetate phthalate (PVAP), sodium alginate Alginates such as thorium and potassium alginate, stearic acid, and Sierra Includes buck.

[0068] In a particular embodiment, the suitable synthetic polymer is methacrylate-ethyl acrylate. It is water-insoluble, such as polymers. Adding water-insoluble polymers to a pH-dependent shell composition... This is thought to make the pH-dependent shell composition more hydrophobic. In cases where the pH-dependent shell composition is more hydrophobic (compared to cases where the shell composition does not contain synthetic polymers) ), which is thought to reduce the amount of water that moves from the filler material into the shell composition. , to enhance the robustness of the shell composition and enable the shell composition to maintain its mechanical strength. This also means that the softgel capsules will harden over a long period (for example, 4-5 days at approximately 40°C). Early release from softgel capsules (containing the pH-dependent shell composition) without the need for further processing. This is thought to enable inhibition of release during the release phase. This benefit is that the pH-dependent shell composition is non-amide. This benefit can even be observed in softgel capsules containing pectin. This benefit is pH-dependent. The shell composition does not contain stabilizers / binders such as gellan gum, and the softgel capsules have no odor. It can also be observed in combination with pectin. Methacrylate-ethyl acrylate copolymer (and other suitable acrylate polymers as recognized by those skilled in the art) are pH-dependent. It is also conceivable to extend the pH performance of the shell composition and, accordingly, the softgel capsule. (For example, extending the durability of softgel capsules at higher pH values ​​and targeting the gastrointestinal tract) (By enabling the targeted release of filler material to the location.)

[0069] In one embodiment, the synthetic polymer is a methacrylate-ethyl acrylate copolymer (1: 1) is Kollicoat MAE-100P. This synthetic polymer has a certain special properties. In certain embodiments, the polymer is already neutralized beforehand, and the polymer is neutralized or solubilized during processing. It can be chosen because it does not require the addition of a base (e.g., ammonia).

[0070] In certain embodiments, the synthetic polymer in the pH-dependent shell composition described herein The amount is approximately 0.5 wt% to approximately 10 wt% relative to the total weight of the dry capsule shell composition, approximately 1 wt.% to approximately 5 wt.%, approximately 1.5 wt.% to approximately 4 wt.%, or approximately 2 wt.% to approximately 3 wt.%, or any single value or subrange within that.

[0071] If synthetic polymers are included, they are not limited to filling from capsule sealing. It is thought to function as a sealant to stop or inhibit the leakage of materials.

[0072] In one embodiment, pH-dependent shell composition and / or pH-dependent soft gel capsule The polymer may not contain any of the synthetic polymers described herein, or may contain substantially none. The pH-dependent protective film on the softgel shell is optional and / or may not be included.

[0073] In certain embodiments, any of the pH-dependent shell compositions described herein is an organic acid It may further include: Suitable organic acids include lactic acid, tannic acid, citric acid, acetic acid, or those. This includes combinations of the above. In one embodiment, the organic acid in the pH-dependent shell composition includes lactic acid. In the application form, the organic acid in the pH-dependent shell composition includes tannic acid. In one embodiment, p The organic acids in the H-dependent shell composition include lactic acid and tannic acid.

[0074] In certain embodiments, the amount of organic acid in the pH-dependent shell composition described herein is Approximately 0.1 wt% to approximately 8 wt%, approximately 0.2 wt% relative to the total weight of the dried capsule shell composition. .% to approximately 5 wt.%, or approximately 0.2 wt.% to approximately 2 wt.%, or any unit within that range. It is a single value or a subrange.

[0075] Organic acids, if present, are not limited to the interaction between gelatin and pectin. It is thought that this promotes the action and forms a more robust softgel capsule.

[0076] In certain embodiments, various components (e.g., pectin, dextrose, gelatin) are used. The amount of synthetic polymers, plasticizers, stabilizers / binders, and the ratio of various components vary across different pH ranges. Adjusted to control the dissolution and / or disintegration properties of the softgel capsule over a wide area. ru.

[0077] For example, the gelatin-to-pectin w:w ratio in pH-dependent shell compositions is approximately 2:1, approximately 3: 1. Approximately 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1 From, approximately 10:1, approximately 11:1, approximately 12:1, approximately 13:1, approximately 14:1, approximately 15:1, approximately A range of 16:1, approximately 17:1, approximately 18:1, approximately 19:1, or approximately 20:1. or any subrange or single value therein. In a particular embodiment, A lower gelatin-to-pectin w:w ratio is more suitable for acidic media (e.g., phosphate buffer, sodium hydroxide). pH adjusted with thorium or potassium hydroxide, containing pepsin if necessary. It is more stable in NHCl (or dissolves / disintegrates more slowly if it does dissolve), pH-dependent. The shell composition is provided, but a higher gelatin-to-pectin w:w ratio is suitable for acidic media (e.g., pH adjusted with phosphate buffer, sodium hydroxide, or potassium hydroxide, as needed. It is not very stable (dissolves / disintegrates more quickly) in 0.1N HCl containing pepsin. ) Provides a pH-dependent shell composition. The gelatin to pectin w:w ratio is determined at a certain pH. The specific dissolution / disintegration time of a softgel capsule in an acidic medium (e.g., 1.2, 2.2 , 3, 4, 5, 6, or a partial range of pH within those ranges, for at least about 15 minutes, less Approximately 30 minutes, at least approximately 45 minutes, at least approximately 60 minutes, at least approximately 90 minutes, or Softening in a buffer medium having a specific pH (at least about 120 minutes) and / or The specific dissolution / disintegration time of the capsule (e.g., pH 6 containing pancreatin as needed) 0.8 Biological solutions such as phosphate buffer, sodium hydroxide buffer, or potassium hydroxide buffer, In an artificial or simulated duodenal environment and / or intestinal fluid, for up to approximately 5 minutes, up to approximately 10 minutes, up to approximately It is adjusted to achieve 20 minutes, a maximum of approximately 30 minutes, a maximum of approximately 45 minutes, or a maximum of approximately 60 minutes. obtain.

[0078] Furthermore, the w:w ratio of gelatin in the pH-dependent shell composition to the total amount of all plasticizers is, It may be adjusted to achieve a specific capsule hardness level, approximately 5:1 to approximately 1:5, approximately The range is 4:1 to approximately 1:4, approximately 3:1 to approximately 1:3, approximately 2:1 to approximately 1:2, approximately 1:1, or It could be any single ratio value or subrange within that range.

[0079] In certain embodiments, a pectin stabilizer and / or binder (e.g., gelang) is used. The w:w ratio for (M) is approximately 1:10 to 50:1; approximately 1:5 to 40:1; approximately 1:1 to Approximately 25:1 or approximately 10:1 to approximately 24:1, or any single ratio within that range. This is a sub-range.

[0080] In a particular embodiment, when the synthetic polymer is included in the pH-dependent shell composition, pH The w:w ratio of synthetic polymers to pectin in the dependent shell composition is approximately 3:1 to approximately 1:2 0, approximately 3:1 to approximately 1:15, approximately 3:1 to approximately 1:10, approximately 2:1 to approximately 1:5, approximately 2:1 to approximately It is a single ratio value or subrange within 1:3, approximately 1:1, or any single ratio within that range.

[0081] In a particular embodiment, when the synthetic polymer is included in the pH-dependent shell composition, pH The w:w ratio of synthetic polymers to gelatin in the dependent shell composition is approximately 1:3 to approximately 1:1. 00, approximately 1:3 to 1:50, approximately 1:3 to 1:25, approximately 1:3 to 1:20, approximately 1:3 ~1:15, ~1:3~1:10, or ~1:3~1:5, or within that range It is a single ratio value or subrange of a given.

[0082] In a particular embodiment, if an organic acid is included in the pH-dependent shell composition, the pH-dependent shell The w:w ratio of organic acids to pectin in the gel composition is approximately 2:1 to approximately 1:60, and approximately 2:1 ~approximately 1:40, approximately 2:1~approximately 1:20, approximately 2:1~approximately 1:15, approximately 2:1~approximately 1:10, It is a ratio of approximately 1:1 to approximately 1:5, or any single ratio value or subrange within that range.

[0083] In a particular embodiment, if an organic acid is included in the pH-dependent shell composition, the pH-dependent shell The w:w ratio of organic acids to gelatin in the gel composition is approximately 1:15 to approximately 1:250, approximately 1 :15~approx. 1:200, approx. 1:15~approx. 1:150, approx. 1:15~approx. 1:100, approx. 1: 20 to approximately 1:75, approximately 1:20 to approximately 1:50, or approximately 1:30 to approximately 1:50, or It is any single ratio value or subrange within that range.

[0084] In certain embodiments, the pH-dependent shell compositions described herein are about 5N, about 6N, From approximately 7N, 8N, 9N, or 10N, choose from approximately 11N, 12N, or 13N. Capsule hardness can be in the range of N, approximately 14N, or approximately 15N. Determined using a meter. The amount of neutral required to cause a 2.0 mm deformation of the capsule. The force in units of 1 is defined as capsule hardness.

[0085] In certain embodiments, the pH-dependent shell composition described herein is approximately 5%, approximately 6% , approximately 7%, approximately 8%, approximately 9%, or approximately 10%, or approximately 11%, approximately 12%, approximately 1 Shell moisture may be in the range of 3%, approximately 14%, or approximately 15%. It is determined by the loss on drying method. A 1-2 gram pH-dependent capsule shell composition sample is used. Place in a 105°C oven for 17 hours. Record the initial weight of the sample. After drying in a bun for 17 hours, the final weight of the sample is recorded. It is calculated according to the following formula. The percentage of weight loss is defined as shell moisture:

[0086] In certain embodiments, the pH-dependent shell composition described herein is approximately 25%, approximately 2 From 8%, approximately 30%, approximately 32%, approximately 34%, or approximately 35%, approximately 38%, approximately 4 It can have an equilibrium relative humidity in the range of 0%, approximately 42%, approximately 45%, or approximately 50%. Equilibrium relative humidity (%) is defined as the humidity condition under which the capsule maintains a constant total weight. This is determined using an environmental chamber maintained at a constant humidity using a saturated salt solution.

[0087] In a particular embodiment, the pH-dependent shell composition described herein is approximately 50 kg, approximately From 60kg, approximately 70kg, approximately 80kg, or approximately 90kg, to approximately 100kg, Approximately 110kg, approximately 120kg, approximately 130kg, approximately 140kg, or approximately 150kg It may have a burst strength within one of the following ranges. The burst strength is determined using a texture analyzer. The texture analyzer pressurizes the capsule until it bursts. The force in kilograms required to rupture a capsule is defined as the bursting strength.

[0088] In one embodiment, the pH-dependent shell composition and the pH-dependent softgel capsule are The pH-dependent protective film on the Futgel shell may be omitted or substantially omitted. .

[0089] In one embodiment, the pH-dependent shell composition and the pH-dependent softgel capsule are C a ++ (e.g., CaCl2) or Mg ++ Divalent cations (e.g., MgCl2) May contain salt. In another embodiment, pH-dependent shell composition and pH-dependent soft gel capsule The cell is Ca ++ (e.g., CaCl2) or Mg ++ (For example, divalent substances such as MgCl2) The cation salt may be omitted or substantially omitted in further embodiments. The pH-dependent shell composition contains Ca in addition to the amount of divalent cation salts that may be present in other components. + + (e.g., CaCl2) or Mg ++ Divalent cation salts such as (for example, MgCl2) The addition step does not need to be included.

[0090] In one embodiment, the pH-dependent shell composition may contain additional agents as needed, for example, Stabilizers or binders (e.g., gellan gum), colorants, flavorings, sweeteners, fillers, antioxidants Diluents, pH adjusters, or other pharmaceutically acceptable excipients or additives, for example, It may contain pigments and mineral oxides.

[0091] Examples of suitable colorants include, but are not limited to, white, black, yellow, and blue. This may include colors such as green, pink, red, orange, violet, indigo, and brown. Specific implementation forms In this case, the color of the dosage form indicates the contents it contains (e.g., one or more active ingredients). It can be demonstrated.

[0092] Examples of suitable flavorings include, but are not limited to, ethanol or water. Extracting a portion of a raw material, such as animal or plant material, by using a solvent. "Flavor extracts" obtained by; essential oils extracted from flowers, fruits, roots, or the whole plant. It may contain natural essences obtained through this process.

[0093] Additional exemplary flavoring agents that may be present in the dosage form include, but are not limited to, menthol. Spearmint and cinnamon-like breath freshening compounds, coffee beans, especially for oral hygiene. Fruit flavorings (for example, cherry, orange, grape) are used for this purpose. Other flavorings or fragrances such as (and), as well as quaternary ammonium bases and other substances that affect teeth and oral cavity. It may contain active ingredients used in cleaning. The flavorings include tartaric acid, citric acid, and vanillin. The flavor can be enhanced using any of the following flavor enhancers.

[0094] Examples of sweeteners include, but are not limited to, one or more artificial sweeteners, or even just one. It may contain or multiple natural sweeteners, or a combination thereof. Artificial sweeteners are, for example, A Cesulfame and its various salts, such as potassium salts (Sunett® registered trademark) (Available), alitame, aspartame (NutraSweet® and E Available as qual (registered trademark), aspartame-acesulfame salt (Twi Available as nsweet (registered trademark), neohesperidin dihydrochalcone, Nari Ginger dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate Saccharin and its various salts, such as sodium salts (Sweet'N Low ( Available as a registered trademark, stevia, sucrose chloro derivatives, e.g., sucralose (Available as Kaltame (registered trademark) and Splenda (registered trademark)), It contains mogrosides. Natural sweeteners include, for example, glucose, dextrose, and invert sugar. Fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (trademark) Sold under the name MagnaSweet (registered trademark); Stevia (Stevia rebaudian) a) (Stevioside), a natural strong sweetener, e.g., Luo Han Guo, polyol, e.g., sol Contains vitol, mannitol, xylitol, erythritol, etc.

[0095] In one embodiment, the pH-dependent shell composition is (a) gelatin, (b) dextrose (c) pH-dependent polymers (e.g., pectins such as low-methoxyl pectin), (d) Glycerin, (e) sorbitol or sorbitol sorbitan solution, and as needed (f) Stabilizers and / or binders (e.g., gellan gum) The quantity and wt:wt ratio may conform to any of the values ​​or ranges specified herein. .

[0096] In one embodiment, the pH-dependent shell composition is (a) gelatin, (b) dextrose (c) pH-dependent polymers (e.g., pectins such as low-methoxyl pectin), (d) Glycerin, (e) sorbitol or sorbitol sorbitan solution, and as needed (f) Essentially consists of a stabilizer and / or binder (e.g., gellan gum). The amounts of these components and the wt:wt ratio may follow any of the above values ​​or ranges. .

[0097] In one embodiment, the pH-dependent shell composition is (a) gelatin, (b) dextrose (c) pH-dependent polymers (e.g., pectins such as low-methoxyl pectin), (d) Glycerin, (e) sorbitol or sorbitol sorbitan solution, and as needed (f) consists of a stabilizer and / or a binder (e.g., gellan gum). The quantity and wt:wt ratio may follow any of the values ​​or ranges mentioned above.

[0098] Dissolution and decay Throughout this disclosure, references to “dissolution” or “dissolution test” range from approximately 50 RPM to approximately 250 RPM. RPM paddles, phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide Approximately 5 A 0.1N HCl acidic medium (also called the "acid stage") in any of the following amounts: 00 ml to approximately 900 ml This refers to the results from tests conducted using the USP Apparatus II. After a period of time, add a phosphate buffer solution, a sodium hydroxide solution, or a potassium hydroxide solution to adjust the pH to 6.8 (also referred to as "pH 6.8 buffer"). In the two-stage dissolution test for soft gel capsules and / or shell compositions, the term "dissolve" can be used interchangeably with the term "rupture". The "two-stage dissolution test" can also be referred to herein as "two-stage enteric dissolution test" or "enteric dissolution test".

[0099] Throughout this disclosure, references to "disintegration" or "disintegration test" refer to results from tests conducted in a USP disintegration apparatus in an approximately 900 ml of any 0 .1N HCL acidic medium (also referred to as the "acid stage") adjusted to pH 1.2, 2.0, 3.0, 4.0, 5 .0, and 6.0 from any of approximately 500 ml adjusted with a phosphate buffer solution, a sodium hydroxide solution, or a potassium hydroxide solution. After 2 hours, add a phosphate buffer solution, a sodium hydroxide solution, or a potassium hydroxide solution to adjust the pH to 6.8 (also referred to as "pH 6.8 buffer") . For soft gel capsules and / or shell compositions in the two-stage disintegration test, the term "disintegrate" can be used interchangeably with the term "rupture". The "two-stage disintegration test" can also be referred to herein as "two-stage enteric disintegration test" or "enteric disintegration test". After a period of time, add a phosphate buffer solution, a sodium hydroxide solution, or a potassium hydroxide solution to adjust the pH to 6.8 (also referred to as "pH 6.8 buffer") . For soft gel capsules and / or shell compositions in the two-stage disintegration test, the term "disintegrate" can be used interchangeably with the term "rupture". The "two-stage disintegration test" can also be referred to herein as "two-stage enteric disintegration test" or "enteric disintegration test".

[0100] In certain embodiments, the shell composition does not dissolve at pH 1.2 in 15 minutes, 30 minutes, 45 minutes , 60 minutes, 90 minutes or 120 minutes (e.g., from any of approximately 500 ml adjusted with a phosphate buffer solution, a sodium hydroxide solution, or a potassium hydroxide solution, in any of approximately 900 ml of any 0.1N HCL acidic medium at any of approximately 50 RPM from any of approximately 500 ml adjusted with a phosphate buffer solution, a sodium hydroxide solution, or a potassium hydroxide solution, in any of approximately 900 ml of any 0.1N HCL acidic medium at any of approximately 50 RPM from any of approximately 500 ml adjusted with a phosphate buffer solution, a sodium hydroxide solution, or a potassium hydroxide solution, in any of approximately 900 ml of any 0.1N HCL acidic medium at any of approximately 50 RPM from Measured using USP Apparatus II with any paddle at 250 RPM Case).

[0101] In certain embodiments, the shell composition does not dissolve at a pH of 1.2 for at least about 15 minutes, at least at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., from any of about 500 ml adjusted to a pH with a phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, in any of about 9 00 ml of any 0.1N HCL acidic medium, from any of about 50 RPM to about 2 50 RPM, measured using USP Apparatus II with any paddle Case). Case).

[0102] In certain embodiments, the shell composition does not dissolve at a pH of 1.2 for about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (e.g., from any of about 500 ml adjusted to a pH with a phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, in any of about 900 ml of any 0.1N HCL acidic medium, from any of about 50R PM to any of about 250 RPM, measured using USP Appara tus II).

[0103] In certain embodiments, the shell composition does not disintegrate at a pH of 1.2 in 15 minutes, 30 minutes, 45 minutes , 60 minutes, 90 minutes or 120 minutes (e.g., from any of about 500 ml adjusted to a pH with a phosphate buffer solution, sodium sodium solution, or potassium hydroxide solution, in any of about 900 ml of any 0.1N HCL acidic medium, measured with a USP disintegration apparatus Case).

[0104] In a particular embodiment, the shell composition is at a pH of 1.2 for at least about 15 minutes. At least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, or do not decay for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either a solution of 100ml or a solution of potassium hydroxide with pH adjusted, approximately 9 (Measured using a USP decay apparatus in any 0.00 ml of 0.1 N HCl acidic medium) .

[0105] In a particular embodiment, the shell composition is prepared at a pH of 1.2 for approximately 15 minutes to approximately 360 minutes. It does not decay for a period of approximately 30 minutes to 240 minutes, or approximately 45 minutes to 180 minutes (for example, phosphoric acid). Approximately 500 pH adjusted with a buffer solution, sodium hydroxide solution, or potassium hydroxide solution. From any of the ml, in approximately 900 ml of any of the 0.1N HCl acidic media, USP (When measured using a disintegration device).

[0106] In a particular embodiment, the shell composition is prepared at a pH of 1.2 to 2 for 15 minutes, 30 minutes, and 4 minutes. If it does not dissolve after 5 minutes, 60 minutes, 90 minutes, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either a thorium solution or a potassium hydroxide solution with pH adjusted to approximately 500 ml or in approximately 900 ml of either of the 0.1N HCl acidic media at approximately 50 RPM Measured with a USP Apparatus II using one of the paddles at approximately 250 RPM. (If that happens).

[0107] In a particular embodiment, the shell composition is prepared at a pH of 1.2–2 for at least about 15 minutes. , at least approximately 30 minutes, at least approximately 45 minutes, at least approximately 60 minutes, at least approximately 90 minutes or does not dissolve for a period of at least about 120 minutes (e.g., from any of about 500 ml adjusted to a pH with a phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, and measured using a paddle at any of about 50 RPM to about 250 RPM in any of about 900 ml of a 0.1N HCL acidic medium). In certain embodiments, the shell composition does not dissolve at a pH of 1.2 - 2 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (e.g., from any of about 500 ml adjusted to a pH with a phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, and measured using a paddle at any of about 50 RPM to about 250 RPM in any of about 900 ml of a 0.1N HCL acidic medium). In certain embodiments, the shell composition does not disintegrate at a pH of 1.2 - 2 for 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes or 120 minutes (e.g., from any of about 500 ml adjusted to a pH with a phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution,

[0108] and measured using a USP disintegration apparatus in any of about 900 ml of a 0.1N HCL acidic medium). In certain embodiments, the shell composition does not disintegrate at a pH of 1.2 - 2 for at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., from any of about 500 ml adjusted to a pH with a phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, and measured using a paddle at any of about 50 RPM to about 250 RPM in any of about 900 ml of a 0.1N HCL acidic medium). In certain embodiments, the shell composition does not dissolve at a pH of 1.2 - 2 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (e.g., from any of about 500 ml adjusted to a pH with a phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, and measured using a paddle at any of about 50 RPM to about 250 RPM in any of about 900 ml of a 0.1N HCL acidic medium).

[0109] In certain embodiments, the shell composition does not disintegrate at a pH of 1.2 - supposing measured by USP Apparatus II using a paddle at any of about 50 RPM to about 250 RPM in any of about 900 ml of a ..... In certain embodiments, the shell composition does not disintegrate at a pH of 1.2 - 2 for 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes or 120 minutes (e.g., from any of about 500 ml adjusted to a pH with a phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, and measured using a USP disintegration apparatus in any of about 900 ml of a 0.1N HCL acidic medium). In certain embodiments, the shell composition does not disintegrate at a pH of 1.2 - 2 for at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., from any of about 500 ml adjusted to a pH with a phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution,

[0110] In certain embodiments, the shell composition does not disintegrate at a pH of 1.2 - 2 for at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about ........ In certain embodiments, the shell composition does not disintegrate at a pH of 1.2 - 2 for at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., from any of about 500 ml adjusted to a pH with a phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, From either a 500 ml solution of lium or a potassium hydroxide solution with pH adjusted, In approximately 900 ml of any 0.1N HCl acidic medium, the measurement was performed using a USP decay device. ).

[0111] In a particular embodiment, the shell composition is prepared at a pH of 1.2 to 2 for approximately 15 minutes to approximately 360 minutes. It does not collapse for a period of time of approximately 30 minutes to 240 minutes, or approximately 45 minutes to 180 minutes (for example, Adjust the pH with a sodium nitrate buffer solution, sodium hydroxide solution, or potassium hydroxide solution to approximately 5 From either 00 ml, in approximately 900 ml of either 0.1N HCl acidic medium, U (Measured using an SP disintegration device)

[0112] In a particular embodiment, the shell composition is prepared at pH 2 for 15 minutes, 30 minutes, 45 minutes, and 6 minutes. If it does not dissolve in 0 minutes, 90 minutes, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either the solution or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 90 In 0 ml of any of the 0.1N HCl acidic media, from about 50 RPM to about 25 When measured with a USP Apparatus II using any of the 0 RPM paddles ).

[0113] In a particular embodiment, the shell composition is at pH 2 for at least about 15 minutes, less Approximately 30 minutes, at least approximately 45 minutes, at least approximately 60 minutes, at least approximately 90 minutes, or It does not dissolve for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide solution) From either the liquid or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 900 In any of the ml of 0.1N HCl acidic medium, from about 50 RPM to about 250 (Measured using USP Apparatus II with either RPM paddle) .

[0114] In a particular embodiment, the shell composition is prepared at pH 2 for approximately 15 minutes to approximately 360 minutes, for approximately 3 It does not dissolve for a period of 0 minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate buffer). Approximately 500 ml of solution with pH adjusted using sodium hydroxide solution or potassium hydroxide solution. From either of these, in approximately 900 ml of either of the 0.1N HCl acidic media at approximately 50 RPM Using one of the following paddles, which has a speed of approximately 250 RPM, the USP Apparatus (When measured with s II).

[0115] In a particular embodiment, the shell composition is prepared at pH 2 for 15 minutes, 30 minutes, 45 minutes, and 6 minutes. It does not disintegrate in 0 minutes, 90 minutes, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide). From either the solution or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 90 (Measured using a USP decay apparatus in any of 0 ml of 0.1 N HCl acidic media).

[0116] In a particular embodiment, the shell composition is at pH 2 for at least about 15 minutes, less Approximately 30 minutes, at least approximately 45 minutes, at least approximately 60 minutes, at least approximately 90 minutes, or It does not decay for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide solution) From either the liquid or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 900 (Measured using a USP decay apparatus in any of the following ml of 0.1N HCl acidic medium.)

[0117] In a particular embodiment, the shell composition is prepared at pH 2 for approximately 15 minutes to approximately 360 minutes, for approximately 3 It does not decay for a period of 0 minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate buffer). Approximately 500 ml of solution with pH adjusted using sodium hydroxide solution or potassium hydroxide solution. USP decay occurs in approximately 900 ml of either of the 0.1N HCl acidic media from either of the following sources. (When measured with a device).

[0118] In a particular embodiment, the shell composition is prepared at pH 2-3 for 15 minutes, 30 minutes, and 45 minutes. If it does not dissolve in 60, 90, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide), From either a 500 ml solution of um or a potassium hydroxide solution with pH adjusted, In 900 ml of any of the 0.1N HCl acidic media, from approximately 50 RPM, Measurements were taken using a USP Apparatus II with one of the 250 RPM paddles. case).

[0119] In a particular embodiment, the shell composition is at a pH of 2-3 for at least about 15 minutes. At least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, or do not dissolve for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either a solution of 100ml or a solution of potassium hydroxide with pH adjusted, approximately 9 In 00 ml of any of the 0.1N HCl acidic media, from about 50 RPM to about 2 Measurements taken with a USP Apparatus II using any of the 50 RPM paddles. ).

[0120] In a particular embodiment, the shell composition is prepared at a pH of 2-3 for approximately 15 minutes to approximately 360 minutes. It does not dissolve for a period of approximately 30 minutes to 240 minutes, or approximately 45 minutes to 180 minutes (for example, phosphoric acid). Approximately 500 pH adjusted with a buffer solution, sodium hydroxide solution, or potassium hydroxide solution. From any of the ml, approximately 50R in approximately 900 ml of any of the 0.1N HCl acidic media. USP Appara uses either PM or any of the paddles with a speed of approximately 250 RPM. (Measured using TUS II).

[0121] In a particular embodiment, the shell composition is prepared at pH 2-3 for 15 minutes, 30 minutes, and 45 minutes. It does not disintegrate in 60, 90, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide). From either a 500 ml solution of um or a potassium hydroxide solution with pH adjusted, When measured in 900 ml of any 0.1N HCl acidic medium using a USP decay device. ).

[0122] In a particular embodiment, the shell composition is at a pH of 2-3 for at least about 15 minutes. At least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, or do not decay for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either a solution of 100ml or a solution of potassium hydroxide with pH adjusted, approximately 9 (Measured using a USP decay apparatus in any 0.00 ml of 0.1 N HCl acidic medium) .

[0123] In a particular embodiment, the shell composition is prepared at a pH of 2-3 for approximately 15 minutes to approximately 360 minutes. It does not decay for a period of approximately 30 minutes to 240 minutes, or approximately 45 minutes to 180 minutes (for example, phosphoric acid). Approximately 500 pH adjusted with a buffer solution, sodium hydroxide solution, or potassium hydroxide solution. From any of the ml, in approximately 900 ml of any of the 0.1N HCl acidic media, USP (When measured using a disintegration device).

[0124] In a particular embodiment, the shell composition is prepared at pH 3 for 15 minutes, 30 minutes, 45 minutes, and 6 minutes. If it does not dissolve in 0 minutes, 90 minutes, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either the solution or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 90 In 0 ml of any of the 0.1N HCl acidic media, from about 50 RPM to about 25 When measured with a USP Apparatus II using any of the 0 RPM paddles ).

[0125] In a particular embodiment, the shell composition is at pH 3 for at least about 15 minutes, less Approximately 30 minutes, at least approximately 45 minutes, at least approximately 60 minutes, at least approximately 90 minutes, or It does not dissolve for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide solution) From either the liquid or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 900 In any of the ml of 0.1N HCl acidic medium, from about 50 RPM to about 250 (Measured using USP Apparatus II with either RPM paddle) .

[0126] In a particular embodiment, the shell composition is prepared at a pH of 3 for approximately 15 minutes to approximately 360 minutes, for approximately 3 It does not dissolve for a period of 0 minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate buffer). Approximately 500 ml of solution with pH adjusted using sodium hydroxide solution or potassium hydroxide solution. From either of these, in approximately 900 ml of either of the 0.1N HCl acidic media at approximately 50 RPM Using one of the following paddles, which has a speed of approximately 250 RPM, the USP Apparatus (When measured with s II).

[0127] In a particular embodiment, the shell composition is prepared at pH 3 for 15 minutes, 30 minutes, 45 minutes, and 6 minutes. It does not disintegrate in 0 minutes, 90 minutes, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide). From either the solution or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 90 (Measured using a USP decay apparatus in any of 0 ml of 0.1 N HCl acidic media).

[0128] In a particular embodiment, the shell composition is at pH 3 for at least about 15 minutes, less Approximately 30 minutes, at least approximately 45 minutes, at least approximately 60 minutes, at least approximately 90 minutes, or It does not decay for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide solution) From either the liquid or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 900 (Measured using a USP decay apparatus in any of the following ml of 0.1N HCl acidic medium.)

[0129] In a particular embodiment, the shell composition is prepared at a pH of 3 for approximately 15 minutes to approximately 360 minutes, for approximately 3 It does not decay for a period of 0 minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate buffer). Approximately 500 ml of solution with pH adjusted using sodium hydroxide solution or potassium hydroxide solution. USP decay occurs in approximately 900 ml of either of the 0.1N HCl acidic media from either of the following sources. (When measured with a device).

[0130] In a particular embodiment, the shell composition is prepared at a pH of 3-4 for 15 minutes, 30 minutes, and 45 minutes. If it does not dissolve in 60, 90, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide), From either a 500 ml solution of um or a potassium hydroxide solution with pH adjusted, In 900 ml of any of the 0.1N HCl acidic media, from approximately 50 RPM, Measurements were taken using a USP Apparatus II with one of the 250 RPM paddles. case).

[0131] In a particular embodiment, the shell composition is at a pH of 1.2 for at least about 15 minutes. At least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, or do not dissolve for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either a solution of 100ml or a solution of potassium hydroxide with pH adjusted, approximately 9 In 00 ml of any of the 0.1N HCl acidic media, from about 50 RPM to about 2 Measurements taken with a USP Apparatus II using any of the 50 RPM paddles. ).

[0132] In a particular embodiment, the shell composition is prepared at a pH of 3-4 for approximately 15 minutes to approximately 360 minutes. It does not dissolve for a period of approximately 30 minutes to 240 minutes, or approximately 45 minutes to 180 minutes (for example, phosphoric acid). Approximately 500 pH adjusted with a buffer solution, sodium hydroxide solution, or potassium hydroxide solution. From any of the ml, approximately 50R in approximately 900 ml of any of the 0.1N HCl acidic media. USP Appara uses either PM or any of the paddles with a speed of approximately 250 RPM. (Measured using TUS II).

[0133] In a particular embodiment, the shell composition is prepared at a pH of 3-4 for 15 minutes, 30 minutes, and 45 minutes. It does not disintegrate in 60, 90, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide). From either a 500 ml solution of um or a potassium hydroxide solution with pH adjusted, When measured in 900 ml of any 0.1N HCl acidic medium using a USP decay device. ).

[0134] In a particular embodiment, the shell composition is at a pH of 3-4 for at least about 15 minutes. At least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, or do not decay for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either a solution of 100ml or a solution of potassium hydroxide with pH adjusted, approximately 9 (Measured using a USP decay apparatus in any 0.00 ml of 0.1 N HCl acidic medium) .

[0135] In a particular embodiment, the shell composition is prepared at a pH of 3-4 for approximately 15 minutes to approximately 360 minutes. It does not decay for a period of approximately 30 minutes to 240 minutes, or approximately 45 minutes to 180 minutes (for example, phosphoric acid). Approximately 500 pH adjusted with a buffer solution, sodium hydroxide solution, or potassium hydroxide solution. From any of the ml, in approximately 900 ml of any of the 0.1N HCl acidic media, USP (When measured using a disintegration device).

[0136] In a particular embodiment, the shell composition is prepared at pH 4 for 15 minutes, 30 minutes, 45 minutes, and 6 minutes. If it does not dissolve in 0 minutes, 90 minutes, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either the solution or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 90 In 0 ml of any of the 0.1N HCl acidic media, from about 50 RPM to about 25 When measured with a USP Apparatus II using any of the 0 RPM paddles ).

[0137] In a particular embodiment, the shell composition is at pH 4 for at least about 15 minutes, less Approximately 30 minutes, at least approximately 45 minutes, at least approximately 60 minutes, at least approximately 90 minutes, or It does not dissolve for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide solution) From either the liquid or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 900 In any of the ml of 0.1N HCl acidic medium, from about 50 RPM to about 250 (Measured using USP Apparatus II with either RPM paddle) .

[0138] In a particular embodiment, the shell composition is prepared at pH 4 for approximately 15 minutes to approximately 360 minutes, for approximately 3 It does not dissolve for a period of 0 minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate buffer). Approximately 500 ml of solution with pH adjusted using sodium hydroxide solution or potassium hydroxide solution. From either of these, in approximately 900 ml of either of the 0.1N HCl acidic media at approximately 50 RPM Using one of the following paddles, which has a speed of approximately 250 RPM, the USP Apparatus (When measured with s II).

[0139] In a particular embodiment, the shell composition is prepared at pH 4 for 15 minutes, 30 minutes, 45 minutes, and 6 minutes. It does not disintegrate in 0 minutes, 90 minutes, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide). From either the solution or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 90 (Measured using a USP decay apparatus in any of 0 ml of 0.1 N HCl acidic media).

[0140] In a particular embodiment, the shell composition is at pH 4 for at least about 15 minutes, less Approximately 30 minutes, at least approximately 45 minutes, at least approximately 60 minutes, at least approximately 90 minutes, or It does not decay for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide solution) From either the liquid or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 900 (Measured using a USP decay apparatus in any of the following ml of 0.1N HCl acidic medium.)

[0141] In a particular embodiment, the shell composition is prepared at pH 4 for approximately 15 minutes to approximately 360 minutes, for approximately 3 It does not decay for a period of 0 minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate buffer). Approximately 500 ml of solution with pH adjusted using sodium hydroxide solution or potassium hydroxide solution. USP decay occurs in approximately 900 ml of either of the 0.1N HCl acidic media from either of the following sources. (When measured with a device).

[0142] In a particular embodiment, the shell composition is at a pH of 4-5 for 15 minutes, 30 minutes, and 45 minutes. If it does not dissolve in 60, 90, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either a solution of 100ml or a solution of potassium hydroxide with pH adjusted, approximately 9 In 00 ml of any of the 0.1N HCl acidic media, from about 50 RPM to about 2 Measurements taken with a USP Apparatus II using any of the 50 RPM paddles. ).

[0143] In a particular embodiment, the shell composition is at a pH of 4-5 for at least about 15 minutes. At least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, and It does not dissolve for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide). From either the solution or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 90 In 0 ml of any of the 0.1N HCl acidic media, from about 50 RPM to about 25 When measured with a USP Apparatus II using any of the 0 RPM paddles ).

[0144] In a particular embodiment, the shell composition is at a pH of 4-5, for about 15 minutes to about 360 minutes, approximately It does not dissolve for a period of 30 minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate slow Approximately 500m of solution with pH adjusted using a char solution, sodium hydroxide solution, or potassium hydroxide solution. From either l, approximately 50 RP in approximately 900 ml of either 0.1N HCl acidic medium. USP Apparat using either M or any of the paddles with a speed of approximately 250 RPM (Measured using US II)

[0145] In a particular embodiment, the shell composition is at a pH of 4-5 for 15 minutes, 30 minutes, and 45 minutes. It does not disintegrate in 60, 90, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either a solution of 100ml or a solution of potassium hydroxide with pH adjusted, approximately 9 (Measured using a USP decay apparatus in any 0.00 ml of 0.1 N HCl acidic medium) .

[0146] In a particular embodiment, the shell composition is at a pH of 4-5 for at least about 15 minutes. At least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, and It does not disintegrate for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide). From either the solution or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 90 (Measured using a USP decay apparatus in any of 0 ml of 0.1 N HCl acidic media).

[0147] In a particular embodiment, the shell composition is at a pH of 4-5, for about 15 minutes to about 360 minutes, approximately It does not disintegrate for a period of 30 minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate slow disintegration). Approximately 500m of solution with pH adjusted using a char solution, sodium hydroxide solution, or potassium hydroxide solution. From either of the l, in approximately 900 ml of either of the 0.1N HCl acidic media, USP breakdown (When measured with a destructive device).

[0148] In a particular embodiment, the shell composition is at pH 5, and is steeped for 15 minutes, 30 minutes, 45 minutes, and 60 minutes. If it does not dissolve in minutes, 90 minutes, or 120 minutes (for example, phosphate buffer solution, sodium hydroxide solution) From either the liquid or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 900 In any of the ml of 0.1N HCl acidic medium, from about 50 RPM to about 250 (Measured using USP Apparatus II with either RPM paddle) .

[0149] In a particular embodiment, the shell composition is at a pH of 5 for at least about 15 minutes, and at least Also about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or less Even without it, it will not dissolve for about 120 minutes (for example, phosphate buffer solution, sodium hydroxide solution). From either approximately 500 ml of either solution or approximately 900 ml of solution with potassium hydroxide pH adjusted, In either of the 0.1N HCl acidic media, at a rate of approximately 50 RPM to approximately 250 RPM. (Measured using USP Apparatus II with either PM paddle).

[0150] In a particular embodiment, the shell composition was left at a pH of 5 for approximately 15 minutes to approximately 360 minutes, and for approximately 30 minutes. It does not dissolve for approximately 240 minutes, or for a period of approximately 45 minutes to 180 minutes (e.g., phosphate buffer solution). Approximately 500 ml of a solution whose pH has been adjusted with sodium hydroxide solution or potassium hydroxide solution. From either of these, in approximately 900 ml of either of the 0.1N HCl acidic media, at approximately 50 RPM From there, use one of the paddles at approximately 250 RPM with the USP Apparatus (When measured with II)

[0151] In a particular embodiment, the shell composition is at pH 5, and is steeped for 15 minutes, 30 minutes, 45 minutes, and 60 minutes. It does not disintegrate in minutes, 90 minutes, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide solution) From either the liquid or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 900 (Measured using a USP decay apparatus in any of the following ml of 0.1N HCl acidic medium.)

[0152] In a particular embodiment, the shell composition is at a pH of 5 for at least about 15 minutes, and at least Also about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or less Even without it, it will not disintegrate for about 120 minutes (for example, phosphate buffer solution, sodium hydroxide solution) From either approximately 500 ml of either solution or approximately 900 ml of solution with potassium hydroxide pH adjusted, (Measured using a USP decay apparatus in any of the 0.1N HCl acidic media.)

[0153] In a particular embodiment, the shell composition is fermented at a pH of 5 for approximately 15 minutes to approximately 360 minutes, for approximately 30 minutes. It does not disintegrate for a period of 1 minute to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate buffer solution) Approximately 500 ml of liquid, with the pH adjusted using sodium hydroxide solution or potassium hydroxide solution. From either of these, in approximately 900 ml of either of the 0.1N HCl acidic media, the USP disintegration device (When measured in place).

[0154] In a particular embodiment, the shell composition is at a pH of 5-6 for 15 minutes, 30 minutes, and 45 minutes. If it does not dissolve in 60, 90, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either a solution of 100ml or a solution of potassium hydroxide with pH adjusted, approximately 9 In 00 ml of any of the 0.1N HCl acidic media, from about 50 RPM to about 2 Measurements taken with a USP Apparatus II using any of the 50 RPM paddles. ).

[0155] In a particular embodiment, the shell composition is at a pH of 5-6 for at least about 15 minutes. At least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, and It does not dissolve for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide). From either the solution or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 90 In 0 ml of any of the 0.1N HCl acidic media, from about 50 RPM to about 25 When measured with a USP Apparatus II using any of the 0 RPM paddles ).

[0156] In a particular embodiment, the shell composition is at a pH of 5-6, for about 15 minutes to about 360 minutes, approximately It does not dissolve for a period of 30 minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate slow Approximately 500m of solution with pH adjusted using a char solution, sodium hydroxide solution, or potassium hydroxide solution. From either l, approximately 50 RP in approximately 900 ml of either 0.1N HCl acidic medium. USP Apparat using either M or any of the paddles with a speed of approximately 250 RPM (Measured using US II)

[0157] In a particular embodiment, the shell composition is at a pH of 5-6 for 15 minutes, 30 minutes, and 45 minutes. It does not disintegrate in 60, 90, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide) From either a solution of 100ml or a solution of potassium hydroxide with pH adjusted, approximately 9 (Measured using a USP decay apparatus in any 0.00 ml of 0.1 N HCl acidic medium) .

[0158] In a particular embodiment, the shell composition is at a pH of 5-6 for at least about 15 minutes. At least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, and It does not disintegrate for at least about 120 minutes (e.g., phosphate buffer solution, sodium hydroxide). From either the solution or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 90 (Measured using a USP decay apparatus in any of 0 ml of 0.1 N HCl acidic media).

[0159] In a particular embodiment, the shell composition is at a pH of 5-6, for about 15 minutes to about 360 minutes, approximately It does not disintegrate for a period of 30 minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate slow disintegration). Approximately 500m of solution with pH adjusted using a char solution, sodium hydroxide solution, or potassium hydroxide solution. From either of the l, in approximately 900 ml of either of the 0.1N HCl acidic media, USP breakdown (When measured with a destructive device).

[0160] In a particular embodiment, the shell composition is at pH 6, and is steeped for 15 minutes, 30 minutes, 45 minutes, and 60 minutes. If it does not dissolve in minutes, 90 minutes, or 120 minutes (for example, phosphate buffer solution, sodium hydroxide solution) From either the liquid or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 900 In any of the ml of 0.1N HCl acidic medium, from about 50 RPM to about 250 (Measured using USP Apparatus II with either RPM paddle) .

[0161] In a particular embodiment, the shell composition is at a pH of 6 for at least about 15 minutes, and at least Also about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or less Even without it, it will not dissolve for about 120 minutes (for example, phosphate buffer solution, sodium hydroxide solution). From either approximately 500 ml of either solution or approximately 900 ml of solution with potassium hydroxide pH adjusted, In either of the 0.1N HCl acidic media, at a rate of approximately 50 RPM to approximately 250 RPM. (Measured using USP Apparatus II with either PM paddle).

[0162] In a particular embodiment, the shell composition is at a pH of 6, and is steeped for approximately 15 minutes to approximately 360 minutes, for approximately 30 minutes. It does not dissolve for a period of minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate buffer solution) Approximately 500 ml of liquid, with the pH adjusted using sodium hydroxide solution or potassium hydroxide solution. From either of these, in approximately 900 ml of either of the 0.1N HCl acidic media, at approximately 50 RPM Use either of the paddles with a speed of approximately 250 RPM to operate the USP Apparatus. (When measured with II)

[0163] In a particular embodiment, the shell composition is at pH 6, and is steeped for 15 minutes, 30 minutes, 45 minutes, and 60 minutes. It does not disintegrate in minutes, 90 minutes, or 120 minutes (e.g., phosphate buffer solution, sodium hydroxide solution) From either the liquid or approximately 500 ml of potassium hydroxide solution with pH adjusted, approximately 900 (Measured using a USP decay apparatus in any of the following ml of 0.1N HCl acidic medium.)

[0164] In a particular embodiment, the shell composition is at a pH of 6 for at least about 15 minutes, and at least Also about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or less Even without it, it will not disintegrate for about 120 minutes (for example, phosphate buffer solution, sodium hydroxide solution) From either approximately 500 ml of either solution or approximately 900 ml of solution with potassium hydroxide pH adjusted, (Measured using a USP decay apparatus in any of the 0.1N HCl acidic media.)

[0165] In a particular embodiment, the shell composition is at a pH of 6, and is steeped for approximately 15 minutes to approximately 360 minutes, for approximately 30 minutes. It does not disintegrate for a period of 1 minute to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate buffer solution) Approximately 500 ml of liquid, with the pH adjusted using sodium hydroxide solution or potassium hydroxide solution. From either of these, in approximately 900 ml of either of the 0.1N HCl acidic media, the USP disintegration device (When measured in place).

[0166] In a particular embodiment, the shell composition is less than 8.4, less than 8.3, less than 8.2, 8 Less than 0.1, less than 8.0, less than 7.9, less than 7.8, less than 7.7, less than 7.6, less than 7.5 , less than 7.4, less than 7.3, less than 7.2, less than 7.1, less than 7.0, less than 6.9, 6.8 Less than 6.7, less than 6.6, less than 6.5, less than 6.4, less than 6.3, less than 6.2, 6 Less than 0.1, less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5 , less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, 4.8 Less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, 4 Less than 0.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5 , less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, 2.8 Less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, 2 Less than 0.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5 , at a pH of less than 1.4, less than 1.3, or less than 1.2, for at least about 15 minutes, at Approximately 30 minutes, at least approximately 45 minutes, at least approximately 60 minutes, at least approximately 90 minutes, or less It does not dissolve for at least 120 minutes (for example, phosphate buffer solution, sodium hydroxide solution, Alternatively, use approximately 500 ml of a solution whose pH has been adjusted with potassium hydroxide solution, and then use approximately 900 ml of either solution. In any of the 0.1N HCl acidic media, at a rate of approximately 50 RPM to approximately 250 RPM. (Measured using a USP Apparatus II with either of the M paddles).

[0167] In a particular embodiment, the shell composition is less than 8.4, less than 8.3, less than 8.2, 8 Less than 0.1, less than 8.0, less than 7.9, less than 7.8, less than 7.7, less than 7.6, less than 7.5 , less than 7.4, less than 7.3, less than 7.2, less than 7.1, less than 7.0, less than 6.9, 6.8 Less than 6.7, less than 6.6, less than 6.5, less than 6.4, less than 6.3, less than 6.2, 6 Less than 0.1, less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5 , less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, 4.8 Less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, 4 Less than 0.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5 , less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, 2.8 Less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, 2 Less than 0.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5 pH less than 1.4, less than 1.3, or less than 1.2, for approximately 15 minutes to approximately 360 minutes, approximately 30 It does not dissolve for a period of minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, phosphate buffer solution) Approximately 500 ml of liquid, with the pH adjusted using sodium hydroxide solution or potassium hydroxide solution. From either of these, in approximately 900 ml of either of the 0.1N HCl acidic media, at approximately 50 RPM Use either of the paddles with a speed of approximately 250 RPM to operate the USP Apparatus. (When measured with II)

[0168] In a particular embodiment, the shell composition is less than 8.4, less than 8.3, less than 8.2, 8 Less than 0.1, less than 8.0, less than 7.9, less than 7.8, less than 7.7, less than 7.6, less than 7.5 , less than 7.4, less than 7.3, less than 7.2, less than 7.1, less than 7.0, less than 6.9, 6.8 Less than 6.7, less than 6.6, less than 6.5, less than 6.4, less than 6.3, less than 6.2, 6 Less than 0.1, less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5 , less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, 4.8 Less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, 4 Less than 0.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5 , less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, 2.8 Less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, 2 Less than 0.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5 , at a pH of less than 1.4, less than 1.3, or less than 1.2, for at least about 15 minutes, at Approximately 30 minutes, at least approximately 45 minutes, at least approximately 60 minutes, at least approximately 90 minutes, or less It does not disintegrate for at least 120 minutes (for example, phosphate buffer solution, sodium hydroxide solution, Alternatively, use approximately 500 ml of a solution whose pH has been adjusted with potassium hydroxide solution, and then use approximately 900 ml of either solution. (Measured in either of the following 0.1N HCl acidic media using a USP decay apparatus).

[0169] In a particular embodiment, the shell composition is less than 8.4, less than 8.3, less than 8.2, 8 Less than 0.1, less than 8.0, less than 7.9, less than 7.8, less than 7.7, less than 7.6, less than 7.5 , less than 7.4, less than 7.3, less than 7.2, less than 7.1, less than 7.0, less than 6.9, 6.8 Less than 6.7, less than 6.6, less than 6.5, less than 6.4, less than 6.3, less than 6.2, 6 Less than 0.1, less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5 , less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, 4.8 Less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, 4 Less than 0.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5 , less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, 2.8 Less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, 2 Less than 0.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5 pH less than 1.4, less than 1.3, or less than 1.2, approximately 15 minutes to approximately 360 minutes, approximately 30 minutes. It does not disintegrate for approximately 240 minutes, or for a period of approximately 45 minutes to 180 minutes (e.g., phosphate buffer solution). Approximately 500 ml of a solution whose pH has been adjusted with sodium hydroxide solution or potassium hydroxide solution. From either side, in approximately 900 ml of either 0.1N HCl acidic medium, the USP decay apparatus (When measured in [location / device]).

[0170] The present invention dissolves and / or disintegrates and / or breaks down a shell composition, and fillers The pH appropriate for releasing the substance is the acidic part of the gastrointestinal tract (for example, a pH of 1.2 to 3.5). In the gastric environment, it inhibits the early release of the activator, and instead, in the intended part of the gastrointestinal tract... It may be selected to program the release of the activator to release the activator. For example, ten The bidenum has a typical pH range of 7.0–8.5; the small and large intestines typically have a pH of 4. The pH ranges from 0 to 7.0; the colon has a typical pH of 6.5, while the jejunum has a pH of 6.1 to 7.2. It has a typical pH. In one embodiment, the shell composition has a pH of about 7.0 to about 8.5. It can be modified to target the release of the activator in the duodenum. In one embodiment, The composition targets the release of the activator in the small and large intestines, where the pH is approximately 4.0 to 7.0. It can be adjusted for this purpose. In one embodiment, the shell composition is prepared in the colon at a pH of about 6.5. The shell composition can be adjusted to target the release of the activator. In one embodiment, the shell composition is It can be adjusted to target the release of the activator in the jejunum at a pH of approximately 6.1 to 7.2. .

[0171] In certain embodiments, the amount and ratio of the pH-dependent shell composition described herein is used in the following amounts and ratios. The combination of glycerin and sorbitol or sorbitol-sorbitan solution is glycerin Contains a plasticizer alone (without sorbitol or sorbitol-sorbitan solution) or Glycerin and / or sorbitol in amounts or ratios other than those intended herein. Or, compared to softgel capsules containing sorbitol / sorbitan solution, longer duration Enhances the pH robustness of softgel capsules across a wider range of pH values.

[0172] Preparation method The encapsulation of the filling material can be accomplished in any conventional manner. For example, rotary die encapsulation is It can be used.

[0173] According to one embodiment, the pH-dependent softgel capsule contains (a) at least one active (b) a step of preparing a filler material containing a pH agent; (b) a pH-dependent filler material from step (a). It is prepared by a process that includes the step of encapsulating it in a shell composition. Step (b) The encapsulation process involves, for example, gelatin, dextrose, pectin, glycerin, By mixing sorbitol or sorbitol-sorbitan solution, pH-dependent sorbitol The process may further include a substep for preparing a cell composition. In one embodiment, a pH-dependent cell composition is prepared. The substep for preparing the gel composition includes, for example, a film-forming agent, glycerin, and soap. This includes mixing rubitol or sorbitol / sorbitan solution.

[0174] The thickness of the ribbon of the pH-dependent shell composition (for example, as used in rotary die encapsulation) is also important. Adjusted to control the pH-dependent dissolution profile of the final pH-dependent softgel capsule. The thickness of the ribbon of the pH-dependent shell composition is not limited to approximately 0.02 inches, approximately 0. 0.022 inches, approximately 0.024 inches, approximately 0.026 inches, approximately 0.028 inches, or It ranges from approximately 0.030 inches to approximately 0.032 inches, approximately 0.034 inches, and approximately 0. 0.036 inches, approximately 0.038 inches, approximately 0.04 inches, approximately 0.042 inches, approximately 0. A range of either 0.44 inches or approximately 0.050 inches, or any portion within that range. This can be a range of minutes or a single value.

[0175] In certain embodiments, pH-dependent softgel capsules (e.g., after encapsulation) are dried and It can be cured as needed. The soft gel capsules can be cured at approximately 25°C to 75°C. Temperatures in the range of 25°C to 70°C, 30°C to 60°C, or 35°C to 50°C. It is possible. The curing temperature is high enough to enhance the delayed release properties of the soft gel capsules. The temperature should not be high enough to dissolve the softgel capsule.

[0176] The curing time is approximately 12 hours to 168 hours, 18 hours to 120 hours, and 24 hours to A range of approximately 72 hours, approximately 24 hours, approximately 48 hours, approximately 72 hours, or any portion of that range. It may be a range or a single value. In one embodiment, the curing of the soft gel capsule is This can be carried out at a temperature of approximately 40°C for approximately 24 hours. In one embodiment, the hardening of the soft gel capsule The process can be carried out at a temperature of approximately 40°C for approximately 48 hours. In one embodiment, soft gel capsules are used. Curing can be carried out at a temperature of approximately 40°C for approximately 72 hours. In certain embodiments, curing is carried out in air This is done in (without any specific control over the nitrogen or oxygen or humidity content) In certain embodiments, curing may be carried out under inert conditions (e.g., in nitrogen).

[0177] In one embodiment, the process for preparing pH-dependent softgel capsules is a) b) the step of preparing one of the filling materials described herein; b) the filling from step a). The filling material is one of the pH-dependent shell compositions described herein (for example, by rotary die encapsulation) (i) the step of encapsulation; (c) the encapsulated pH-dependent softgel capsule (for example, in a tank Drying step (by normal drying in a basket without bull drying or tumbling) and; d) pH-dependent soft gel according to any of the curing conditions described herein, if necessary. Including the step of hardening the capsules, essentially consisting of them or comprising them .

[0178] In certain embodiments, drying is performed at approximately 10°C to approximately 50°C, approximately 15°C to approximately 40°C, or approximately At temperatures between 20°C and approximately 35°C, the humidity levels are approximately 5% to 40%, 10% to 30%, or 15% to 25%. It is performed using % relative humidity.

[0179] In certain embodiments, references to drying and curing should be distinguished here. The purpose of drying the delayed-release softgel capsules described herein is to allow for delayed release immediately after encapsulation. The purpose is to remove excess water from the softgel capsule. Therefore, the capsule is physically To become stable. The purpose of curing the delayed-release softgel capsules described herein is to delay The objective is to enhance the delayed release properties of the release softgel capsule. Therefore, the drying step The presence of the step is not the same as the curing step, and similarly, the presence of the curing step is the same as the drying step. It's not.

[0180] In certain embodiments, the pH-dependent shell composition described herein is cured It does not exhibit any of the delayed release properties described herein (for example, dissolution as described herein). (or follows one of the collapse profiles). For example, in a particular embodiment, the synthetic profile Including a rimer means that the soft gel capsule does not need to be further cured. This can enhance the delayed emission characteristics of the cell.

[0181] In certain embodiments, a process for preparing the softgel capsules described herein is used. The procedure may further include a step of washing the softgel capsules with an organic acid. Acids include, without limitation, lactic acid, tannic acid, citric acid, acetic acid, or combinations thereof. In a particular embodiment, the step of washing the softgel capsule with an organic acid is performed. Further enhance the robustness of the capsule and its delayed release properties (for example, as described herein). Proven by achieving any one or more of the dissolution or decay release profiles. (As it is).

[0182] Soft gel capsule stability In certain embodiments, a delayed-release sonar having the pH-dependent shell composition described herein is used. Futgel capsules are chemically and physically stable.

[0183] For example, their chemical stability depends on the amount of activators in the filler material (for example, if the filler material is fish If oil is included, this can be demonstrated by the content of fish oil components. In certain embodiments, The content of the filler material components is for a maximum of 12 months, a maximum of 6 months, a maximum of 3 months, or a maximum of 1 After storage for 1 month (during any of these periods, under ambient conditions or at 40°C and 75% relative humidity) (Under humidity stress conditions), it is substantially similar to the raw material before storage during the aforementioned period. (It is within specifications.)

[0184] In certain embodiments, the delayed-release softgel capsule is made of gellan gum (e.g., syl It may contain at least 0.4 wt% of the total weight of the gel composition, at 100 rpm Using the USP APP II paddle speed control, at 37°C and 750cc of 4.0 pH water. When subjected to a dissolution test in, at least about 30 minutes, at least about 40 minutes, at least Approximately 45 minutes, at least approximately 50 minutes, at least approximately 60 minutes, at least approximately 65 minutes, at least It may remain intact for approximately 70 minutes, or at least approximately 75 minutes. In other embodiments, delay The release softgel capsule contains gellan gum (for example, a small amount relative to the total weight of the shell composition). It may contain at least 0.4% wt%, and the USP APP for a paddle speed of 100 rpm When used in a dissolution test at 37°C and 5.0 pH in 750cc of solution, At least approximately 20 minutes, at least approximately 30 minutes, at least approximately 40 minutes, at least approximately 45 minutes, At least approximately 50 minutes, at least approximately 60 minutes, at least approximately 65 minutes, or at least approximately 7 It is possible to remain unharmed for 0 minutes.

[0185] In certain embodiments, the delayed-release softgel capsule is made of gellan gum (e.g., syl Even if the shell composition contains at least 0.4% wt% of the total weight of the shell composition Often, when cured at 40°C for 3 days, and with a paddle speed of 75 rpm, the USP APP... When used in a dissolution test with II at 37°C and 1.2 pH in 750cc of solution. , at least about 45 minutes, at least about 50 minutes, at least about 60 minutes, at least about 70 minutes , at least approximately 71 minutes, at least approximately 72 minutes, at least approximately 73 minutes, at least approximately 74 minutes , at least approximately 75 minutes, at least approximately 76 minutes, at least approximately 77 minutes, at least approximately 78 minutes It may remain intact for at least approximately 79 minutes, or at least approximately 80 minutes. Other implementations In this configuration, the delayed-release softgel capsule contains gellan gum (for example, the total weight of the shell composition). The shell composition may contain at least 0.4% wt%, and can be fermented at 40°C for 3 days. If inter-cured, and using USP APP II with a paddle speed of 75 rpm, 3 When subjected to a dissolution test in 750cc at 7℃ and 5.0pH, at least about 20 minutes, at least about 30 minutes, at least about 35 minutes, at least about 45 minutes, at least about 60 minutes minutes, at least about 61 minutes, at least about 62 minutes, at least about 63 minutes, at least about 64 minutes minutes, at least about 65 minutes, at least about 66 minutes, at least about 67 minutes, at least about 68 minutes It may remain intact for at least approximately 69 minutes, or at least approximately 70 minutes.

[0186] In certain embodiments, the delayed-release softgel capsule is made of gellan gum (e.g., syl Even if the shell composition contains at least 0.4% wt% of the total weight of the shell composition Often, after storing at 66% humidity (for example, in a conditioning chamber) for 3 days, 75r Using a paddle velocity of pm with USP APP II, at 37°C and pH 1.2 or 5. When subjected to a dissolution test in 750cc, it took at least approximately 45 minutes, and at least approximately 50 minutes. minutes, at least about 60 minutes, at least about 70 minutes, at least about 71 minutes, at least about 72 minutes minutes, at least about 73 minutes, at least about 74 minutes, at least about 75 minutes, at least about 76 minutes minutes, at least about 77 minutes, at least about 78 minutes, at least about 79 minutes, or at least It may remain intact for approximately 80 minutes, at least approximately 90 minutes, or at least approximately 120 minutes. In this embodiment, the humidity is approximately 40% to approximately 95%, or approximately 50% to approximately 85%, or approximately 60%. It is approximately 75%, and the time is approximately 1 hour to 7 days, or approximately 12 hours to 5 days, or approximately 1 day to 4 days. It could be within a few days.

[0187] In certain embodiments, the delayed-release softgel capsule is made of gellan gum (e.g., syl Even if the shell composition contains at least 0.4% wt% of the total weight of the shell composition Often, when washing with a calcium chloride solution (for example, about 5%) for about 30 seconds, at 75 rpm... Using the USP APP II for paddle speed, at 37°C and pH 1.2 or 5, 7 When subjected to a dissolution test in 50cc, it took at least approximately 45 minutes, at least approximately 50 minutes, and less At least about 60 minutes, at least about 70 minutes, at least about 71 minutes, at least about 72 minutes, At least about 73 minutes, at least about 74 minutes, at least about 75 minutes, at least about 76 minutes, At least about 77 minutes, at least about 78 minutes, at least about 79 minutes, at least about 80 minutes, It may remain intact for at least approximately 90 minutes or at least approximately 120 minutes. (Some embodiments) So, a calcium chloride solution is approximately 2% to 20% calcium chloride, or approximately 2% to 1% It may also contain 5%, or approximately 2% to 10%, or approximately 2% to 5% calcium chloride. Rinsing time: approximately 2 seconds to 5 minutes, approximately 5 seconds to 4 minutes, approximately 10 seconds to 2 minutes, or approximately 20 seconds. It could take approximately 1 minute.

[0188] In certain embodiments, the delayed-release softgel capsule is made of gellan gum (e.g., syl It may contain at least 0.4% wt% of the total weight of the gel composition, at 100 rpm Using the USP APP II with a paddle speed of 37°C and 6.8 pH, at 1000°C When subjected to the dissolution test in c, the results were approximately less than 20 minutes, less than 15 minutes, less than 10 minutes, and approximately 8 minutes. It can break in less than 6 minutes or approximately less than 6 minutes.

[0189] In a particular embodiment, the physical stability of the delayed-release softgel capsule is determined by the acidic medium. This can be demonstrated by the dissolution profile of the capsule in a buffering medium, for example, an acidic medium. The dissolution profiles of the capsules in the body and buffering media are up to 12 months, up to 6 months, and up to 12 months. After storage for a maximum of 3 months, or a maximum of 1 month (during any of these periods, under ambient conditions or Dissolution profile of capsules before storage (under stress conditions of 40°C and 75% relative humidity) It is substantially similar (or within the standard) to [another standard].

[0190] The term "substantially similar" means that the corresponding comparison values ​​are within approximately 30%, within approximately 25%, and approximately A specific percentage within 20%, approximately 15%, approximately 10%, approximately 5%, or approximately 1%. It can refer to a value. The percentage is calculated based on the nominal value of the comparison value. For example, 2 A dissolution time range of 7 to 33 minutes can be considered within 10% of a comparative dissolution time of 30 minutes.

[0191] In certain embodiments, the pH-dependent shell composition described herein is used in an acidic environment (for example). A robust delayed-release sole that exhibits little to no premature release of the filling material in the gastric environment. Softgel capsules are produced. For example, the delayed-release softgel capsules described herein are , acid stage (for example, as defined for dissolution or disintegration tests described herein) Up to approximately 120 minutes, up to approximately 105 minutes, up to approximately 90 minutes, up to approximately 75 minutes, up to approximately 60 minutes, After exposure for approximately 45 minutes, a maximum of approximately 30 minutes, a maximum of approximately 15 minutes, a maximum of approximately 10 minutes, or a maximum of approximately 5 minutes In the acid stage, the filler material is approximately 10 wt% of the total weight of the filler material, and approximately 9 wt% of the total weight of the filler material. %, maximum approximately 8wt%, maximum approximately 7wt%, maximum approximately 6wt%, maximum approximately 5wt%, maximum approximately 4wt It may emit %, up to approximately 3 wt%, up to approximately 1 wt%, or 0 wt%. [Examples]

[0192] Specific embodiments of the present invention will now be demonstrated by reference to the following examples. These embodiments are disclosed solely to illustrate the present invention and are not intended to limit the scope of the invention. It should be understood that this should not be interpreted in that way.

[0193] [Example 1] Combinations of plasticizers in the dry shell to inhibit premature release during the acidic phase. pH-dependent shell compositions having the dry shell compositions shown in Table 1 were prepared.

[0194] [Table 1]

[0195] In the compositions shown in Table 1, a small amount of glycerin was used. The majority of the plasticizer was sorbitol. Or it was a sorbitol sorbitan solution. Glycerin sorbitol or sorbitan The w:w ratio for the sorbitan solution was between 1:2 and 1:5.

[0196] Fish oil and peppermint oil are encapsulated in a pH-dependent shell composition having the wet gel mass composition shown in Table 1. Then, it was dried. After drying, the softgel capsules were placed in a USP using a 100 RPM paddle. It was subjected to a two-stage dissolution test conducted in Apparatus II, and in the first stage, the soft Togel capsules undergo an acid phase (0.1N HCl) for 2 hours (120 minutes), followed by a second phase. The softgel capsule was in the buffering stage (buffer water pH 6.8). Fish oil capsule ( The results of the two-stage dissolution test for (20MC-72B) are summarized in Table 2.

[0197] [Table 2]

[0198] Fish oil softgel capsules (lot number 20MC-72B) are subjected to acid for 2 hours (120 minutes). In the first stage (0.1N HCl), followed by the buffering stage (pH 6.8 buffer), the USP disintegration device was subjected to a buffering stage. It was also subjected to a two-stage disintegration test conducted at the location. (Regarding the fish oil capsules (lot 20MC-72B)) The results of the two-stage collapse test are summarized in Table 3.

[0199] [Table 3]

[0200] Table 4 shows the results of a two-stage dissolution test on peppermint oil capsules (lot 20MC-96). Summarize.

[0201] [Table 4]

[0202] Peppermint oil softgel capsules (lot number 20MC-96) are used for 2 hours (120 minutes). USP decay occurs in the acid stage (0.1N HCl) followed by the buffer stage (pH 6.8 buffer). It was also subjected to a two-stage disintegration test conducted using a device. Peppermint oil capsules (Lot 20MC-96) The results of the two-stage collapse test are summarized in Table 5.

[0203] [Table 5]

[0204] Comparative Example Dependent shell compositions having the dry shell compositions shown in Table 6 were prepared.

[0205] [Table 6]

[0206] Breaking of capsules having the dried shell composition of Table 6 in 0.1N HCl containing pepsin. The interruption time was 50 rpm using the USP Apparatus II with paddles. The paddle speed was 12 minutes at 37°C. In this example, glycerin versus sorbitol. The sorbitol-sorbitan solution ratio is in the range of 1:1.5 to 1:4, but in this example... The amounts of glycerin and sorbitol or sorbitol-sorbitan solution are as follows: The amount was greater than intended. Therefore, the decay test is considered more aggressive than the dissolution test. Therefore, the comparative example is not expected to pass the two-stage intestinal disintegration test (two-stage intestinal dissolution test) (Considering the rapid fracture time in the experiment). In comparison, the present invention shown in Example 1 The compositions intended in this specification are subject to the two-step enteric lysis described herein and the method described herein. It passed the two-stage bowel disintegration test.

[0207] [Example 2] Effect of gellan gum on pH-dependent shell compositions pH-dependent shell compositions were prepared using the dry shell compositions shown in Table 7.

[0208] [Table 7]

[0209] The effect of gellan gum on the pH-dependent shell composition of samples F-1 to F-5 was studied. A gel mass was prepared and molded into a film with a thickness of 0.050 inches. The film was then subjected to ambient conditions. Dry. After drying, the softgel capsules were placed using a 100 RPM paddle with USP A Dissolution tests were performed using pparatus II. Acid and buffer were used at a medium temperature of 37°C. Using the solution, dissolution media at pH 4 and pH 5 were prepared. The film was completely dissolved. The time taken is summarized in Table 8.

[0210] [Table 8]

[0211] The addition of gellan gum enhances the enteric properties of pectin films in a higher pH medium environment. This improved the situation. As can be seen in Table 8, higher gellan gum concentrations than 0.4% were Intact for at least 60 minutes in a pH 4 medium and at least 45 minutes in a pH 5 medium It brought back the film as it was.

[0212] 0.5% gellan gum and pectin, gelatin, and plasticizer as listed in Table 7. Fish oil was encapsulated in a pH-dependent shell composition and dried. After drying, softgel capsules were formed. Dissolution test performed on USP Apparatus II using a 75 RPM paddle. Half of the softgels were conditioned in a 66% relative humidity chamber. The other half of the Futogel was washed with a 5% calcium chloride solution for 30 seconds. The results are summarized in Table 9.

[0213] [Table 9]

[0214] As can be seen in Table 9, the softgels remained intact for at least 60 minutes in a pH 5.0 medium. It was found that...

[0215] Fish oil softgel capsules treated with 5% CalCl2 solution for 30 seconds (Lot No. 21) MC-83) was treated in an acid step (0.1N HCl) for 2 hours (120 minutes), followed by buffering. It was also subjected to a two-stage decay test performed in a USP decay apparatus at the stage (pH 6.8 buffer). The results of the two-stage disintegration test for fish oil capsules (Lot 21MC-83) are shown in Table 10. Stop.

[0216] [Table 10]

[0217] [Example 3] Effects of softgel capsules containing 0.5% gellan gum in a pH-dependent shell under different conditions Additional soft fish oil encapsulated in a pH-dependent shell composition containing 0.5% gellan gum. Gel capsules were produced and subjected to another dissolution test. The softgels were tested under the following conditions: 1) Initial conditions, (2) curing at 40°C for 3 days, (3) 3 days in a chamber with 66% relative humidity. Conditioning, and (4) washing for 30 seconds with a 5% calcium chloride solution. The results of the exam are shown in Tables 11-14.

[0218] [Table 11]

[0219] [Table 12]

[0220] [Table 13]

[0221] [Table 14]

[0222] The comparative example is as described above, except that the pH-dependent shell composition does not contain gellan gum. Prepared by encapsulating fish oil in a gellan gum-free pH-dependent shell (19MC-03). After drying, the softgel capsules are placed in a USP Apparatus using a 100 RPM paddle. It was subjected to dissolution tests conducted in TUS II. Dissolution media with pH 2, 3, 4, and 5.5 were used. The solution was prepared at a medium temperature of 7°C. The results of the dissolution test are summarized in Table 15.

[0223] [Table 15]

[0224] As can be seen in Table 15, when gellan gum is not present in the pH-dependent shell composition The softgel capsules, when exposed to a medium having a pH of 3.0 or higher, will have a pH of at least about 5 It fractured after minutes. In contrast, 0.5% gellan gum was included in the pH-dependent shell composition. If so, the softgel capsule will remain in various pH media for at least about 45 minutes. It broke.

[0225] For the sake of brevity, embodiments of the method of this disclosure are represented as a series of actions, and are described as follows: It is included. However, the actions resulting from this disclosure may occur in various orders and / or simultaneously. This may be done in conjunction with other actions not presented or described in the specification. Furthermore, all The actions described may not necessarily be required to carry out the methods of the disclosed subject. i. In addition, the method can be expressed as a series of interrelated states using a state diagram or events. Those skilled in the art will understand and recognize that it can be represented.

[0226] In the foregoing description, in order to provide a complete understanding of the present invention, specific materials, dimensions, and processes are described. Numerous specific details such as ceth parameters are shown. Specific features, structure, materials, These features can be combined in any suitable manner in one or more embodiments. The words "example" or "exemplary" mean to serve as an example, case, or illustration. Used herein for the purpose of any example or illustrative use of any other term used herein. One aspect or design is not necessarily preferable or advantageous to another aspect or design. It should not be interpreted in this way. Rather, the use of the words "example" or "exemplary" specifically refers to the concept. It is intended to present. When used in this application, the term "or" means exclusively It is intended to mean a comprehensive "or" rather than a specific "or". In other words, Unless otherwise specified or evident from the context, "X contains A or B" is This is intended to mean either a natural, inclusive substitution, i.e., X contains A; If X contains B; or if X contains both A and B, then "X contains either A or B" is preceded by "X contains either A or B". This is satisfied in all of the cases described. "One embodiment," "A particular embodiment" , or any reference in this specification to “one embodiment” is described in relation to that embodiment. This means that a specific feature, structure, or characteristic is included in at least one embodiment. Therefore, the phrases “one embodiment” and “a particular” appear in various places throughout this specification. The appearance of "a specific embodiment" or "one embodiment" does not necessarily mean that all instances refer to the same embodiment. They don't exist.

[0227] The present invention has been described with reference to certain exemplary embodiments thereof. The documents and drawings described herein should be considered illustrative, not restrictive. In addition to those shown and described, various modifications of the present invention will be obvious to those skilled in the art. It is intended to fall within the scope of the attached claims.

Claims

1. (a) a filler material containing at least one activator; and (b) containing gelatin, pectin, dextrose, glycerin, and sorbitol pH-dependent shell composition A delayed-release softgel capsule containing, The pH-dependent shell composition is approximately 5 wt% of the total weight of the dry pH-dependent shell composition. It contains approximately 40 wt% glycerin. The w:w ratio of glycerin to sorbitol in the pH-dependent shell composition is approximately 1:1.

5. Delayed-release softgel capsules with a ratio of approximately 1:

7.

2. The pH-dependent shell composition is approximately 10 wt in relation to the total weight of the dry pH-dependent shell composition. Claim 1, comprising glycerin in an amount of % to about 25 wt% or about 15 wt% to about 20 wt% Delayed-release softgel capsules as described above.

3. The pH-dependent shell composition is approximately 10 wt in relation to the total weight of the dry pH-dependent shell composition. % to approximately 20 wt%, approximately 10 wt% to approximately 18 wt%, approximately 12 wt% to approximately 17 wt%, or The delay according to claim 1 or 2, comprising an amount of approximately 13 wt% to approximately 15 wt% of sorbitol. Release softgel capsule.

4. The pectin is low-methoxyl pectin, according to any one of claims 1 to 3. Delayed-release softgel capsules.

5. The pectin consists of amidated pectin, non-amidate pectin, and combinations thereof. A delayed-release softgel capsule according to any one of claims 1 to 4, selected from the group. 。

6. The pH-dependent shell composition is approximately 40 wt% of the weight of the dry pH-dependent shell composition. ~80 wt%, ~45 wt% to ~75 wt%, or ~45 wt% to ~65 wt% A delayed-release softgel capsule according to any one of claims 1 to 5, comprising latin.

7. The pH-dependent shell composition is present in an amount of about 2 wt% relative to the weight of the dry pH-dependent shell composition. Approximately 20 wt%, approximately 3 wt% to approximately 15 wt%, or approximately 7 wt% to approximately 15 wt% of pectin A delayed-release softgel capsule according to any one of claims 1 to 6, comprising n.

8. The pH-dependent shell composition is approximately 0.01 wt relative to the weight of the dry pH-dependent shell composition. t% to approximately 4 wt%, approximately 0.05 wt% to approximately 0.5 wt%, or approximately 0.1 wt% to approximately 0. A delayed-release softener according to any one of claims 1 to 7, comprising 2 wt% dextrose. Togel Capsule.

9. The group comprising the gelatin described above consists of type A gelatin, type B gelatin, and mixtures thereof. A delayed-release softgel capsule according to any one of claims 1 to 8, selected from the above.

10. The gelatin consists of fish gelatin, animal hide gelatin, bone gelatin, and mixtures thereof. A delayed-release softgel capsule according to any one of claims 1 to 9, selected from the group. 。

11. The pectin is non-amidated pectin, according to any one of claims 1 to 10. Delayed-release softgel capsules.

12. A paddle with a rotation speed of approximately 50 RPM to approximately 250 RPM, phosphate buffer solution, sodium hydroxide solution, Alternatively, approximately 500 ml to 900 ml of 0.1N solution adjusted to an acidic pH using potassium hydroxide solution. When measured with USP Apparatus II using HCl, the pH-dependent shade The composition is 1.2, 2.0, 3.0, 4.0, 5.0, 6.0, or a portion thereof. At the aforementioned acidic pH levels, for at least about 15 minutes, at least about 30 minutes, and at least about 45 minutes. , remain undissolved for at least approximately 60 minutes, at least approximately 90 minutes, or at least approximately 120 minutes; A paddle with a rotation speed of approximately 50 RPM to 250 RPM, and approximately 500 ml to 900 ml of buffered pH water. USP using 1 phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution When measured with Apparatus II, the pH-dependent shell composition was approximately 6.5 Above approximately 6.8, above approximately 7.0, above approximately 7.5, above approximately 8.0, or approximately 8 At a buffer pH above 5, the maximum duration is approximately 60 minutes, 45 minutes, 30 minutes, and 15 minutes. Delayed release according to any one of claims 1 to 11, which dissolves in minutes or up to approximately 10 minutes. Soft gel capsules.

13. Adjust the pH to an acidic level using phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution. When measured using a USP decay device with approximately 500 ml to 900 ml of prepared 0.1 N HCl. The pH-dependent shell composition is 1.2, 2.0, 3.0, 4.0, 5.0, 6.0, and Or, at a partial range of the aforementioned acid pH levels, for at least about 15 minutes, at least about 30 minutes, At least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 1 It did not collapse for 20 minutes; Approximately 500 ml to 900 ml of phosphate buffer solution adjusted to buffer pH, sodium hydroxide. When measured using a USP decay device with a solution or potassium hydroxide solution, the pH-dependent shell The composition is approximately 6.5 or higher, approximately 6.8 or higher, approximately 7.0 or higher, approximately 7.5 or higher, and approximately 8. At the buffer pH above 0 or above approximately 8.5, for a maximum of approximately 60 minutes, a maximum of approximately 45 minutes, and a maximum It disintegrated in approximately 30 minutes, a maximum of approximately 15 minutes, or a maximum of approximately 10 minutes, any one of claims 1 to 12. Delayed-release softgel capsule as described in item 1.

14. The pH-dependent shell composition is in the range of approximately 2:1 to approximately 20:1 or approximately 6:1 to approximately 18:

1. Delay according to any one of claims 1 to 13, having a gelatin-to-pectin w:w ratio Release softgel capsule.

15. The w:w ratio of glycerin to sorbitol in the pH-dependent shell composition is about 1:2 to about A delayed-release soft gel capsule according to any one of claims 1 to 14, in the range of 1:5 cell.

16. (a) the step of preparing a filler material containing an activator; (b) The step of encapsulating the filling material with a pH-dependent shell composition A delayed-release softgel capsule according to any one of claims 1 to 15 is prepared, including the following: How to do it.

17. Claim 1 further comprises the step of drying the enclosed delayed-release softgel capsule. The method described in 6.

18. Claim 16 or further comprises the step of curing the delayed-release softgel capsule. Method 17.

19. Claims 16 to 18 further include the step of preparing the pH-dependent shell composition. The method described in either of the above terms.

20. The preparation steps involve gelatin, dextrose, pectin, glycerin, and sol The method described in claim 19, which includes mixing bitol to form a pH-dependent shell composition ribbon. Method of loading.

21. The pH-dependent shell composition ribbon is in the range of approximately 0.020 inches to approximately 0.050 inches. The method according to claim 20, having the thickness of the following.

22. p A method for adjusting the H-dependent dissolution / disintegration profile, wherein the pH-dependent shell composition The amount of pectin in the substance, as well as the amounts of glycerin and sorbitol, are adjusted, and an acidic medium and The step includes achieving a target pH-dependent dissolution / disintegration profile in and / or a buffer medium. Hmm, a method.

23. The step of adjusting the wt:wt ratio of gelatin to pectin in the pH-dependent shell composition. The method according to claim 22, further comprising:

24. The further step includes adjusting the amount of dextrose in the pH-dependent shell composition. The method according to claim 22 or 23.

25. Claim 2 further includes the step of adjusting the thickness of the ribbon of the pH-dependent shell composition. The method described in any one of items 2 to 24.

26. A delayed-release softgel capsule according to any one of claims 1 to 15, which requires A method for treating a condition, which includes the step of administering an agent to a subject.

27. (a) Filling material containing an activator; and (b) containing gelatin, pectin, dextrose, glycerin, and sorbitol pH-dependent shell composition The step includes administering a delayed-release softgel capsule containing the capsule to a subject requiring it. a method for reducing the occurrence of belching, The pH-dependent shell composition is approximately 5 wt% of the total weight of the dry pH-dependent shell composition. Contains approximately 40 wt% glycerin. The w:w ratio of glycerin to sorbitol in the pH-dependent shell composition is approximately 1:1.

5. A method with a ratio of approximately 1:

7.

28. The filling material is fish oil, krill oil, garlic oil, polyethylene glycol, or the same. The method according to claim 27, including a combination thereof.

29. Adjust the pH to an acidic level using phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution. When measured using a USP decay device with approximately 500 ml to 900 ml of prepared 0.1 N HCl. The delayed-release softgel capsules are 1.2, 2.0, 3.0, 4.0, 5.0, and 6. At 0, or a partial range of the acidic pH, for at least about 15 minutes, and at least about 3 0 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or less It did not collapse for approximately 120 minutes; Approximately 500 ml to 900 ml of phosphate buffer solution adjusted to buffer pH, sodium hydroxide. When measured using a USP decay device with a solution or potassium hydroxide solution, the delayed release soft The gel capsules were approximately above 6.5, above 6.8, above 7.0, and above 7.

5. At a buffer pH above approximately 8.0 or above approximately 8.5, for a maximum of approximately 60 minutes, or a maximum of approximately 45 minutes. Claim 27 or 28, which disintegrates in a maximum of approximately 30 minutes, a maximum of approximately 15 minutes, or a maximum of approximately 10 minutes. Methods used.

30. (a) a filler material containing at least one activator; and (b) pH-dependent shell composition comprising a film-forming agent, glycerin, and sorbitol A delayed-release softgel capsule containing, The pH-dependent shell composition is approximately 5 wt% of the total weight of the dry pH-dependent shell composition. Contains approximately 40 wt% glycerin. The w:w ratio of glycerin to sorbitol in the pH-dependent shell composition is approximately 1:1.

5. Delayed-release softgel capsules with a ratio of approximately 1:

7.

31. The pH-dependent shell composition comprises at least dextrose, pectin, or gelatin. A delayed-release softgel capsule according to claim 30, further comprising one of the above.

32. The film-forming agent is carrageenan, starch, pregelatinized starch, xanthan gum Agar, pectin, alginate, sugar, high molecular weight polyethylene glycol, sugar-derived Alcohol, cellulose derivatives, cellulose polymers, hydroxyethylcellulose, hydr Roxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose Lullose, microcrystalline cellulose, attapulgite, bentonite, dextrin, argy Calcium sulfate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbomer Ingredients: cellulose, silicon dioxide, curdlan, fercerelan, albumin, soy protein, ki Claim 30 or 3 comprises a non-animal derived gelling agent including tosan or a combination thereof. The delayed-release softgel capsule described in 1.

33. The pH-dependent shell composition is approximately 5 wt% of the total weight of the dry pH-dependent shell composition. Claim 30, comprising glycerin in an amount of approximately 15 wt% or approximately 20 wt% to approximately 40 wt% A delayed-release softgel capsule as described in any one of items 32 to 32.

34. The pH-dependent shell composition is approximately 10 wt in relation to the total weight of the dry pH-dependent shell composition. % to approximately 20 wt%, approximately 10 wt% to approximately 18 wt%, approximately 12 wt% to approximately 17 wt%, or Any of claims 30 to 33, comprising an amount of sorbitol of approximately 13 wt% to approximately 15 wt%. Delayed-release softgel capsule as described in item 1.

35. Adjust the pH to an acidic level using phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution. When measured using a USP decay device with approximately 500 ml to 900 ml of prepared 0.1 N HCl. , 1.2, 2.0, 3.0, 4.0, 5.0, 6.0, or a partial range of the acid therein Stepwise pH, at least approximately 15 minutes, at least approximately 30 minutes, at least approximately 45 minutes, and at least It will not collapse for approximately 60 minutes, at least approximately 90 minutes, or at least approximately 120 minutes; Approximately 500 ml to 900 ml of phosphate buffer solution adjusted to buffer pH, sodium hydroxide. When measured using a USP decay device with a solution or potassium hydroxide solution, the value is above approximately 6.

5. Above 6.8, above approximately 7.0, above approximately 7.5, above approximately 8.0, or above approximately 8.5 At the aforementioned buffering pH, the maximum duration is approximately 60 minutes, 45 minutes, 30 minutes, and 15 minutes. The delayed emission software according to any one of claims 30 to 34 disintegrates in a maximum of approximately 10 minutes. Gel capsules.

36. A paddle with a rotation speed of approximately 50 RPM to 250 RPM, phosphate buffer solution, sodium hydroxide Approximately 500 ml to 900 ml of solution or potassium hydroxide solution adjusted to an acidic pH. When measured with USP Apparatus II using 0.1N HCl, 1.2 2.0, 3.0, 4.0, 5.0, 6.0, or a partial range of the acid pH levels therein So, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 It will not dissolve for at least 90 minutes, or at least about 120 minutes; A paddle with a rotation speed of approximately 50 RPM to 250 RPM, and approximately 500 ml of water adjusted to a buffered pH. Approximately 900 ml of phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution When measured with the USP Apparatus II, the reading was above approximately 6.5 and above approximately 6.

8. Above approximately 7.0, above approximately 7.5, above approximately 8.0, or above approximately 8.5 At buffered pH, for a maximum of approximately 60 minutes, 45 minutes, 30 minutes, 15 minutes, or approximately A delayed-release soft gel capsule according to any one of claims 30 to 35, which dissolves in 10 minutes. cell.

37. A filler material containing at least one activator; and pH-dependent shell composition containing approximately 0.1 wt% to approximately 2 wt% gellan gum A delayed-release softgel capsule containing, when in a medium having a pH of 4, releases approximately 6 Delayed-release softgel capsules that begin to dissolve after 0 minutes.

38. The delayed-release solvent according to claim 37, which begins to dissolve after about 45 minutes in a medium having a pH of 5. Futogel Capsules.

39. The delayed release according to claim 37, wherein the gellan gum is contained in an amount of about 0.4 wt% to about 2 wt%. Softgel capsules.

40. The delayed release according to claim 37, wherein the gellan gum is contained in an amount of about 0.4 wt% to about 1 wt%. Softgel capsules.

41. The slow drink according to claim 37, wherein the gellan gum is contained in an amount of about 0.4 wt% to about 0.6 wt%. Extended-release softgel capsules.

42. A paddle with a rotation speed of approximately 50 RPM to 250 RPM, phosphate buffer solution, sodium hydroxide Approximately 500 ml to 900 ml of solution or potassium hydroxide solution adjusted to an acidic pH. When measured with USP Apparatus II using 0.1N HCl, 1.2 2.0, 3.0, 4.0, 5.0, 6.0, or a partial range of the acid pH levels therein So, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 It will not dissolve for at least 90 minutes, or at least about 120 minutes; A paddle with a rotation speed of approximately 50 RPM to 250 RPM, and approximately 500 ml of water adjusted to a buffered pH. Approximately 900 ml of phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution When measured with the USP Apparatus II, the reading was above approximately 6.5 and above approximately 6.

8. Above approximately 7.0, above approximately 7.5, above approximately 8.0, or above approximately 8.5 At buffered pH, for a maximum of approximately 60 minutes, 45 minutes, 30 minutes, 15 minutes, or approximately A delayed-release soft gel capsule according to any one of claims 37 to 41, which dissolves in 10 minutes. cell.

43. The delayed soft gel capsule is washed with a calcium chloride solution, according to claim 37. A method for preparing Togel capsules.

44. The calcium chloride solution contains approximately 2% to approximately 20% calcium chloride, according to claim 41. method.

45. The method according to claim 41, wherein the softgel capsule is washed for about 5 seconds to about 30 seconds.

46. Adjust the pH to an acidic level using phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution. When measured using a USP decay device with approximately 500 ml to 900 ml of prepared 0.1 N HCl. The delayed-release softgel capsules are 1.2, 2.0, 3.0, 4.0, 5.0, and 6. At 0, or a partial range of the acidic pH, for at least about 15 minutes, and at least about 3 0 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or less It did not collapse for approximately 120 minutes; Approximately 500 ml to 900 ml of phosphate buffer solution adjusted to buffer pH, sodium hydroxide. When measured using a USP decay device with a solution or potassium hydroxide solution, the delayed release soft The gel capsules were approximately above 6.5, above 6.8, above 7.0, and above 7.

5. At a buffer pH above approximately 8.0 or above approximately 8.5, for a maximum of approximately 60 minutes, or a maximum of approximately 45 minutes. , which disintegrates in a maximum of approximately 30 minutes, a maximum of approximately 15 minutes, or a maximum of approximately 10 minutes, according to claims 43 to 45 The method described in any one of the items.

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