Delayed-release softgel capsules

Abstract

The present invention provides a delayed-release softgel capsule that does not require the application of a pH-dependent coating or the addition of a conventional pH-dependent polymer to the shell, a method for preparing a delayed-release softgel capsule, and a method for treating a condition (e.g., a colonic disease or other condition treatable by targeted administration of an activator to the colon) by administering the delayed-release softgel capsule to the target. [Solution] A delayed-release softgel capsule comprising (a) a filling material and (b) a pH-dependent shell composition, wherein the filling material comprises at least one pharmaceutically active ingredient, the pH-dependent shell composition comprises gelatin, pectin, and dextrose, and the pH-dependent shell composition dissolves / disintegrates / breaks down in the colonic environment.

Description

Technical Field

[0001] The present invention relates to delayed-release soft gel capsules, wherein the gelatin-based shell composition has delayed-release properties that require neither a pH-dependent coating nor the addition of conventional pH-dependent synthetic polymers. The delayed-release soft gel capsules described herein are particularly suitable for colonic delivery.

Background Art

[0002] Soft capsules, particularly soft gelatin capsules (or soft gel capsules), provide dosage forms that are more easily accepted by patients because they are easy to swallow and do not require flavoring to mask any unpleasant taste of the active agent. Soft gel encapsulation of drugs further offers the potential to improve the bioavailability of pharmaceutical products. For example, as soon as the gelatin shell breaks, the active ingredient can be rapidly released in liquid form.

[0003] Efforts have been made to produce delayed-release dosage forms. Delayed-release dosage forms are designed to protect the contents of the dosage form from gastric conditions. For example, delayed-release dosage forms can be produced by adding a pH-dependent coating to the surface of a manufactured dosage form such as a tablet or capsule. Such a coating can be applied by spraying onto the dosage form, followed by drying the dosage form, usually at an elevated temperature. This method of coating capsules with a pH-dependent coating can bring about disadvantages with respect to performance and appearance. For example, the capsules may appear rough, the coating may be applied unevenly, and / or the coating may be prone to cracking or peeling off from the dosage form. In addition, the process of applying a pH-dependent coating is very inefficient. ​

[0004] 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. The seal can result in capsules that are prone to leakage.

[0005] Therefore, the application of pH-dependent coatings is also the same as the addition of conventional pH-dependent polymers to the shell. There is currently a need for delayed-release softgel capsules that do not require any additional processing. [Overview of the project]

[0006] 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 require neither pH-dependent coating nor conventional pH-dependent polymers to be added. No. Therefore, pH-dependent shell compositions do not require the addition of a pH-dependent coating. Furthermore, this also minimizes the risk of damaging the capsules during the coating process. The delayed-release softgel capsules described in the specification are particularly suitable for colonic delivery.

[0007] In one embodiment, the pH-dependent shell composition is (a) gelatin, (b) dextrose (c) pectin such as low-methoxypectin and (d) a plasticizer as needed. pH-dependent shell composition (e.g., amount of pectin, amount of dextrose, gelatin vs. pectin) The ratio and its preparation process (e.g., curing time, ribbon thickness) are influenced by various pH environments. The target pH solubility profile of the shell composition (e.g., breaking down in acidic and buffered media) The invention can be adjusted / modified / converted to achieve the interruption / dissolution / decay time. also relates to a process for producing softgel capsules. In particular, the pH-dependent de xtrose amount in the gel composition can be adjusted to delay release of the active agent until it re aches the colonic environment in a human subject.

[0008] The present invention also covers a method for treating a condition (e.g., a colonic disorder or other condition treatable by targeted delivery of an active agent to the colon) by administering to a subject any of the delayed-release softgel compositions described herein. Delivery may be for treati ng a colonic disease or condition, or may also be used to treat a systemic condition with a drug su itable for absorption in the colon.

[0009] The present invention also relates to a method of delivering an active agent to the colon of a p atient by orally administering any of the delayed-release softgel capsules described herein. In cer tain specific embodiments, at least 80%, at least 85%, at least 90%, at least 95% , or at least 99% of the active agent is delivered to the patient's colon. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The above and other features of the present disclosure, their nature, and various advantages will become more apparent upon consideration of the following detailed description taken in conjunction [Figure 1] It is a graph showing the viscosity of shell compositions containing and not containing amidated pectin as a function of aging time. DESCRIPTION OF EMBODIMENTS

[0011] The present invention does not require applying a pH-dependent coating nor does it rely on conve The present invention advances the state of the art by developing delayed-release oral dosage forms, particularly delayed-release softgel capsules, that achieve the advantages associated with conventional delayed-release dosage forms without also requiring addition to the capsule shell . The delayed-release softgel capsules of the present invention do not dissolve in the gastric environment of the stomach, but rather dissolve in the intestine, particularly the colon of a human subject. The dissolution profile of the delayed-release softgel capsules described herein can be adjusted by modifying the shell composition of the softgel capsule. Such a mechanism is beneficial for the delivery of active ingredients that may 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 fill material that tends to contribute to belching

[0012] For example, belching often occurs upon ingestion of vitamin, mineral, supplement, and / or pharmaceutical products formulated into 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 that have an unpleasant odor perception such as fish oil and garlic, which are commonly delivered in softgels. The delayed-release softgel capsules described herein can be formulated in a manner that minimizes and / or eliminates premature leakage resulting in premature release of the capsule fill in the gastric environment of the stomach and any other regions of the gastrointestinal tract preceding the colon. As used herein, the term "pH-dependent" means that the dosage form remains intact in the gastric environment of the stomach and any other regions of the gastrointestinal tract preceding the colon for a period of at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours before beginning to dissolve or disintegrate to release its fill. In some embodiments, the delayed-release softgel capsule disperses or dissolves and releases its fill at a location distal to the stomach, for example in the small intestine and / or the colon, upon reaching a region of the gastrointestinal tract having a pH above about 5, above about 5.5, above about 6, or above about 6.5 . The delayed-release softgel capsules described herein can allow for targeted delivery to the colon

[0013] As used herein, the term "pH-dependent" means, for example, that for a period of at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours, the gastric environment of the stomach and the stomach preceding the colon No or substantial dissolution or breakdown occurs in any other part of the intestinal tract. Una is used to refer to the resistance of a substance to dissolution or disintegration. In certain embodiments, the stomach The gastric environment is simulated here by adding 0.1N HCl and, if necessary, pepsin. It is possible. The pharmacopoeia method does not include pepsin, but it better simulates / imitates in vivo conditions. Therefore, pepsin was added in the specific dissolution / disintegration tests described herein. It should be noted that, therefore, without being interpreted as being limited, a certain actual In application, the compositions described herein contain a 0.1N HCl ring containing the enzyme pepsin. Even at the boundary (which is presumed to be a more aggressive environment than 0.1N HCl without pepsin) It is resistant to dissolution / disintegration for the above period of time.

[0014] For example, the embodiments described herein provide approximately 3.5% of the benefits compared to biological, artificial, or simulated gastric juice. At a pH of 5 or higher (for example, in a living, artificial, or simulated colon environment and / or intestinal fluid) The solution contains a pH-dependent shell composition that dissolves preferentially. For example, the pH-dependent shell composition is At a pH of approximately 3.5 or higher (for example, in a living, artificial, or simulated colon environment and / or intestine) (In the liquid) at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, At least approximately 25 minutes later, at least approximately 30 minutes later, at least approximately 35 minutes later, at least approximately 40 minutes later After a few minutes, or after approximately 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes. Then, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, approximately 60 minutes, approximately 75 minutes, or Dissolve within approximately 90 minutes, or any single value or sub-range within that time. In certain embodiments, the colon or intestinal environment is here pH 6.8 phosphate buffer This can be simulated by adding pancreatin as needed. The pharmacopoeia method is pancreatin Although it does not contain tin, pancreatin is used to better simulate / mimic in vivo conditions. It should be noted that it was added in the specific dissolution / disintegration tests described in the specification. Therefore, without being construed as limiting, in certain embodiments, this specification The composition described above is a pH 6.8 buffered environment containing pancreatin (without pancreatin) Similar dissolution / disintegration occurs in an environment that is presumed to be more aggressive than a pH 6.8 buffer environment. Show the profile.

[0015] 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 may contain: Exemplary delayed-release softgel capsules may 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.

[0016] 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].

[0017] 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.

[0018] 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.

[0019] In a particular embodiment, the active ingredient contained in the capsule is intended to be delivered to the small intestine. Any pharmaceutical or therapeutic agent, e.g., pancreatin and other proteolytic enzymes Ingredients, diclofenac, naproxen, aspirin, indomethacin, omeprazole, strong Electrolyte preparations using cardiac glycosides, sodium, potassium, and magnesium salts, and These may be calcium and iron preparations, bisacodyl preparations, and valproic acid.

[0020] In certain embodiments, the activator may be a drug that is desirable to deliver to the colon, Drugs for treating diseases, such as 5-ASA; hydrocortisone, budesonide, etc. Teroids; laxatives; octreotide; cisapride; anticholinergics; calcium channel blockers Drugs such as ondansetron (5HT3 antagonists) and peptides such as insulin It may include.

[0021] In certain embodiments, the active agents suitable for colonic delivery are, without limitation, antimicrobial and antiviral agents. Anti-infective drugs such as russinus; analgesics and combinations of analgesics; appetite suppressants; anthelmintics; anti-arthritis drugs Antiasthma drugs; anticonvulsants; antidepressants; antidiabetic drugs; antidiarrheals; antihistamines; anti-inflammatory drugs; antiseptics Headache preparations; anti-nausea drugs; antineoplastic drugs; anti-Parkinson's disease drugs; antipruritics; antipsychotics; antipyretics Antispasmodics; anticholinergics; sympathomimetic agents; xanthine derivatives; potassium and calcium Cardiovascular preparations including channel blockers, beta-blockers, alpha-blockers, and antiarrhythmic drugs Substances; antihypertensive drugs; diuretics and antidiuretics; vasodilators; general coronary, peripheral and cerebral blood vessels Cough and cold preparations containing dilators, central nervous system stimulants, vasoconstrictors, and decongestants; Hormones such as estradiol and other steroids including corticosteroids; sleep Drugs; immunosuppressants; muscle relaxants; parasympathetic nerve blockers; psychostimulants; sedatives; and tranquilizers Probiotics; anticancer drugs (e.g., colon cancer-specific anticancer drugs or in the colon) One of the anticancer drugs for other types of cancer that can be systemically treated with an anticancer drug suitable for absorption. It is one species or more.

[0022] Examples of anticancer drugs for colon cancer include, without limitation, Avastin (bevacizumab), bevacizumab, and Amputosal (irinotecan hydrochloride), capecitabine, cetuximab, Cyramza (ramza) Silumab, Eloxatin (oxaliplatin), Elbitux (cetuximab), 5 -FU (Fluorouracil Injection), Fluorouracil Injection, Ipilimumab, Irinote Can hydrochloride, Keytruda (pembrolizumab), leucovorin calcium, Lonsurf (Trifluridine and tipiracil hydrochloride), Mvasi (bevacizumab), Nivolumab Opdivo (nivolumab), oxaliplatin, panitumumab, pembrolizumab, ra mucirumab, regorafenib, stivarga (regorafenib), trifluridine and ti Pyracyl hydrochloride, Vectibix (panitumumab), Xeloda (capecitabine), Ya Boy (ipilimumab), Zaltrap (Ziv-aflibercept), Ziv-aflibercept This includes Lucept and any combination thereof.

[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 Other oils and fats may be selected from the group consisting of watermelon seed oil. 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-hydroxytryptopher 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'-dibenzylethyl 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, the terms "shell" or "shell composition" or "pH-dependent shell" are used. "Soft gel composition" refers to the shell of a soft gel capsule that encloses the filling material.

[0038] As used herein, “conventional pH-dependent polymers” are not limited to these, but Acrylic and methacrylic available under the trademark name EUDRAGIT (registered trademark) Acid polymers and other conventional acid-insoluble polymers, such as methyl methacrylate. This refers to acid copolymers. Other conventional acid-insoluble polymers are, without limitation, cellulose succinate acetate. Cellulose acetate, cellulose butyrate acetate, hydroxypropyl methylcellulose Sphthalate, hydroxypropyl methylcellulose acetate succinate (hyprom (Rose acetate succinate), polyvinyl acetate phthalate (PVAP), aluminum Alginates such as sodium ginate and potassium alginate, stearic acid, and It contains shellac. Pectin and pectin derivatives are considered conventional pH-dependent polymers. In some embodiments, the pH-dependent shell composition of the present invention contains an acid-insoluble polymer. No. In other words, in certain embodiments, pH-dependent shell composition and pH-dependent so Futogel capsules "do not contain or substantially contain conventional pH-dependent polymers."

[0039] 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.

[0040] 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.

[0041] As used herein, “filling material” or “filling” refers to a pH-dependent shell composition. This refers to a composition encapsulated by a encapsulation agent, containing at least one pharmaceutically active ingredient.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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 pharmaceutically active ingredient, pH The dependent shell composition is gelatin, dextrose, pH-dependent material (e.g., low methoxylpectin) It contains (tin) and, if necessary, a plasticizer. Preferably, the pH-dependent shell composition contains additional p It does not contain H-dependent polymers. In certain embodiments, pH-dependent softgel capsules or The pH-dependent shell composition remains intact in acidic media such as the gastric environment or a simulated gastric juice environment. Yes (for example, at least about 5 hours, at least about 4 hours, at least about 3 hours, less For approximately 2 hours, or at least 1 hour, in the colon (or simulated intestinal fluid environment) At the target time (for example, at least about 10 minutes later, at least about 15 minutes later, at least about 20 minutes later) After a few minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least Also, after about 40 minutes, or if more than 0 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, or about 25 minutes You can choose from any of the following options: approximately 30 minutes, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, approximately By 60 minutes, approximately 75 minutes, or approximately 90 minutes, or any single value within that period. Alternatively, it is configured to dissolve / disintegrate (in a partial area).

[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., calf 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 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 0.05wt%, or approximately 0.1wt% Approximately 0.4 wt%, approximately 0.5 wt%, or any single value or sub-range within that range. It is enclosed.

[0050] Dextrose is added to the delayed-release capsule shell to mitigate the potential decrease in gel strength. It can be added. The amount of dextrose in the pH-dependent shell composition is also a delayed-release soft gel. To achieve a targeted dissolution profile for the capsule, for example, a delayed-release softgel capsule The cells are formulated to dissolve / disintegrate at specific locations within the gastrointestinal tract (for example, in the colon). It can be restricted. In one embodiment, the amount of dextrose in the pH-dependent shell composition is delayed release. The dissolution of the softgel capsule is delayed until it reaches the colon, where it targets the target. It is adjusted to achieve a solubility profile. For example, dextrose in pH-dependent shell compositions The amount of straw is the buffering medium (for example, necessary to simulate the colon environment in human subjects). Dissolution / disintegration / breakdown in pH 6.8 phosphate buffer containing pancreatin, depending on the circumstances. An acidic medium (e.g., 0.1N HCl containing pepsin as needed) is used while controlling the time. It can be adjusted to prevent premature leakage / rupture during the buffering phase. The time until disconnection is at least approximately 10 minutes, at least approximately 15 minutes, at least approximately 20 minutes. , at least approximately 25 minutes later, at least approximately 30 minutes later, at least approximately 35 minutes later, at least approximately 40 minutes later, or approximately 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes later. From there, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, approximately 60 minutes, approximately 75 minutes, if 'k' can be any single value or subrange within approximately 90 minutes. The dissolution / disintegration / breakdown time in acidic media can be controlled. Take the capsule for at least approximately 15 minutes, at least approximately 30 minutes, at least approximately 45 minutes, at Approximately 60 minutes, at least approximately 90 minutes, at least approximately 120 minutes, or at least approximately 150 minutes It can be controlled to maintain its state.

[0051] Without being interpreted as restrictive, dextrose interacts with gelatin in the shell composition. It is thought that the gelatin is crosslinked. Dextrose is thought to affect the solubility of the shell composition. The effect of the amount of is further explained in the examples. Dextro in pH-dependent shell composition The concentration of the substance may be an effective amount to improve gel strength, but the sealing of the capsule or the product performance may be affected. It doesn't need to be so high that it interferes with manufacturability.

[0052] 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 other embodiments, low methoxyl (LM) pectin is a non-amidated pectin. In certain embodiments, pectin is a combination of amidated and unamidated pectin. It is a combination. The addition of pectin contributes to the pH dependence of the dosage form.

[0053] 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.

[0054] Therefore, the pectin content is high enough to form a delayed-release dosage form, while simultaneously reducing gel strength. It can be added to the dosage form at a concentration low enough to mitigate the slight increase in viscosity.

[0055] 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.

[0056] 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.

[0057] In certain embodiments, the pH-dependent shell composition includes a stabilizer containing gellan gum and / or includes a binder. In certain embodiments, a pectin stabilizer and / or binder. The ratio to the agent (e.g., gellan gum) is approximately 1:10 to 50:1; approximately 1:5 to 40: 1; is approximately 1:1 to 25:1 or 10:1 to 24:1.

[0058] In certain embodiments, stabilizers and / or binders in pH-dependent shell compositions (e.g., For example, the amount of gellan gum is approximately 0.05 wt relative to the total weight of the dry capsule shell composition. t% to approximately 5 wt%, approximately 0.1 wt% to approximately 3 wt%, or approximately 0.2 wt% to approximately 2 wt% Stabilizers and / or binders (e.g., gellan gum), or any single one of them It is a value or a subrange.

[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 related to Figure 1. As will be described in more detail in the following examples, the rheometer was used at 60°C and the measurement was taken. The gel mass sample (for example, one of the pH-dependent shell compositions described herein) is used in 6 The sample is placed on the rheometer's sample stage, which is maintained at 0°C. The disk rotates at a specific speed, and at a constant speed. This results in a shear rate. Viscosity is determined by measuring the shear stress and shear rate. It can be obtained.

[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 plasticizer in the pH-dependent shell composition is glycerol, glycerin This may include sorbitol and combinations thereof. Other suitable plasticizers are not limited to these. However, sugar alcohol plasticizers, such as isomalt, maltitol, xylitol, etc., are not available. Risritol, Adonitol, Dulcitol, Pentaerythritol, or Mannitol L; or polyol plasticizers, e.g., diglycerin, dipropylene glycol, up to 1 0,000 MW polyethylene glycol, neopentyl glycol, propylene glycol 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylol Contains ethanolpropane, polyether polyols, ethanolamine; and mixtures thereof. Other exemplary plasticizers include, without limitation, low molecular weight polymers, oligomers, and copolymers. Oil, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-based plasticizers Glycol ether, poly(propylene glycol), multiblock polymer, syn It may also contain glubrock polymers, citrate ester plasticizers, and triacetin. Plasticizers such as 1,2-butylene glycol, 2,3-butylene glycol, styrene Propylene glycol, monopropylene glycol monoisopropyl ether, propylene glycol Diethylene monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol Monoethyl ether, sorbite lactate, ethyl lactate, butyl lactate, ethyl glycolate L, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, monostearate Glyceryl phosphate, polysorbate 80, acetyl triethyl citrate, triethyl citrate It may contain butyl and allyl glycolate, as well as mixtures thereof.

[0062] In one embodiment, the amount of plasticizer in the pH-dependent shell composition is the amount of plasticizer in the dry capsule shell. Approximately 15 wt% to 45 wt%, approximately 15 wt% to 40 wt%, and approximately 1 8wt%~about 45wt%, about 18wt%~about 42wt%, about 20wt%~about 35wt%, Approximately 25 wt% to approximately 30 wt%, or any single value or subrange within that range.

[0063] In certain embodiments, various components (e.g., pectin, dextrose, gelatin) are used. The amount of plasticizers and the ratio of various components affect the softgel capsules across a wide pH range. It is regulated to control dissolution and / or disintegration properties.

[0064] 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 better suited to acidic media (e.g., pepsin if necessary). It is more stable (or dissolves more slowly, if at all) in pH (including 0.1N HCl). It provides a dependent shell composition, but a higher gelatin-to-pectin w:w ratio is suitable for acidic media (e.g.) For example, if necessary, it is not very stable in 0.1N HCl containing pepsin (faster Provides a pH-dependent shell composition that dissolves in acidic media. The gelatin to pectin w:w ratio is... The specific dissolution time of the softgel capsule inside (for example, about 10 minutes, about 15 minutes, about 30 minutes, Achieve approximately 45 minutes, 60 minutes, 90 minutes, or any portion of these time ranges. It can be adjusted accordingly.

[0065] Furthermore, the gelatin-to-plasticizer w:w ratio in the pH-dependent shell composition is related to the specific capsule hardness level. It may be adjusted to achieve a ratio of approximately 5:1 to 1:5, approximately 4:1 to 1:4, and approximately 3 :1 to approximately 1:3, approximately 2:1 to approximately 1:2, approximately 1:1, or any single ratio within that range. It can be a value or a subrange of .

[0066] 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.

[0067] 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:

[0068]

number

[0069] 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.

[0070] 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.

[0071] In one embodiment, the pH-dependent shell composition and the pH-dependent softgel capsule are, The conventional pH-dependent polymer may be omitted or substantially omitted and / or Alternatively, it may not include a pH-dependent protective film on the soft gel shell.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] In some embodiments, pH-dependent shell composition and / or pH-dependent soft gel capsule The solution is an acidic medium (for example, pH 1.2 (0.1N HCl) containing pepsin as needed). ), followed by a buffering medium to simulate the colon environment and / or intestinal fluid (e.g., as needed) Approximately 1% pancreatin (including pancreatin-containing phosphate buffer at pH 6.8) is used for 50 Collapse in USP Apparatus II using a paddle with a speed of rpm / Can be tested in a dissolution test. pH-dependent softgel capsules according to this embodiment In an acidic medium for at least about 10 minutes, at least about 15 minutes, at least about 30 minutes, and at least Approximately 1 hour, at least approximately 2 hours, at least approximately 3 hours, at least approximately 4 hours, or less At the very least, it can remain intact for about 5 hours, in the intestinal fluid and / or colonic environment, as / or after at least about 10 minutes, at least about 15 minutes, in simulated intestinal fluid (e.g., buffering medium) , at least about 20 minutes later, at least about 25 minutes later, at least about 30 minutes later, at least about After 35 minutes, at least after about 40 minutes, or after about 10 minutes, about 15 minutes, about 20 minutes, or about 25 minutes. Or, starting from one of the following 30-minute intervals, approximately 35 minutes, 40 minutes, 45 minutes, 50 minutes, or 55 minutes. Within approximately 60 minutes, 75 minutes, or 90 minutes, or any single within that timeframe. It may collapse in terms of values ​​or subranges.

[0079] The buffer medium in the two-phase dissolution / disintegration test has a pH of 6.8, but a similar dissolution / disintegration profile This is achieved using a buffer medium with a pH of approximately 3.5 or higher (including pancreatin if necessary). It should be noted that this is possible. Pepsin (in an acidic medium) and pancreatin ( The presence of a buffering medium is not required by the pharmacopoeia method, but it better mimics in vivo conditions. To simulate a more aggressive environment, it is used in this specification in certain examples. This should also be taken into consideration.

[0080] In some embodiments, the two-phase disintegration / dissolution test is performed on the total (both the acidic medium and the buffered medium) (Including) Approximately 420 minutes, approximately 360 minutes, approximately 300 minutes, approximately 240 minutes, approximately 210 minutes, approximately 180 minutes, approximately 150 minutes, approximately 120 minutes, approximately 105 minutes, approximately 90 minutes, approximately 75 minutes, approximately 60 minutes, approximately 45 minutes, approximately 30 minutes It can be done for 10 minutes, approximately 15 minutes, approximately 10 minutes, or approximately 5 minutes.

[0081] The encapsulation of the filling material can be accomplished in any conventional manner. For example, rotary die encapsulation is It can be used.

[0082] According to one embodiment, a pH-dependent softgel capsule contains (a) at least one drug (b) the step of preparing a filler material containing a scientifically active ingredient; (b) the filler material of step (a) It is prepared by a process that includes the step of encapsulating in a pH-dependent shell composition. The encapsulation process by (b) is, for example, performed with gelatin, dextrose, pectin and essential A substep to prepare a pH-dependent shell composition by mixing in a plasticizer as needed. The pH-dependent shell composition may further include additional pH-dependent polymers (e.g. It does not contain conventional pH-dependent synthetic polymers.

[0083] 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.

[0084] 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. °C, in the range of approximately 25°C to 70°C, or approximately 30°C to 60°C, or approximately 35°C to 50°C. This can be done by temperature. The curing temperature is sufficient to enhance the delayed release properties of the soft gel capsule. The temperature should be high, but not high enough to dissolve the softgel capsule.

[0085] The curing time is approximately 12 to 168 hours, 18 to 120 hours, and 24 hours. 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).

[0086] 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, which are essentially made from them or consist of them .

[0087] 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.

[0088] 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 characteristics of the release softgel capsule. Therefore, the drying step The presence of the pu is not the same as the curing step, and similarly, the presence of the curing step is not the same as the drying step. It's not.

[0089] In certain embodiments, a delayed-release sonar having the pH-dependent shell composition described herein is used. Futgel capsules are chemically and physically stable.

[0090] 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), substantially similar to (or within specifications of) the raw material before storage. (That is.)

[0091] 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].

[0092] 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.

[0093] In certain embodiments, this disclosure relates to the delayed-release softgel capsule described herein. Methods for stabilizing the displacement may also be included. The method may be any of the filler materials described herein. or (containing at least one activator) any of the pH-dependent shell compositions described herein The step of protecting any of the filling materials described herein by sealing them in ( This may include, for example, oxidation or other potential causes of chemical decomposition.

[0094] In certain embodiments, the pH-dependent shell composition described herein is used in an acidic environment (for example). If necessary, a gastric environment or simulated gastric environment, for example, simulated gastric juice, containing pepsin (0.1N) as needed. The premature release of the filler material in HCl is reduced to at least approximately 10 minutes, at least approximately 15 minutes, and less At least 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, Robust delayed discharge with little or no presence for at least approximately 4 hours, or at least approximately 5 hours. To produce delayed-release softgel capsules. For example, the delayed-release softgel capsules described herein The maximum exposure time to an acidic environment is approximately 150 minutes, 120 minutes, 105 minutes, and 90 minutes. Maximum of approximately 75 minutes, Maximum of approximately 60 minutes, Maximum of approximately 45 minutes, Maximum of approximately 30 minutes, Maximum of approximately 15 minutes, Maximum of approximately 10 After exposure for minutes, or up to approximately 5 minutes, the total weight of the filler material in an acidic environment is compared with the filler material Maximum approximately 10 wt%, maximum approximately 9 wt%, maximum approximately 8 wt%, maximum approximately 7 wt%, maximum approximately 6 wt %, maximum approximately 5 wt%, maximum approximately 4 wt%, maximum approximately 3 wt%, maximum approximately 1 wt%, or 0 wt It can release %.

[0095] In certain embodiments, the delayed-release softgel capsule described herein (i.e., p Curing (encased in an H-dependent shell composition) takes approximately 10 minutes, 15 minutes, and 30 minutes. After minutes, approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, or approximately 5 hours, or these Reduce the number of capsules exhibiting premature release in any amount in an acidic environment within any portion of the time range. It can be reduced or eliminated. For example, in an acidic environment (up to approximately 5 hours in an acidic environment, Maximum of approximately 4 hours, maximum of approximately 3 hours, maximum of approximately 150 minutes, maximum of approximately 120 minutes, maximum of approximately 105 minutes, maximum Approximately 90 minutes, maximum approximately 75 minutes, maximum approximately 60 minutes, maximum approximately 45 minutes, maximum approximately 30 minutes, maximum approximately 15 minutes, The number of hardened capsules showing early release (after exposure of up to approximately 10 minutes, or up to approximately 5 minutes) is Up to approximately 30%, up to approximately 25%, up to approximately 20%, and up to approximately 15% of the total number of capsules in the batch. The maximum percentages are approximately 10%, 5%, 3%, 2%, 1%, or 0%. obtain.

[0096] For comparison, without curing, in an acidic environment (maximum of approximately 5 hours in an acidic environment, maximum of approximately 4 hours) time, up to about 3 hours, up to about 150 minutes, up to about 120 minutes, up to about 105 minutes, up to about 90 minutes, Maximum of approximately 75 minutes, Maximum of approximately 60 minutes, Maximum of approximately 45 minutes, Maximum of approximately 30 minutes, Maximum of approximately 15 minutes, Maximum of approximately 10 The number of capsules (with the same composition) showing early release (after exposure of 1 minute, or up to approximately 5 minutes) Approximately 2%, 5%, 10%, 15%, and 20% of the total number of capsules in the batch. Over, over approximately 30%, over approximately 40%, over approximately 50%, over approximately 60%, over approximately 70%, over approximately 80%, and also This could be over 90%.

[0097] In certain specific embodiments, curing the delayed-release soft gel capsules described herein (i.e., p H-dependent shell compositions) can reduce or eliminate the amount of filler material released from capsules that exhibit some premature release in an acidic environment (e.g., after exposure to an acidic environment for up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 150 minutes, up to about 12 0 minutes, up to about 105 minutes, up to about 90 minutes, up to about 75 minutes, up to about 60 minutes, up to about 45 minutes, up to about 30 minutes, up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes). For example, after exposure to an acidic environment (e.g., exposure to an acidic environment for up to about 150 minutes, up to about 120 minutes,

[0098] up to about 105 minutes, up to about 90 minutes, up to about 75 minutes, up to about 60 minutes, up to about 45 minutes, up to about 3 0 minutes, up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes), the amount of filler material released from cured capsules that exhibits some premature release can be up to about 5 wt%, up to about 4 wt%, up to about 3 wt%, up to about 2 wt%, up to about 1 wt %, or 0% of the total weight of the filler material in the capsule. For comparison, without curing, in an acidic environment (e.g., after exposure to an acidic environment for up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 150 minutes, up to about 120 minutes, up to about 105 minutes, up to about

[0099] 90 minutes, up to about 75 minutes, up to about 60 minutes, up to about 45 minutes, up to about 30 minutes, up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes of exposure), the amount of filler material released from capsules (having the same composition ) that exhibit premature release is more than about 1 wt%, more than about 2 wt%, more than about 3 wt%, more than about 4 wt%, more than about 5 wt%, more than about 6 wt%, more than about 7 wt%, based on the total weight of the filler material in the capsules. ​Over approximately 8 wt%, over approximately 9 wt%, over approximately 10 wt%, over approximately 15 wt%, or over approximately 20 wt% It is possible.

[0100] In certain embodiments, the pH-dependent shell composition described herein is used in an acidic environment (for example). If necessary, a gastric environment or simulated gastric environment, for example, simulated gastric juice, containing pepsin (0.1N) as needed. In HCl, for at least about 10 minutes, at least about 15 minutes, at least about 30 minutes, At least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, It remains intact for at least about 5 hours, but the colon environment (or Panclear if necessary) In a simulated environment such as a pH 6.8 buffer medium containing tin, relative to the total weight of the packing material At least approximately 50 wt%, at least approximately 60 wt%, at least approximately 70 wt%, and at least Also about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, or at least about 98 wt% t% of the filler material after at least approximately 10 minutes, at least approximately 15 minutes, and at least approximately 20 minutes. , at least approximately 25 minutes later, at least approximately 30 minutes later, at least approximately 35 minutes later, at least approximately After 40 minutes, or at approximately 10, 15, 20, 25, or 30 minutes. From there, it takes approximately 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 75 minutes, and more. (or within approximately 90 minutes, or any single value or subrange within that time) Robust delayed-release softgel capsules released in such a colon or simulated colon environment. To produce.

[0101] 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) Plasticizers (e.g., glycerin, sorbitol, and combinations thereof), as needed (e) containing stabilizers and / or binders (e.g., gellan gum) accordingly. The quantity and wt:wt ratio may follow any of the values ​​or ranges mentioned above.

[0102] In one embodiment, the pH-dependent shell composition is (a) gelatin, (b) dextrose (c) pH-dependent polymers (e.g., pectin such as low-methoxypectin), (d) Plasticizers (e.g., glycerin, sorbitol, gellan gum, and combinations thereof), (e) Stabilizers and / or binders (e.g., gellan gum) may be removed as needed from the essence. The amounts of these components and the wt:wt ratio should be within the values ​​or ranges listed above. It's okay to do that.

[0103] 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) Plasticizers (e.g., glycerin, sorbitol, gellan gum, and combinations thereof), (e) Stabilizers and / or binders (e.g., gellan gum) as needed. The amounts of these components and the wt:wt ratios follow either of the values ​​or ranges mentioned above. That's fine.

[0104] In one embodiment, the pH-dependent shell composition is (a) about 30 wt% to about 85 wt%, 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 gelatin in an amount of about 45 wt% to about 75 wt%, or about 50 wt% to about 70 wt% by weight, (b) dextrose in an amount of about 0.01 wt% to about 4 wt%, or about 0.1 wt% to about 3 wt%, about 0.2 w t% to about 2 wt%, or about 0.01 wt% to about 0.1 wt%, or about 0.05 wt% to about 0.5 wt%, or about 0.1 wt% to about 0.2 wt%, or about 0.15 wt% to about 0.25 wt%, or about 0.2 wt% to about 0.4 wt%, (c) a pH-dependent polymer in an amount of about 2 wt% to about 20 wt%, about 3 wt% to about 15 wt%, about 7 wt% to about 15 wt%, about 3 wt% to about 5.5 wt%, or about 7 wt% to about 12 wt% (e.g. pectin such as low methoxy pectin), (d) a plasticizer in an amount of about 15 wt% to about 45 wt%, about 15 w t% to about 40 wt%, about 20 wt% to about 35 wt%, or about 25 wt% to about 30 wt% and, optionally, (e) a stabilizer and / or binder (for example, about 0.05 wt% to about 5 wt%, about 0.1 wt% to about 3 wt%, or about 0.2 wt% to about 2 wt% of gellan gum) comprising the same. All wt% are based on the total weight of the dry pH-dependent shell composition.

[0105] In one embodiment, the pH-dependent shell composition comprises: (a) gelatin in an amount of about 30 wt% to about 85 wt%, about 30 wt% to about 75 wt%, about 30 wt% to about 65 wt%, about 30 wt% to about 55 wt %, about 30 wt% to about 40 wt%, about 40 wt% to about 80 wt%, about 45 wt% to about 65 wt%, about 45 wt% to about 75 wt%, or about 50 wt% to about 70 wt% gelatin, (b) about 0.01 wt% to about 4 wt%, or about 0.1 wt% to about 3 wt%, or about 0 .2 wt% to about 2 wt%, or about 0.01 wt% to about 0.1 wt%, or about 0.05 wt% to approximately 0.5 wt%, or approximately 0.1 wt% to approximately 0.2 wt%, or approximately 0.15 wt% t% to approximately 0.25 wt%, or approximately 0.2 wt% to approximately 0.4 wt% of dextrose, ( c) About 2wt% to about 20wt%, about 3wt% to about 15wt%, about 7wt% to about 15wt% , or approximately 3 wt% to 5.5 wt%, or approximately 7 wt% to 12 wt% pH-dependent polymer (e.g., pectin such as low-methoxypectin), (d) approximately 15 wt% to approximately 45 wt %, approximately 15 wt% to 40 wt%, approximately 20 wt% to 35 wt%, or approximately 25 wt% Approximately 30 wt% plasticizer, and (e) approximately 0.05 wt% to approximately 5 wt%, as needed. 0.1 wt% to approximately 3 wt%, or approximately 0.2 wt% to approximately 2 wt%, of stabilizers and / or Essentially consists of a binder (e.g., gellan gum). All wt% is dry pH-dependent shell compound. Based on the total weight of the finished product.

[0106] In one embodiment, the pH-dependent shell composition is (a) about 30 wt% to about 85 wt%, 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 45wt% to 75wt%, or approximately 50wt% to 70wt% of gelatin, (b) Approximately 0.01 wt% to approximately 4 wt%, or approximately 0.1 wt% to approximately 3 wt%, or approximately 0 0.2 wt% to approximately 2 wt%, or approximately 0.01 wt% to approximately 0.1 wt%, or approximately 0.05 wt% to approximately 0.5 wt%, or approximately 0.1 wt% to approximately 0.2 wt%, or approximately 0.15 wt% t% to approximately 0.25 wt%, or approximately 0.2 wt% to approximately 0.4 wt% of dextrose, ( c) About 2wt% to about 20wt%, about 3wt% to about 15wt%, about 7wt% to about 15wt% , or approximately 3 wt% to 5.5 wt%, or approximately 7 wt% to 12 wt% pH-dependent polymer (e.g., pectin such as low-methoxypectin), (d) approximately 15 wt% to approximately 45 wt %, approximately 15 wt% to 40 wt%, approximately 20 wt% to 35 wt%, or approximately 25 wt% Approximately 30 wt% plasticizer, and (e) approximately 0.05 wt% to approximately 5 wt%, as needed. 0.1 wt% to approximately 3 wt%, or approximately 0.2 wt% to approximately 2 wt%, of stabilizers and / or It consists of a binder (e.g., gellan gum). All wt% is the total wt% of the dry pH-dependent shell composition. Based on weight. [Examples]

[0107] 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.

[0108] [Example 1] Effect of dextrose concentration on the production of the composition pH-dependent shell compositions containing dextrose at various concentrations were prepared, and the manufacturability of the compositions was improved. The effect of dextrose concentration on this was studied. The pH-dependent shell compositions are shown in Table 1. ru.

[0109] [Table 1] pH-dependent break time at pH 6.8 for various amounts of dextrose in the shell composition. The effects are shown in Table 2.

[0110] [Table 2]

[0111] Dextrose is a reducing sugar, and by cross-linking it with gelatin, it interacts with gelatin. It is thought to be used. When gelatin is crosslinked, its solubility decreases. Dextrose is , Stabilizes pectin softgel capsules in an acidic medium (i.e., reduces leakage) It was shown that dextrose is an activator (vitamin, mineral) released in a buffering medium. The amount of active ingredients (supplements, or pharmaceutical components) and the dissolution time of the active ingredient in the buffer medium also play a role. This may be the case. This is shown with respect to samples 3 and 4 in Table 2 in Example 7 below.

[0112] Table 2 shows that some capsules (e.g., groups 2, 3, and 4) absorb pancreatate into the buffering medium. When adding the phosphate buffer (which is thought to better mimic in vivo conditions), the pH becomes 6.8. This indicates that it did not rupture in liquid for 60 minutes, but the shell composition is shown in Example 7 below. It dissolved in less than 45 minutes.

[0113] [Example 2] Effect of hardening on capsule release properties pH-dependent shell compositions were prepared, and the effect of hardening on the capsule release properties was studied. pH-dependent shell compositions are shown in Table 3.

[0114] [Table 3]

[0115] Existing commercially available products exhibited early release in many capsules, and the premature release of the filler material... The amount increases, and in some cases, nearly 100 wt% of the filler material is released within 10 minutes in an acidic medium. It will be released.

[0116] Coated softgel capsules were intended, but they lasted for a long time (more than about 60 minutes). It did not dissolve in the buffer medium for a long time, in some cases as long as 120 minutes. Prolonged dissolution suggests that the coated softgel capsules are not biocompatible. This was considered to be the case. This, along with the challenges of the two-step manufacturing process, is due to the lack of another coating. This prompted the search for pH-dependent shell compositions for forming delayed-release softgel capsules.

[0117] Using the pH-dependent shell compositions shown in Table 3, the occurrence of premature release and early release Pectin Soft reduces the amount of filling material dispensed to some extent (compared to existing commercially available products). A gel was formed.

[0118] However, as summarized in Table 3 under "Capsules with early release before hardening" Furthermore, a significant proportion of the soft gel capsules in each lot were exposed to an acidic environment (for example, 0 At 0.1N HCl, some premature release of the filler material continued to be observed. Approximately 72 capsules were tested from each lot, and the percentage of capsules exhibiting early release before curing was identified. I evaluated it.

[0119] In a particular embodiment, about 10 wt% of the filler material is a cap that has premature release before curing. Released from the cell. In certain embodiments, more than 10 wt% of the filler material or filler material Less than 10 wt% of the substance was released from capsules with premature release before curing.

[0120] As shown in subsequent examples, curing occurs when premature release occurs, and when premature release occurs, release The amount of filler material dispensed was reduced, and in some cases, premature release was completely eliminated.

[0121] The pectin softgel capsules are cured and then subjected to an acidic environment (e.g., 0.1N HCl). Their stability was enhanced. Pectin softgels are packaged in cartons (for bulk use) or high-density plastics. The contents were packed into polyethylene (HDPE) bottles and placed in an oven preheated to 40°C. Humidity control device It was not used. The only variable between samples was curing time. Lots 1, 2, and 3 The hardening research results are summarized in Table 4 below.

[0122] [Table 4]

[0123] US for two-step enteric lysis applicable to uncoated enteric-coated softgels Dissolution after curing was evaluated according to the P enteric coating test method. Unless otherwise specified, this specification For all dissolution tests throughout the book, the acidic medium, buffer medium, apparatus, and dissolution test conditions are as follows: This was performed according to the two-stage enteric solubility test.

[0124] Using the USP Apparatus II with paddles, at a paddle speed of 50 rpm, 3 The test was performed at 7°C. The acidic step medium was 0.1N HCl. The buffer step medium was pH 6.8. It was a phosphate buffer. (Regarding vitamin and mineral supplements and / or dietary supplements) The enteric-coated capsule remains intact in an acidic medium for at least 60 minutes to pass the first stage. It remains in that state and should rupture within 45 minutes in the buffering medium in order to pass through the second stage. Regarding pharmaceutical products, enteric-coated capsules require less processing in an acidic medium to pass through the first stage. Both remained unharmed for 120 minutes, and were in the buffering medium for 45 minutes to pass through the second phase. It should break internally.

[0125] The soft gel capsules harden in 24 hours, 48 ​​hours, 72 hours, 120 hours, and 168 hours. The evaluation was conducted over 288 hours. However, only data up to 72 hours is presented herein. .

[0126] Table 5 shows the pre-curing and cured state in an acidic medium according to USP enteric coating test standards at the end of 2 hours. This represents the amount of premature release of the filling material from the pectin softgel capsules of subsequent batch 3. The maximum amount of filling material used was 5%. The pectin softgel capsules of Lot 3 were filled The filling material contains fish oil (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) It included (including).

[0127] [Table 5]

[0128] The curing data indicates that curing leads to premature release of the filling material from the pectin capsule in an acidic medium. Capsules and high-quality enteric-coated products that significantly reduce or eliminate enteric coatings and possess robust enteric-coating properties. It demonstrated that this would lead to something.

[0129] All of the pectin softgel capsules tested in Table 5 were 1 in pH 6.8 buffer. Please note that it dissolved within 5 minutes.

[0130] [Example 3] Enteric lysis data in pepsin-containing simulated gastric juice (SGF) The hardened pectin capsules having the gel mass formulation summarized in Table 6A are processed in two steps. For enteric lysis research, SGF containing pepsin (0.1N HCl) (in human in vivo conditions) It was subjected to an intra-intestinal rupture test (to simulate the intestinal rupture).

[0131] [Table 6]

[0132] [Table 7]

[0133] When using an appropriate shell composition, such as a gelatin-to-pectin ratio, pepsin is 0.1 NHCl did not affect the dissolution of pectin shells. (See Tables 6A and 6B) In lots 4 and 5, the gelatin-to-pectin w:w ratio was 7:1. Without being interpreted as a limitation, pectin softgels are robust and enzyme-free pharmacopoeias Unlike the method, even in 0.1N HCl in the presence of pepsin, which represents a bio-related medium, 1 As evidenced by pectin softgel capsules that remain intact for 20 minutes, gelatin The pectin network is thought to be strong enough to withstand the effects of pepsin. However, Therefore, pectin softgel capsules are considered to be sufficiently robust even in vivo.

[0134] [Example 4] Changing the gelatin-to-pectin ratio affects the time it takes for pectin capsules to break down in the intestinal medium. Simulation Pectin softgel capsules were prepared with various gelatin-to-pectin ratios. Various lots The composition is summarized in Table 7B below. As summarized in Table 7A below, it contains pepsin. The rupture time of pectin capsules in SGF (0.1N HCl) is different for various gelatin-pectin-pectin solutions. It changed along with the cuticle ratio.

[0135] [Table 8]

[0136] [Table 9]

[0137] All pectin softgel capsules in Table 7A ruptured within 45 minutes in pH 6.8 buffer. Table 7A shows the rupture time of pectin softgel capsules in an acidic medium compared to gelatin. This demonstrates that it can be modulated by changing the cuticin ratio.

[0138] [Example 5] Effect of softgel ribbon thickness on enteric coating performance of pectin softgel capsules Pectin softgel capsules were prepared with ribbons of various thicknesses. The composition of the dry pH-dependent shell composition of the manufactured lot is summarized in Table 8A below. Approximately 72 SGF (0.1N HC) pectin capsules of various ribbon thicknesses after curing for 96 hours. l) and solubility in pH 6.8 buffer were evaluated. The results are summarized in Table 8B below.

[0139] [Table 10]

[0140] [Table 11]

[0141] The dissolution results shown in Table 8B are for ribo in the range of 0.028 inches to 0.038 inches. The cured pectin softgel capsules, which have a thickness of 1, have been shown to be robust, and medical Meets enteric coating standards for pharmaceutical products and VMS (vitamin, mineral, and supplement) products. This indicates that this is shown. This range of thickness should not be interpreted as limiting. A particular implementation In terms of form, thicker or thinner ribbons may also be used.

[0142] [Example 6] pH-dependent viscosity of aged shell composition Pectin and gelatin interact with each other, resulting in a significant increase in gel mass viscosity, as shown in Figure 1. It forms a network that contributes to the capsule. The interaction between pectin and gelatin is This is thought to contribute to the delayed release characteristics of the gel composition. However, as shown in Figure 1, pH-dependent The viscosity of the gel mass in the shell composition decreases over time. The viscosity and the percentage decrease are shown in Table 9 below. Stop.

[0143] Viscosity in this example and throughout this specification is measured using a rheometer (Thermo Fi). Measurements were taken using HAAKE Rheostress 6000 (SHER) at 60°C. The test was conducted under ambient conditions. The gel mass sample was placed on the sample stage of a rheometer maintained at 60°C. I uploaded it. A 40mm disc vibrated at a frequency of 0.1Hz, resulting in a constant shear rate. Viscosity was obtained by measuring shear stress and shear rate.

[0144] [Table 12]

[0145] As can be seen from Table 9, aging at 60°C for 48 hours, aging at 60°C for 72 hours, and 60 After aging at °C for 96 hours, the viscosity of non-amidated pectin was compared to the viscosity of amidated pectin. The percentage decrease is even smaller.

[0146] The decrease in viscosity is caused by the thermal decomposition of the molecular chain lengths of pectin and gelatin. It is conceivable. Despite this viscosity reduction, the gel mass of the pH-dependent shell composition will remain in place. It maintains a viscosity suitable for manufacturability and machinability even after being held in a 60°C heat environment for 4 days. Furthermore, softgel capsules made with aged gel still exhibit sufficient pH-dependent delayed release. It possesses certain characteristics.

[0147] [Example 7] Effect of dextrose addition on dissolution time in a buffer medium in the presence of pancreatin Pectin softgel capsules containing various dextrose amounts in a pH-dependent shell composition. Dissolution in an acidic medium (0.1N HCl, pH=1.2) and a buffer medium (1% puncture). These pectin soft gel capsules were evaluated in a pH 6.8 phosphate buffer containing atin. Cell dissolution was evaluated according to the two-step enteric lysis test described in Example 2 above. The results were then evaluated. This is summarized in Table 10 below.

[0148] [Table 13]

[0149] Three samples from groups 3 and 4 respectively in Tables 1 and 2 (Example 1) above were evaluated. The averages were summarized. As shown in Table 10, the samples from group 3 (pH-dependent shell composition 0 0.1 wt% dextrose) is 120 in an acidic medium (0.1N HCl, pH 1.2). It remains intact for minutes, and in a buffer medium (pH 6.8 phosphate buffer containing 1% pancreatin) It fractured in approximately 25.7 minutes (average). Sample from group 4 (0.1 in pH-dependent shell composition) (5 wt% dextrose) was incubated in an acidic medium (0.1N HCl, pH 1.2) for 120 minutes. It remained intact throughout, in a buffering medium (pH 6.8 phosphate buffer containing 1% pancreatin). It fractured after approximately 39.0 minutes (on average).

[0150] Therefore, as shown in Table 10, the amount of dextrose in the pH-dependent shell composition is , regulated to achieve targeted lysis / disintegration / breakdown times in a buffering medium containing pancreatin This can happen. This is due to the colon of active ingredients such as vitamins, minerals, supplements, or pharmaceutical components. It is useful for targeting delivery.

[0151] [Example 8] Chemical stability of pectin softgel capsules Table 11 below shows the results of 6 months of storage under ambient conditions, 40°C, and 75% relative humidity (RH). Fish oil encapsulated in a pectin pH-dependent shell composition according to embodiments described herein. This indicates the chemical stability. Acceptable capsules are those with EPA TG ≥ 160 mg / g and DHA TG ≥ 100 mg / g, peroxide ≤ 5 meq O2 / kg, p-anisidine ≤ 20, 0 Dissolution time of more than 120 minutes in 0.1N HCl (pH 1.2), and buffer medium (pH 6.8) The dissolution time in the acid buffer should be a maximum of 45 minutes. The values ​​shown are for a control (fish oil raw material) and a delayed-release soft gel peptide stored under ambient conditions for 6 months. Capsules, as well as delayed-release pectin sorbates stored at 40°C and 75% RH for 6 months. Table 11 summarizes the information about Futogel capsules.

[0152] [Table 14]

[0153] The accelerated stability data (summarized in Table 11) shows that, compared to the raw material, after 6 months (around the surrounding environment) Peroxides and p-anisine (under stress conditions of 40°C and 75%RH) The slight / substantial similarities between gin titers and EPA and DHA assays clearly indicate a common understanding. Furthermore, the pH-tolerant pectin shell composition according to the embodiment uses a filler material (e.g., fish oil components) This demonstrates protection from oxidation.

[0154] [Example 9] Valproic acid pectin softgel capsules Table 12A below shows the results after 3 months of storage at T=0, 40°C, and 75% relative humidity (RH). (T=3 months), and after storage at 40°C and 75%RH for 6 months (T=6 months) Pectin pH-dependent shell composition (dry shell composition) according to the embodiments described herein The dissolution profile of valproic acid enclosed in the gel formulation is summarized in Table 12B. This indicates stability. As demonstrated in Table 12A, the product has been stable for 3 months at 40°C and 75%RH. Dissolution of pH-dependent shell composition after storage and after storage at 40°C and 75%RH for 6 months. The solution profile remains substantially similar to the dissolution profile at T=0.

[0155] [Table 15]

[0156] [Table 16]

[0157] [Example 10] Physical attributes of pectin softgel capsules The delayed-release softgel capsules having the pH-dependent shell composition described herein are as follows: It is robust, as can be proven based on the physical attributes summarized in Table 13.

[0158] [Table 17]

[0159] Shell moisture content was determined by the loss on drying method. 1-2 gram pH-dependent capsule shell assembly. The finished sample was placed in an oven at 105°C for 17 hours. The initial weight of the sample was recorded. After drying in an oven at 0.5°C for 17 hours, the final weight of the sample was recorded. According to the following formula: The percentage of weight loss calculated in this way was defined as shell moisture:

[0160]

number

[0161] Capsule hardness was determined using a hardness tester. A deformation of 2.0 mm in the capsule was observed. The force required in Newtons was defined as capsule hardness.

[0162] Equilibrium relative humidity (%) was defined as the humidity condition under which the capsule maintained a constant total weight. This was determined using an environmental chamber maintained at a constant humidity using a saturated salt solution.

[0163] The bursting strength was determined using a texture analyzer. This pressurizes the capsule until it ruptures. The kilograms required to rupture the capsule We defined burst strength as the force measured in grams.

[0164] [Example 11] Exemplary composition of pectin and gellan gum delayed-release softgel capsules Delayed-release softgel capsules containing a combination of pectin and gellan gum were prepared. The formulations based on the dried shell composition are summarized in Table 14 below.

[0165] [Table 18]

[0166] [Example 12] Stability study of gel mass compositions according to embodiments described herein. The stability of the gel mass compositions according to the embodiments described herein was evaluated at various levels. Three gel blocks containing chistrose were prepared. From the gel blocks, 1000 mg of fish oil was extracted. Softgel capsules were prepared. The softgel capsules were dried and placed in an HDPE bin. The gels were packed and then induced sealed. The formulations for each gel mass (based on the dried shell mass) are shown in Table 15. As shown in Table 15, the base gel formulation is the same, and the amount of dextrose is 0 The values ​​were changed to 0.05 wt%, 0.10 wt%, and 0.15 wt%.

[0167] [Table 19]

[0168] All three batches of softgel capsules packed in HDPE bins were stored at 40°C / 75% relative temperature. The samples were placed in a humidity-stabilized chamber. Samples were removed and tested at 3 and 6 months. During the stability test, the enzyme was added before the start of the buffering phase. Stability and test results are shown in Tables 16A-16. Summarized in D. The results show that it contains dextrose in amounts of approximately 0.05 wt% to 0.10 wt%. This indicates that the formulation maintains stability under accelerated conditions for approximately 6 months. When including , formulations containing 0.15 wt% showed good stability at 6 months under accelerated conditions. Qualitative results were shown.

[0169] [Table 20]

[0170] [Table 21]

[0171] [Table 22]

[0172] [Table 23]

[0173] Table 17 summarizes the stability results of softgel capsules stored under ambient conditions for two years.

[0174] [Table 24]

[0175] As shown in Table 17, formulations containing approximately 0.05 wt% to approximately 0.1 wt% are found at room temperature. The sample showed good stability for two years. In summary, the addition of various amounts of dextrose resulted in... This improves the enteric coating robustness of kucin softgel capsules, which is effective against certain drug molecules in the colon. This made delivery possible.

[0176] 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.

[0177] 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, especially 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.

[0178] 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) Filling material; and (b) pH-dependent shell composition A delayed-release softgel capsule containing, The filling material contains at least one pharmaceutically active ingredient, The pH-dependent shell composition comprises gelatin, pectin, and dextrose. The pH-dependent shell composition dissolves / disintegrates / breaks down in the colonic environment, and is a delayed-release soft gel. Lu Capsule.

2. The delayed-release soft gel according to claim 1, wherein the pH-dependent shell composition further comprises a plasticizer. Lu Capsule.

3. The delayed-release softener according to claim 1 or 2, wherein the pectin is low-methoxyl pectin. Togel Capsule.

4. 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 3, selected from the group. 。

5. The pH-dependent shell composition is approximately 40 wt% of the weight of the dry pH-dependent shell composition. A delayed-release softener according to any one of claims 1 to 4, comprising approximately 80 wt% gelatin. Togel Capsule.

6. 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. Delayed-release soft according to any one of claims 1 to 5, comprising approximately 20 wt% pectin. Gel capsules.

7. The pH-dependent shell composition is approximately 0.01 wt relative to the weight of the dry pH-dependent shell composition. Delay according to any one of claims 1 to 6, comprising t% to about 4 wt% dextrose. Release softgel capsule.

8. The pH-dependent shell composition is approximately 15 wt% of the weight of the dry pH-dependent shell composition. Delayed release soft according to any one of claims 2 to 7, comprising approximately 40 wt% plasticizer. Gel capsules.

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. The plasticizer is selected from the group consisting of glycerin, sorbitol, and combinations thereof. A delayed-release softgel capsule according to any one of claims 2 to 11.

13. The delayed-release softgel capsule according to claim 12, wherein the plasticizer is glycerin.

14. The pH-dependent shell composition is approximately 45 wt relative to the total weight of the dry pH-dependent shell composition. A delayed-release softgel capsule according to claim 5, comprising % to approximately 75 wt% of the gelatin. 。

15. The pH-dependent shell composition is approximately 45 wt relative to the total weight of the dry pH-dependent shell composition. The delayed-release soft gel capsule according to claim 14, comprising % to approximately 65 wt% of the gelatin. Ru.

16. The pH-dependent shell composition is approximately 3 wt% of the total weight of the dry pH-dependent shell composition. A delayed-release softgel capsule according to claim 6, comprising approximately 15 wt% pectin.

17. The pH shell composition is approximately 7 wt% to approximately 15% of the total weight of the dry pH-dependent shell composition. A delayed-release softgel capsule according to claim 16, comprising wt% pectin.

18. The pH-dependent shell composition is approximately 20 wt relative to the total weight of the dry pH-dependent shell composition. The delayed release according to any one of claims 2 to 17, comprising % to approximately 35 wt% of the plasticizer. Softgel capsules.

19. The pH-dependent shell composition is approximately 25 wt relative to the total weight of the dry pH-dependent shell composition. A delayed-release softgel capsule according to claim 18, comprising % to approximately 30 wt% of the plasticizer. 。

20. The pH-dependent shell composition is approximately 0.05% of the total weight of the dry pH-dependent shell composition. The method according to any one of claims 1 to 19, comprising wt% to about 3 wt% dextrose. Delayed-release softgel capsules.

21. The pH-dependent shell composition is approximately 0.1 wt relative to the total weight of the dry pH-dependent shell composition. A delayed-release soft gel capsule according to claim 20, containing t% to about 2 wt% dextrose. cell.

22. If necessary, in pH 6.8 phosphate buffer containing pancreatin, at a rate of 50 rpm Based on dissolution / disintegration tests conducted on the USP Apparatus II using US dollars. And in the intestinal environment, at least about 10 minutes, at least about 15 minutes, at least about 20 After a few minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least Also, after about 40 minutes, or after about 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes From the start, approximately 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, and 75 minutes. Dissolves / disintegrates within approximately 90 minutes, or any one of claims 1 to 21. Delayed-release softgel capsules as described above.

23. Use a paddle at a speed of 50 rpm in 0.1 N HCl containing pepsin, if necessary. Based on dissolution / disintegration tests conducted in USP Apparatus II, throughout the body: at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 Dissolution / disintegration takes at least approximately 3 hours, at least approximately 4 hours, or at least approximately 5 hours. A delayed-release softgel capsule according to any one of claims 1 to 22, which breaks down.

24. The delayed release according to any one of claims 1 to 23, which does not contain additional pH-dependent polymers. Softgel capsules.

25. The pH-dependent shell composition is in the range of approximately 110,000 cPs to approximately 125,000 cPs. A delayed-release softgel capsule having the viscosity of any one of claims 1 to 24 。

26. 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 25, having a gelatin-to-pectin w:w ratio Release softgel capsule.

27. The pH-dependent shell composition has a plasticizer-to-gelatin w:w ratio in the range of approximately 5:1 to approximately 1:

5. A delayed-release softgel capsule according to any one of claims 1 to 26.

28. (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 27 is prepared, comprising: How to do it.

29. Claim 2 further comprises the step of drying the enclosed delayed-release softgel capsule. The method described in 8.

30. Claim 28 or further comprises the step of curing the delayed-release softgel capsule. Method 29.

31. Curing occurs in the range of approximately 25°C to 75°C, approximately 30°C to 60°C, or approximately 35°C to 60°C. The method according to claim 30, which is caused by temperature.

32. The aforementioned curing times are approximately 12 hours to 168 hours, approximately 18 hours to 120 hours, and approximately 24 hours to 7 hours. A claim that occurs over a period of time ranging from 2 hours, approximately 24 hours, approximately 48 hours, or approximately 72 hours. The method described in item 30 or 31.

33. Claims 28 to 32 further include the step of preparing the pH-dependent shell composition. The method described in either of the above terms.

34. The preparation step involves gelatin, dextrose, pectin, and, if necessary, plasticizers. The method according to claim 33, comprising mixing to form a pH-dependent shell composition ribbon. 。

35. 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 34, having the thickness of the following.

36. p A method for adjusting the H-dependent solubility profile, wherein in the pH-dependent shell composition Adjust the amounts of pectin and dextrose and mark in an acidic medium and / or a buffered medium. The method comprising the step of achieving a pH-dependent solubility profile.

37. The claim further includes the step of adjusting the curing time of the delayed-release softgel capsule. The method described in 36.

38. Adjusting the wt:wt ratio of gelatin to pectin in the pH-dependent shell composition. The method according to claim 36 or 37, further comprising a step.

39. The further step includes adjusting the amount of dextrose in the pH-dependent shell composition. The method according to any one of claims 36 to 38.

40. Claim 3 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 6 to 39.

41. A delayed-release softgel capsule according to any one of claims 1 to 27, which requires A method for treating a condition, which includes the step of administering an agent to a subject.

42. (a) Filling material; and (b) 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 filling material contains at least one pharmaceutically active ingredient, The pH-dependent shell composition comprises gelatin, pectin, and dextrose. A method for causing the pH-dependent shell composition to dissolve / disintegrate / break down in the colonic environment.

43. Claims that the filling material includes fish oil, krill oil, garlic oil, or a combination thereof. The method described in 42.

44. The delayed-release softgel capsule is optionally contained in 0.1N HCl containing pepsin. This was performed on the USP Apparatus II using a paddle with a speed of 50 rpm. Based on the dissolution / disintegration test, in an acidic medium for at least about 15 minutes, and at least about 30 minutes, At least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, The method according to claim 42 or 43, which dissolves / disintegrates in at least about 5 hours.

45. The aforementioned delayed-release softgel capsule contains pancreatin as needed, at pH 6.8 USP Apparatus II using a paddle at a speed of 50 rpm in an acid buffer solution Based on dissolution / disintegration tests conducted in the intestinal environment, at least approximately 10 minutes later, At least about 15 minutes later, at least about 20 minutes later, at least about 25 minutes later, at least about 30 minutes later Then, at least approximately 35 minutes later, at least approximately 40 minutes later, or approximately 10 minutes, approximately 15 minutes, approximately 2 0 minutes, approximately 25 minutes, or approximately 30 minutes, then approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 5 It will dissolve / disintegrate within 0 minutes, approximately 55 minutes, approximately 60 minutes, approximately 75 minutes, or approximately 90 minutes. The method according to any one of claims 42 to 44.

45. The delay according to any one of claims 1 to 27, further comprising a conventional pH-dependent polymer. Release softgel capsule.

46. Any of claims 1 to 27 that are substantially free of or do not contain conventional pH-dependent polymers Delayed-release softgel capsules as described in item one.

47. (a) Filling material; and (b) pH-dependent shell composition A delayed-release softgel capsule containing, The filling material contains at least one pharmaceutically active ingredient, The pH-dependent shell composition comprises gelatin, a pH-dependent polymer, and dextrose. 、 The pH-dependent shell composition dissolves / disintegrates / breaks down in the colonic environment, and is a delayed-release soft gel. Lu Capsule.

48. (a) Filling material; and (b) pH-dependent shell composition The drug is delivered to the patient's colon, comprising the step of orally administering a delayed-release softgel capsule containing the drug. A method of delivery, The filling material contains at least one pharmaceutically active ingredient, The pH-dependent shell composition comprises gelatin, a pH-dependent polymer, and dextrose. ,method.

49. The method according to claim 48, wherein at least 80% of the pharmaceutically active ingredient is delivered to the colon. 。

50. The method according to claim 48, wherein at least 85% of the pharmaceutically active ingredient is delivered to the colon. 。

51. The method according to claim 48, wherein at least 90% of the pharmaceutically active ingredient is delivered to the colon. 。

52. The method according to claim 48, wherein at least 95% of the pharmaceutically active ingredient is delivered to the colon. 。

53. The method according to claim 48, wherein at least 99% of the pharmaceutically active ingredient is delivered to the colon. 。

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