Soft gel capsule

Abstract

To provide a soft gel capsule that maintains integrity with high liquid content.SOLUTION: Disclosed is a softgel capsule comprising (a) a fill material and (b) a shell composition, wherein the fill material comprises at least 10% of a liquid medium and the shell composition comprises gelatin and a pH-dependent polymer that solubilizes at a pH of less than about 6.0.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a softgel capsule, wherein the gelatin-based shell composition has a high liquid content. A softgel capsule can encapsulate a fill composition having a content (e.g., water). Regarding. [Background technology]

[0002] Soft capsules, especially soft gelatin capsules (or soft gel capsules), are difficult to swallow. It is easy to incorporate and does not require flavoring to mask any unpleasant taste of the active agent. and provides a dosage form that is more readily accepted by patients. It also offers the possibility of improving the bioavailability of pharmaceuticals. For example, gelatin As soon as the shell is broken, the active ingredient can be rapidly released in liquid form.

[0003] Softgels contain a liquid medium in a fill material that suspends or solubilizes the active agent, and the amount and selection of the liquid medium. Many of these vehicles solubilize the softgels during storage. If acceptable media exceed a threshold amount, they may solubilize the softgel. For these reasons, it is possible to provide soft gels that are acceptable for a variety of active pharmaceutical ingredients. There are limits to what can be done.

[0004] Similarly, in the cosmetics industry, higher concentrations are required for lotions and creams for topical application. There are certain fill formulations that require a higher percentage of water. By making it possible to encapsulate the above, the soft gels have become a popular choice in the cosmetics industry. This is likely to open up a wider range of applications for the

[0005] Thus, an improved softener is provided that can be used to incorporate a variety of filler materials. Togel is needed now. Summary of the Invention

[0006] An object of certain embodiments of the present invention is to provide a soft, To provide a gel capsule.

[0007] Another embodiment of the present invention is directed to the softgel capsules disclosed herein. and (ii) providing a method for treating a disease or condition (e.g., thyroid dysfunction) caused by .

[0008] Another object of the present invention is to provide a method for treating a pulmonary arthritis with the softgels disclosed herein. The present invention provides a method for packaging and distributing cosmetic formulations.

[0009] An object of a further embodiment of the present invention is to provide a softgel capsule as disclosed herein. A method for preparing a cell is provided.

[0010] One or more of the above objectives and others can be achieved in certain embodiments by providing a composition comprising: (a) a filler material; and (b) filling a softgel capsule comprising the shell composition according to the present invention. The filler material can be water, polyol, glycol, alcohol or a combination thereof. and the shell composition comprises at least 10% of a liquid medium selected from gelatin and about 6. The polymers include pH-dependent polymers that are solubilized at a pH below 0.

[0011] In another embodiment, the present invention provides a method for administering the softgel capsules disclosed herein. and treating a disease or condition (e.g., by providing thyroid replacement therapy), including administering The present invention relates to a method for treating

[0012] In a further embodiment, the present invention provides a softgel capsule as disclosed herein. A process for preparing a fill material having at least 10% liquid medium. and a pH-dependent process for solubilizing the filler material at a pH below about 6.0 with gelatin. and encapsulating the polymer with a shell composition comprising a polymer. do. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention provides a softgel capsule that can encapsulate a wide variety of fill compositions. The soft gel is a gelatin shell that is used to encapsulate the There are limitations regarding the amount of various hydrophilic solvents that can be used to dissolve a particular hydrophilic API. Use solvents such as water, glycerin, and propylene glycol for solubilization These limitations make it difficult to develop softgel-filled formulations for these compounds. It is difficult to develop gelatin and the pH-dependent By developing a gelatin shell containing a polymer, the fill composition to be encapsulated can be Improved softgels are provided that can accommodate a broader range of substances, APIs and excipients. can be.

[0014] Similarly, in the cosmetics industry, higher concentrations are required for lotions and creams for topical application. There are certain fill formulations that require a high percentage of water. Higher concentrations of water or glycerin, polyethylene glycol and ethanol Soft gels can be used to encapsulate other liquid media, and in the cosmetics industry , which is likely to open up a wider range of applications for softgels.

[0015] Additionally, typical softgel capsules contain extremely acidic and basic pHs. For example, a fill composition and / or active agent having a pH of 2.5 cannot be included. Filling formulations that do this can hydrolyze the gelatin (leading to leakage). Filler materials with a higher pH may have a tanning effect on the gelatin. The coating process involves cross-linking the gelatin, which hardens the shell. It becomes insoluble in water and is resistant to digestion by the enzymes of the gastrointestinal tract: trypsin and chymotrypsin. In some embodiments, the softgel has a pH greater than about 4 but does not dissolve or or does not interact with it (e.g., to prevent leakage and / or release of the fill compound). ), so that the softgel dissolves properly in the digestive tract (e.g., It is desirable to encapsulate the fill formulation so that it can be delivered to the colon before it reaches the large intestine. Therefore, softgels may contain more than about 4, more than about 5, more than about 6, more than about 7, more than about 8, more than about 9, or between about 4 and Approximately 14, approximately 4 to approximately 6, approximately 5 to approximately 7, approximately 6 to approximately 8, approximately 7 to approximately 9, approximately 8 to approximately 10, approximately 9 to approximately 1 1, about 10 to about 12, about 11 to about 13, about 12 to about 14, about 10 to about 14, about 10 to about 1 3, a pH of about 10 to about 12, or any individual pH, or subrange within these ranges The fill compound can be used to encapsulate the active agent and / or the fill formulation.

[0016] As used herein, the term "pH dependent" means that dissolution or disintegration occurs, e.g., at least does not occur or is substantially not generated in a basic environment for a period of at least about 1 hour is used to refer to the resistance of a material to dissolution or disintegration. Some embodiments may prefer biological, artificial, or simulated gastric fluid over biological, artificial, or simulated intestinal fluid. As used herein, "a pharmaceutically active ingredient" refers to a shell composition that dissolves in a pH-dependent manner. " or "active pharmaceutical ingredient (API)" means any substance or compound that is used in the diagnosis, cure, mitigation, treatment, or prevention of a condition. The term "condition" or "condition" refers to a drug or compound that can be used to treat a condition. "conditions" refers to any condition that can be treated or prevented by administration to a subject of an effective amount of an active agent. These include, but are not limited to, medical conditions that can benefit from softgel capsules. Steady state includes thyroid replacement, such as levothyroxine or a pharmaceutically acceptable salt thereof. Capsules can include, but are not limited to, capsules.

[0017] As used herein, the term "active ingredient" refers to any ingredient approved by a government agency for that purpose. Any substance, whether approved or not, that is not capable of producing the therapeutic, preventative, or other intended effect This term, in reference to a specific drug, refers to any substance for which it is intended. and all pharmaceutically acceptable salts, solvates and crystalline forms thereof, including salts, solvates and and crystalline forms are pharmaceutically active.

[0018] Any pharmaceutically active ingredient, including both water-soluble and poorly water-soluble ingredients, can be used in the present invention. Suitable pharmaceutical active ingredients that may be used for the purposes of the invention include, without limitation, analgesics and anti-inflammatory drugs. Anti-inflammatory, antacid, anthelmintic, antiarrhythmic, antibacterial, anticoagulant, antidepressant, antidiabetic, antidiarrheal , antiepileptic, antifungal, antigout, antihypertensive, antimalarial, antimigraine, antimuscarinic Antiprotozoal drugs, anti-rheumatic drugs, antithyroid drugs, antiviral drugs anti-anxiety drugs, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropes, Tychosteroids, cough suppressants, cytotoxics, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, lipid control agents, local anesthetics, neuromuscular agents , nitrates and antianginal agents, nutritional supplements, opioid analgesics, oral vaccines, proteins, peptide and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and This includes combinations of:

[0019] In some embodiments, the active pharmaceutical ingredient may include, without limitation, dabigatran, dronedarone, tika Grel, iloperidone, ivacaftor, midostaurin, asimadoline, beclometha Zon, Apremilast, Sapacitabine, Linsitinib, Abiraterone, Vitamin D analogues (e.g., calcifediol, calcitriol, paricalcitol, doxercalcium ferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib, sib), tacrolimus, testosterone, lubiprostone, and their pharmaceutically acceptable The compound may be selected from the group consisting of: a hydroxybenzoate, ...

[0020] In certain embodiments, the active ingredient is a thyroid replacement, e.g., levothyroxine (T4 ), liothyronine (T3), or levothyroxine sodium and liothyronine sodium In certain embodiments, the softgel is and levothyroxine sodium in an amount of 0.01 mg to about 0.5 mg. This soft gel contains levothyroxine sodium at 0.013 mg, 0.025 mg, 0.05mg, 0.075mg, 0.088mg, 0.1mg, 0.112mg, 0.1 Available in amounts of 25mg, 0.137mg, 0.15mg, 0.175mg or 0.2mg .

[0021] In some embodiments, the lipid in the dosage form may be, without limitation, almond oil, argan oil, avocado oil, or the like. Corn oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter , palm oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp Oil, hydroxylated lecithin, lecithin, flaxseed oil, macadamia oil, mango oil, manila oil, mon Gongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla Oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower Na oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, walnut oil, and melon seed Other oils and fats may be selected from the group consisting of, but not limited to, fish oil (omega-3), krill oil, animal or vegetable fats, e.g., in their hardened form, free fatty acids and C8-, C10-, C12-, C14-, C16-, C18-, C20- and Monoglycerides, diglycerides, and triglycerides containing C22-fatty acids, and It may include combinations thereof.

[0022] According to certain embodiments, the active agent may be, but is not limited to, a statin (e.g. , lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin , rosuvastatin, and pitavastatin), fibrates (e.g., clofibrate , ciprofibrate, bezafibrate, fenofibrate, and gemfibrozine niacin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, and and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, of the foregoing. Lipid lowering agents, including mixtures of any of these, may be included.

[0023] Suitable nutraceutical active agents include, but are not limited to, 5-hydroxytryptophan. Acetyl L-Carnitine, Alpha Lipoic Acid, Alpha Ketoglutaric Acid, Beeswax Ingredients: betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan , choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, Cyanocobalamin (Vitamin 812), Dimethylaminoethanol, Fumaric Acid, Dioxide Germanium, Glandular Products, Glucosamine HCl, Glucosamine Sulfate, Hydroxymethyl Lactic Acid, L-Carnitine, Liver Products, Malic Acid, Malic Anhydride Lutose, mannose (d-mannose), methylsulfonylmethane, phytosterol , picolinic acid, pyruvic acid, red yeast extract, S-adenosylmethionine, selenium yeast, May contain shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0024] Suitable nutritional supplements include vitamins, minerals, fiber, fatty acids, amino acids, The composition may comprise a nutrient-rich extract, ...

[0025] Suitable vitamin active agents may include, but are not limited to, ascorbic acid ( Vitamin C), Vitamin B, Biotin, Fat-soluble Vitamins, Folic Acid, Hydroxycitric Acid, Inositol, 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 oil-soluble vitamins.

[0026] Suitable herbal supplement active agents may include, but are not limited to: Arni Mosquito, bilberry, black cohosh, cat's claw, chamomile, echinacea, pine Night primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginkgo (gi nkgo biloba), ginseng, goldenrod, hawthorn, kava kava, licorice Coral, milk thistle, plantain, Indian jabboku, senna, soybean, St. John's wort, Saw palmetto, turmeric, valerian.

[0027] Mineral activators may include, but are not limited to: boron, calcium, potassium, Pre-treated minerals, chloride, chromium, coated minerals, cobalt, copper, mud Mite, iodine, iron, magnesium, manganese, mineral premix, mineral products, Molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvate Salt, zinc, and other minerals.

[0028] Examples of other possible active agents include, but are not limited to, antihistamines (e.g., ranitidine, thiamin ... diphenhydramine, dimenhydrinate, diphenhydramine, chlorpheniramine and dextromethorphan flupheniramine maleate), nonsteroidal anti-inflammatory drugs (e.g., aspirin, celecoxib Sib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, Fenoprofen, flubufen, indoprofen, pyroprofen, Luprofen, Oxaprozin, Pramoprofen, Muroprofen, Trioxaprofen phen, suprofen, aminoprofen, fluprofen, buclofenac, indomethacin sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fenthiazol clofenamic acid, clidanac, oxypinac, meclofenamic acid, flufenamic acid, niflumic acid, thorax Fenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam Cam, aceclofenac, aloxipirin, azapropazone, benorilate, bromfe Nacl, Carprofen, Choline Magnesium Salicylate, Diflunisal, Etodolac, E Tricoxib, faislamine, fenbufen, fenoprofen, Ibuprofen, indomethacin, ketoprofen, ketorolac, Lunoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, salicylic acid Methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxytocin Phenbutazone, parecoxib, phenylbutazone, salicylate, sulindac, Sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, and their pharmaceutical acceptable salts and mixtures thereof) and acetaminophen, antiemetics (e.g., methicillin-resistant toclopramide, methylnaltrexone), antiepileptic drugs (e.g., phenyloin, mepramine, thiazolam, ... lutiazem and nicardipine), antitussives and expectorants (e.g., codeine phosphate), antihistamines Asthma medications (e.g., theophylline), antacids, antispasmodics (e.g., atropine, scopolamine) , antidiabetic drugs (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluthia) zide), antihypertensive drugs (e.g., propranolol, clonidine), antihypertensive drugs (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline, Icrin), anti-hemorrhoidal drugs, hypnotics, psychotropic drugs, antidiarrheals, mucolytics, sedatives, decongestants (e.g. (e.g., pseudoephedrine), laxatives, vitamins, stimulants (e.g., phenylpropanolamine and cannabinoids, and pharmaceutically acceptable salts thereof. Includes salts, hydrates, solvates, and prodrugs.

[0029] The active agent may be a benzodiazepine, a barbiturate, a stimulant, or a mixture thereof. The term "benzodiazepine" refers to benzodiazepines, which are drugs that can depress the central nervous system. It refers to drugs that are derivatives of benzodiazepines and benzodiazepines. including but not limited to alprazolam, bromazepam, chlordiazepoxide, clorazepate , diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, Trazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs and mixtures thereof. Benzodiazepine antagonists that can be used as active agents include, but are not limited to: However, flumazenil and its pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof Includes:

[0030] The term "barbiturate" refers to barbituric acid (2,4,6-trioxohexahydro These include but are not limited to barbiturates. However, amobarbital, aprobarbital, butabarbital, butalbital, Methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital secobarbital, secobarbital and their pharmaceutically acceptable salts, hydrates and solvates Barbiturate amines that may be used as active agents include compounds, prodrugs, and mixtures thereof. Agonists include, but are not limited to, amphetamines and their pharmaceutically acceptable derivatives. This includes salts, hydrates, solvates and mixtures thereof.

[0031] The term "stimulant" includes, but is not limited to, amphetamines, e.g., dextromethorphan Amphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidamine Dates, and pharmaceutically acceptable salts, hydrates, and solvates and mixtures thereof Stimulant antagonists that may be used as active agents include, but are not limited to: Benzodiazepines and their pharmaceutically acceptable salts, hydrates, solvates and mixtures Includes:

[0032] Dosage forms according to the present disclosure include various active agents and their pharmaceutically acceptable salts. Environmentally acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, salts, sulfates, phosphates, etc.; organic acid salts, for example, formates, acetates, trifluoroacetates, maleates, tartrates, etc.; sulfonates, for example, methanesulfonates, benzenesulfonates, etc. sulfonates, p-toluenesulfonates, etc.; amino acid salts, e.g., alginates, ascorbic acids, Paragic acid salts, glutamic acid salts, etc., and metal salts, for example, sodium salts, potassium salts cesium salts, etc.; alkaline earth metals, for example, calcium salts, magnesium salts, etc.; Organic amine salts, for example, triethylamine salts, pyridine salts, picoline salts, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylene These include benzodiamine salts.

[0033] In some embodiments, the active agent (or a filler material containing the active agent dissolved therein) ) has a pH greater than about 4. In one or more embodiments, the active agent (or The pH of the filler material (containing the dissolved active agent) is greater than about 4, greater than about 5, greater than about 6, greater than about 7, More than about 8, more than about 9, or about 4 to about 14, about 4 to about 6, about 5 to about 7, about 6 to about 8, about 7 to about 9, about 8 to about 10, about 9 to about 11, about 10 to about 12, about 11 to about 13, about 12 to about 14, about 10 to about 14, about 10 to about 13, about 10 to about 12, or any individual pH, or is a subrange within these ranges.

[0034] As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount of a compound or compound that is effective to provide the desired treatment. It refers to the amount of an active agent or the rate at which it is administered that is required to produce a result.

[0035] As used herein, a "shell" or "shell composition" refers to a material that encapsulates a filler material. This refers to the shell of the softgel capsule.

[0036] As used herein, "free or substantially free" means less than about 1 wt.% , less than about 0.5 wt%, less than about 0.25 wt%, less than about 0.1 wt%, about 0.05 wt% "compositions containing less than about 0.01 wt.%, or 0 wt.% of said component"

[0037] All references to wt % throughout this specification and claims are to the weight of the total composition. It refers to the weight of an ingredient in relation to its mass and may also be expressed as w / w.

[0038] As used herein, "fill material" or "fill" refers to a pH-dependent capsule shell. It refers to a composition encapsulated by a capsule, optionally containing at least one pharmaceutically active ingredient. Has.

[0039] As used herein, "about" refers to any value within a variance of ±10%. Thus, "about 10" includes 9 to 11. As used herein, "one (a)," " "An" or "the" means one or more unless otherwise specified Thus, for example, reference to "an excipient" refers to a single excipient as well as two or more excipients. Mixtures of different excipients are also included.

[0040] Unless otherwise indicated herein, the recitation of ranges of values ​​herein represents the amount of any value within the range. are only intended to serve as a shorthand way of referring individually to each separate value. and each separate value is incorporated herein as if individually recited herein. Unless otherwise indicated herein or clearly contradicted by context, All methods described herein may be performed in any suitable order.

[0041] The use of any and all examples or exemplary language (e.g., "such as") provided herein The use is intended merely to illustrate certain materials and methods and is not limited in scope. The language in this specification does not impose any restrictions on the disclosure of any unclaimed element. It should not be construed as indicating a requirement to practice the method.

[0042] In certain embodiments, the present invention provides a method for preparing a polymeric composite comprising: (a) a filler material; and (b) a shell composition. , soft gel capsules, wherein the fill material is water, polyol, glycol or the like. and the shell composition comprises at least 10% of a liquid medium selected from the combination of gelatin, and a pH-dependent polymer that is solubilized at a pH of less than about 6.0. Targets a cell.

[0043] The softgel capsules contain an active agent dissolved or suspended in a liquid medium. It may be included as needed.

[0044] In certain embodiments, the pH dependent polymer has a pH of less than about 5.5, less than about 5.0, less than about 4. It solubilizes at a pH below 5 or below about 4.0.

[0045] In certain embodiments, the pH dependent polymer is an acrylic polymer or a cellulose polymer. It's Rimmer.

[0046] In certain embodiments, the pH-dependent polymer is an amino methacrylate copolymer, such as It is an acrylic polymer.

[0047] In certain embodiments, the shell composition comprises from about 1% to about 60% of a pH-dependent polymer; About 5% to about 50%, about 10% to about 40%, or about 15% to about 35% (w / w) .

[0048] In certain embodiments, the shell composition contains between about 5% and about 75%, about 10% gelatin. about 60%, about 15% to about 50%, or about 20% to about 40% (w / w).

[0049] In certain embodiments, the shell composition comprises an organic acid, such as oxalic acid, malonic acid, Succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, phthalic acid, isophthalic acid, Terephthalic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, cinnamic acid, lactic acid, benzoic acid, In certain embodiments, the composition further comprises a solubilizing agent, such as licylic acid, gallic acid, or toluic acid. , the organic acid is lactic acid.

[0050] In certain embodiments, the shell composition comprises from about 0.0001% to about 1% of a solubilizing agent; Contains about 0.001% to about 0.5%, or about 0.005%, or about 0.1% (w / w) nothing.

[0051] In certain embodiments, the shell composition may contain a plasticizer, for example, from about 0.1 wt % to about 50 wt%, about 5% to about 45%, about 10% to about 40%, or about 15% to about 35% (w / w) further includes.

[0052] In certain embodiments, the plasticizer is glycerol, glycerin, sorbitol, or A combination thereof is selected.

[0053] In certain embodiments, the gelatin is Type A gelatin, Type B gelatin, or the like. The compound is selected from a mixture of these.

[0054] In certain embodiments, the gelatin is fish gelatin, hide gelatin, bone gelatin, or The compound is selected from the group consisting of a mixture thereof.

[0055] In certain embodiments, the liquid medium is water, a polyol, a glycol, an alcohol, or and combinations thereof. The polyol can be glycerol. Glycol The solvent may be polyethylene glycol and the alcohol may be ethanol. can.

[0056] In certain embodiments, the fill composition comprises at least 20% liquid medium, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, in an amount of at least 80%, at least 90%, at least 95% or at least 99% In certain embodiments, the fill composition comprises 5% to 50% of the liquid medium, about 10% to 20% of the liquid medium, and about 10% to 20% of the liquid medium. Contains about 40% or about 15% to about 30%.

[0057] In certain embodiments, the capsules are heated at 50 rpm in a buffer solution of pH 1.2. Based on disintegration tests performed in a USP Apparatus II using paddles In a gastric environment, the duration of administration is less than about 60 minutes, less than about 45 minutes, less than about 30 minutes, less than about 20 minutes, or less than about 1 minute. disintegrates in less than 0 minutes or in less than about 5 minutes.

[0058] In certain embodiments, the capsules are prepared in a volume of 1000 mL at about 37° C.±2° C. Disintegration tests were conducted in a beaker using a basket-rack assembly NT-40H model device. Based on the above, in a basic medium, at least about 1 hour, at least about 2 hours, at least about 3 hours The disintegration occurs in at least about 4 hours or at least about 5 hours.

[0059] Suitable fill materials, optionally including at least one pharmaceutically active ingredient, can be formulated in a manner known in the art. In addition to at least one pharmaceutically active ingredient, suitable fill materials may be prepared according to the following: Additional filler ingredients, such as flavorings, sweeteners, coloring agents and fillers or other pharmaceutically acceptable The pharmaceutical composition may contain excipients or additives such as synthetic dyes and mineral oxides. The appropriate amounts of the active ingredients and pharmaceutically acceptable excipients can be readily determined by one skilled in the art. do.

[0060] In some embodiments, fill materials (with or without an active agent) within a dosage form according to the present disclosure may be used. ) has a pH greater than about 4. For example, the pH of the fill material is greater than about 4, greater than about 5, greater than about 6, or greater than about More than 7, more than about 8, more than about 9, or about 4 to about 14, about 4 to about 6, about 5 to about 7, about 6 to about 8, about 7 to about 9, about 8 to about 10, about 9 to about 11, about 10 to about 12, about 11 to about 13, about 12 to about 14, about 10 to about 14, about 10 to about 13, about 10 to about 12, or any individual pH, or a subrange within these ranges.

[0061] In one embodiment, the gelatin in the pH-dependent shell composition is used alone or in combination. Type A gelatin, Type B gelatin, hide or skin gelatin and / or It may include bone gelatin. In one embodiment, the gelatin is 250 Bloom gelatin. In some embodiments, there is only one type of gelatin. The gelatin is a combination of at least two types of gelatin. In one embodiment, the pH-dependent The amount of gelatin in the shell composition is about 5 wt% to about 90 wt%, about 10 wt% to about 80 wt%. t%, about 20wt% to about 80wt%, about 40wt% to about 80wt%, or about 45wt% ~ about 75 wt%, or about 50 wt% to about 70 wt%.

[0062] In one embodiment, the pH dependent capsule shell composition may include dextrose. In one embodiment, the amount of dextrose in the pH-dependent capsule shell composition is about 0. 0.05 wt% or about 0.01 wt% to about 4 wt%, or about 0.1 wt% or about 0.15 wt% to about 3 wt%, or about 0.15 wt% or about 0.2 wt% to about 2 wt% t%, or about 0.1 wt% to about 0.2 wt%.

[0063] In one embodiment, the plasticizer in the pH-dependent shell composition is glycerol, glycerin Other suitable plasticizers may include, but are not limited to, sorbitol, and combinations thereof. However, sugar alcohol plasticizers, such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol or polyol plasticizers, such as diglycerin, ethylene glycol, diethylene Glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol polyethylene glycol up to 10,000 MW, neopentyl glycol, Pyrene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol , trimethylolpropane, polyether polyol, ethanolamine; and Other exemplary plasticizers may also include, but are not limited to, low molecular weight polymers, oligomers, and mixtures thereof. copolymers, oils, organic small molecules, low molecular weight polyols with aliphatic hydroxyl groups , ester type plasticizer, glycol ether, poly(propylene glycol), multi-bromo block polymer, single block polymer, citrate ester type plasticizer and triacetin Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, Recall, styrene glycol, monopropylene glycol monoisopropyl ether, Propylene glycol monoethyl ether, ethylene glycol monoethyl ether, di Ethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, Ethyl glycolate, dibutyl sebacate, acetyltributyl citrate, tricitric acid Ethyl, Glyceryl Monostearate, Polysorbate 80, Acetyl Triethyl Citrate may include butyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof .

[0064] In one embodiment, the amount of plasticizer in the pH-dependent shell composition is from about 0.1 wt % to about 5 0 wt%, about 15 wt% to about 40 wt%, or about 20 wt% to about 35 wt%, or about It is 25wt% to about 30wt%.

[0065] In one embodiment, the pH dependent shell composition optionally contains an additional agent, e.g. Coloring agents, flavoring agents, sweetening agents, fillers, antioxidants, diluents, pH adjusters or other pharmaceutically acceptable The formulation may contain excipients or additives such as synthetic dyes and mineral oxides.

[0066] Exemplary suitable colorants include, but are not limited to, white, black, yellow, and blue. , green, pink, red, orange, violet, indigo, and brown. In some cases, the color of the dosage form may indicate the contents (e.g., one or more active ingredients) contained therein. It can be shown.

[0067] Exemplary suitable flavoring agents are often, but not limited to, ethanol or water. Extracting a raw material, e.g., a part of animal or plant material, by using a solvent of "Flavor extracts" obtained by extracting essential oils from flowers, fruits, roots, etc., or whole plants; It may contain natural essences obtained by

[0068] Additional exemplary flavoring agents that may be present in the dosage form include, but are not limited to, menthol, Spearmint and cinnamon, as well as coffee beans, are particularly good for oral hygiene. Fruit flavors (e.g., cherry, orange, grape, etc.) used for Other flavorings or fragrances, such as quaternary ammonium bases, and dental and oral It may contain active ingredients used in cleaning. The flavoring effect may be tartaric acid, citric acid, vanillin, etc. Any flavor enhancer may be used to enhance the flavor.

[0069] Exemplary sweeteners include, but are not limited to, one or more artificial sweeteners, one or more The sweetener may comprise a mixture of natural sweeteners or a combination thereof. Cesulfam and its various salts, such as the potassium salt (available as Sunett®) available), alitame, aspartame (NutraSweet® and E qual®), aspartame-acesulfame salt (Twi Available as nsweet®), neohesperidin dihydrochalcone, Gingin dihydrochalcone, dihydrochalcone compound, neotame, sodium cyclamate saccharin and its various salts, e.g., sodium salt (Sweet'N Low (available under the trademark "Stevia"), chloro derivatives of sucrose, e.g., sucralose (available as Kaltame® and Splenda®), Natural sweeteners include, for example, glucose, dextrose, invert sugar, and mogrosides. , Fructose, Sucrose, Glycyrrhizin; Monoammonium Glycyrrhizinate (trademark sold under the name MagnaSweet®); stevia (Stevia rebaudian) a) (stevioside), natural intense sweeteners such as luo han guo, polyols such as sol These include sorbitol, mannitol, xylitol, erythritol, etc.

[0070] In some embodiments, the pH-dependent shell composition and / or the pH-dependent softgel capsule The sample was prepared using a USP Apparatus with paddles at a speed of 50 rpm at pH 1.2. The capsules can be tested in a disintegration test carried out in accordance with the method of Example 1. The capsules can be tested in a disintegration test carried out in accordance with the method of Example 1. disintegrates in less than 5 minutes, less than about 30 minutes, less than about 20 minutes, less than about 10 minutes, or less than about 5 minutes, pH dependent softgel capsules according to embodiments.

[0071] The encapsulation of the fill material can be accomplished in any conventional manner. For example, rotary die encapsulation can be used. It can be used.

[0072] According to one embodiment, the pH dependent softgel capsule comprises: (a) at least one drug (b) preparing a fill material optionally containing a biologically active ingredient; and encapsulating the filler material in a pH-dependent shell composition. The encapsulation process according to step (b) can be carried out using, for example, gelatin, pH-dependent polymers and and optionally a plasticizer to prepare a pH-dependent shell composition. The device may further include a top. [Example]

[0073] Certain embodiments of the present invention will now be demonstrated by reference to the following examples. These examples are disclosed only to illustrate the present invention and in no way limit the scope of the present invention. It should be understood that this should not be construed as an endorsement of the principles set forth herein.

[0074] Water, glycerin, and lactic acid are mixed in a jacket with vacuum sweeping, pressure, and heating capabilities. Add to a container with a cap.

[0075] While sweeping and mixing, add Eudragit E PO( Slowly add Eudragit E PO. The mixture is mixed with sweeping motions until completely dissolved.

[0076] While continuing to mix with the sweep, slowly add the gelatin until a fluffy mass forms. Mix until complete. Stop sweeping. Degas the fluff.

[0077] Once the fluff is formed, the heating unit for the container is set to 70°C. After the material begins to melt, the sweep is turned on at about 15 RPM and mixed under vacuum. After all the acetone has melted, add approximately 2 kg of water to the mix. Mix with the lump of ru.

[0078] After degassing is complete, nitrogen pressure is used to remove the melt from the jacketed vessel to the jacketed Forcefully transfer the mixture into the gel receiver.

[0079] Using this process, two gel melts are prepared. The first gel melt is used to prepare three The species type loading solution was enclosed: Filling solution containing 50% water and 50% PEG 400. The filling material provides good sealing. The filling material was easily encapsulated. The filling material did not dissolve in the gelatin shell. It seems difficult to seal a fill solution containing 0% water. If formed, a poor seal The gelatin shell is then transferred to a conveyor belt or to a basket in a dryer. It seems that somewhere inside it will start to dissolve.

[0080] The second filling solution contained 100% glycerin. A good seal was obtained using an encapsulation machine. Obtained in a vessel.

[0081] The third loading solution was Transcutol. These softgels were well tolerated. They have a good seal and maintain their shape and appearance after being removed from a shallow tray. Ta.

[0082] For the second gel melt, the following filling solution was encapsulated:

[0083] A fill solution containing 99% glycerin and 1% gelatin was encapsulated. A good seal was obtained while the softgel was in place and the softgel had a good appearance.

[0084] The two gel melts prepared had the following formulations: Gel Melt No. 1 Purified water - 31.5% Glycerin - 21.6% Lactic acid - 0.00736% Eudragit E PO - 14.1% Gelatin - 32.8% Gel Melt No. 2 Purified water - 33.4% Glycerin - 17.6% Lactic acid - 0.01% Eudragit E PO - 14.7% Gelatin - 34.3%

Claims

1. (a) a filler material; and (b) Shell Composition A softgel capsule comprising: The filler material is selected from the group consisting of water, polyols, glycols, alcohols, and combinations thereof. at least 10% of a liquid medium selected from the group consisting of The shell composition comprises gelatin and a pH that is solubilized at a pH of less than about 6.

0. A soft gel capsule comprising a dependent polymer.

2. the filler material further comprising an active agent dissolved or suspended in the liquid medium; 10. The softgel capsule of claim 1, wherein the filling comprises a pH greater than about 4.

3. The pH dependent polymer is less than about 5.5, less than about 5.0, less than about 4.5 or less than about 4.0 3. The softgel capsule of claim 1, wherein the softgel capsule is solubilized at a pH below 0.

1.

4. 2. The method of claim 1, wherein the pH-dependent polymer is an acrylic polymer or a cellulose polymer.

1. A soft gel capsule according to claim 1.

5. 5. The softgel capsule of claim 4, wherein the pH-dependent polymer is an acrylic polymer. Lu.

6. 6. The method of claim 5, wherein the acrylic polymer is an amino methacrylate copolymer. Soft gel capsule.

7. the shell composition comprises from about 1% to about 60%, from about 5% to about 50%, of the pH-dependent polymer; 10% to about 40% or about 15% to about 35% (w / w) of the composition of claim 1 Soft gel capsule.

8. The shell composition may comprise from about 5% to about 75%, from about 10% to about 60%, from about 15% to about 75 ...0% to about 60%, from about 2. The soft drink of claim 1, comprising from about 20% to about 40% (w / w) of the soluble fiber. Gel capsule.

9. 10. The softgel capsule of claim 1, wherein the shell composition further comprises a solubilizer.

10. 10. The softgel capsule of claim 9, wherein the solubilizing agent is an organic acid.

11. The organic acid is oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, Maleic acid, phthalic acid, isophthalic acid, terephthalic acid, formic acid, acetic acid, propionic acid, butyric acid , valeric acid, cinnamic acid, lactic acid, benzoic acid, salicylic acid, gallic acid or toluic acid The softgel capsule of claim 10.

12. 12. The softgel capsule of claim 11, wherein the organic acid is lactic acid.

13. The shell composition may contain the solubilizer in an amount of from about 0.0001% to about 1%, from about 0.001% to about Claims 9 to 12, comprising 0.5% or about 0.005% or about 0.1% (w / w) 1. The soft gel capsule according to any one of the preceding claims.

14. 10. The softgel capsule of claim 1, wherein the shell composition further comprises a plasticizer.

15. The shell composition may contain the plasticizer in an amount of from about 5 wt % to about 50 wt %, from about 10% to about 40% or in an amount (w / w) of about 15% to about 35%. Lu.

16. The plasticizer is selected from glycerol, glycerin, sorbitol, or a combination thereof.

16. The softgel capsule of claim 14 or 15, wherein the softgel capsule is selected from the group consisting of:

17. The gelatin is selected from type A gelatin, type B gelatin, or a mixture thereof.

2. The softgel capsule of claim 1,

18. The gelatin is selected from the group consisting of fish gelatin, animal skin gelatin, bone gelatin, and mixtures thereof.

2. The softgel capsule of claim 1, wherein the softgel capsule is selected from the group consisting of:

19. 10. The softgel capsule of claim 1, wherein the liquid medium is water.

20. 10. The softgel capsule of claim 1, wherein the polyol is glycerol.

21. 2. The softgel capsule of claim 1, wherein the glycol is polyethylene glycol. cell.

22. The softgel capsule according to any of the preceding claims, wherein the alcohol is ethanol. Lu.

23. The fill composition may contain at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, 10. The method of claim 1, comprising: Softgel capsules.

24. The fill composition may comprise 5% to 50%, about 10% to about 40%, or about 15% of the liquid medium.

10. The softgel capsule of claim 1, comprising in an amount of from about 30% to about 30%.

25. The capsules were prepared by subjecting the capsules to a pH 1.2 buffer solution using paddles at a speed of 50 rpm in accordance with USP Based on disintegration tests performed in a D. Apparatus II, in the gastric environment, Less than 60 minutes, less than about 45 minutes, less than about 30 minutes, less than about 20 minutes, less than about 10 minutes, or less than about 5 minutes 10. The softgel capsule of claim 1, wherein the softgel capsule disintegrates completely.

26. The capsules are placed in a basket in a 1000 mL beaker at about 37°C ± 2°C. - In a basic medium, based on the disintegration test carried out in the rack assembly NT-40H model apparatus , at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours 10. The release softgel capsule of claim 1, wherein the capsule disintegrates in about 5 hours or at least about 5 hours.

27. 10. The softgel capsule of claim 1, comprising a water-soluble active agent.

28. 10. The softgel of claim 1 comprising levothyroxine or a pharmaceutically acceptable salt thereof. capsule.

29. 10. The softgel capsule of claim 1, wherein the fill material comprises a pH greater than about 4.

30. 29. A method for administering thyroid replacement therapy comprising administering the softgel capsule of claim 28. How to provide.

31. (a) preparing the fill material comprising at least 10% liquid medium; (b) comprising gelatin and a pH-dependent polymer that is solubilized at a pH of less than about 6.

0. encapsulating the filler material with a shell composition; 10. A method for preparing the softgel capsule of claim 1, comprising: