Softgel capsules

Abstract

In certain embodiments, a softgel capsule is disclosed that includes (a) a fill material and (b) a shell composition, wherein the fill material includes at least 10% of a liquid medium, and the shell composition includes gelatin and a pH-dependent polymer that solubilizes at a pH of less than about 6.0.

Description

[Technical Field]

[0001] The present invention relates to softgel capsules in which a gelatin-based shell composition is capable of encapsulating a fill composition having a high liquid content (e.g., water). [Background technology]

[0002] Soft capsules, particularly soft gelatin capsules (or soft gel capsules), are easy to swallow and do not require flavoring to mask any unpleasant taste of the active agent, providing a dosage form that is more readily accepted by patients. Soft gel encapsulation of drugs also offers the potential for improving the bioavailability of pharmaceuticals. For example, the active ingredient can be rapidly released in liquid form as soon as the gelatin shell ruptures.

[0003] Softgels have limitations regarding the amount and choice of liquid vehicle in the fill material that suspends or solubilizes the active agent. Many of these vehicles solubilize the softgel during storage. Other acceptable vehicles may solubilize the softgel if present in amounts above a threshold. This limits the ability to provide acceptable softgels for a variety of active pharmaceutical ingredients.

[0004] Similarly, in the cosmetics industry, there are certain fill formulations that require a higher percentage of water, such as lotions and creams for topical application. The ability to encapsulate higher concentrations of water in the fill would open up a wider range of applications for softgels in the cosmetics industry.

[0005] Therefore, there is currently a need for improved softgels that can be used to incorporate a variety of fill materials. Summary of the Invention

[0006] It is an object of certain embodiments of the present invention to provide a softgel capsule that maintains its integrity with a high liquid content.

[0007] It is an object of another embodiment of the present invention to provide a method of treating a disease or condition (e.g., thyroid dysfunction) with the softgel capsules disclosed herein.

[0008] It is an object of another embodiment of the present invention to provide a method for packaging and distributing the softgel cosmetic formulations disclosed herein.

[0009] It is an object of a further embodiment of the present invention to provide a method for preparing the softgel capsules disclosed herein.

[0010] One or more of the above objects and others can be met, in certain embodiments, by the present invention, which is directed to 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 selected from water, a polyol, a glycol, an alcohol, or a combination thereof; and the shell composition comprises gelatin and a pH-dependent polymer that solubilizes at a pH of less than about 6.0.

[0011] In other embodiments, the present invention is directed to a method of treating a disease or condition (e.g., by providing thyroid replacement therapy) comprising administering the softgel capsules disclosed herein.

[0012] In a further embodiment, the present invention is directed to a process for preparing the softgel capsules disclosed herein, comprising preparing a fill material having at least 10% liquid medium, and encapsulating the fill material with a shell composition comprising gelatin and a pH-dependent polymer that is solubilized at a pH of less than about 6.0. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention advances the current technology by developing a softgel capsule that can encapsulate a wide variety of fill compositions. Softgels are limited in the amount of various hydrophilic solvents that can be encapsulated in the gelatin shell. Solvents such as water, glycerin, and propylene glycol can be used to solubilize certain hydrophilic APIs. These limitations make it difficult to develop softgel fill formulations for these compounds. By developing a gelatin shell containing gelatin and the pH-dependent polymer disclosed herein, an improved softgel is provided that can encapsulate a wider range of fill compositions, APIs, and excipients.

[0014] Similarly, in the cosmetic industry, there are certain fill formulations that require a higher percentage of water, such as lotions and creams for topical application. Thanks to the present invention, softgels can be used to encapsulate higher concentrations of water or other liquid media, such as glycerin, polyethylene glycol, and ethanol, in the fill, which will open up a wider range of applications for softgels in the cosmetic industry.

[0015] Furthermore, typical softgel capsules cannot accommodate fill compositions and / or active agents with extremely acidic or basic pH. For example, a fill formulation with a pH of 2.5 can hydrolyze gelatin (leading to leakage). Similarly, a fill material with a pH higher than 9 can cause a tanning effect on gelatin. The tanning process involves cross-linking of gelatin, which hardens the shell. The shell becomes insoluble in water and resistant to digestion by the enzymes trypsin and chymotrypsin in the gastrointestinal tract. In some embodiments, it is desirable to encapsulate a fill formulation that has a pH greater than about 4 but does not dissolve or interact with the softgel (e.g., to prevent leakage and / or release of the fill formulation), thereby allowing the softgel to dissolve appropriately in the digestive tract (e.g., before the softgel reaches the large intestine). By virtue of the present invention, softgels can be used to encapsulate fill formulations and / or active agents having a pH of greater than about 4, greater than about 5, greater than about 6, greater than about 7, greater than about 8, greater than about 9, or from about 4 to about 14, from about 4 to about 6, from about 5 to about 7, from about 6 to about 8, from about 7 to about 9, from about 8 to about 10, from about 9 to about 11, from about 10 to about 12, from about 11 to about 13, from about 12 to about 14, from about 10 to about 14, from about 10 to about 13, from about 10 to about 12, or any individual pH, or subrange within these ranges.

[0016] As used herein, the term "pH-dependent" refers to the resistance of a substance to dissolution or disintegration, such that dissolution or disintegration does not occur, or is substantially not observed, in a basic environment, for example, for a period of at least about one hour. For example, embodiments described herein include pH-dependent shell compositions that dissolve preferentially in biological, artificial, or simulated gastric fluid compared to biological, artificial, or simulated intestinal fluid. As used herein, "active pharmaceutical ingredient" or "active pharmaceutical ingredient (API)" refers to a drug or compound that can be used in the diagnosis, cure, mitigation, treatment, or prevention of a condition. The term "condition" or "conditions" refers to those medical conditions that can be treated or prevented by administering an effective amount of an active agent to a subject. Exemplary conditions that can benefit from softgel capsules include, but are not limited to, capsules containing thyroid supplements, such as levothyroxine or a pharmaceutically acceptable salt thereof.

[0017] As used herein, the term "active ingredient" refers to any substance intended to produce a therapeutic, preventative, or other intended effect, whether or not approved by a government agency for that purpose. This term, with reference to a particular drug, includes the pharmaceutically active agent and all pharmaceutically acceptable salts, solvates, and crystalline forms thereof, which salts, solvates, and crystalline forms are pharmaceutically active.

[0018] Any pharmaceutically active ingredient, including both water-soluble and poorly water-soluble ones, can be used for the purpose of the present invention.Suitable pharmaceutically active ingredients include, without limitation, analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterial agents, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarials, antimigraine agents, antimuscarinic agents, antineoplastic agents and immunosuppressants, antiprotozoal agents, antirheumatic agents, antithyroid agents, antiviral agents, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, Includes cardiac inotropes, corticosteroids, cough suppressants, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritionals, opioid analgesics, oral vaccines, protein, peptide and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and combinations thereof.

[0019] In some embodiments, the active pharmaceutical ingredient may be selected from the group consisting of, but not limited to, dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurin, asimadoline, beclomethasone, apremilast, sapacitabine, linsitinib, abiraterone, vitamin D analogs (e.g., calcifediol, calcitriol, paricalcitol, doxercalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, pharmaceutically acceptable salts thereof, and combinations thereof.

[0020] In certain embodiments, the active ingredient is a thyroid supplement, such as levothyroxine (T4), liothyronine (T3), or a pharmaceutically acceptable salt thereof, such as levothyroxine sodium and liothyronine sodium. In certain embodiments, the softgel contains levothyroxine sodium in an amount of 0.01 mg to about 0.5 mg. In certain embodiments, the softgel contains levothyroxine sodium in an amount of 0.013 mg, 0.025 mg, 0.05 mg, 0.075 mg, 0.088 mg, 0.1 mg, 0.112 mg, 0.125 mg, 0.137 mg, 0.15 mg, 0.175 mg, or 0.2 mg.

[0021] In some embodiments, the lipid in the dosage form may be selected from the group consisting of, without limitation, almond oil, argan oil, avocado 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, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, walnut oil, and melon seed oil. Other oils and fats may include, but are not limited to, fish oil (omega-3), krill oil, animal or vegetable fats such as their hardened forms, free fatty acids and monoglycerides, diglycerides, and triglycerides containing C8-, C10-, C12-, C14-, C16-, C18-, C20-, and C22-fatty acids, and combinations thereof.

[0022] According to certain embodiments, the active agent may include a lipid-lowering agent, including, but not limited to, statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), fibrates (e.g., clofibrate, ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil), niacin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof, mixtures of any of the foregoing, and the like.

[0023] Suitable dietary supplement active agents may include, but are not limited to, 5-hydroxytryptophan, acetyl L-carnitine, alpha lipoic acid, alpha-ketoglutaric acid, honeybee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin 812), dimethylaminoethanol, fumaric acid, germanium sesquioxide, glandular products, glucosamine HCl, glucosamine sulfate, hydroxymethylbutyrate, immunoglobulins, lactic acid, L-carnitine, liver products, malic acid, maltose anhydrous, mannose (d-mannose), methylsulfonylmethane, phytosterols, picolinic acid, pyruvic acid, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0024] Suitable nutritional supplement active agents may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements or combinations thereof.

[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 ascorbates, mixed tocopherols, niacin (vitamin B3), orotic acid, para-aminobenzoic acid, pantothenate, pantothenic acid (vitamin B5), pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamine (vitamin B1), tocotrienols, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oils and oil-soluble vitamins.

[0026] Suitable herbal supplement active agents may include, but are not limited to, arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginkgo biloba, ginseng, goldenrod, hawthorn, kava kava, licorice, milk thistle, plantain, Indian jasmine, senna, soybean, St. John's wort, saw palmetto, turmeric, and valerian.

[0027] Mineral activators may include, but are not limited to: boron, calcium, chelated minerals, chloride, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvate, zinc, and other minerals.

[0028] Examples of other possible active agents include, but are not limited to, antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), nonsteroidal anti-inflammatory drugs (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, pyroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, sprosulfone ... Phen, aminoprofen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxypinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxipirin, azapropazone, benorilate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, physlamine (f aislamine), fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, pharmaceutically acceptable salts thereof, and mixtures thereof) and acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., phenyloin, meprobumate, and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem, and nicardipine), antitussives and expectorants (e.g., codeine phosphate), antiasthmatics (e.g., theophylline), antacids, antispasmodics (e.g., atropine, scopolamine), antidiabetic drugs (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluthiazide), antihypertensives (e.g., propranolol, clonidine),Antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), anti-hemorrhoids, hypnotics, psychotropic drugs, antidiarrheals, mucolytics, sedatives, decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine), and cannabinoids, as well as pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof.

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

[0030] The term "barbiturate" refers to a sedative-hypnotic drug derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists that can be used as active agents include, but are not limited to, amphetamine, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0031] The term "stimulant" includes, but is not limited to, amphetamines, such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof. Stimulant antagonists that may be used as the active agent include, but are not limited to, benzodiazepines, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0032] The dosage forms according to the present disclosure contain various active agents and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; amino acid salts such as alginate, aspartate, glutamate, etc., and metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

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

[0034] As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount of an active agent, or the rate at which it is administered, necessary to bring about the desired therapeutic result.

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

[0036] As used herein, "free or substantially free" refers to a composition that contains less than about 1 wt%, less than about 0.5 wt%, less than about 0.25 wt%, less than about 0.1 wt%, less than about 0.05 wt%, less than about 0.01 wt%, or 0 wt% of said component.

[0037] All references to wt % throughout this specification and claims refer to the weight of the component in relation to the weight of the total composition, which may also be expressed as w / w.

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

[0039] As used herein, "about" refers to any value within a ±10% variance, so that "about 10" includes 9 to 11. As used herein, "a," "an," or "the" refers to one or more unless otherwise specified. Thus, for example, reference to "an excipient" includes a single excipient as well as mixtures of two or more different excipients, and the like.

[0040] Unless otherwise indicated herein, the recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, with each separate value being incorporated herein as if it were individually recited herein. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order.

[0041] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to clarify certain materials and methods and does not pose a limitation on scope. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods.

[0042] In certain embodiments, the present invention is directed to 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 selected from water, a polyol, a glycol, or a combination thereof, and the shell composition comprises gelatin and a pH-dependent polymer that solubilizes at a pH of less than about 6.0.

[0043] The softgel capsule may optionally contain an active agent dissolved or suspended in a liquid medium.

[0044] In certain embodiments, the pH dependent polymer is solubilized at a pH of less than about 5.5, less than about 5.0, less than about 4.5, or less than about 4.0.

[0045] In certain embodiments, the pH-dependent polymer is an acrylic polymer or a cellulose polymer.

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

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

[0048] In certain embodiments, the shell composition comprises gelatin in an amount (w / w) of about 5% to about 75%, about 10% to about 60%, about 15% to about 50%, or about 20% to about 40%.

[0049] In certain embodiments, the shell composition further comprises a solubilizing agent such as an organic acid, for example, 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. In certain embodiments, the organic acid is lactic acid.

[0050] In certain embodiments, the shell composition comprises a solubilizing agent in an amount (w / w) of about 0.0001% to about 1%, about 0.001% to about 0.5%, or about 0.005% or about 0.1%.

[0051] In certain embodiments, the shell composition further comprises a plasticizer, for example, in an amount (w / w) of about 0.1 wt % to about 50 wt %, about 5% to about 45%, about 10% to about 40%, or about 15% to about 35%.

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

[0053] In certain embodiments, the gelatin is selected from Type A gelatin, Type B gelatin, or a mixture thereof.

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

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

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

[0057] In certain embodiments, the capsule disintegrates in a gastric environment in less than about 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, based on disintegration testing performed in a USP Apparatus II with paddles at a speed of 50 rpm in a pH 1.2 buffer solution.

[0058] In certain embodiments, the capsule disintegrates in 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 in a basic medium, based on a disintegration test performed in a 1000 mL beaker at about 37°C ± 2°C using a basket-rack assembly NT-40H model apparatus.

[0059] Suitable filling material may contain at least one pharmaceutically active ingredient as needed, and may be prepared according to known methods.In addition to at least one pharmaceutically active ingredient, suitable filling material may contain additional filling ingredients, such as flavoring agents, sweeteners, coloring agents, and fillers, or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides.The appropriate amount of pharmaceutically active ingredients and pharmaceutically acceptable excipients may be easily determined by those skilled in the art.

[0060] In some embodiments, the fill material (with or without an active agent) in a dosage form according to the present disclosure 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, greater than about 7, greater than about 8, greater than about 9, or from about 4 to about 14, from about 4 to about 6, from about 5 to about 7, from about 6 to about 8, from about 7 to about 9, from about 8 to about 10, from about 9 to about 11, from about 10 to about 12, from about 11 to about 13, from about 12 to about 14, from about 10 to about 14, from about 10 to about 13, from about 10 to about 12, or any individual pH or subrange within these ranges.

[0061] In one embodiment, the gelatin in the pH-dependent shell composition can include Type A gelatin, Type B gelatin, hide or skin gelatin, and / or bone gelatin, used alone or in combination. In one embodiment, the gelatin is 250 Bloom gelatin. In another embodiment, there is only one type of gelatin. In yet another embodiment, the gelatin is a combination of at least two types of gelatin. In one embodiment, the amount of gelatin in the pH-dependent shell composition is about 5 wt% to about 90 wt%, about 10 wt% to about 80 wt%, about 20 wt% to about 80 wt%, about 40 wt% to about 80 wt%, or about 45 wt% to 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 0.005 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%, or about 0.1 wt% to about 0.2 wt%.

[0063] In one embodiment, the plasticizer in the pH-dependent shell composition may include glycerol, glycerin, sorbitol, and combinations thereof. Other suitable plasticizers may include, but are not limited to, sugar alcohol plasticizers such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers such as diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine; and mixtures thereof. Other exemplary plasticizers may also include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single-block polymers, citrate ester-type plasticizers, and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0064] In one embodiment, the amount of plasticizer in the pH-dependent shell composition is from about 0.1 wt% to about 50 wt%, from about 15 wt% to about 40 wt%, or from about 20 wt% to about 35 wt%, or from about 25 wt% to about 30 wt%.

[0065] In one embodiment, the pH-dependent shell composition may optionally include additional agents, such as colorants, flavoring agents, sweeteners, fillers, antioxidants, diluents, pH adjusters or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides.

[0066] Exemplary suitable colorants may include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, violet, indigo, and brown, etc. In certain embodiments, the color of the dosage form may indicate the contents (e.g., one or more active ingredients) contained therein.

[0067] Exemplary suitable flavoring agents may include, but are not limited to, "flavor extracts," which are obtained by extracting a source, e.g., a part of an animal or plant material, often by using a solvent such as ethanol or water; natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or whole plants.

[0068] Additional exemplary flavoring agents that may be present in the dosage form include, but are not limited to, breath freshening compounds such as menthol, spearmint, and cinnamon, coffee bean, other flavors or fragrances such as fruit flavors (e.g., cherry, orange, grape, etc.), particularly those used for oral hygiene, and actives used in tooth and mouth rinses, such as quaternary ammonium bases. The effect of the flavoring may be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

[0069] Exemplary sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof.Artificial sweeteners include, for example, acesulfame and its various salts, such as potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salt (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trademark MagnaSweet®); stevia (Stevia rebaudiana) (stevioside), natural high-intensity sweeteners such as swingle fruit, polyols such as sorbitol, mannitol, xylitol, erythritol, and the like.

[0070] In some embodiments, the pH-dependent shell composition and / or pH-dependent softgel capsule may be tested in a disintegration test conducted in a USP Apparatus II using paddles at a speed of 50 rpm at pH 1.2. The pH-dependent softgel capsule according to the present embodiments disintegrates in less than about 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.

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

[0072] According to one embodiment, the pH-dependent softgel capsule is prepared by a process comprising the steps of: (a) preparing a fill material optionally comprising at least one pharmaceutically active ingredient; and (b) encapsulating the fill material of step (a) in a pH-dependent shell composition. The encapsulation process according to step (b) may further comprise the substep of preparing the pH-dependent shell composition, for example, by mixing gelatin, a pH-dependent polymer, and optionally a plasticizer. [Example]

[0073] Specific embodiments of the present invention will now be demonstrated by reference to the following examples, which should be understood as being set forth solely for the purpose of illustrating the present invention and should not be construed as limiting the scope of the present invention in any way.

[0074] Water, glycerin, and lactic acid are added to a jacketed vessel equipped with vacuum sweep, pressure, and heating capabilities.

[0075] While sweeping and mixing, slowly add Eudragit E PO (amino methacrylate copolymer) to the jacketed vessel. Sweep and mix this mixture until the Eudragit E PO is completely dissolved.

[0076] While continuing to mix with sweeping, slowly add gelatin and mix until a fluff forms. Stop sweeping. Degas the fluff.

[0077] Once the fluff has formed, set the heating unit for the container to 70°C. After the fluff begins to melt, switch on the sweep at about 15 RPM and mix under vacuum. After all the gel has melted, add about 2 kg of water to the mix. Mix the water with the gel mass while degassing.

[0078] After degassing is complete, nitrogen pressure is used to force the melt from the jacketed vessel into a jacketed gel receiver.

[0079] Using this process, two gel melts are prepared. The first gel melt was used to encapsulate three types of loading solutions: Fill solution containing 50% water and 50% PEG400. The fill material was easily encapsulated with a good seal. The fill did not dissolve into the gelatin shell. For a normal gel, it would be difficult to encapsulate a fill solution containing 50% water. If formed, a poor seal would form and the gelatin shell would begin to dissolve either on the conveyor belt or in the dryer basket.

[0080] The second fill solution contained 100% glycerin. A good seal was obtained with the encapsulation equipment.

[0081] The third filling solution encapsulated was Transcutol. These softgels had good sealing and maintained their shape and appearance after removal from the shallow tray.

[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 during encapsulation 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% The present invention also includes the following aspects. <1> (a) filler material; and (b) Shell Composition A softgel capsule comprising: the filler material comprises at least 10% of a liquid medium selected from water, a polyol, a glycol, an alcohol, or a combination thereof; A softgel capsule, wherein the shell composition comprises gelatin and a pH-dependent polymer that solubilizes at a pH of less than about 6.0. <2> 10. The softgel capsule of claim 1, wherein the fill material further comprises an active agent dissolved or suspended in the liquid medium, and the fill material comprises a pH greater than about 4. <3> 3. The softgel capsule according to claim 1 or 2, wherein the pH-dependent polymer is solubilized at a pH of less than about 5.5, less than about 5.0, less than about 4.5, or less than about 4.0. <4> 2. The softgel capsule of claim 1, wherein the pH-dependent polymer is an acrylic polymer or a cellulose polymer. <5> 5. The softgel capsule of claim 4, wherein the pH-dependent polymer is an acrylic polymer. <6> 6. The softgel capsule of claim 5, wherein the acrylic polymer is an amino methacrylate copolymer. <7> 2. The softgel capsule according to claim 1, wherein the shell composition comprises the pH-dependent polymer in an amount (w / w) of about 1% to about 60%, about 5% to about 50%, about 10% to about 40%, or about 15% to about 35%. <8> 2. The softgel capsule according to claim 1, wherein the shell composition comprises the gelatin in an amount (w / w) of about 5% to about 75%, about 10% to about 60%, about 15% to about 50%, or about 20% to about 40%. <9> 10. The softgel capsule of claim 1, wherein the shell composition further comprises a solubilizing agent. <10> 10. The softgel capsule according to claim 9, wherein the solubilizing agent is an organic acid. <11> 11. The softgel capsule of claim 10, wherein the organic acid is selected from 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. <12> 12. The softgel capsule according to claim 11, wherein the organic acid is lactic acid. <13> 13. The softgel capsule according to any one of claims 9 to 12, wherein the shell composition comprises the solubilizer in an amount (w / w) of about 0.0001% to about 1%, about 0.001% to about 0.5%, or about 0.005% or about 0.1%. <14> 10. The softgel capsule of claim 1, wherein the shell composition further comprises a plasticizer. <15> 15. The softgel capsule according to claim 14, wherein the shell composition comprises the plasticizer in an amount (w / w) of about 5 wt% to about 50 wt%, about 10% to about 40%, or about 15% to about 35%. <16> 16. The softgel capsule according to claim 14 or 15, wherein the plasticizer is selected from glycerol, glycerin, sorbitol, or a combination thereof. <17> 2. The softgel capsule of claim 1, wherein the gelatin is selected from type A gelatin, type B gelatin, or a mixture thereof. <18> 2. The softgel capsule of claim 1, wherein the gelatin is selected from the group consisting of fish gelatin, animal hide gelatin, bone gelatin, or a mixture thereof. <19> 2. The softgel capsule of claim 1, wherein the liquid medium is water. <20> 2. 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. <22> The softgel capsule of any of the above, wherein the alcohol is ethanol. <23> 2. The softgel capsule of claim 1, wherein the fill composition comprises the liquid medium in an amount of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. <24> 2. The softgel capsule of claim 1, wherein the fill composition comprises the liquid medium in an amount of 5% to 50%, about 10% to about 40%, or about 15% to about 30%. <25> 2. The softgel capsule of claim 1, wherein the capsule disintegrates in a gastric environment in less than about 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, based on a disintegration test conducted in a USP Apparatus II using paddles at a speed of 50 rpm in a buffer solution of pH 1.2. <26> 10. The release softgel capsule of claim 1, wherein the capsule disintegrates in a basic medium in 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, based on a disintegration test conducted in a 1000 mL beaker at about 37°C ± 2°C using a basket-rack assembly NT-40H model apparatus. <27> 10. A softgel capsule according to claim 1, comprising a water-soluble active agent. <28> 2. The softgel capsule according to claim 1, comprising levothyroxine or a pharmaceutically acceptable salt thereof. <29> 10. The softgel capsule of claim 1, wherein the fill material comprises a pH greater than about 4. <30> 29. A method of providing thyroid replacement therapy comprising administering the softgel capsule of claim 28. <31> (a) preparing the fill material comprising at least 10% liquid medium; (b) encapsulating the fill material with a shell composition comprising gelatin and a pH-dependent polymer that is solubilized at a pH of less than about 6.0; 2. A method for preparing the softgel capsule described in 1 above, comprising:

Claims

1. (a) Filling material; (b) a shell composition; and (c) levothyroxine or a pharmaceutically acceptable salt thereof A softgel capsule comprising: the filler material comprises at least 10% (w / w) of a liquid medium selected from water, a polyol, a glycol, an alcohol, or a combination thereof; A softgel capsule, wherein the shell composition comprises gelatin and a pH-dependent polymer that solubilizes at a pH of less than 5.

0.

2. 10. The softgel capsule of claim 1, wherein the fill material further comprises an active agent dissolved or suspended in the liquid medium, and wherein the fill material has a pH greater than 4.

3. the pH-dependent polymer solubilizes at a pH below 4.5 or below 4.0; and / or the pH-dependent polymer is an acrylic polymer or a cellulose polymer; and / or 3. The softgel capsule of claim 1, wherein the acrylic polymer is an amino methacrylate copolymer.

4. the shell composition comprises the pH-dependent polymer in an amount (w / w) of 1% to 60%, 5% to 50%, 10% to 40%, or 15% to 35%; and / or 4. The softgel capsule of claim 1, wherein the shell composition comprises the gelatin in an amount (w / w) of 5% to 75%, 10% to 60%, 15% to 50%, or 20% to 40%.

5. 5. The softgel capsule of claim 1, wherein the shell composition further comprises a solubilizer selected from 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.

6. The softgel capsule of claim 5, wherein the shell composition comprises the solubilizer in an amount (w / w) of 0.0001% to 1%, 0.001% to 0.5%, or 0.005% or 0.1%.

7. the shell composition further comprises a plasticizer; and / or the shell composition comprises the plasticizer in an amount (w / w) of 5 wt % to 50 wt %, 10% to 40%, or 15% to 35%; and / or 7. The softgel capsule of claim 1, wherein the plasticizer is selected from glycerol, glycerin, sorbitol, or a combination thereof.

8. the gelatin is selected from type A gelatin, type B gelatin or a mixture thereof; and / or 8. The softgel capsule of claim 1, wherein the gelatin is selected from the group consisting of fish gelatin, animal hide gelatin, bone gelatin, or a mixture thereof.

9. the liquid medium is water, and / or the polyol is glycerol, and / or the glycol is polyethylene glycol, and / or The softgel capsule according to any one of claims 1 to 8, wherein the alcohol is ethanol.

10. the filler material comprises the liquid medium in an amount of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99%; or 10. The softgel capsule of claim 1, wherein the fill material comprises the liquid medium in an amount of 5% to 50%, 10% to 40%, or 15% to 30%.

11. The softgel capsule disintegrates in a gastric environment in less than 60 minutes based on a disintegration test conducted in a pH 1.2 buffer solution using a paddle at a speed of 50 rpm according to USP Apparatus II; or 11. The softgel capsule according to any one of claims 1 to 10, wherein the softgel capsule disintegrates in a basic medium in at least 1 hour, based on a disintegration test performed in a 1000 mL beaker at 37°C ± 2°C using a basket-rack assembly NT-40H model apparatus.

12. 12. The softgel capsule of any one of claims 1 to 11, comprising a water-soluble active agent.

13. 13. The softgel capsule of claim 1, wherein the fill material has a pH greater than 4.

14. (a) preparing the filler material comprising at least 10% (w / w) of a liquid medium; (b) encapsulating the fill material with a shell composition comprising gelatin and a pH-dependent polymer that is solubilized at a pH of less than 5.0; A method for preparing the softgel capsule of any one of claims 1 to 13, comprising: