Modified release softgel capsules

Abstract

Modified-release softgel capsules, methods for preparing them, and methods for using them are described, each containing a pH-dependent shell composition encapsulating a controlled-release fill composition. The pH-dependent shell composition can be characterized in that the delayed release properties of the capsule can be achieved without a separate pH-dependent coating or the addition of conventional pH-dependent polymers. The softgel provides a dual controlled-release platform that facilitates delivery of an active agent to a target location in the gastrointestinal tract and a controlled-release profile of the active agent at the target location in the gastrointestinal tract.

Description

Technical Field

[0001] The present disclosure relates to modified-release soft gel capsules encapsulating a controlled-release filling composition. The pH-dependent shell composition of the gelatin-based capsule has delayed-release characteristics that do not require another pH-dependent coating or the addition of conventional pH-dependent synthetic polymers. The controlled-release filling composition has controlled-release characteristics. Together, the pH-dependent shell composition and the controlled-release filling composition enable delivery of an active agent to a target location in the gastrointestinal tract and enable adjustment of the release profile of the active agent at the target location.

Background Art

[0002] Soft capsules, particularly soft gelatin capsules (or soft gel capsules), provide a dosage form that is more readily acceptable to patients because they are easy to swallow and do not require flavoring to mask any unpleasant taste of the active agent.

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

[0004] Other delayed-release dosage forms have been developed in which a conventional pH-dependent polymer (i.e., an acid-insoluble polymer) is added to the capsule shell. However, the addition of a conventional pH-dependent polymer can result in capsules that are prone to leakage due to insufficient sealing.

[0005] Therefore, there is a need for modified release softgel capsules that do not require the application of another pH-dependent coating or the addition of conventional pH-dependent polymers to the shell.

[0006] Softgel capsules also benefit from their ability to modulate and / or control the release profile of the activator from the filling composition of the softgel capsule after the shell composition has ruptured / dissolved / collapsed. [Overview of the project]

[0007] This disclosure relates to modified release softgel capsules, such as dual controlled release softgel capsules. A modified release softgel capsule comprises (a) a controlled release filling composition and (2) a pH-dependent shell composition enclosing the controlled release filling composition. In one embodiment, the pH-dependent shell composition comprises gelatin. In one embodiment, the pH-dependent shell composition comprises a pH-dependent release material (e.g., pectin). In one embodiment, the pH-dependent shell composition comprises dextrose. In one embodiment, the pH-dependent shell composition comprises a plasticizer (e.g., glycerol, sorbitol, or a combination thereof). In one embodiment, the pH-dependent shell composition comprises a binder (e.g., gellan gum). In one embodiment, the pH-dependent shell composition comprises two or more combinations of gelatin, pectin, dextrose, a plasticizer, and a binder.

[0008] In some embodiments, the modified release softgel capsules do not require a separate pH-dependent coating (e.g., on the pH-dependent shell composition). Therefore, the pH-dependent shell composition contained in the modified release softgel capsules eliminates the need to add a separate pH-dependent coating in some embodiments, which also minimizes the risk of damaging the capsule during the coating process.

[0009] In one embodiment, the pH-dependent shell composition comprises (a) gelatin, (b) dextrose, (c) pectin such as low-methoxyl pectin, and optionally (d) a plasticizer. The pH-dependent shell composition (e.g., amount of pectin, amount of dextrose, gelatin-to-pectin ratio) and its preparation process (e.g., curing time, ribbon thickness) can be adjusted / modified to achieve a target pH dissolution profile (e.g., rupture / dissolution / collapse time in acidic and buffered media) of the shell composition in various pH environments.

[0010] The controlled-release filling composition comprises at least one activator and a controlled-release material. The activator may be a pharmaceutical active ingredient or a nutritional supplement. The controlled-release material may be polyethylene oxide, a cellulose derivative, gum, or a combination thereof. In certain embodiments, the controlled-release filling composition further comprises a hydrophilic carrier, such as a polyol (e.g., polyethylene glycol, polypropylene glycol), or water.

[0011] In one embodiment, the controlled-release filling composition (e.g., the type and amount of activator, the type and amount of controlled-release material, and optionally the type and amount of hydrophilic support, as well as the ratio between these materials) and its preparation process (e.g., annealing time) may be adjusted / modified to achieve a targeted release profile (e.g., zero-order release) of the activator from the controlled-release filling composition. In certain embodiments, the modified-release softgel capsule may be annealed. In one embodiment, the annealed modified-release softgel capsule comprises a controlled-release filling composition in the form of a matrix (solid or liquid) of controlled-release material encapsulated in a pH-dependent shell composition.

[0012] In certain embodiments, a modified release softgel capsule is disclosed comprising: (i) at least one activator; (ii) polyethylene oxide having a number average molecular weight of about 0.05 M dalton to about 15 M dalton; and (iii) optionally a hydrophilic carrier; and a pH-dependent shell composition for encapsulating the control release fill composition, the pH-dependent shell composition comprising gelatin, pectin, dextrose, and optionally a plasticizer.

[0013] The modified release softgel capsules described herein may also be referred to as dual controlled release softgel capsules due to the two levels of controlled release they possess. The first level of controlled release is due to the pH-dependent shell composition of the softgel capsule. The second level of controlled release is due to the controlled release filling composition of the softgel capsule.

[0014] This disclosure also covers processes for preparing modified release softgel capsules. In certain embodiments, a process for preparing modified release softgel capsules is disclosed, comprising: mixing at least one activator with polyethylene oxide and optionally a hydrophilic carrier to form a controlled release filling composition; encapsulating the controlled release filling composition in a pH-dependent shell composition comprising gelatin, pectin, dextrose, and optionally a plasticizer; and annealing the encapsulated controlled release filling composition.

[0015] In certain embodiments, the disclosure also covers methods for modulating each level of the dual controlled release mechanism of a softgel capsule to facilitate targeted release of the activator to specific regions within the gastrointestinal tract and a targeted activator release profile. For example, in certain embodiments, the modified release softgel capsule described herein delivers the activator to the lower part of the gastrointestinal tract (e.g., near the colon) and releases the activator in a controlled manner (e.g., in a zero-order release over a period of time of about 2 to about 24 hours).

[0016] This disclosure also covers methods of treating a condition by administering one of the delayed-release softgel compositions described herein.

[0017] The above and other features of this disclosure, their nature, and various advantages will become more apparent upon consideration of the following detailed description in conjunction with the attached drawings. [Brief explanation of the drawing]

[0018] [Figure 1] This graph shows the viscosity of shell compositions containing amidated pectin and unamidated pectin according to the aging time. [Figure 2] This graph shows the release profiles of ibuprofen from modified release softgel capsules according to embodiments described herein, having various concentrations of the controlled release material in the controlled release filling composition. [Figure 3] This graph shows the release profile of diphenhydramine from a modified release softgel capsule according to one embodiment. [Figure 4] This graph shows the release profile of acetaminophen from a modified release softgel capsule according to one embodiment. [Figure 5] This figure illustrates an exemplary process for preparing a modified release softgel capsule according to one embodiment. [Figure 6] This graph shows the dissolution profiles of capsules in multiple embodiments, obtained in optical fiber dissolution tests using a USP Apparatus II with a paddle speed of 100 RPM in 500 ml of water running at 100 RPM at 37°C. [Figure 7] This graph shows the dissolution profiles of capsules in multiple embodiments, obtained in optical fiber dissolution tests using USP Apparatus II with a paddle speed of 50 RPM at 37°C in 500 ml of water. [Figure 8-1]Figures 8A - 8D and 9 - 10 show residual plots for 90% of the time (h) for the statistical analysis of the dissolution data of Examples 13 - 18. Figure 8A is a normal probability plot for the time (h) until 90% is released. Figure 8B is a fitted value plot for the time (h) until 90% is released. [Figure 8-2] Figures 8A - 8D and 9 - 10 show residual plots for 90% of the time (h) for the statistical analysis of the dissolution data of Examples 13 - 18. Figure 8C is a histogram for the time (h) until 90% is released. Figure 8D is a rank - order plot for the time (h) until 90% is released. [Figure 9] Figures 8A - 8D and 9 - 10 show residual plots for 90% of the time (h) for the statistical analysis of the dissolution data of Examples 13 - 18. Figure 9 is an interaction plot for the time (h) until 90% is released. [Figure 10] Figures 8A - 8D and 9 - 10 show residual plots for 90% of the time (h) for the statistical analysis of the dissolution data of Examples 13 - 18. Figure 10 is a main effect plot for the time (h) until 90% is released. [Figure 11] A graph representing the dissolution profiles of capsules according to a plurality of embodiments filled with Formulations 13 - 15, obtained in an optical fiber dissolution test using USP Apparatus II with a paddle speed of 100 RPM at 37°C in 500 ml of water. [Figure 12] A graph representing the dissolution profiles of capsules according to a plurality of embodiments, obtained in an optical fiber dissolution test using USP Apparatus II at 37°C in 500 ml of water with a paddle speed of 100 RPM. [Figure 13] A graph representing the dissolution profiles of capsules according to a plurality of embodiments, obtained in an optical fiber dissolution test using USP Apparatus II at 37°C in 500 ml of water with a paddle speed of 50 RPM. [Figure 14]This graph shows the DSC curve of heat flow versus temperature for a capsule-filled composition containing polyethylene oxide with a number-average molecular weight of 900,000 Da. [Figure 15] This graph shows the DSC curve of heat flow versus temperature for a capsule filling composition containing MC18-30 filling mix. [Figure 16] This graph shows the DSC curve of heat flow versus temperature for a capsule-filled composition containing polyethylene oxide having a number-average molecular weight of 5,000,000 Da. [Figure 17] This graph shows the DSC curve of heat flow versus temperature for a capsule filling composition containing MC18-31 filling mix. [Figure 18] This graph shows the DSC curve of heat flow versus temperature for a capsule filling composition containing polyethylene oxide having a number-average molecular weight of 7,000,000 Da. [Figure 19] This graph shows the DSC curve of heat flow versus temperature for a capsule filling composition containing MC18-32 filling mix. [Modes for carrying out the invention]

[0019] This disclosure advances the existing art by developing a dual controlled-release oral dosage form, in particular a modified-release softgel capsule having two levels of controlled release. The first level is attributed to a pH-dependent shell composition that achieves the advantages associated with conventional delayed-release dosage forms without requiring the application of a pH-dependent coating or the addition of conventional pH-dependent synthetic polymers to the capsule shell. The second level is attributed to a controlled-release filling composition.

[0020] The pH-dependent shell compositions of the modified release softgel capsules described herein do not dissolve in the gastric environment, but rather dissolve at a pH of approximately 3.5 or higher (e.g., in the duodenal region and / or intestine). The dissolution profile of the pH-dependent shell compositions described herein can be adjusted by modifying the components and preparation method of the shell composition.

[0021] The controlled-release filling compositions for modified-release softgel capsules described herein can be modified by altering the components and preparation methods of the filling compositions. Among several factors, the controlled-release properties of the filling compositions can be modified by incorporating controlled-release materials (e.g., polyethylene oxide, cellulose derivatives, gum, or a combination of two or more thereof).

[0022] The dual controlled release mechanism of the modified release softgel capsules described herein is beneficial for the delivery of activators that can cause gastric irritation or bleeding (such as NSAIDs) or activators that are sensitive to the acidic environment of the stomach (such as peptides and proteins / enzymes). Such mechanisms are also beneficial for reducing belching after ingesting capsules containing filling compositions that tend to contribute to belching (such as fish oil, garlic oil, or krill oil). Belching often occurs when ingesting vitamins, minerals, supplements, and / or pharmaceutical products formulated in dosage forms that exhibit some leakage (even very small amounts) in the stomach before reaching the intestines. Leakage can be particularly problematic when belching is associated with substances that have an unpleasant odor, such as fish oil and garlic oil, which are commonly delivered in softgels. The modified release softgel capsules described herein can be formulated in a manner that minimizes and / or eliminates premature leakage (and consequently, premature release of the capsule's filling) in the gastric environment of the stomach. The modified release softgel capsules described herein may also be used to deliver activators (e.g., peptides and proteins) near the lower gastrointestinal tract and / or colon region where certain activators are better absorbed.

[0023] definition As used herein, the term “pH-dependent” is used to refer to the dissolution or disintegration resistance of a substance such that no or substantially no dissolution or disintegration occurs in the gastric environment of the stomach for a period of time, for example, 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. In certain embodiments, the gastric environment of the stomach may be simulated here by the addition of 0.1N HCl and, optionally, pepsin. It should be noted that while the pharmacopoeial method does not include pepsin, pepsin was added in certain dissolution / disintegration tests described herein to better simulate / mimic in vivo conditions. Thus, without being construed as limiting, in certain embodiments, the compositions described herein are resistant to dissolution / disintegration for the above-mentioned time even in a 0.1N HCl environment containing pepsin (which is presumed to be a more aggressive environment than 0.1N HCl without pepsin).

[0024] For example, embodiments described herein include pH-dependent shell compositions that preferentially dissolve at a pH of about 3.5 or higher (e.g., in a biological, artificial, or simulated duodenal environment and / or intestinal fluid) compared to biological, artificial, or simulated gastric juice. In certain embodiments, the intestinal environment may be simulated here with a pH 6.8 phosphate buffer containing or without pancreatin. For example, the pH-dependent shell compositions described herein dissolve at a pH of about 3.5 or higher (e.g., in a biological, artificial, or simulated duodenal environment and / or intestinal fluid, such as a pH 6.8 phosphate buffer containing pancreatin as needed) 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. It should be noted that while the pharmacopoeial methods do not contain pancreatin, pancreatin was added in certain dissolution / disintegration tests described herein to better simulate / mimic in vivo conditions. Therefore, without being construed as limiting, in certain embodiments, the compositions described herein exhibit similar dissolution / disintegration profiles in a pH 6.8 buffered environment containing pancreatin (which is presumed to be a more aggressive environment than a pH 6.8 buffered environment without pancreatin).

[0025] As used herein, “pharmaceutically active ingredient” and “activator” refer to drugs or compounds that may be used in the diagnosis, treatment, relief, management, or prevention of a condition. In certain embodiments, a suitable “activator” includes nutritional supplements such as vitamins, minerals, and supplements (VMS). Exemplary modified-release softgel capsules may include, without limitation, capsules containing in the filling composition lactic acid bacteria, probiotics, fish oil, krill oil, valproic acid, garlic oil, peppermint oil, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen solution or suspension), proton pump inhibitors, aspirin, antihistamines (e.g., diphenhydramine), acetaminophen, drugs that are easily abused (e.g., opioids), drugs that are less likely to be abused, and similar products.

[0026] The term “condition” or “conditions” refers to medical conditions that can be treated or prevented by administering an effective amount of the active agent to the subject.

[0027] As used herein, the term “active ingredient” refers to any substance intended to produce a therapeutic, preventative, or other intended effect, whether or not it has been approved by a government agency for that purpose. With respect to a particular drug, this term includes the pharmaceutically active agent, as well as all pharmaceutically acceptable salts, solvates, and crystalline forms thereof, all of which are pharmaceutically active.

[0028] Any pharmaceutically active ingredient, including both water-soluble and sparingly water-soluble substances, may be used for the purposes of this disclosure. Suitable pharmaceutically active ingredients include, without limitation, analgesics and anti-inflammatory agents (e.g., ibuprofen, naproxen sodium, aspirin), antacids, anthelmintics, antiarrhythmics, antibacterial agents, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensive agents, antimalarial agents, antimigraine agents, antimuscarinic agents, antineoplastic and immunosuppressant agents, antiparasitic agents, antirheumatic agents, antithyroid agents, antihistamines (e.g., diphenhydramine), antivirals, anxiolytics, and sedatives. This includes hypnotics and tranquilizers, beta-blockers, cardiac inotropic agents, corticosteroids, cough suppressants, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, lipid regulators, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritional supplements, opioid analgesics, anticonvulsants (e.g., valproic acid), oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and combinations thereof.

[0029] In some embodiments, the active pharmaceutical ingredient may be selected without limitation from the group consisting of dabigatran, doronedarone, ticagrelor, iloperidone, ibakhtol, midostaurin, acimadrine, beclomethasone, apremilast, sapacitabine, lincitinib, abiraterone, vitamin D analogues (e.g., calcifediol, calcitriol, paricalcitol, doxelcalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, pharmaceutically acceptable salts thereof, and combinations thereof.

[0030] In some embodiments, the lipids in the dosage form may be selected without limitation from the group consisting of almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, Manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, peppermint 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, garlic oil, animal or vegetable fats such as their hydrogenated forms, free fatty acids, and monoglycerides, diglycerides, and triglycerides containing C8-, C10-, C12-, C14-, C16-, C18-, C20-, and C22- fatty acids, fatty acid esters such as EPA and DHA3, and combinations thereof.

[0031] According to certain embodiments, the activators may include, but are 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 chelating agents, ezetimibe, lomitapide, phytosterols, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof, or mixtures of any of the foregoing, which are lipid-lowering agents.

[0032] Appropriate dietary supplement activators may include, but are not limited to, 5-hydroxytryptophan, acetyl L-carnitine, alpha-lipoic acid, alpha-ketoglutaric acid, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin 812), dimethylaminoethanol, fumaric acid, germanium trioxide, glandular products, glucosamine HCl, glucosamine sulfate, hydroxylmethylbutyrate, immunoglobulin, lactic acid, L-carnitine, liver products, malic acid, anhydrous maltose, mannose (d-mannose), methylsulfonylmethane, phytosterols, picolinic acid, pyruvic acid, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0033] Appropriate nutritional supplement activators may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, or combinations thereof.

[0034] Suitable vitamin activators 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 fat-soluble vitamins.

[0035] Suitable herbal supplement activators may include, but are not limited to, arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, linseed, feverfew, garlic oil, ginger root, ginkgo biloba, Korean ginseng, goldenrod, hawthorn, birch, licorice, milk thistle, plantain, Indian jasmine, senna, soybean, St. John's wort, yarrow palmetto, turmeric, and valerian.

[0036] Mineral activators may include, but are not limited to, boron, calcium, chelated minerals, chlorides, 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.

[0037] Other possible activators 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, spro Fen, aminoprofen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, thiopinac, didomethacin, acemetacin, fentiazac, clidanac, oxypinac, meclofenamic acid, flufenamic acid, diflumic acid, tolfenamic acid, diflurisal, fluphenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, alloxypyrine, azapropazon, benolilate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faislamin (f aislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimeslide, oxyfenbutazone, parecoxib, phenylbutazone, salicylate salicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetine, their pharmaceutically acceptable salts and mixtures thereof) and This includes acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., pheniloin, meprobmate, 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., ethacrine, bendrofluthiazide), antihypertensives (e.g., propranolol, clonidine),This includes antihypertensive drugs (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibacterial agents (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 their pharmaceutically acceptable salts, hydrates, solvates, and prodrugs.

[0038] The activator may be a benzodiazepine, barbiturate, 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, clorazepic acid, diazepam, estazolam, flurazepam, harazepam, 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 activators include, but are not limited to, flumazenil and its pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0039] The term "barbiturate" refers to sedatives and hypnotics derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbital, butabarbital, butarbital, methhexital, mehobarbital, metalbital, pentobarbital, phenobarbital, secobarbital, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures. Barbiturate antagonists that can be used as activators include, but are not limited to, amphetamines and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0040] The term “stimulant” includes, but is not limited to, amphetamines, e.g., dextroamphetamine resin complexes, dextroamphetamine, methamphetamine, methylphenidate, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures. Stimulant antagonists that can be used as activators include, but is not limited to, benzodiazepines, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0041] In one embodiment of the present invention, the active pharmaceutical ingredient is an analgesic such as ibuprofen or an opioid. The term “opioid” refers to a psychoactive compound that acts by binding to an opioid receptor. Opioids are commonly used in the medical field for their analgesic effects. Opioids are considered to be APIs that are easily abused. Examples of opioids include codeine, tramadol, anirelidine, prozine, pethidine, hydrocodone, morphine, oxycodone, methadone, diamorphine, hydromorphone, oxymorphone, 7-hydroxymitraginine, buprenorphine, fentanyl, sufentanil, levorphanol, meperidine, tyridine, dihydrocodeine, dihydromorphine, and their pharmaceutically acceptable salts.

[0042] Examples of added active pharmaceutical ingredients include: N-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide; alfentanil; 5,5-diallylbarbiturate; allobarbital; allylprozine; alphaprozine; 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine; alprazolam; 2-diethylaminopropiophenone; amfepramon, (±)-α-methylphenethylamine; amphetamine ;2-(α-methylphenethylamino)-2-phenylacetonitrile; amphetaminyl; 5-ethyl-5-isopentylbarbiturate; amobarbital; anilelysine; apocodeine; 5,5-diethylbarbiturate; barbital; benzylmorphine; vegitramide; 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2(3H)-one; bromazepam; 2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine; brotizo Lam, 17-cyclopropylmethyl-4,5a-epoxy-7a[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol; buprenorphine; 5-butyl-5-ethylbarbiturate; butobarbital; butorphanol; (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-3-yl)dimethylcarbamate; chamazepam; (1S,2S)-2-amino-1-phenyl-1-propanol; catin; d- Norpsoid ephedrine; 7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepine-2-ylamine 4-oxide; chlordiazepoxide, 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; clobazam, 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepine-2(3H)-one; clonazepam; clonitazen; 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid; clorazepic acid;5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepine-2(3H)-one; clotiazepam; 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydroxazole-o[3,2-d][1,4]benzodiazepine-6(5H)-one; cloxazolam; (-)-methyl-[3β-benzoyloxy-2β(1αH,5αH)-tropanecarboxylate]; cocaine; (5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphina 6-ol; 4,5α-epoxy-3-methoxy-17-methyl-7-morphinan-6α-ol; codeine; 5-(1-cyclohexenyl)-5-ethylbarbiturate; cyclobarbital; cyclorphan; cyprenorphine; 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-2(3H)-one; delorazepam; desomorphine; dextromoramide; (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate; dextropropoxyfen; dezosine; diampromide Diamorphone; 7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one; diazepam; 4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol; dihydrocodeine; 4,5α-epoxy-17-methyl-3,6a-morphinanediol; dihydromorphine; dimenoxadol; dimephetamol; dimethylthiambutene; dioxafetyl butyrate; dipipanone; (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10 a-tetrahydro-6H-benzo[c]chromen-1-ol; dronabinol; eptazosine; 8-chloro-6-phenyl-4H-[1,2,4]-triazolo[4,3-(a)][1,4]benzodiazepine; estazolam; etoheptadine; ethylmethylthiambutene; ethyl[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate]; ethyl loflazepate; 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinan-6α-ol; ethylmorphine;Etonitazene; 4,5α-Epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol; Etorphine; N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine; Fencanfamine; 7-[2-(α-methylphenethylamino)ethyl]-theophylline; Phenethyline; 3-(α-methylphenethylamino)propionitrile; Fenproporex; N-(1-phenethyl-4-piperidyl)propionanilide; Fentanyl; 7- LOLO-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one; fludiazepam; 5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepine-2(3H)-one; flunitrazepam; 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2(3H)-one; flurazepam; 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepine-2(3H)-one; harazepa Mu; 10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolyl[3,2-d][1,4]benzodiazepine-6(5H)-one; haloxazolam; heroin; 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanon; hydrocodone; 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanon; hydromorphone; hydroxypethidine; isometadone; hydroxymethylmorphinan; 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl- 4H-[1,3]oxazino[3,2d][1,4]benzodiazepine-4,7(6H)-dione; ketazolam; 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone; ketobemidone; (3S,6S)-6-dimethylamino-4,4-diphenylheptane-3-ylacetate; revacetylmetador; LAAM; (-)-6-dimethylamino-4,4-diphenol-3-heptanone; levometadone; (-)-17-methyl-3-morphinol; levofenacilmorphan; levofenacilmorphan; lofentanil;6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepine-1(4H)-one; loprazolam; 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepine-2(3H)-one; lorazepam; 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepine-2(3H)-one; lormetazepam; 5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo [2,1a] Isoindole-5-ol; mazindol; 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine; medazepam; N-(3-chloropropyl)-α-methylphenethylamine; mephenorex; meperidine; 2-methyl-2-propyl trimethylenedicarbamate; meprobamate; meptadinol; metazosine; methylmorphine; N,α-dimethylphenethylamine; methamphetamine; (±)-6-dimethylamino-4,4-diphenol-3-heptanone; methadone; 2-meth Lu-3-o-tolyl-4(3H)-quinazolinone; metakalon; methyl[2-phenyl-2-(2-piperidyl)acetate]; methylphenidate; 5-ethyl-1-methyl-5-phenylbarbiturate; methylphenobarbital; 3,3-diethyl-5-methyl-2,4-piperidinedione; metiprilone; metopone; 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine; midazolam; 2-(benzhydrylsulfinyl)acetamide; modafinil; (5α,6 α)-7,8-didehydro-4,5-epoxy-17-methyl-7-methylmorphinan-3,6-diol; morphine; mirofin; (±)-trans-3-(1,1-dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo-[b,d]pyran-9(6αH)one; nabilone; nalbuphene; nalolphin; narcein; nicomorphine; 1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one; nimetazepam;7-Nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one;nitrazepam; 7-chloro-5-phenyl-1H-1,4-benzodiazepine-2(-3H)-one; norazepam; norlevorphanol; 6-dimethylamino-4,4-diphenyl-3-hexanone; normethadone; normorphine; norpipanone; opium; 7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one; oxazepam; (cis- / trans-)-10-chloro-2,3,7,11b-tetrahydr Ro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepine-6-(5H)-one; oxazolam; 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanon; oxycodone; oxymorphone; papaveretam; 2-imino-5-phenyl-4-oxazolidinone; pemoline; 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzoazosin-8-ol; pentazocine; 5-ethyl-5-(1-methyl Butyl)-barbiturate; pentobarbital; ethyl-(1-methyl-4-phenyl-4-piperidine carboxylate); pethidine; phenadoxone; phenomorphan; phenazosin; phenoperidine; piminodin; holcodeine; 3-methyl-2-phenylmorpholine; fenmetrazine; 5-ethyl-5-phenylbarbiturate; phenobarbital; α,α-dimethylphenethylamine; phentermine; (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol; phenylef Phosphorus, 7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepine-2(3H)-one; pinazepam; α-(2-piperidyl)benzhydryl alcohol; piperadol; 1'-(3-cyano-3,3-diphenylpropyl)[1,4'-bipiperidine]-4'-carboxamide; pyritramide; 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one; prazepam; profadol; proheptadine; promedol; properidine; propoxifene;N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide; methyl{3-[4-methoxycarbonyl-4-(N-phenylpropanamide)piperidino]propanoate}; (S,S)-2-methylamino-1-phenylpropan-1-ol; pseudoephedrine, remifentanil; 5-sec-butyl-5-ethylbarbiturate; secbutabarbital; 5-allyl-5-(1-methylbutyl)-; Barbiturates; Secobarbital; N-{4-Methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide; Sufentanil; 7-Chloro-2-hydroxymethyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one; Temazepam; 7-Chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one; Tetrazepam; Ethyl (2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylate; cis- / trans-tyridine; Tramadol; 8-Chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; Triazolam; 5-(1-methylbutyl)-5-vinylbarbiturate; Vinylbital; (1R * ,2R * It may contain )-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol; (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol.

[0043] In addition to the compounds mentioned above, the active pharmaceutical ingredient also includes a prodrug of any of these compounds. The term "prodrug" refers to a compound that is a metabolic precursor of the active pharmaceutical ingredient. This precursor is converted in vivo to provide an active pharmaceutical ingredient with the desired therapeutic effect.

[0044] The dosage forms provided herein include a variety of activators and their pharmaceutically acceptable salts. These pharmaceutically acceptable salts include, but are not limited to, inorganic salts such as hydrochlorides, hydrobroms, sulfates, and phosphates; organic salts such as formates, acetates, trifluoroacetates, maleates, and tartrates; sulfonates such as methanesulfonates, benzenesulfonates, and p-toluenesulfonates; amino acid salts such as alginates, aspartates, and glutamates; and metal salts such as sodium salts, potassium salts, and cesium salts; alkaline earth metals such as calcium salts and magnesium salts; and organic amine salts such as triethylamine salts, pyridine salts, picolines, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, and N,N'-dibenzylethylenediamine salts.

[0045] The phrase "pharmaceutically acceptable" generally means that a pharmaceutical composition is safe, non-toxic, useful in the preparation of a pharmaceutical composition that is not biologically or otherwise undesirable, and is acceptable for pharmaceutical use in humans.

[0046] Furthermore, in addition to the compounds described above, the active pharmaceutical ingredient also includes a solvate of any of the compounds described above. The term "solvate" refers to an aggregate containing one or more molecules of the active pharmaceutical ingredient together with one or more molecules of the solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. In one embodiment, "solvate" refers to the active pharmaceutical ingredient in its pre-dissolution state. Alternatively, the suspended solid particles of the active pharmaceutical ingredient may contain a co-precipitating solvent.

[0047] As used herein, the terms “therapeutably effective” and “effective dose” refer to the amount or proportion of the active agent administered that is necessary to produce the desired therapeutic effect.

[0048] As used herein, “shell” or “shell composition” refers to the shell or outer portion of a softgel capsule that encloses a filling composition.

[0049] The term “filling material” may be used interchangeably with the terms “filling composition” and “filler” throughout this specification. These terms refer to the inner portion of a softgel capsule encapsulated by a shell composition.

[0050] As used herein, “conventional pH-dependent polymers” refers to acrylic and methacrylic polymers, as well as other conventional acid-insoluble polymers, including, but not limited to, those available under the trademark name EUDRAGIT®, such as methyl acrylate-methacrylic copolymers. Other conventional acid-insoluble polymers include, without limitation, cellulose succinate acetate, cellulose phthalate acetate, cellulose butyrate acetate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), alginates such as sodium alginate and potassium alginate, stearic acid, and shellac. Pectin and pectin derivatives are not considered conventional pH-dependent polymers. Gellan gum and its derivatives are also not considered conventional pH-dependent polymers. In some embodiments, the pH-dependent shell compositions of this disclosure do not contain acid-insoluble polymers. In other words, in certain embodiments, the pH-dependent shell compositions and pH-dependent softgel capsules are “conventional pH-dependent polymer-free or substantially free.”

[0051] As used herein, “not containing or substantially not containing” means a composition containing 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 the said component.

[0052] All references to "molecular weight" in this specification refer to the number-average molecular weight unless otherwise specified.

[0053] As used herein, the term "ambient temperature" refers to a temperature of approximately 20 to 35°C.

[0054] Throughout this specification and the claims, all references to wt% refer to the weight of the component relative to the total weight of the composition in question, unless otherwise explicitly indicated, and may also be expressed as w / w.

[0055] As used herein, “delayed-release capsule,” “delayed-release softgel capsule,” “pH-dependent capsule,” or “pH-dependent softgel capsule” refers to a capsule in which a filling composition is encapsulated in a pH-dependent shell composition and, upon drying, exhibits delayed or pH-dependent properties. In certain embodiments, these terms may also refer to a capsule that has been cured after drying. In certain embodiments, no further processing steps are required after drying. In certain embodiments, no further processing steps are required after curing. The terms “cured” and their variations may be used interchangeably with the terms “annealed” and their variations.

[0056] As used herein, “modified release softgel capsule” refers to a capsule in which a controlled release filling composition is encapsulated in a pH-dependent shell composition.

[0057] As used herein, the term “controlled release” refers to an activator released over a period of time to provide, for example, a dosage form administered once or twice daily.

[0058] As used herein, “about” refers to any value within a ±10% variation, and therefore “about 10” includes 9 to 11. As used herein, “a,” “an,” or “the” refers to one or more unless otherwise specified. For example, a reference to “a single excipient” includes a single excipient and mixtures of two or more different excipients, etc.

[0059] Unless otherwise specifically indicated herein, the enumeration of value ranges herein is intended solely as a simplified method of referring individually to each separate value within the range, and each separate value is incorporated herein as if it were individually enumerated herein. Unless otherwise specifically indicated herein or clearly contradicted by the context, all methods described herein may be performed in any suitable order.

[0060] The use of any example or illustrative language provided herein (e.g., "etc.") is intended merely to illustrate certain materials and methods and does not impose any limitation on their scope. The language herein should not be construed as indicating that any non-claimed element is essential to the practice of the disclosed materials and methods.

[0061] Controlled release filling composition According to several embodiments, the modified release softgel capsule filling composition described herein is a controlled release filling composition comprising at least one activator and a controlled release material.

[0062] The activator may be any of the above-mentioned activators, without limitation, such as a pharmaceutical active ingredient or a nutritional supplement (e.g., vitamins, minerals, or supplements). Particularly suitable activators are those that benefit from controlled release over a long period, e.g., 12 or 24 hours, for once-daily or twice-daily administration. Activators that are unstable in the gastric region or that benefit from protection from low pH in gastric juice (e.g., peptides, proteins, enzymes, etc.) can also be advantageously utilized with the softgel capsules described herein. In addition, activators that can irritate or damage the gastric mucosa (e.g., NSAIDs) can be incorporated into the softgel capsules described herein without requiring costly tableting and coating processes. In general, any activator that benefits from the ability of the softgel capsule to facilitate targeted release of the activator to specific areas within the gastrointestinal tract (GIT) and the ability of the softgel capsule to control the release of the activator to specific areas within the GIT is included herein.

[0063] In one embodiment, the activator includes fish oil, garlic oil, krill oil, or any other activator that may cause discomfort due to premature release of the activator, for example, belching.

[0064] In one embodiment, the activator includes an NSAID, such as ibuprofen, or any other activator that can stimulate the gastric mucosa due to the early release of the activator in the gastric region rather than at a later point in the gastric tract.

[0065] In one embodiment, the activator includes a peptide, protein, enzyme, or any other activator that may be unstable in the acidic environment of the stomach and / or that can be better absorbed closer to the colonic region.

[0066] In certain embodiments, the activator includes an antihistamine (e.g., diphenhydramine) or acetaminophen.

[0067] In one embodiment, the activator is a drug that is easily abused. In an alternative embodiment, the activator is a drug that is less likely to be abused.

[0068] As long as some examples are given for a particular surfactant, these examples should not be interpreted as being limited to only that surfactant, but can be considered proof of concept applicable to a variety of surfactants.

[0069] In certain embodiments, the activator is present in the controlled-release-filled composition in an amount of at least about 1 wt%, at least about 5 wt%, at least about 10 wt%, at least about 15 wt%, at least about 20 wt%, at least about 25 wt%, or at least about 30 wt% and up to about 35 wt%, up to about 40 wt%, up to about 45 wt%, up to about 50 wt%, up to about 55 wt%, or up to about 60 wt%, relative to the total weight of the controlled-release-filled composition. In certain embodiments, the controlled-release-filled composition contains the activator in an amount of about 12 wt% to about 18 wt%, about 19 wt% to about 25 wt%, about 24 wt% to about 32 wt%, about 4 wt% to about 10 wt%, or about 25 wt% to about 42 wt%, relative to the total weight of the controlled-release-filled composition. In one embodiment, the activator is present in the controlled-release filling composition in an amount of about 5 wt% to about 60 wt% relative to the total weight of the controlled-release filling composition. In another embodiment, the activator is present in the controlled-release filling composition in an amount of about 10 wt% to about 30 wt% relative to the total weight of the controlled-release filling composition. The concentration range of the activator described herein may refer to the concentration of a single activator (regardless of the number of activators in the filling composition) or the cumulative concentration of all activators in the filling composition (if two or more activators are present in the filling composition).

[0070] In certain embodiments, the controlled-release materials that may be incorporated into the controlled-release filling composition include, without limitation, polyethylene oxide, cellulose derivatives, gums, or combinations thereof.

[0071] In several embodiments, the polyethylene oxide that can be used has a number-average molecular weight ranging from about 0.05 M, about 0.5 M Daltons, about 1 M Dalton, about 2 M Daltons, about 3 M Daltons, or about 4 M Daltons to about 5 M, about 7 M Daltons, about 10 M Daltons, about 12 M Daltons, about 15 M Daltons, or about 20 M Daltons, or any sub-range or single value within that range. In one embodiment, the number-average molecular weight of polyethylene oxide in the controlled-release filling composition is in the range of about 0.05 M Daltons to about 15 M Daltons. In one embodiment, the number-average molecular weight of polyethylene oxide in the controlled-release filling composition is in the range of about 1 M Dalton to about 10 M Daltons. In one embodiment, the number-average molecular weight of polyethylene oxide in the controlled-release filling composition is in the range of about 2 M Daltons to about 5 M Daltons.

[0072] Suitable polyethylene oxides are typically nonionic, high molecular weight, water-soluble polyethylene oxide resins. An exemplary PEO resin of this type is Polyox® water-soluble resin, available from DuPont Pharma Solutions. These PEO resins are typically used as thickeners and rheology control agents. In this disclosure, these water-soluble PEO resins may be used to modify or control the release of activators from filler compositions. If the APIs contained in the filler composition are prone to abuse, PEO resins may also be used in the filler composition to prevent the abuse of the APIs.

[0073] A major advantage of using polyethylene oxide as a rate control component in filler compositions is that it does not tend to be as tacky or sticky as other rate control polymers, thereby facilitating the encapsulation process and ensuring a more homogeneous filler composition. Other additional rate control polymers may be used, but the amount of such polymers must be carefully selected to prevent this stickiness or tackiness from causing problems that could result in a low-quality product during the encapsulation process.

[0074] In several embodiments, the cellulose derivatives that can be used include microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, or combinations thereof. In one embodiment, the cellulose derivative is hydroxypropylmethylcellulose.

[0075] In several embodiments, the gums that can be used include tragacanth gum, acacia gum, agar, tara gum, karaya, gellan gum, welan gum, ramzan gum, guar gum, xanthan gum, locust bean gum, or combinations thereof. In one embodiment, the gum includes xanthan gum, locust bean gum, or combinations thereof. In one embodiment, the gum includes xanthan gum. In one embodiment, the gum includes locust bean gum.

[0076] Additional release-controlled polymers as needed may include pectin, starch, carbomer, sodium alginate, gelatin, casein, carrageenan, collagen, dextran, succinoglucon, polyvinyl alcohol clay, and combinations thereof.

[0077] In certain embodiments, the controlled-release material comprises one of the polyethylene oxides described herein by itself. In certain embodiments, the controlled-release material comprises one of the polyethylene oxides described herein in combination with one of the cellulose derivatives described herein. In certain embodiments, the controlled-release material comprises one of the polyethylene oxides described herein in combination with one of the gums described herein.

[0078] In several embodiments, the controlled-release material is present in the controlled-release-filled composition in an amount of at least about 8 wt%, at least about 10 wt%, at least about 12 wt%, at least about 14 wt%, at least about 16 wt%, at least about 18 wt%, or at least about 20 wt% to a maximum of about 25 wt%, a maximum of about 35 wt%, a maximum of about 45 wt%, a maximum of about 55 wt%, or a maximum of about 65 wt%, or any partial range thereof, relative to the total weight of the controlled-release-filled composition. In certain embodiments, the controlled-release filling composition comprises about 8 wt% to about 15 wt%, about 16 wt% to about 20 wt%, about 22 wt% to about 28 wt%, about 15 wt% to about 30 wt%, about 20 wt% to about 42 wt%, about 10 wt% to about 35 wt%, or about 11 wt% to about 40.5 wt% of controlled-release material based on the total weight of the controlled-release filling composition.

[0079] In one embodiment, a controlled-release filler material (e.g., PEO) is used in the controlled-release filler composition in an amount of at least 21.5 wt% of the total weight of the controlled-release filler composition. In one embodiment, the controlled-release filler material (e.g., PEO) is present in the controlled-release filler composition in an amount of about 10 wt% to about 65 wt% of the total weight of the controlled-release filler composition. In one embodiment, the controlled-release filler material (e.g., PEO) is present in the controlled-release filler composition in an amount of about 25 wt% to about 40 wt% of the total weight of the controlled-release filler composition.

[0080] In alternative embodiments, if the hydrophilic carrier is present in an amount of up to 65 wt% of the total weight of the controlled-release filling composition, PEO may be present in any suitable amount in the controlled-release filling composition. In this embodiment, the minimum amount of hydrophilic carrier may be at least about 30 wt%, or at least about 40 wt%, or at least about 55 wt%, of the total weight of the controlled-release filling composition, as needed. In these alternative embodiments, the amount of PEO in the controlled-release filling composition may be about 5 wt% to about 35 wt%, or about 20 wt%, of the total weight of the controlled-release filling composition.

[0081] The concentration ranges of controlled-release materials described herein may refer to the concentration of a single controlled-release material (regardless of the number of controlled-release materials in the filling composition) or the cumulative concentration of all controlled-release materials in the filling composition (if two or more controlled-release materials are present in the filling composition).

[0082] The concentration of the controlled-release material in the filler composition can be modified to achieve a targeted release profile for the activator. For example, as shown in Example 11 and Figure 2, the amount of polyethylene oxide affects the release rate of the activator in the controlled-release filler composition in certain embodiments. Polyethylene oxide with a number-average molecular weight of 4M Dalton achieved a 12-hour release profile for the activator when incorporated into the filler composition at concentrations of about 12 wt% and about 18 wt% relative to the total weight of the filler composition. For comparison, the same polyethylene oxide achieved a 24-hour zero-order release profile for the activator when incorporated into the filler composition at a concentration of about 24 wt% relative to the total weight of the filler composition.

[0083] Similarly, the weight ratio of the controlled-release material to other components of the packing composition (e.g., the activator or, if present, the hydrophilic carrier) can be adjusted to achieve a targeted release profile for the activator. In certain embodiments, the wt:wt ratio of the controlled-release material to the activator may range from about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, or about 1:1.

[0084] In certain embodiments, a controlled-release material (e.g., PEO) and water and / or hydrophilic carrier may be present in the controlled-release filling composition in any suitable amount such that the weight ratio of the controlled-release material (e.g., PEO) to the water and / or hydrophilic carrier is (individually or cumulatively) in the range of about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, about 2:1 to about 1:2, about 10:1 to a maximum of 1:3, about 8:1 to a maximum of 1:3, about 5:1 to a maximum of 1:3, about 3:1 to a maximum of 1:3, about 2:1 to a maximum of 1:3, about 1:1 to a maximum of 1:3, about 10:1 to a maximum of 1:2, about 8:1 to a maximum of 1:2, about 5:1 to a maximum of 1:2, about 3:1 to a maximum of 1:2, about 1:1 to a maximum of 1:2, or any sub-range or single weight ratio value within that range. In one embodiment, the weight ratio of the controlled-release material (e.g., PEO) to water and / or hydrophilic carrier is in the range of approximately 2:1 to approximately 1:2 (individually or cumulatively). In another embodiment, the weight ratio of the controlled-release material (e.g., PEO) to water and / or hydrophilic carrier is in the range of approximately 3:1 to a maximum of 1:3 (individually or cumulatively).

[0085] Without limitation, other factors such as the type of controlled release material and the molecular weight of the controlled release material may also affect the release rate of the activator in the filler composition.

[0086] In certain embodiments, the controlled-release filling composition may further include a hydrophilic carrier. The hydrophilic carrier may be a low molecular weight polyol, such as polyethylene glycol, polypropylene glycol, or a combination thereof. The hydrophilic carrier may also be water. Examples of additional suitable hydrophilic carriers are hydrophilic solvents, including polyoxyethylene derivatives of sorbitan esters, such as sorbitan monolaurate (polysorbate 20), polysorbate 80, polysorbate 60, polyoxyethylene 20 sorbitan trioleate (polysorbate 85), acetic acid, formic acid, other hydrophilic surfactants, and mixtures thereof.

[0087] In certain embodiments, the controlled-release filling composition comprises a hydrophilic carrier having a number-average molecular weight ranging from about 200 Daltons, about 400 Daltons, about 600 Daltons, about 800 Daltons, or about 1000 Daltons to about 2000 Daltons, about 3000 Daltons, about 4000 Daltons, about 5000 Daltons, about 6000 Da, or about 7000 Da, or any sub-range or single value thereamin. Examples of hydrophilic carriers that may be used in the controlled-release filling composition include polyethylene glycol 400, polyethylene glycol 600, water, or a combination thereof.

[0088] In certain embodiments, the hydrophilic support in the filling composition comprises polyethylene glycol having a number average molecular weight of 300 daltons to about 7000 daltons. In certain embodiments, the hydrophilic support in the filling composition has a number average molecular weight of about 200 daltons to 5000 daltons, more preferably about 300 daltons to about 3000 daltons, and most preferably about 400 daltons to about 1500 daltons. In certain embodiments, the hydrophilic support may comprise a compound having a number average molecular weight of less than 200 daltons.

[0089] In certain embodiments, the hydrophilic carrier is present in the controlled-release-filled composition in an amount greater than 0 wt%, at least about 15 wt%, or at least about 30 wt% to a maximum of about 45 wt%, a maximum of about 60 wt%, a maximum of about 70 wt%, or a maximum of about 80 wt%, relative to the total weight of the controlled-release-filled composition. In certain embodiments, the controlled-release-filled composition comprises approximately 5 wt% to approximately 15 wt%, approximately 15 wt% to approximately 28 wt%, approximately 20 wt% to approximately 32 wt%, approximately 20 wt% to approximately 42 wt%, approximately 22 wt% to approximately 45 wt%, approximately 40 wt% to approximately 45 wt%, approximately 40 wt% to approximately 55 wt%, approximately 35 wt% to approximately 55 wt%, approximately 56 wt% to approximately 77 wt%, approximately 40 wt% to approximately 79 wt%, or approximately 29 wt% to approximately 66 wt%, based on the total weight of the controlled-release-filled composition.

[0090] In one embodiment, the hydrophilic carrier is included in the controlled-release-filled composition in an amount of up to 65 wt% of the total weight of the controlled-release-filled composition. In another embodiment, the hydrophilic carrier is included in the controlled-release-filled composition in an amount of about 10 wt% to about 75 wt%, or 30 wt% to about 70 wt%, of the total weight of the controlled-release-filled composition. Preferably, the hydrophilic carrier is included in the controlled-release-filled composition in an amount of about 40 wt% to about 60 wt%, of the total weight of the controlled-release-filled composition.

[0091] In another embodiment, the hydrophilic carrier may be present in any amount in the controlled-release filling composition, as long as the controlled-release material (e.g., polyethylene oxide) is present in an amount of at least 21.5 wt% of the total weight of the controlled-release filling composition. In this embodiment, the hydrophilic carrier is typically present in an amount of up to 65 wt%, or 10 wt% to 65 wt%, or 30 wt% to 60 wt%, or 30 wt% to 55 wt%, of the total weight of the controlled-release filling composition. The hydrophilic carrier is used to dissolve, disperse and / or suspend other components of the liquid filling composition in the liquid and may also function to adjust the viscosity of the liquid filling composition to the desired viscosity for the encapsulation step.

[0092] The concentration range of hydrophilic carriers described herein may refer to the concentration of a single hydrophilic carrier material (regardless of the number of hydrophilic carrier materials in the packing composition) or the cumulative concentration of all hydrophilic carrier materials in the packing composition (when two or more types of hydrophilic carrier materials are present in the packing composition).

[0093] In certain embodiments, the filling composition is a liquid having a viscosity in the range of 1,000 cP to 100,000 cP, 5,000 cP to 80,000 cP, or 10,000 cP to 60,000 cP at the time of filling (or encapsulation within) the capsule shell composition. The viscosity of the liquid filling composition was determined at 20°C using a HAAKE RheoStress 600 rheometer with a 40 mm flat plate geometry. The geometry was vibrated at 1 Hz with a 2 mm gap setting. A major advantage of the filling composition being liquid during processing is that, in contrast to tablet dosage forms which generally require handling of powder throughout the process of forming the dosage form, there is no need to handle powder in the process of forming the dosage form, except for the initial mixing step. Furthermore, the processing of the liquid filling compositions described herein avoids the need to include flow enhancers or processability enhancers to facilitate processing. Similarly, considering that the filling composition may be liquid at ambient temperature, it is not necessary to heat them before encapsulation, as this may be detrimental to heat-sensitive materials, such as those used in the shell composition of certain softgel capsules.

[0094] In a particular embodiment, the controlled-release filling composition releases less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, or less than 30% of the activator after about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours in a pH 6.8 phosphate buffer containing pancreatin as needed, based on a fiber optic dissolution test using a USP Apparatus II at a paddle speed of 50 rpm.

[0095] In certain embodiments, the controlled-release filling composition releases, in each case, approximately 10 wt% to 30 wt% of the activator in 1 hour, approximately 15 wt% to 50 wt% of the activator in 2 hours, approximately 20 wt% to 80 wt% of the activator in 4 hours, approximately 40 wt% to 95 wt% of the activator in 8 hours, approximately 65 wt% to 100 wt% of the activator in 12 hours, and over 90 wt% of the activator in 24 hours, as measured by in vitro dissolution in a fiber optic dissolution test using a USP Apparatus II (paddle) at 50 rpm in biological, artificial, or simulated gastric fluid, e.g., 0.1 N HCl and / or biological, artificial, or simulated intestinal fluid, e.g., pH 6.8 phosphate buffer and / or water (including pancreatin as appropriate).

[0096] In a particular embodiment, the activator release rate from the controlled-release filling composition is such that less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, or less than 30% of the activator is released after approximately 0.5 hours, approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, or approximately 5 hours in a fiber optic dissolution test using USP Apparatus II with a paddle speed of 100 RPM at 37°C in 500 ml of biological, artificial, or simulated gastric fluid, e.g., 0.1 N HCl and / or biological, artificial, or simulated intestinal fluid, e.g., pH 6.8 phosphate buffer and / or water.

[0097] As described in further detail below, the modified release softgel capsules may be annealed at the annealing temperature for an annealing time. In certain embodiments, annealing facilitates the formation of the matrix inside the modified release softgel capsule. For example, if the controlled release material is polyethylene oxide, annealing may facilitate the melting of the polyethylene oxide, forming a matrix (liquid or solid) that is encapsulated inside the pH-dependent shell composition.

[0098] Another embodiment relates to a method for producing a controlled-release filling composition containing polyethylene oxide resin. This process is designed to accommodate softgel capsule shell compositions that are not suitable for high encapsulation temperatures due to the relatively low melting point of the capsule shell composition. For example, gelatin-based softgels may begin to melt at temperatures of 33–45°C, depending to some extent on the water content of the capsule shell material at the time of encapsulation. For capsule shell materials with lower melting temperatures, a method has been devised to fill the capsule with a liquid filling composition at a lower temperature. A major advantage of this method is that it can be used to ultimately encapsulate highly viscous liquid or semi-solid or solid filling compositions. In this method, a solid solution or semi-solid filling is formed in situ inside the capsule as a result of a heating step performed after encapsulation.

[0099] In this method, suspensions and dispersions may be used instead of solutions. Softgel capsule shells typically contain up to 20 wt% water relative to the total weight of the capsule shell at the completion of the encapsulation step. During the encapsulation and subsequent drying steps, a significant portion of the water in the capsule shell, i.e., up to about 70%, migrates into the filling composition, solubilizing solid components in the suspension / dispersion of the filling composition, e.g., PEO, in situ to form the desired solution. Using this method, the solubilization of solid components (e.g., PEO) in the filling composition occurs in situ. The water content in the filling composition before encapsulation is low enough to limit or avoid the solubilization of at least some of the components of the filling composition (e.g., PEO) before the encapsulation and drying steps. Premature solubilization of certain components in the filling composition (i.e., before encapsulation and drying) can increase the viscosity of the filling composition and hinder processability. Typically, the initial filling composition has a water content of approximately 2 wt% to 10 wt% relative to the total weight of the filling composition to avoid premature solubilization of the PEO component of the filling composition before encapsulation. After encapsulation of the filling composition, some of the water from the softgel capsule shell moves into the filling composition, typically increasing the water content of the filling composition to approximately 15 wt% to 20 wt% relative to the total weight of the encapsulated filling composition, thereby causing the solubilization of the PEO in the encapsulated filling composition. During subsequent drying, water is gradually removed until the water content of the encapsulated filling composition falls below 10 wt% relative to the total weight of the encapsulated and dried filling composition. After the final heating step (also called the annealing step), the water content of the final encapsulated filling composition further decreases to approximately 5 wt% to 8 wt% relative to the total weight of the final encapsulated filling composition. The final encapsulated filling composition forms a solid solution of PEO in a hydrophilic carrier.

[0100] This process of forming a solid solution in situ is important because, unlike powder-filled capsules or other solid dosage forms, it provides a more uniform distribution of the API in the filling composition. Uniform distribution of the API is a crucial feature for the delivery of high-potency and / or low-dose APIs, because such APIs should be delivered at a relatively constant rate over time to avoid over- or under-dosing. In certain embodiments, uniform distribution of the API in the filling composition allows for zero-order release of the API from a controlled-release filling composition (where the API is delivered at a relatively constant rate over time, for example, about 2 hours to about 12 hours, or about 2 hours to about 24 hours).

[0101] In one embodiment, the controlled-release filling composition comprises, or essentially comprises, at least one activator (e.g., a pharmaceutically active ingredient, e.g., an NSAID (e.g., ibuprofen), an antihistamine (e.g., diphenhydramine), acetaminophen, a dietary supplement (e.g., garlic oil, fish oil, krill oil, or other vitamins, minerals, or supplements)), a controlled-release material (e.g., polyethylene oxide having a number average molecular weight of about 0.05 M daltons to about 15 M daltons, optionally combined with a cellulose derivative (e.g., hydroxypropyl methylcellulose) or gum (e.g., xanthan gum)), and a hydrophilic carrier (e.g., polyethylene glycol having a number average molecular weight of about 200 daltons to about 5000 daltons, optionally combined with water).

[0102] In certain embodiments, the controlled-release filling composition may include additional filling components, such as flavoring agents, sweeteners, colorants, and fillers or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides.

[0103] pH-dependent shell composition According to one embodiment, the pH-dependent shell composition comprises gelatin, dextrose, a pH-dependent material (e.g., low-methoxyl pectin), and optionally a plasticizer. Preferably, the pH-dependent shell composition does not contain additional pH-dependent polymers.

[0104] In one embodiment, the gelatin in the pH-dependent shell composition may include type A gelatin, type B gelatin, animal hide or skin gelatin (e.g., cowhide, pighide) and / or bone gelatin (e.g., cowhide, pighide), used alone or in combination. In one embodiment, the gelatin is 250 bloom gelatin. In another embodiment, the gelatin is 150 bloom gelatin. In yet 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 approximately 25 wt% to approximately 85 wt%, approximately 25 wt% to approximately 80 wt%, approximately 30 wt% to approximately 85 wt%, approximately 30 wt% to approximately 75 wt%, approximately 35 wt% to approximately 70 wt%, approximately 30 wt% to approximately 65 wt%, approximately 40 wt% to approximately 65 wt%, approximately 30 wt% to approximately 55 wt%, approximately 30 wt% to approximately 40 wt%, approximately 40 wt% to approximately 80 wt%, approximately 45 wt% to approximately 65 wt%, approximately 45 wt% to approximately 60 wt%, approximately 45 wt% to approximately 75 wt%, or approximately 50 wt% to approximately 70 wt%, or any single value or partial range thereof, relative to the total weight of the dry capsule shell composition.

[0105] In one embodiment, the pH-dependent capsule shell composition contains dextrose. In one embodiment, the amount of dextrose in the pH-dependent capsule shell composition is about 0.001 wt% to about 1.0 wt%, about 0.002 wt% to about 0.008 wt%, about 0.005 wt%, or about 0.01 wt% to about 4 wt%, about 0.1 wt%, or about 0.15 wt% to about 3 wt%, about 0.1 wt% to about 1 wt%, about 0.1, or about 0.15 wt%, or about 0.2 wt%, or about 0.25 wt% to about 2 wt%, about 0.1 wt% to about 0.2 wt%, about 0.1 wt% to about 0.4 wt%, about 0.05 wt% to about 0.5 wt%, or any single value or sub-range thereof, based on the total weight of the dry capsule shell composition. Dextrose may be added to pH-dependent capsule shell compositions to mitigate a potential decrease in gel strength. Without being interpreted as limiting, dextrose is thought to interact with gelatin in the shell composition, causing crosslinking of the gelatin. The effect of the amount of dextrose on the solubility of the shell composition is further explained in the examples. The concentration of dextrose in the pH-dependent shell composition may be an effective amount to improve gel strength, but it does not need to be so high as to interfere with capsule sealing or manufacturability or product performance.

[0106] In some embodiments, the pH-dependent shell composition may contain pectin, such as low-methoxyl pectin. In one embodiment, the pectin is low-methyl ester (LM) pectin having a degree of esterification of less than 50. In some embodiments, the pectin is amidated pectin. In other embodiments, the low-methoxyl (LM) pectin is unamidated pectin. In certain embodiments, the pectin is a combination of amidated and unamidated pectin. The addition of pectin contributes to the pH dependence of the shell composition.

[0107] Excessive pectin in a dosage form can reduce the gel strength of the shell composition, which in turn can negatively affect the sealability of the softgel capsule. Excessive pectin in a pH-dependent shell composition can also increase its viscosity, making processing difficult or impossible from a manufacturing standpoint.

[0108] Therefore, pectin can be added to the dosage form at a concentration high enough to form a modified release softgel capsule, while simultaneously mitigating the decrease in gel strength and preventing the viscosity increase from reaching levels that would impede manufacturability.

[0109] In one embodiment, the amount of pectin in the pH-dependent shell composition is approximately 2 wt% to approximately 20 wt%, approximately 3 wt% to approximately 15 wt%, approximately 3 wt% to approximately 18 wt%, approximately 5 wt% to approximately 15 wt%, approximately 3 wt% to approximately 5.5 wt%, approximately 3.5 wt% to approximately 6.5 wt%, approximately 2.5 wt% to approximately 7 wt%, approximately 4 wt% to approximately 11 wt%, approximately 7 wt% to approximately 12 wt%, approximately 8 wt% to approximately 13 wt%, or approximately 5 wt% to approximately 10 wt%, or any single value or partial range thereof, relative to the total weight of the dry capsule shell composition.

[0110] The degree of esterification of pectin incorporated into the pH-dependent shell composition may be less than approximately 50%, or may be in the range of approximately 10% to approximately 50%, approximately 20% to approximately 40%, or approximately 25% to approximately 35%. Furthermore, the pectin may be amidated or unamidated.

[0111] In certain embodiments, the pH-dependent shell composition comprises a stabilizer and / or binder, including gellan gum. In certain embodiments, the wt:wt ratio of pectin to the stabilizer and / or binder (e.g., gellan gum) is about 1:10 to about 70:1; about 1:10 to about 50:1; about 1:5 to about 40:1; about 1:1 to about 25:1; about 1:1 to about 5:1; or about 10:1 to about 24:1.

[0112] In certain embodiments, the amount of stabilizer and / or binder (e.g., gellan gum) in the pH-dependent shell composition is about 0.05 wt% to about 5 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 2 wt%, or about 0.2 wt% to about 2 wt% of the stabilizer and / or binder (e.g., gellan gum) relative to the total weight of the dry capsule shell composition, or any single value or partial range thereof.

[0113] In a particular embodiment, the pH-dependent shell composition may have a viscosity ranging from approximately 20,000 cPs, approximately 30,000 cPs, approximately 40,000 cPs, approximately 50,000 cPs, approximately 60,000 cPs, or approximately 70,000 cPs to approximately 80,000 cPs, approximately 90,000 cPs, approximately 100,000 cPs, approximately 110,000 cPs, approximately 120,000 cPs, approximately 130,000 cPs, approximately 140,000 cPs, approximately 150,000 cPs, approximately 160,000 cPs, or approximately 170,000 cPs, or any sub-range or single value within that range. In one embodiment, the pH-dependent shell composition has a viscosity in the range of about 100,000 cPs to about 130,000 cPs, or about 110,000 cPs to about 125,000 cPs, or about 115,000 cPs, or about 120,000 cPs. The viscosity is measured using a rheometer at 60°C, as described in more detail in the example related to Figure 1. A gel mass sample (e.g., of any of the pH-dependent shell compositions described herein) is placed on the sample stage of a rheometer maintained at 60°C. The disk is rotated at a specific speed to yield a constant shear rate. The viscosity is obtained by measuring the shear stress and shear rate.

[0114] In certain embodiments, the pH-dependent shell composition may maintain a manufacturability-suitable viscosity even after thermal aging for up to approximately 24 hours, up to approximately 48 hours, up to approximately 72 hours, up to approximately 96 hours, or up to approximately one week. In certain embodiments, the viscosity of the pH-dependent shell composition may decrease by up to approximately 80%, up to approximately 70%, up to approximately 60%, up to approximately 50%, up to approximately 40%, up to approximately 35%, or up to approximately 30% (from the viscosity value of the composition before aging) after thermal aging (up to approximately 24 hours, up to approximately 48 hours, up to approximately 72 hours, up to approximately 96 hours, or up to approximately one week).

[0115] In one embodiment, the plasticizer in the pH-dependent shell composition may include glycerol, sorbitol, and combinations thereof. Other suitable plasticizers may include, but are not limited to, sugar alcohol plasticizers such as triacetin, 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, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine; and mixtures thereof. Other exemplary plasticizers may also include, without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, singleblock polymers, citrate ester plasticizers, and triacetins. 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.

[0116] In one embodiment, the amount of plasticizer in the pH-dependent shell composition is about 10 wt% to about 40 wt%, about 15 wt% to about 35 wt%, about 15 wt% to about 45 wt%, about 15 wt% to about 40 wt%, about 18 wt% to about 45 wt%, about 18 wt% to about 42 wt%, about 20 wt% to about 35 wt%, about 20 wt% to about 30 wt%, about 25 wt% to about 30 wt%, or any single value or partial range thereof, based on the total weight of the dry capsule shell composition.

[0117] In certain embodiments, the amounts of various components (e.g., pectin, dextrose, gelatin, plasticizers) and the ratios of these components are adjusted to control the solubility and / or disintegration properties of the pH-dependent shell composition across a range of pH values, thereby facilitating the targeted release of the activator in specific areas of the gastrointestinal tract.

[0118] For example, the gelatin-to-pectin w:w ratio in a pH-dependent shell composition can range from about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, or about 9:1 to about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, or about 20:1, or any sub-range or single value within that range. In certain embodiments, a lower gelatin-to-pectin w:w ratio provides a pH-dependent shell composition that is more stable (dissolves more slowly, if any) in an acidic medium (e.g., 0.1N HCl, optionally containing pepsin), while a higher gelatin-to-pectin w:w ratio provides a pH-dependent shell composition that is less stable (dissolves more quickly) in an acidic medium (e.g., 0.1N HCl, optionally containing pepsin). The gelatin-to-pectin w:w ratio can be adjusted to achieve a specific dissolution time for the softgel capsule in an acidic medium (e.g., about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, etc.).

[0119] Furthermore, the gelatin-to-plasticizer w:w ratio in the pH-dependent shell composition may be adjusted to achieve a specific capsule hardness level and may be in the range of approximately 5:1 to approximately 1:5, approximately 5:1 to approximately 1:2, approximately 4:1 to approximately 1:4, approximately 4:1 to approximately 1:2, approximately 3:1 to approximately 1:3, approximately 3:1 to approximately 1:2, approximately 2:1 to approximately 1:2, approximately 1:1, or any single ratio or sub-range within that range.

[0120] In certain embodiments, the pH-dependent shell compositions described herein may have hardness ranging from about 5N, about 6N, about 7N, about 8N, about 9N, or about 10N to about 11N, about 12N, about 13N, about 14N, or about 15N. Capsule hardness is determined using a hardness tester. Capsule hardness is defined as the force in Newtons required to cause a 2.0 mm deformation of the capsule.

[0121] In certain embodiments, the pH-dependent shell compositions described herein may have a shell moisture content ranging from about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, to about 11%, about 12%, about 13%, about 14%, or about 15%. Shell moisture content is determined by the loss on drying method. A 1-2 gram sample of the pH-dependent capsule shell composition is placed in an oven at 105°C for 17 hours. The initial weight of the sample is recorded. After drying the sample in an oven at 105°C for 17 hours, the final weight of the sample is recorded. The percentage of weight loss calculated according to the following formula is defined as shell moisture content:

[0122]

number

[0123] In certain embodiments, the pH-dependent shell compositions described herein may have equilibrium relative humidity ranging from about 25%, about 28%, about 30%, about 32%, about 34%, or about 35%, to about 38%, about 40%, about 42%, about 45%, or about 50%. Equilibrium relative humidity (%) is defined as the humidity conditions under which the capsule maintains a constant total weight. It is determined using an environmental chamber maintained at a constant humidity using a saturated salt solution.

[0124] In certain embodiments, the pH-dependent shell compositions described herein may have burst strengths ranging from about 50 kg, about 60 kg, about 70 kg, about 80 kg, or about 90 kg to about 100 kg, about 110 kg, about 120 kg, about 130 kg, about 140 kg, or about 150 kg. Burst strength is an indicator of the robustness of the capsule and is determined using a texture analyzer. The texture analyzer pressurizes the capsule until it bursts. The force in kilograms required to burst the capsule is defined as the burst strength.

[0125] In one embodiment, the pH-dependent shell composition and the pH-dependent softgel capsule may be without or substantially without conventional pH-dependent polymers and / or without a pH-dependent protective film on the softgel shell.

[0126] In one embodiment, the pH-dependent shell composition and pH-dependent softgel capsule are Ca ++ (e.g., CaCl2) or Mg ++ It may contain a divalent cation salt such as (e.g., MgCl2). In another embodiment, the pH-dependent shell composition and pH-dependent softgel capsule may contain Ca ++ (e.g., CaCl2) or Mg ++ Divalent cation salts such as (e.g., MgCl2) may be omitted or substantially omitted. In a further embodiment, the pH-dependent shell composition may contain Ca other than the amount of divalent cation salts that may be present in other components. ++ (e.g., CaCl2) or Mg ++The step of adding a divalent cation salt (such as MgCl2) does not need to be included.

[0127] In one embodiment, the pH-dependent shell composition may optionally contain additional agents, such as stabilizers or binders (e.g., gellan gum), colorants, flavorings, sweeteners, fillers, antioxidants, diluents, pH adjusters, or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides.

[0128] Exemplary suitable colorants for filling compositions and shell compositions may include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, violet, indigo, and brown. In certain embodiments, the color of the dosage form may indicate the contents contained therein (e.g., one or more active ingredients).

[0129] Exemplary suitable flavorings for filling and shell compositions include, but are not limited to, “flavoring extracts” obtained by extracting raw materials, e.g., parts of animal or plant material, often using a solvent such as ethanol or water; and may include natural essences obtained by extracting essential oils from flowers, fruits, roots, or whole plants.

[0130] Additional exemplary flavorings for the filling and shell compositions may include, but are not limited to, other flavorings or fragrances such as breath-freshening compounds like menthol, spearmint, and cinnamon, coffee beans, especially those used for oral hygiene, fruit flavorings (e.g., cherry, orange, grape, etc.), and active substances used in tooth and mouth washing, such as quaternary ammonium bases. The flavoring effect may be enhanced using flavor enhancers such as tartaric acid, citric acid, and vanillin.

[0131] Exemplary sweeteners for filling and shell compositions may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Artificial sweeteners include, for example, acesulfame and its various salts, e.g., potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salts (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, e.g., sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose, e.g., 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 name MagnaSweet®); stevia (Stevia rebaudiana) (stevioside); natural potent sweeteners such as monk fruit; polyols such as sorbitol, mannitol, xylitol, and erythritol.

[0132] In some embodiments, pH-dependent shell compositions and / or pH-dependent softgel capsules may be tested in a disintegration / dissolution test performed on a USP Apparatus II using a paddle at a speed of 50 rpm in an acidic medium of 0.1 N HCl (pH 1.2, optionally containing pepsin), followed by a buffer medium (pH 6.8 phosphate buffer, optionally containing pancreatin). pH-dependent shell compositions according to this embodiment may remain intact in the acidic medium 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, or at least about 5 hours, and may disintegrate in the buffer medium in about 60 minutes or less, about 45 minutes or less, about 30 minutes or less, about 20 minutes or less, about 15 minutes or less, about 10 minutes or less, or about 5 minutes or less.

[0133] It should be noted that while the buffer medium in the two-step dissolution / disintegration test has a pH of 6.8, a similar dissolution / disintegration profile can be achieved with a buffer medium having a pH of approximately 3.5 or higher (including pancreatin if necessary). It should also be noted that the presence of pepsin (in the acidic medium) and pancreatin (in the buffer medium) is not required for the pharmacopoeia method, but is used herein in certain examples to simulate a more aggressive environment that better mimics in vivo conditions.

[0134] In certain embodiments, the pH-dependent shell compositions described herein remain intact 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, or at least about 5 hours in an acidic environment (e.g., a gastric environment or a simulated gastric environment, e.g., simulated gastric juice, optionally containing pepsin and 0.1N HCl), but break / dissolve / disintegrate for up to about 5 minutes, up to about 10 minutes, up to about 15 minutes, up to about 20 minutes, up to about 25 minutes, up to about 30 minutes, up to about 35 minutes, up to about 40 minutes, up to about 45 minutes, or up to about 60 minutes at a pH of about 3.5 or higher (e.g., a duodenal region and / or a simulated environment of the intestine or therein, e.g., in a pH 6.8 buffer medium optionally containing pancreatin).

[0135] In one embodiment, the pH-dependent shell composition comprises (a) gelatin, (b) dextrose, (c) a pH-dependent polymer (e.g., pectin such as low-methoxyl pectin), (d) a plasticizer (e.g., glycerin, sorbitol, and combinations thereof), and optionally (e) a stabilizer and / or binder (e.g., gellan gum). The amounts and wt:wt ratios of these components may conform to any of the values ​​or ranges described above.

[0136] In one embodiment, the pH-dependent shell composition essentially consists of (a) gelatin, (b) dextrose, (c) a pH-dependent polymer (e.g., pectin such as low-methoxypectin), (d) a plasticizer (e.g., glycerin, sorbitol, gellan gum, and combinations thereof), and optionally (e) a stabilizer and / or binder (e.g., gellan gum). The amounts and wt:wt ratios of these components may conform to any of the values ​​or ranges described above.

[0137] In one embodiment, the pH-dependent shell composition comprises (a) gelatin, (b) dextrose, (c) a pH-dependent polymer (e.g., pectin such as low-methoxyl pectin), (d) a plasticizer (e.g., glycerin, sorbitol, gellan gum, and combinations thereof), and optionally (e) a stabilizer and / or binder (e.g., gellan gum). The amounts and wt:wt ratios of these components may conform to any of the values ​​or ranges described above.

[0138] In one embodiment, the pH-dependent shell composition is (a) gelatin of approximately 25 wt% to 85 wt%, approximately 25 wt% to 80 wt%, approximately 30 wt% to 85 wt%, approximately 30 wt% to 75 wt%, approximately 35 wt% to 70 wt%, approximately 30 wt% to 65 wt%, approximately 40 wt% to 65 wt%, approximately 30 wt% to 55 wt%, approximately 30 wt% to 40 wt%, approximately 40 wt% to 80 wt%, approximately 45 wt% to 65 wt%, approximately 45 wt% to 60 wt%, approximately 45 wt% to 75 wt%, or approximately 50 wt% to 70 wt%, (b) gelatin of approximately 0.001 wt% to 1.0 wt%, approximately 0.002 wt% (c) dextrose in amounts of t% to approximately 0.008 wt%, approximately 0.005 wt%, or approximately 0.01 wt% to approximately 4 wt%, approximately 0.1 wt%, or approximately 0.15 wt% to approximately 3 wt%, approximately 0.1 wt% to approximately 1 wt%, approximately 0.1, or approximately 0.15 wt%, or approximately 0.25 wt%, or approximately 2 wt%, approximately 0.1 wt%, to approximately 0.2 wt%, approximately 0.1 wt%, to approximately 0.4 wt%, approximately 0.05 wt%, to approximately 0.5 wt%, (c) approximately 2 wt%, to approximately 20 wt%, approximately 3 wt%, to approximately 15 (d) pH-dependent polymers (e.g., pectin such as low methoxypectin) in wt%, approximately 3wt% to 18wt%, approximately 5wt% to 15wt%, approximately 3wt% to 5.5wt%, approximately 3.5wt% to 6.5wt%, approximately 2.5wt% to 7wt%, approximately 4wt% to 11wt%, approximately 7wt% to 12wt%, approximately 8wt% to 13wt%, or approximately 5wt% to 10wt% of pectin, (d) approximately 10wt% to 40wt%, approximately 15wt% to 35wt%, approximately 15wt% to 45wt% Essentially consisting of / comprising (e) approximately 15 wt% to approximately 40 wt%, approximately 18 wt% to approximately 45 wt%, approximately 18 wt% to approximately 42 wt%, approximately 20 wt% to approximately 35 wt%, approximately 20 wt% to approximately 30 wt%, and approximately 25 wt% to approximately 30 wt%, as well as (e) approximately 0.05 wt% to approximately 5 wt%, approximately 0.1 wt% to approximately 3 wt%, approximately 0.1 wt% to approximately 2 wt%, or approximately 0.2 wt% to approximately 2 wt%, a stabilizer and / or binder (e.g., gellan gum), as optional. All wt%s are based on the total weight of the dry pH-dependent shell composition.

[0139] Process for preparing modified release softgel capsules In certain embodiments, the disclosure includes a process for preparing any of the modified release softgel capsules described herein, as shown in Figure 5. Process 500 may include the step (520) of encapsulating any of the controlled release filling compositions described herein inside any of the pH-dependent shell compositions described herein. The encapsulation of the filling composition may be accomplished in any conventional manner. For example, rotary die encapsulation may be used.

[0140] In certain embodiments, the modified release softgel capsules may be dried (530) after encapsulation. The softgel capsules may then be annealed (also referred to as curing) (540) at an annealing (or curing) temperature for an annealing (or curing) time to prepare the final modified release softgel capsules (550).

[0141] The annealing temperature may be in the range of approximately 25°C to 80°C, approximately 30°C to 70°C, or approximately 40°C to 60°C, approximately 25°C to 55°C, approximately 25°C to 50°C, approximately 30°C to 60°C, or approximately 35°C to 50°C. If annealing is performed, the annealing temperature should be high enough to enhance the delayed release properties of the pH-dependent shell composition and facilitate matrix formation within the pH-dependent shell composition, but not high enough to melt or decompose any components of the softgel capsule or the pH-dependent shell composition or controlled-release filling composition.

[0142] The annealing time may range from approximately 10 minutes to approximately 24 hours, approximately 30 minutes to approximately 12 hours, approximately 45 minutes to approximately 5 hours, or approximately 60 minutes to approximately 3 hours. In some embodiments, the annealing time may range from approximately 12 hours to approximately 168 hours, approximately 18 hours to approximately 120 hours, approximately 24 hours to approximately 72 hours, approximately 24 hours, approximately 48 hours, approximately 72 hours, or any sub-range or a single value within that range.

[0143] In one embodiment, the annealing of the softgel capsule may be carried out at a temperature of approximately 40°C for approximately 24 hours. In one embodiment, the annealing of the softgel capsule may be carried out at a temperature of approximately 40°C for approximately 48 hours. In one embodiment, the annealing of the softgel capsule may be carried out at a temperature of approximately 40°C for approximately 72 hours. In one embodiment, the annealing of the softgel capsule may be carried out at a temperature of approximately 60°C for approximately 1 to 3 hours. In one embodiment, the annealing of the softgel capsule may be carried out at a temperature of approximately 65°C for approximately 90 minutes.

[0144] In certain embodiments, curing may be carried out in air (without any specific control over the nitrogen or oxygen or humidity content). In certain embodiments, annealing may be carried out under inert conditions (e.g., in nitrogen).

[0145] In certain embodiments, prior to encapsulation, process 500 may include the preparation of a controlled-release filling composition. The controlled-release filling composition may be prepared by combining, for example, mixing, at least one activator with a controlled-release material and, optionally, a hydrophilic carrier if one is present. Any other optional components, such as pharmaceutically acceptable excipients, may also be mixed into the mixture to form the controlled-release filling composition. For example, in process 500 in Figure 5, the activator (referred to as the active pharmaceutical ingredient 512) is mixed with a controlled-release material (exemplified by polyethylene oxide 514), a hydrophilic carrier (exemplified by polyethylene glycol 516), and other components (518).

[0146] In certain embodiments, prior to encapsulation, process 500 may include the preparation of a pH-dependent shell composition (not shown in Figure 5). pH-dependent softgel capsules can be prepared, for example, by mixing gelatin, dextrose, pectin, a plasticizer if necessary, a binder if necessary (e.g., gellan gum), and any other optional components, such as pharmaceutically acceptable excipients. In preferred embodiments, the pH-dependent shell composition does not include additional pH-dependent polymers (e.g., conventional pH-dependent synthetic polymers), and when preparing the pH-dependent shell composition according to certain embodiments, they may not be added to the mixture.

[0147] The thickness of the pH-dependent shell composition ribbon (e.g., as used during rotary die encapsulation) can also be adjusted to control the pH-dependent dissolution profile of the final pH-dependent shell composition and to facilitate targeted release of the filling composition to specific areas within the GIT. The thickness of the pH-dependent shell composition ribbon can be any of the following ranges, or any sub-range or single value, from approximately 0.02 inches, 0.022 inches, 0.024 inches, 0.026 inches, 0.028 inches, or 0.030 inches to approximately 0.032 inches, 0.034 inches, 0.036 inches, 0.038 inches, 0.04 inches, 0.042 inches, 0.044 inches, or 0.050 inches, without limitation.

[0148] In one embodiment, a process for preparing pH-dependent softgel capsules comprises, essentially, or consists of, the steps of: a) preparing one of the controlled-release filling compositions described herein; b) encapsulating the controlled-release filling composition from step a) into one of the pH-dependent shell compositions described herein (e.g., by rotary die encapsulation); c) drying the encapsulated pH-dependent softgel capsule (e.g., by tumble drying or normal drying in a basket without tumbling); and optionally d) curing / annealing the pH-dependent softgel capsule according to one of the curing / annealing conditions described herein.

[0149] In certain embodiments, drying is performed at a temperature of approximately 10°C to 50°C, approximately 15°C to 40°C, or approximately 20°C to 35°C, with a relative humidity of approximately 5% to 40%, approximately 10% to 30%, or approximately 15% to 25%.

[0150] In certain embodiments, references to drying and curing / annealing should be distinguished herein. The purpose of drying the modified release softgel capsules described herein is to remove excess water from the modified release softgel capsules immediately after encapsulation. Thus, the capsules become physically stable. The purpose of curing / annealing the modified release softgel capsules described herein is to enhance the delayed release properties of the modified release softgel capsules. Therefore, the presence of a drying step is not the same as the curing / annealing step, and similarly, the presence of a curing / annealing step is not the same as the drying step.

[0151] Stability of modified release softgel capsules In certain embodiments, the pH-dependent shell compositions described herein are chemically and physically stable.

[0152] For example, their chemical stability can be demonstrated by the content of activators in the filler composition (e.g., the content of fish oil components if the filler composition contains fish oil). In certain embodiments, the content of filler composition components is substantially similar (or within specifications) to the original composition before storage after storage for up to 12 months, up to 6 months, up to 3 months, or up to 1 month (during any of these periods, under ambient conditions or under stress conditions of 40°C and 75% relative humidity).

[0153] In certain embodiments, the physical stability of modified release softgel capsules and pH-dependent shell compositions can be demonstrated by the dissolution profiles of the capsules in acidic and buffered media. For example, the dissolution profiles of the capsules in acidic and buffered media are substantially similar (or within specifications) to the dissolution profiles of the capsules before storage after storage for up to 12 months, up to 6 months, up to 3 months, or up to 1 month (during any of these periods, under ambient conditions or under stressed conditions of 40°C and 75% relative humidity).

[0154] The term "substantially similar" can refer to a specific value that is within approximately 30%, 25%, 20%, 15%, 10%, 5%, or 1% of the corresponding comparison value. The percentages are calculated based on the nominal value of the comparison value. For example, a dissolution time range of 27 to 33 minutes may be considered within 10% of a comparison dissolution time of 30 minutes.

[0155] In certain embodiments, the disclosure may also cover methods for stabilizing any of the modified release softgel capsules described herein. The method may include protecting any of the filling compositions described herein (e.g., from another potential cause of oxidation or chemical degradation) by encapsulating any of the filling compositions described herein (containing at least one activator) in any of the pH-dependent shell compositions described herein.

[0156] In certain embodiments, the pH-dependent shell compositions described herein produce robust, modified-release softgel capsules that exhibit little to no premature release of the filling composition in an acidic environment (e.g., a gastric environment). For example, the modified-release softgel capsules described herein may release up to approximately 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 1 wt%, or 0 wt% of the filling composition relative to the total weight of the filling composition in an acidic environment after exposure to an acidic environment for up to approximately 150 minutes, 120 minutes, 105 minutes, 90 minutes, 75 minutes, 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes. The release time of the filling composition should not be confused with the release time of the activator in the filling composition, because, as detailed in the section on controlled-release filling compositions, the release profile of the activator from the filling composition is determined by the components of the controlled-release filling composition.

[0157] In certain embodiments, curing / annealing the modified release softgel capsules described herein (i.e., those encapsulated in a pH-dependent shell composition) can reduce or eliminate the number of capsules exhibiting any amount of premature release in an acidic environment. For example, the number of cured / annealed capsules exhibiting premature release in an acidic environment (after exposure to an acidic environment for up to approximately 150 minutes, up to approximately 120 minutes, up to approximately 105 minutes, up to approximately 90 minutes, up to approximately 75 minutes, up to approximately 60 minutes, up to approximately 45 minutes, up to approximately 30 minutes, up to approximately 15 minutes, up to approximately 10 minutes, or up to approximately 5 minutes) may be up to approximately 30%, up to approximately 25%, up to approximately 20%, up to approximately 15%, up to approximately 10%, up to approximately 5%, up to approximately 3%, up to approximately 2%, up to approximately 1%, or 0% of the total number of capsules in a batch.

[0158] For comparison, without curing / annealing, the number of capsules (having the same composition) exhibiting early release in an acidic environment (after exposure to an acidic environment for up to approximately 150 minutes, 120 minutes, 105 minutes, 90 minutes, 75 minutes, 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes) may be more than 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the total number of capsules in the batch.

[0159] In certain embodiments, curing / annealing the modified release softgel capsules described herein (i.e., those encapsulated in a pH-dependent shell composition) may reduce or eliminate the amount of filling composition released from capsules exhibiting some premature release in an acidic environment (e.g., after exposure to an acidic environment for up to about 150 minutes, up to about 120 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).

[0160] For example, in an acidic environment (e.g., after exposure to an acidic environment for up to approximately 150 minutes, 120 minutes, 105 minutes, 90 minutes, 75 minutes, 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes), the amount of the filling composition released from a cured / annealed capsule exhibiting some early release may be up to approximately 5 wt%, 4 wt%, 3 wt%, 2 wt%, 1 wt%, or 0% of the total weight of the filling composition in the capsule.

[0161] For comparison, without curing, the amount of filling composition released from a capsule (having the same composition) exhibiting early release in an acidic environment (for example, after exposure to an acidic environment for up to approximately 150 minutes, 120 minutes, 105 minutes, 90 minutes, 75 minutes, 60 minutes, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes) may be more than approximately 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, or 20 wt% of the total weight of the filling composition in the capsule.

[0162] Dual-release softgel capsules The softgel capsules described herein include two levels of controlled release. The first level is determined by the pH-dependent shell composition, which facilitates the targeted release of the filling composition in a specific region within the GIT. The second level is determined by the controlled release filling composition, which facilitates a controlled release profile of the activator in a specific region within the GIT.

[0163] In certain embodiments, this disclosure relates to methods for modulating / modulating / controlling the dissolution location and dissolution profile of any of the delayed-release capsules described herein (i.e., consisting of a controlled-release filling material encapsulated in a pH-dependent shell composition). The methods include at least one of i) to iv): i) an amount of at least one pectin, gelatin, dextrose, and plasticizer in the pH-dependent shell composition; ii) an annealing temperature of the modified-release softgel capsule; iii) an annealing time of the modified-release softgel capsule; or iv) a step of adjusting the thickness of the ribbon of the pH-dependent shell composition to control the dissolution location of the pH-dependent shell composition along the gastrointestinal tract of interest. The methods further include at least one of (v) to (vii): v) an amount of controlled-release material in the controlled-release filling composition; or vi) an annealing temperature of the modified-release softgel capsule; or vii) an annealing time of the modified-release softgel capsule to achieve a targeted dissolution profile of at least one activator.

[0164] In certain embodiments, the Disclosure also includes a method of treating a condition treatable by any of the modified-release softgel capsules described herein by administering any of the modified-release softgel capsules described herein to a subject requiring such treatment. [Examples]

[0165] Specific embodiments of this disclosure will now be demonstrated by reference to the following examples. These examples are disclosed solely for illustrative purposes of this disclosure and should not be construed as limiting the scope of this disclosure.

[0166] [Example 1] Effect of dextrose concentration on the production of pH-dependent shell compositions pH-dependent shell compositions containing various concentrations of dextrose were prepared, and the effect of dextrose concentration on the manufacturability of the compositions was studied. The pH-dependent shell compositions are shown in Table 1.

[0167] [Table 1]

[0168] The effects of various amounts of dextrose in the pH-dependent shell composition on the rupture time at pH 6.8 are shown in Table 2.

[0169] [Table 2]

[0170] Dextrose is a reducing sugar and is thought to interact with gelatin by cross-linking it. When gelatin is cross-linked, its solubility decreases. Dextrose has been shown to stabilize pectin softgel capsules in acidic media (i.e., reduce their leakage).

[0171] [Example 2] Effect of hardening on capsule release properties pH-dependent shell compositions were prepared, and the effect of curing on the capsule release properties related to the overall filling composition was studied (note that the activator release profile from the filling composition is a second level of controlled release not illustrated in this particular example). The pH-dependent shell compositions are shown in Table 3.

[0172] [Table 3]

[0173] Existing commercially available products exhibit early release in many capsules, with an increasing amount of the filler composition released early, and in some cases, nearly 100 wt% of the filler composition is released within 10 minutes in an acidic medium.

[0174] Coated softgel capsules were attempted, but they did not dissolve in the buffer medium for extended periods (longer than approximately 60 minutes, and in some cases as long as 120 minutes). This prolonged dissolution in the buffer medium suggested that the coated softgel capsules were not bioavailable. This, along with the challenges of the two-step manufacturing process, prompted the search for pH-dependent shell compositions to form modified release softgel capsules without additional coating.

[0175] Using the pH-dependent shell compositions shown in Table 3, pectin softgels were formed that reduced the occurrence of premature release and the amount of prematurely released filler composition to some extent (compared to existing commercial products).

[0176] However, as summarized in Table 3 under "Percentage of capsules exhibiting premature release before curing," a significant percentage of softgel capsules in each lot still exhibited some premature release of the filling composition in an acidic environment (e.g., 0.1N HCl) before curing. Approximately 60 to 72 capsules were tested from each lot to evaluate the percentage of capsules exhibiting premature release before curing.

[0177] In certain embodiments, approximately 10 wt% of the filling composition was released from a capsule having early release before curing. In certain embodiments, more than 10 wt% of the filling composition or less than 10 wt% of the filling composition was released from a capsule having early release before curing.

[0178] As shown in subsequent examples, curing reduces the occurrence of premature release, the amount of filler composition released when premature release occurs, and in some cases completely eliminates premature release.

[0179] Pectin softgel capsules were cured to enhance their stability in acidic environments (e.g., 0.1N HCl). The pectin softgels were packed into cartons (bulk) or high-density polyethylene (HDPE) bins and placed in an oven heated to 40°C. No humidity control was used. The only variable between samples was curing time. The curing study results for lots 1, 2, and 3 are summarized in Table 4 below.

[0180] [Table 4]

[0181] The dissolution of the pH-dependent shell composition after curing was evaluated according to the USP Enteric Composition Test Method for a two-step enteric complication test applicable to uncoated enteric softgels. Unless otherwise specified, the acidic media, buffering media, apparatus, and dissolution test conditions for all dissolution / disintegration / breakdown / breakage results and / or properties throughout this application were as described herein for the two-step enteric complication test.

[0182] A USP Apparatus II with a paddle was used at a paddle speed of 50 rpm at 37°C. The acidic step medium was 0.1N HCl. The buffering step medium was pH 6.8 phosphate buffer. For vitamin and mineral supplements and / or dietary supplements, enteric-coated capsules should remain intact in the acidic medium for at least 60 minutes to pass through the first step and should rupture within 45 minutes in the buffering step medium to pass through the second step. For pharmaceutical products, enteric-coated capsules should remain intact in the acidic medium for at least 120 minutes to pass through the first step and should rupture within 45 minutes in the buffering step medium to pass through the second step.

[0183] The curing of the softgel capsules was evaluated at 24 hours, 48 ​​hours, 72 hours, 120 hours, 168 hours, and 288 hours. However, only data up to 72 hours are presented herein.

[0184] Table 5 shows the amount of premature release of the filling composition from Lot 3 pectin softgel capsules before and after curing in an acidic medium according to USP enteric coating standards at the end of 2 hours. The maximum amount of released filling composition was 5%. The Lot 3 pectin softgel capsules contained fish oil (containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) in the filling composition.

[0185] [Table 5]

[0186] The curing data showed that curing significantly reduces or eliminates the premature release of the filling composition from the pectin capsule in an acidic medium, resulting in capsules with robust enteric coating properties and high-quality enteric-coated products.

[0187] Note that all of the pectin softgel capsules tested in Table 5 dissolved within 15 minutes in pH 6.8 buffer.

[0188] [Example 3] Enteric lysis data in pepsin-containing simulated gastric juice (SGF) The hardened pectin capsules containing the gel mass formulations summarized in Table 6A were subjected to an intestinal rupture test using pepsin-containing SGF (0.1N HCl) (to simulate human in vivo conditions) for a two-step enteric lysis study.

[0189] [Table 6]

[0190] [Table 7]

[0191] When an appropriate shell composition, such as a gelatin-to-pectin ratio, was used, pepsin did not affect the dissolution of the pectin shell in a 0.1N HCl medium. In lots 4 and 5, shown in Tables 6A and 6B, the gelatin-to-pectin w:w ratio was 7:1. Without interpretation as limitation, the pectin softgel is robust, and unlike enzyme-free pharmacopoeia methods, the gelatin-pectin network is considered strong enough to withstand the effects of pepsin, as demonstrated by the pectin softgel capsules remaining intact for 120 minutes even in 0.1N HCl in the presence of pepsin, representing a biocompatible medium. Therefore, the pectin softgel capsules are considered sufficiently robust even in vivo.

[0192] [Example 4] Modulation of pectin capsule rupture time in the intestinal medium by changing the gelatin-to-pectin ratio. Pectin softgel capsules were prepared with various gelatin-to-pectin ratios. The compositions of various lots are summarized in Table 7B below. As summarized in Table 7A below, the rupture time of pectin capsules in pepsin-containing SGF (0.1N HCl) changed with various gelatin-to-pectin ratios.

[0193] [Table 8]

[0194] [Table 9]

[0195] All pectin softgel capsules in Table 7A ruptured within 45 minutes in pH 6.8 buffer. Table 7A shows that the rupture time of pectin softgel capsules in acidic media can be modulated by changing the gelatin-to-pectin ratio.

[0196] [Example 5] Effect of softgel ribbon thickness on enteric coating performance of pectin softgel capsules Pectin softgel capsules were prepared with various ribbon thicknesses. The composition of the dried pH-dependent shell from lots produced with various ribbon thicknesses is summarized in Table 8A below. The solubility of pectin capsules of various ribbon thicknesses in SGF (0.1N HCl) and pH 6.8 buffer after curing for approximately 72 to 96 hours was evaluated. The results are summarized in Table 8B below.

[0197] [Table 10]

[0198] [Table 11]

[0199] The dissolution results shown in Table 8B indicate that cured pectin softgel capsules with ribbon thicknesses ranging from 0.028 inches to 0.038 inches are robust and meet enteric coating standards for pharmaceutical and VMS (vitamin, mineral, and supplement) products. This thickness range should not be interpreted as limiting. In certain embodiments, thicker or thinner ribbons may also be available.

[0200] [Example 6] pH-dependent viscosity of aged shell composition Pectin and gelatin interact with each other, forming a network that contributes to the significant increase in gel mass viscosity shown in Figure 1. This interaction between pectin and gelatin is thought to contribute to the delayed release properties of the capsule shell composition. However, as shown in Figure 1, the viscosity of the gel mass of the pH-dependent shell composition decreases over time. The viscosity and percentage decrease are summarized in Table 9 below.

[0201] Viscosity in this example and throughout this specification was measured using a rheometer (Thermo Fisher Rheostress 6000) at 60°C. The tests were conducted under ambient conditions. A gel mass sample was placed on the sample stage of a rheometer maintained at 60°C. A 40 mm disc vibrated at a frequency of 0.1 Hz, resulting in a constant shear rate. Viscosity was obtained by measuring the shear stress and shear rate.

[0202] [Table 12]

[0203] As can be seen from Table 9, after aging at 60°C for 48 hours, 60°C for 72 hours, and 60°C for 96 hours, the viscosity of non-amidated pectin decreases by a smaller percentage compared to the viscosity of amidated pectin.

[0204] The decrease in viscosity is thought to be caused by the thermal decomposition of the molecular chain lengths of pectin and gelatin. Despite this viscosity reduction, the gel mass of the pH-dependent shell composition maintains a viscosity suitable for manufacturability and machinability, even after the composition has been held in heat at 60°C for four days. Furthermore, softgel capsules manufactured with aged gel still exhibit sufficient pH-dependent delayed release properties.

[0205] [Example 7] Chemical stability of pectin softgel capsules Table 10 below shows the chemical stability of fish oil encapsulated in pectin pH-dependent shell compositions according to the embodiments described herein after storage for 6 months under ambient conditions and at 40°C and 75% relative humidity (RH). Acceptable capsules should have EPA TG ≥ 160 mg / g, DHA TG ≥ 100 mg / g, peroxide ≤ 5 meq O2 / kg, p-anisidine ≤ 20, a dissolution time of more than 120 minutes in 0.1N HCl (pH 1.2), and a maximum dissolution time of 45 minutes in a buffer medium (pH 6.8 phosphate buffer). The values ​​for these parameters are summarized in Table 10 for the control (fish oil raw material), delayed-release softgel pectin capsules stored for 6 months under ambient conditions, and delayed-release pectin softgel capsules stored for 6 months at 40°C and 75% RH.

[0206] [Table 13]

[0207] The accelerated stability data (summarized in Table 10) demonstrates that the pH-tolerant pectin shell composition according to the embodiment protected the filler composition (e.g., fish oil components) from oxidation, as is evident from the slight / substantial similarity of peroxide and p-anisidine values ​​and EPA and DHA assays after 6 months (under ambient conditions and under stress conditions of 40°C and 75% RH) compared to the raw material.

[0208] [Example 8] Valproic acid pectin softgel capsules Table 11A below shows the stability of the solubility profile of valproic acid encapsulated in pectin pH-dependent shell compositions (the gel formulations of the dry shell compositions are summarized in Table 11B) according to the embodiments described herein, after storage for 3 months at 40°C and 75% relative humidity (RH) (T=3 months) and after storage for 6 months at 40°C and 75% RH (T=6 months). As demonstrated in Table 11A, the solubility profile of the pH-dependent shell compositions after storage for 3 months at 40°C and 75% RH and after storage for 6 months at 40°C and 75% RH remains substantially similar to the solubility profile at T=0.

[0209] [Table 14]

[0210] [Table 15]

[0211] [Example 9] Physical attributes of pectin softgel capsules The modified release softgel capsules having the pH-dependent shell composition described herein are robust, as demonstrated by the physical attributes summarized in Table 12 below.

[0212] [Table 16]

[0213] Shell moisture content was determined by the loss on drying method. 1-2 grams of pH-dependent capsule shell composition samples were placed in a 105°C oven for 17 hours. The initial weight of the sample was recorded. After drying the sample in a 105°C oven for 17 hours, the final weight of the sample was recorded. The percentage of weight loss, calculated according to the following formula, was defined as shell moisture content:

[0214]

number

[0215] Capsule hardness was determined using a hardness tester. Capsule hardness was defined as the force in Newtons required to cause a deformation of 2.0 mm in the capsule.

[0216] 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.

[0217] The burst strength was determined using a texture analyzer. The texture analyzer pressurizes the capsule until it bursts. The force required in kilograms to burst the capsule was defined as the burst strength.

[0218] [Example 10] Exemplary composition of pectin and gellan gum modified release softgel capsules Modified release softgel capsules containing a combination of pectin and gellan gum were prepared. The formulations based on the dry shell composition are summarized in Table 13 below.

[0219] [Table 17]

[0220] Examples 1-10 illustrate a first level of controlled release in the dual controlled-release softgel capsule described herein. The first level is a pH-dependent shell composition. Examples 11-12 illustrate a dual level of controlled release, where the first level may be attributed to a pH-dependent shell composition and the second level to a controlled-release filling composition.

[0221] [Example 11] Exemplary compositions of pectin and gellan gum modified release softgel capsules containing controlled-release filling compositions Dual controlled-release softgel capsules were prepared containing the pH-dependent shell composition described in Table 14 and the controlled-release filling composition described in Table 15.

[0222] [Table 18]

[0223] [Table 19]

[0224] The polyethylene oxide polymer grade used in the controlled-release filling compositions summarized in Table 15 was POLYOX® WSR301. POLYOX® WSR301 is a water-soluble polymer. It is based on a long-chain nonionic polyethylene oxide polymer. POLYOX® WSR301 has a high molecular weight of 4,000,000 Daltons and a viscosity of 1650 to 5500 cPs.

[0225] Modified release softgel capsules were prepared by encapsulating each of the controlled release filling compositions in Table 15 within the pH-dependent shell compositions in Table 14. After encapsulation, the modified release softgel capsules were dried. After drying, the capsules were annealed at 60°C for 1 to 3 hours. After annealing, the capsules were cooled to ambient conditions. Annealing facilitated the melting of the polyethylene oxide polymer, forming a solid matrix inside the capsule.

[0226] Dissolution tests were performed on the obtained capsules using a USP Apparatus II with a 50 rpm paddle. 0.1N HCl was used as the dissolution medium for the first 120 minutes. Then, phosphate buffer was added to adjust the pH to 6.8. The drug release profile was monitored for up to 24 hours using a fiber optic probe. Figure 2 shows the ibuprofen release profile from the capsules.

[0227] As shown in Figure 2, no ibuprofen was released during the first two hours in a 0.1N HCl medium, demonstrating the robust enteric coating properties of the pH-dependent shell composition. It should be noted that according to the pharmacopoeia, up to 10% release is observed in acidic media. When the pH was adjusted to pH 6.8, ibuprofen was gradually released from the polyethylene oxide polymer matrix (i.e., from the controlled-release filling composition).

[0228] The amount of polyethylene oxide polymer had an effect on the rate of ibuprofen release. The higher the amount of polyethylene oxide polymer, the slower the ibuprofen release. Filler-3, a formulation containing 24 wt% polyethylene oxide polymer, achieved a zero-order release profile over a 24-hour period. Filler-1 and Filler-2, formulations containing 12 wt% and 18 wt% polyethylene oxide polymer, respectively, achieved release profiles over a 12-hour period.

[0229] This data demonstrated that the drug release profile can be modulated by changing the filler composition.

[0230] [Example 12] Exemplary composition of pectin-modified release softgel capsules containing a controlled-release filling composition Dual controlled-release softgel capsules were prepared containing the pH-dependent shell composition described in Table 16 and the controlled-release filling compositions described in Tables 17 (diphenhydramine) and 18 (acetaminophen). The controlled-release filling compositions were encapsulated in the pH-dependent shell compositions, and the capsules were then dried.

[0231] [Table 20]

[0232] [Table 21]

[0233]

Table 22

[0234] Each diphenhydramine capsule contained 50 mg of diphenhydramine. Each acetaminophen capsule contained 325 mg of acetaminophen.

[0235] Next, the filled capsules were placed in an oven at 65 °C for 90 minutes to anneal the capsules. After annealing, the capsules were subjected to a two-stage dissolution test. The paddle speed was set at 50 RPM. For the first 120 minutes, 0.1 N HCl was used as the dissolution medium. Then, phosphate buffer was added to adjust the pH to 6.8. The drug release profile was monitored for up to 12 hours using an optical fiber probe. Figures 3 and 4 show the release of diphenhydramine and acetaminophen from the capsules, respectively.

[0236] In summary, the combination of pectin in the shell composition and Polyox™ polymer in the fill composition has provided a new drug delivery platform that has the potential to be used for colon drug delivery and other drug delivery applications.

[0237] [Examples 13 - 18] Dissolution Profile of Fill Composition For the design of six filling compositions used in Samples 1 to 12 shown in Table 19 below, a two - series 2×3 full - factorial experimental design was utilized. To enable the evaluation of compositional variations, each composition was prepared twice. Diphenhydramine HCl was used as a model drug for the active pharmaceutical ingredient in the filling composition. "PEG400" is an abbreviation for polyethylene glycol having a number - average molecular weight of 400, "PEO" is an abbreviation for polyethylene oxide, "M" represents "one million", "HCl" is an abbreviation for hydrogen chloride, and "Mn" is an abbreviation for number - average molecular weight. All PEOs used in Samples 1 to 12 were non - ionic and water - soluble, and were Polyox (trademark) products available from DuPont Pharma Solutions.

[0238] [Table 23]

[0239] Diphenhydramine capsules of Samples 1 to 12 using the filling compositions shown in Table 19 were prepared as follows. First, diphenhydramine HCl (DHP) was solubilized in 2 ml of water, and the filling composition was prepared by mixing PEG400 with PEO to form two components. Then, the DPH aqueous solution was added to the PEG / PEO mixture. Each No. 0 capsule was filled with 0.55 g of the filling composition, providing a dose of 50 mg of diphenhydramine per capsule. Then, the capsules were annealed in an oven at 60 °C for 1 hour.

[0240] Dissolution studies were carried out using filled No. 0 gelatin hard - shell capsules containing the filling composition by fiber - optic dissolution using USP Apparatus II at 37 °C in 500 ml of water as the dissolution medium, with paddle speeds of 50 rpm and 100 rpm. The filling compositions used for the dissolution study are shown in Table 20.

[0241] [Table 24]

[0242] Figure 6 shows the dissolution profiles of the six filling compositions listed in Table 20 at a paddle speed of 100 RPM. Figure 7 shows the dissolution profiles of the six filling compositions listed in Table 20 at a paddle speed of 50 RPM.

[0243] The dissolution profiles were similar for each filler composition at paddle speeds of 50 RPM and 100 RPM, indicating that the drug release mechanism was primarily by diffusion. The dissolution results showed that higher molecular weight PEO and higher PEO concentrations resulted in slower drug release, respectively. As shown in Figures 6-7, filler compositions 5 and 6 prepared from 0.1 M PEO had immediate release profiles, while all other filler compositions showed variable drug release rates.

[0244] The collected lysis datasets were analyzed using the Minitab 16 software package. The time to reach 90% drug release was used as the dependent variable. The effects of PEO content and PEO molecular weight on the dependent variable were analyzed using the General Linear Model module within the Minitab 16 software package. The results are summarized in Tables 21-22 and 24 below.

[0245] [Table 25]

[0246] [Table 26]

[0247] [Table 27]

[0248] [Table 28]

[0249] In the foregoing table, the following abbreviations were used: DF - Degree of freedom Seq SS - Sequential sum of squares, which is a measure of the variation for different components of the model. Adj SS - Adjusted sum of squares for a term is the increase in the regression sum of squares compared to a model having only the other terms. Adj MS - Adjusted mean square measures how much variation a term or model explains. F - The F - value is a test statistic used to determine whether a model is missing higher - order terms that include the predictor variables in the current model. P - Probability. P < 0.05 indicates that the result is significant; otherwise, the result is not significant. N - Number of data points

[0250] Figures 8A - 8D show residual plots for 90% of the time (h). Figure 8A is a normal probability plot, Figure 8B is against the fitted values, Figure 8C is a histogram, and Figure 8D is against the order. Figure 9 shows an interaction plot for the time (h) until 90% is released. Figure 10 is a graph showing the main effect plot for the time (h) until 90% is released.

[0251] Based on these statistical analyses, there is an interaction between the time until release and the PEO molecular weight and concentration. The higher the PEO molecular weight and the higher the PEO concentration, the slower the API release.

[0252] [Example 19] PEO polymer, high Mn polyethylene glycol, and immediate - release composition of HPMC polymer For potential applications in abuse-preventing softgel capsules, we developed immediate-release compositions based on PEO resin, high molecular weight polyethylene glycol (1,000-5,000 Daltons), and low viscosity hydroxypropyl methylcellulose (HPMC). Three formulations were prepared, as shown in Table 25 below. Formulation 13 contained PEO and PEG3350 with a number-average molecular weight of 100,000 Da. Formulation 14 contained PEO and HPMC. Formulation 15 contained PEO, PEG3350, and HPMC.

[0253] [Table 29]

[0254] Diphenhydramine (DPH) capsules No. 0 were prepared by mixing PEG400 with PEO and PEG3350 and / or HPMC. DPH was solubilized in water, and the DPH solution was added to the PEG / PEO mixture, HPMC / PEO mixture, or PEO / PEO / HPMC mixture. Each capsule was filled with 0.5 g of the filling mixture (25 mg of diphenhydramine per capsule). Finally, the capsules were annealed in an oven at 60°C for 1 hour.

[0255] For dissolution studies, optical fiber dissolution was performed using a USP Apparatus II in 500 ml of water at 37°C with a paddle speed of 100 RPM as the dissolution medium. The dissolution profiles for formulations 13-15 are shown in Figure 11.

[0256] Compositions 13-15 were shown to be immediate-release formulations. Diphenhydramine release from these formulations reached 100% in approximately one hour. Composition 15 had the fastest drug release rate among the three formulations. While we should not be bound by theory, this is thought to be due to the higher amount of PEG3350 in formulation 15.

[0257] [Examples 20-22] Controlled-release PEO softgel capsules Three batches of softgel capsules containing filling compositions made from PEO resins with various number-average molecular weights (900,000 Da, 5,000,000 Da, and 7,000,000 Da) were manufactured using a softgel capsule encapsulation machine. The filling compositions used for batch manufacturing are shown in Tables 26-28 below.

[0258] [Table 30]

[0259] [Table 31]

[0260] [Table 32]

[0261] After encapsulation, the softgel capsules were sealed in aluminum bags for 5 days to allow moisture to move from the moist capsule shell into the filler. This moisture movement was used to solubilize the PEO in the filler composition, forming a gel and providing a sustained release profile. After 5 days, the moisture content of the filler in each capsule was tested, and the results are shown in Table 29 below.

[0262] [Table 33]

[0263] Although the moisture content of the filler was sufficiently high, the results showed that the PEO resin particles inside the softgel capsules were not completely solubilized. Without being constrained by theory, it appears that PEG400 bound to the moisture in the filler, preventing the complete solubilization of the PEO resin particles. Therefore, the softgel capsules were annealed in an oven at 60°C for 1 hour to melt and solubilize the PEO resin particles. The annealed softgel capsules were then subjected to a dissolution test.

[0264] In vitro drug release rates were evaluated using fiber optic dissolution with USP Apparatus II at paddle speeds of 50 RPM and 100 RPM in 500 ml of aqueous dissolution medium at 37°C. Comparative dissolution results of capsules prepared using three different PEO resins with varying number-average molecular weights are shown in Figures 12-13.

[0265] At a paddle speed of 100 RPM, capsules containing PEO with a number-average molecular weight of 900,000 Da showed a faster drug release rate compared to capsules prepared with PEO having a number-average molecular weight of 5,000,000 or 7,000,000 Da. Capsules prepared with PEO having number-average molecular weights of 5,000,000 and 7,000,000 Da showed similar drug release rates. At 50 RPM, the dissolution profiles were similar for all three capsules in Examples 20-22.

[0266] As shown in Figures 14-19, differential scanning calorimetry (DSC) analysis was performed on the PEO resins and filler compositions used for softgel encapsulation. The blue curve represents the initial heating at 10°C per minute. The green curve represents the cooling at 10°C per minute. The red curve represents the second heating at 10°C per minute. All three PEO resins had melt temperatures below 60°C during the initial heating cycle. While not bound by theory, this reduced melt temperature of the filler compositions was thought to be due to the plasticizing effect of PEG400 on the PEO resins. DSC analysis can be used to select appropriate processing and annealing temperatures for specific filler compositions.

[0267] A controlled-release softgel-filled composition based on polyethylene oxide resin was developed according to the experimental design. The effects of PEO concentration and molecular weight on drug release rate were studied. Drug release rate was significantly affected by both PEO molecular weight and PEO polymer concentration. Higher PEO molecular weight or PEO polymer concentration resulted in slower drug release rates. The dissolution profiles were similar for the same composition at paddle speeds of 50 rpm and 100 rpm, indicating that the drug release mechanism is primarily due to diffusion through the polymer matrix.

[0268] For immediate-release softgel capsules, we also developed compositions containing low molecular weight PEO, PEG3350, and low viscosity HPMC. These compositions exhibited immediate-release profiles when subjected to dissolution studies.

[0269] Three batches of softgel capsules containing various Mn PEO resins were manufactured. The softgel capsules were subjected to dissolution testing. All three batches of softgel capsules exhibited long-term release profiles. DSC analysis was performed on the PEO resins and the three compositions. PEG400 in the compositions appears to act as a plasticizer for the PEO resins, resulting in a lower melting temperature (<60°C) of the PEO resins, which is beneficial for product manufacturing.

[0270] [Example 23] Viscosity adjustment of filling compositions using polyethylene oxide Three compositions containing only polyethylene oxide (Polyox®) and polyethylene glycol 400 were prepared, and it was demonstrated how the viscosity of the filler composition could be controlled by varying the amounts of polyethylene oxide and polyethylene glycol in the filler composition. The filler compositions and their viscosities are shown in Table 30 below.

[0271] [Table 34]

[0272] For the sake of brevity, embodiments of the methods disclosed herein are represented and described as a series of actions. However, the actions of this disclosure can be performed in various orders and / or simultaneously, in conjunction with other actions not presented and described herein. Furthermore, not all described actions may be required to perform the methods of the disclosed subject matter. In addition, those skilled in the art will understand and recognize that the methods can be alternatively represented by state diagrams or events as a series of interrelated states.

[0273] In the foregoing description, numerous specific details, such as specific materials, dimensions, and process parameters, are given in order to provide a full understanding of the present disclosure. Specific features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The words “example” or “exemplary” are used herein to mean that they serve as examples, cases, or illustrations. Any embodiment or design described herein as “example” or “exemplary” should not necessarily be construed as being preferable or favorable to other embodiments or designs. Rather, the use of the words “example” or “exemplary” is intended to present a specific concept. Where used in this application, the term “or” is intended to mean an inclusive “or” rather than an exclusive “or.” That is, unless otherwise specified or evident from the context, “X includes A or B” is intended to mean any of the natural inclusive substitutions. That is, if X includes A; X includes B; or X includes both A and B, then “X includes A or B” is satisfied in any of the aforementioned examples. Any reference throughout this specification to “one embodiment,” “a particular embodiment,” or “one embodiment” means that any particular feature, structure, or characteristic described in relation to that embodiment is included in at least one embodiment. Therefore, the appearances of the phrases “one embodiment,” “a particular embodiment,” or “one embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment.

[0274] This disclosure has been described with reference to certain exemplary embodiments. Therefore, this specification and the drawings should be considered illustrative rather than restrictive. In addition to those shown and described herein, various modifications of this disclosure will be apparent to those skilled in the art and are intended to fall within the scope of the appended claims. Furthermore, the present invention also includes the following embodiments. <1> (a)(i) at least one activator; and (ii) Controlled emission materials A controlled release filling composition containing; (b) A pH-dependent shell composition containing the filling composition, comprising gelatin, pectin, and dextrose. Modified release softgel capsules containing the above. <2> The modified release softgel capsule according to claim 1, wherein the controlled release material is selected from polyethylene oxide, cellulose derivatives, gum, or a combination thereof. <3> The modified release softgel capsule according to claim 2, wherein the controlled release material comprises polyethylene oxide having a number average molecular weight of about 0.05 M daltons to about 15 M daltons, about 1 M daltons to about 10 M daltons, or about 2 M daltons to about 5 M daltons. <4> A modified release softgel capsule according to claim 2 or 3, wherein the controlled release material comprises a cellulose derivative selected from microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and combinations thereof. <5> A modified release softgel capsule according to any one of the above 2 to 4, wherein the controlled release material comprises a gum selected from tragacanth gum, acacia gum, guar gum, xanthan gum, locust bean gum, or a combination thereof. <6> A modified release softgel capsule according to any one of 1 to 5 above, wherein the controlled release material is present in the controlled release filling composition in an amount of at least about 8 wt%, at least about 10 wt%, at least about 12 wt%, at least about 14 wt%, at least about 16 wt%, at least about 18 wt%, or at least about 20 wt% to a maximum of about 25 wt%, a maximum of about 35 wt%, a maximum of about 45 wt%, a maximum of about 55 wt%, or a maximum of about 65 wt%, or any partial range thereof, relative to the total weight of the controlled release filling composition. <7> The modified release softgel capsule according to any one of 1 to 6, wherein the controlled release filling composition further comprises (iii) a hydrophilic carrier having a number average molecular weight of about 200 daltons to about 5000 daltons. <8> The modified release softgel capsule according to claim 7, wherein the hydrophilic carrier comprises polyethylene glycol, propylene glycol, water, or a combination thereof. <9> The modified release softgel capsule according to 7 or 8, wherein the hydrophilic carrier is present in the controlled release filling composition in an amount greater than 0 wt%, at least about 15 wt%, or at least about 30 wt% to a maximum of about 45 wt%, a maximum of about 60 wt%, or a maximum of about 70 wt%, relative to the total weight of the controlled release filling composition. <10> A modified release softgel capsule according to any one of 1 to 9, wherein at least one of the activators is present in the controlled release filling composition in an amount of about 5 wt% to about 60 wt% relative to the total weight of the controlled release filling composition. <11> A modified releasing softgel capsule according to any one of items 1 to 10 above, wherein, based on a fiber optic dissolution test using Apparatus II with a paddle speed of 50 rpm in pH 6.8 phosphate buffer containing pancreatin as needed at 37°C, less than 85%, less than 70%, less than 50%, or less than 30% of the activator is released after 0.5 hours. <12> A modified release softgel capsule according to any of items 1 to 11 above, which is annealed. <13> The modified release softgel capsule according to 12, wherein the annealed modified release softgel capsule comprises a matrix of the controlled release material encapsulated in the pH-dependent shell composition. <14> The modified release softgel capsule according to 13, wherein the matrix is ​​solid or liquid. <15> A modified release softgel capsule according to any one of 1 to 14, wherein the pH-dependent shell composition further comprises a plasticizer. <16> A modified release softgel capsule according to any one of 1 to 15, wherein the pectin is low-methoxyl pectin. <17> A modified release softgel capsule according to any one of 1 to 16 above, wherein the pectin is selected from the group consisting of amidated pectin, non-amidate pectin, and combinations thereof. <18> A modified release softgel capsule according to any one of 1 to 17 above, wherein the pH-dependent shell composition contains approximately 25 wt% to approximately 80 wt%, approximately 30 wt% to approximately 75 wt%, approximately 35 wt% to approximately 70 wt%, approximately 40 wt% to approximately 65 wt%, or approximately 45 wt% to approximately 60 wt% of gelatin relative to the weight of the dry pH-dependent shell composition. <19> A modified release softgel capsule according to any one of 1 to 18, wherein the pH-dependent shell composition contains approximately 2 wt% to approximately 20 wt%, approximately 3 wt% to approximately 18 wt%, or approximately 5 wt% to approximately 15 wt% of pectin relative to the weight of the dry pH-dependent shell composition. <20> A modified releasing softgel capsule according to any one of 1 to 19 above, wherein the pH-dependent shell composition contains about 0.005 wt% to about 4 wt%, about 0.01 wt% to about 2 wt%, about 0.05 wt% to about 0.5 wt%, or about 0.1 wt% to about 0.2 wt% of dextrose relative to the weight of the dry pH-dependent shell composition. <21> A modified release softgel capsule according to any one of the above 15 to 20, wherein the pH-dependent shell composition contains a plasticizer in an amount of about 10 wt% to about 40 wt%, about 15 wt% to about 35 wt%, or about 20 wt% to about 30 wt% relative to the weight of the dry pH-dependent shell composition. <22> A modified release softgel capsule according to any one of 1 to 21 above, wherein the gelatin is selected from the group consisting of type A gelatin, type B gelatin and mixtures thereof. <23> A modified release softgel capsule according to any one of 1 to 22 above, wherein the gelatin is selected from the group consisting of fish gelatin, animal hide gelatin, bone gelatin, and mixtures thereof. <24> A modified release softgel capsule according to any one of the above 1 to 23, wherein the pectin is non-amidated pectin. <25> A modified release softgel capsule according to any one of 15 to 21 above, wherein the plasticizer is selected from glycerin, sorbitol, and combinations thereof. <26> The modified release softgel capsule according to 25, wherein the plasticizer is glycerin. <27> A modified release softgel capsule according to any one of 1 to 26 above, wherein the pH-dependent shell composition dissolves / disintegrates in the intestinal environment in less than approximately 60 minutes, less than approximately 45 minutes, less than approximately 30 minutes, less than approximately 20 minutes, less than approximately 10 minutes, or less than approximately 5 minutes, based on a dissolution / disintegration test performed in a USP Apparatus II using a paddle at a speed of 50 rpm in a pH 6.8 phosphate buffer containing pancreatin, if necessary. <28> A modified releasing softgel capsule according to any one of items 1 to 27, wherein the pH-dependent shell composition remains intact in an acidic medium for 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, based on a dissolution / disintegration test performed in a USP Apparatus II using a paddle at a speed of 50 rpm in 0.1 N HCl containing pepsin, if necessary. <29> A modified release softgel capsule according to any one of items 1 to 28 above, which does not contain additional pH-dependent polymers. <30> A modified release softgel capsule according to any one of claims 1 to 29, wherein the pH-dependent shell composition has a viscosity in the range of about 110,000 cPs to about 125,000 cPs. <31> A modified release softgel capsule according to any one of claims 1 to 30, wherein the pH-dependent shell composition has a gelatin-to-pectin w:w ratio in the range of about 2:1 to about 20:1 or about 6:1 to about 18:1. <32> A modified release softgel capsule according to any one of 1 to 31, wherein the pH-dependent shell composition has a plasticizer-to-gelatin w:w ratio in the range of about 5:1 to about 1:5. <33> A modified release softgel capsule according to any one of 1 to 32, wherein the controlled release filling composition has a w:w ratio of the controlled release material to the at least one activator in the range of about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, or about 1:1. <34> A modified release softgel capsule according to any one of 1 to 33 above, wherein the at least one activator is selected from pharmaceutical active ingredients, nutritional supplements, and combinations thereof. <35> The modified release softgel capsule according to 34, wherein the activator comprises at least one pharmaceutically active ingredient selected from nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, antihistamines, and combinations thereof. <36> The modified release softgel capsule according to 34 above, wherein the activator comprises vitamins, minerals, supplements, and combinations thereof. <37> The modified release softgel capsule according to 36 above, wherein the activator comprises fish oil, garlic oil, krill oil, or a combination thereof. <38> A process for preparing a modified release softgel capsule as described in any of items 1 to 37 above, (a) the step of preparing the controlled release filling composition; (b) The step of encapsulating the controlled release filling composition with the pH-dependent shell composition A process that includes this. <39> The process according to 38 above, further comprising the step of drying the encapsulated modified release softgel capsule. <40> The process according to 38 or 39, further comprising the step of annealing the modified release softgel capsule. <41> The process described in 40 above, wherein the annealing is performed at a temperature in the range of approximately 25°C to approximately 80°C, approximately 30°C to approximately 70°C, or approximately 40°C to approximately 60°C. <42> The process according to 40 or 41 above, wherein the annealing is performed over a period of time ranging from approximately 10 minutes to approximately 24 hours, approximately 30 minutes to approximately 12 hours, approximately 45 minutes to approximately 5 hours, or approximately 60 minutes to approximately 3 hours. <43> The process according to any one of 38 to 42, wherein (a) is to mix the at least one activator with the controlled release material and optionally with a hydrophilic carrier. <44> The process according to any one of 38 to 43, further comprising the step of preparing the pH-dependent shell composition. <45> The process according to 44, wherein the preparation step includes mixing gelatin, dextrose, pectin and optionally a plasticizer to form a pH-dependent shell composition ribbon. <46> The process according to 45, wherein the pH-dependent shell composition ribbon has a thickness in the range of about 0.020 inches to about 0.050 inches. <47> A method for adjusting the dissolution position and profile of a modified release softgel capsule comprising a controlled release filling composition encapsulated in a pH-dependent shell composition, i)~iv): i) At least one amount of pectin, gelatin, dextrose, and plasticizer in the pH-dependent shell composition; ii) Annealing temperature of the modified release softgel capsule; iii) Annealing time of the modified release softgel capsule; or iv) Thickness of the ribbon of the pH-dependent shell composition The steps include adjusting at least one of the pH-dependent shell composition to control the dissolution location along the target gastrointestinal tract; (v)~(vii): v) The amount of controlled release material in the controlled release filling composition, or vi) Annealing temperature of the modified release softgel capsule; or vii) Annealing time of the modified release softgel capsule The steps include adjusting at least one of the following to achieve a targeted lysis profile for at least one activator and Methods that include... <48> A method for treating a condition, comprising the step of administering a modified release softgel capsule described in any of items 1 to 38 above to a subject requiring it. <49> (a)(i) at least one activator; and (ii) polyethylene oxides having a number-average molecular weight of approximately 0.05 M Dalton to approximately 15 M Dalton; and (iii) Hydrophilic carrier as needed A controlled release filling composition containing; (b) A pH-dependent shell composition containing the controlled release filling composition, comprising gelatin, pectin, dextrose, and optionally a plasticizer. Modified release softgel capsules containing the above. <50> A method for preparing a modified release softgel capsule, The steps include: mixing at least one activator with polyethylene oxide and optionally a hydrophilic carrier to form a controlled-release filling composition; The steps include: encapsulating the controlled release filling composition in a pH-dependent shell composition comprising gelatin, pectin, dextrose, and optionally a plasticizer; The steps include annealing the enclosed controlled release filling composition and Methods that include... <51> A modified release softgel capsule according to 49 above, or a modified release softgel capsule prepared by the method described in 50 above, wherein the delayed-release capsule exhibits primary release of the activator over a period of time of approximately 2 hours to approximately 24 hours. <52> Based on dissolution / disintegration tests performed in USP Apparatus II using a 50 rpm paddle in pH 6.8 phosphate buffer containing pancreatin as needed, the pH-dependent shell composition dissolves / disintegrates in the intestinal environment in less than approximately 60 minutes, less than approximately 45 minutes, less than approximately 30 minutes, less than approximately 20 minutes, less than approximately 10 minutes, or less than approximately 5 minutes; The pH-dependent shell composition remains intact in an acidic medium for 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, based on dissolution / disintegration tests performed on a USP Apparatus II using a paddle at a speed of 50 rpm in 0.1 N HCl containing pepsin, if necessary. A modified release softgel capsule as described in item 49 above, or a modified release softgel capsule prepared by the method described in item 50 above. <53> The modified release softgel capsule according to 52 above, wherein in the second pH 6.8 phosphate buffer step of a two-step optical fiber dissolution test using Apparatus II with a paddle speed of 50 rpm, less than 85%, less than 70%, less than 50%, and less than 30% of the activator are released after 0.5 hours, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, or 12 hours. <54> (a)(i) at least one activator; and (ii) Controlled emission materials A controlled release filling composition containing; (b) pH-dependent shell composition containing the controlled release filling composition Modified release softgel capsules containing the above. <55> The modified release softgel capsule according to 54, wherein the pH-dependent shell composition contains gelatin. <56> A modified release softgel capsule according to 54 or 55, wherein the pH-dependent shell composition comprises a pH-dependent release material. <57> The modified release softgel capsule according to 56, wherein the pH-dependent release material contains pectin. <58> A modified release softgel capsule according to any one of 54 to 57, wherein the pH-dependent shell composition comprises dextrose. <59> A modified release softgel capsule according to any one of 54 to 58, wherein the pH-dependent shell composition contains a plasticizer. <60> A modified release softgel capsule according to any one of items 54 to 59 above, which is annealed. <61> The modified release softgel capsule according to 60, wherein the annealed softgel capsule comprises the controlled release filling composition in the form of a matrix of the controlled release material encapsulated in the pH-dependent shell composition. <62> A modified release softgel capsule according to any one of 54 to 61, wherein the at least one activator is selected from pharmaceutical active ingredients, nutritional supplements, and combinations thereof. <63> The modified release softgel capsule according to 62, wherein the activator comprises at least one pharmaceutically active ingredient selected from nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, antihistamines, and combinations thereof. <64> The modified release softgel capsule according to 62 above, wherein the activator comprises vitamins, minerals, supplements, and combinations thereof. <65> The modified release softgel capsule according to 64 above, wherein the activator comprises fish oil, garlic oil, krill oil, or a combination thereof. <66> A modified release softgel capsule according to any one of the above 54 to 65, wherein the activator is a pharmaceutical active ingredient that is less likely to be abused. <67> A modified release softgel capsule according to any one of the above 54 to 66, wherein the controlled release material comprises polyethylene oxide. <68> The modified release softgel capsule according to 67, wherein the polyethylene oxide has a number-average molecular weight of approximately 0.05 M Dalton to approximately 15 M Dalton. <69> A modified release softgel capsule according to any one of the above 54 to 68, wherein the controlled release material further comprises a hydrophilic carrier. <70> The modified release softgel capsule according to 69, wherein the hydrophilic carrier contains polyethylene glycol having a number-average molecular weight of about 200 daltons to about 7000 daltons. <71> A modified release softgel capsule according to 69 or 70, wherein the weight ratio of the controlled release material to the hydrophilic carrier is in the range of about 10:1 to about 1:10. [Explanation of Symbols]

[0275] 500 processes 510 mixed 512 Active Pharmaceutical Ingredients 514 Polyethylene oxide 516 Polyethylene glycol 518 Other ingredients 520 included 530 Dry 540 Heating / Annealing, Curing 550 softgel capsules, final modified release softgel capsules

Claims

1. (a) (i) at least one activator; and (ii) Controlled emission materials A controlled release filling composition comprising; (b) A pH-dependent shell composition containing the filling composition, comprising 45 wt% to 65 wt% gelatin, 5 wt% to 15 wt% pectin, and 0.05 wt% to 0.2 wt% dextrose. Modified release softgel capsules containing the above.

2. The modified release softgel capsule according to claim 1, wherein the controlled release material is selected from polyethylene oxide, cellulose derivatives, gum, or a combination thereof.

3. The modified release softgel capsule according to claim 2, wherein the controlled release material comprises polyethylene oxide having a number average molecular weight of 0.05 M Dalton to 15 M Dalton, 1 M Dalton to 10 M Dalton, or 2 M Dalton to 5 M Dalton.

4. The modified release softgel capsule according to claim 2 or 3, wherein the controlled release material comprises a cellulose derivative selected from microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and combinations thereof.

5. A modified release softgel capsule according to any one of claims 2 to 4, wherein the controlled release material comprises a gum selected from tragacanth gum, acacia gum, guar gum, xanthan gum, locust bean gum, or a combination thereof.

6. A modified release softgel capsule according to any one of claims 1 to 5, wherein the controlled release material is present in the controlled release filling composition in an amount of at least 8 wt%, at least 10 wt%, at least 12 wt%, at least 14 wt%, at least 16 wt%, at least 18 wt%, or at least 20 wt% to a maximum of 25 wt%, a maximum of 35 wt%, a maximum of 45 wt%, a maximum of 55 wt%, or a maximum of 65 wt%, or any partial range thereof, based on the total weight of the controlled release filling composition.

7. The modified release softgel capsule according to any one of claims 1 to 6, wherein the controlled release filling composition further comprises (iii) a hydrophilic carrier having a number average molecular weight of 200 daltons to 5000 daltons.

8. The modified release softgel capsule according to claim 7, wherein the hydrophilic carrier comprises polyethylene glycol, propylene glycol, water, or a combination thereof.

9. The modified release softgel capsule according to claim 7 or 8, wherein the hydrophilic carrier is present in the controlled release filling composition in an amount greater than 0 wt%, at least 15 wt%, or at least 30 wt% to a maximum of 45 wt%, a maximum of 60 wt%, or a maximum of 70 wt%, based on the total weight of the controlled release filling composition.

10. A modified release softgel capsule according to any one of claims 1 to 9, wherein at least one of the activators is present in the controlled release filling composition in an amount of 5 wt% to 60 wt% relative to the total weight of the controlled release filling composition.

11. A modified release softgel capsule according to any one of claims 1 to 10, wherein, based on an optical fiber dissolution test using Apparatus II with a paddle speed of 50 rpm in pH 6.8 phosphate buffer, less than 85%, less than 70%, less than 50%, and less than 30% of the activator are released after 0.5 hours.

12. A modified release softgel capsule according to any one of claims 1 to 11, which is annealed.

13. The modified release softgel capsule according to claim 12, wherein the annealed modified release softgel capsule comprises a matrix of the controlled release material encapsulated in the pH-dependent shell composition.

14. The modified release softgel capsule according to any one of claims 1 to 13, wherein the pH-dependent shell composition further comprises a plasticizer.

15. The modified release softgel capsule according to any one of claims 1 to 14, wherein the pectin is low-methoxyl pectin.

16. The modified release softgel capsule according to any one of claims 1 to 15, wherein the pectin is selected from the group consisting of amidated pectin, non-amidate pectin, and combinations thereof.

17. The modified release softgel capsule according to any one of claims 1 to 16, wherein the pH-dependent shell composition comprises 45 wt% to 60 wt% gelatin based on the weight of the dry pH-dependent shell composition.

18. The modified release softgel capsule according to any one of claims 1 to 17, wherein the pH-dependent shell composition comprises 0.1 wt% to 0.2 wt% of dextrose based on the weight of the dry pH-dependent shell composition.

19. The modified release softgel capsule according to claim 14, wherein the pH-dependent shell composition contains 10 wt% to 40 wt%, 15 wt% to 35 wt%, or 20 wt% to 30 wt% of a plasticizer based on the weight of the dry pH-dependent shell composition.

20. The modified release softgel capsule according to any one of claims 1 to 19, wherein the gelatin is selected from the group consisting of type A gelatin, type B gelatin and mixtures thereof.

21. The modified release softgel capsule according to any one of claims 1 to 20, wherein the gelatin is selected from the group consisting of fish gelatin, animal hide gelatin, bone gelatin, and mixtures thereof.

22. The modified release softgel capsule according to any one of claims 1 to 21, wherein the pectin is non-amidated pectin.

23. The modified release softgel capsule according to claim 14 or 19, wherein the plasticizer is selected from glycerin, sorbitol, and combinations thereof.

24. A modified release softgel capsule according to any one of claims 1 to 23, wherein the pH-dependent shell composition dissolves / disintegrates in the intestinal environment in less than 60 minutes, less than 45 minutes, less than 30 minutes, less than 20 minutes, less than 10 minutes, or less than 5 minutes, based on a dissolution / disintegration test performed in USP Apparatus II using a paddle at a speed of 50 rpm in pH 6.8 phosphate buffer.

25. A modified releasing softgel capsule according to any one of claims 1 to 24, wherein the pH-dependent shell composition remains intact in an acidic medium for at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, or at least 5 hours, based on a dissolution / disintegration test performed in a USP Apparatus II using a paddle at a speed of 50 rpm in 0.1 N HCl.

26. A modified release softgel capsule according to any one of claims 1 to 25, wherein the pH-dependent shell composition has a viscosity in the range of 110,000 cPs to 125,000 cPs.

27. A modified release softgel capsule according to any one of claims 1 to 26, wherein the pH-dependent shell composition has a gelatin-to-pectin w:w ratio in the range of 4:1 to 12:

1.

28. The modified release softgel capsule according to any one of claims 1 to 27, wherein the pH-dependent shell composition has a plasticizer-to-gelatin w:w ratio in the range of 5:1 to 1:

5.

29. A modified release softgel capsule according to any one of claims 1 to 28, wherein the controlled release filling composition has a w:w ratio of the controlled release material to the at least one activator in the range of 10:1 to 1:10, 8:1 to 1:8, 5:1 to 1:5, 3:1 to 1:3, or 1:

1.

30. The modified release softgel capsule according to any one of claims 1 to 29, wherein the at least one activator is selected from pharmaceutical active ingredients, nutritional supplements, and combinations thereof.

31. The modified release softgel capsule according to claim 30, wherein the activator comprises at least one pharmaceutically active ingredient selected from nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, antihistamines, and combinations thereof.

32. The modified release softgel capsule according to claim 30, wherein the activator comprises vitamins, minerals, supplements, and combinations thereof.

33. The modified release softgel capsule according to claim 32, wherein the activator comprises fish oil, garlic oil, krill oil, or a combination thereof.

34. A process for preparing a modified release softgel capsule according to any one of claims 1 to 33, (a) the step of preparing the controlled release filling composition; (b) The step of encapsulating the controlled release filling composition with the pH-dependent shell composition A process that includes this.

35. (a) (i) at least one activator; and (ii) Polyethylene oxide having a number-average molecular weight of 0.05 M Dalton to 15 M Dalton A controlled release filling composition comprising; (b) A pH-dependent shell composition containing the controlled-release filling composition, comprising 45 wt% to 65 wt% gelatin, 5 wt% to 15 wt% pectin, and 0.05 wt% to 0.2 wt% dextrose. Modified release softgel capsules containing the above.

36. A method for preparing a modified release softgel capsule, The steps include: mixing at least one activator with polyethylene oxide to form a controlled-release filling composition; The process involves encapsulating the controlled-release filling composition in a pH-dependent shell composition containing 45 wt% to 65 wt% gelatin, 5 wt% to 15 wt% pectin, and 0.05 wt% to 0.2 wt% dextrose; The steps include annealing the enclosed controlled release filling composition and Methods that include...

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