Modified release softgel capsules and preparation process and uses thereof

Abstract

This invention describes modified release soft capsules comprising a pH-dependent shell composition of a controlled-release filling composition, methods for their preparation, and methods of use. The pH-dependent shell composition is characterized in that the delayed-release properties of these capsules can be achieved without separate pH-dependent coating or the addition of a known pH-dependent polymer. The soft gel provides a dual controlled-release platform, which facilitates the delivery of the active agent to a target location in the gastrointestinal tract and the controlled-release profile of the active agent at that target location in the gastrointestinal tract.

Description

Technical Field

[0001] This invention relates to modified release soft capsules with encapsulated controlled-release filling compositions. The gelatin-based capsules have pH-dependent shell compositions that exhibit delayed-release properties without requiring separate pH-dependent coatings or the addition of conventional pH-dependent synthetic polymers. The controlled-release filling compositions possess controlled-release properties. Both the pH-dependent shell compositions and the controlled-release filling compositions allow for the delivery of the active agent to a target location within the gastrointestinal tract and allow for the adjustment of the release profile of the active agent at that target location. Prior Technology

[0002] Soft capsules, specifically soft gelatin capsules (or softgel capsules), offer a more palatable dosage form for patients because they are easy to swallow and do not require flavoring to mask any unpleasant taste of the active ingredient.

[0003] Efforts have been made to develop delayed-release dosage forms. Delayed-release dosage forms are designed to protect the contents of the dosage form from the effects of gastric conditions. For example, delayed-release dosage forms can be produced by adding a pH-dependent coating to the surface of a prepared dosage form such as a tablet or capsule. Such coatings can be applied by spraying the dosage form, followed by drying the dosage form at high temperatures. This method of coating capsules with a pH-dependent coating can lead to disadvantages in terms of efficacy and appearance. For example, the capsule may appear rough, the coating may be applied unevenly, and / or the coating may be prone to cracking or peeling off from the dosage form. Furthermore, the method of applying a pH-dependent coating is very inefficient.

[0004] Other delayed-release formulations have been developed, in which conventional pH-dependent polymers (i.e., acid-insoluble polymers) are added to the capsule shell. However, the addition of conventional pH-dependent polymers may lead to leakage of the capsules due to insufficient sealing.

[0005] Therefore, there is a need for a modified release soft capsule that does not require a separate pH-dependent coating or the addition of a known pH-dependent polymer to the shell.

[0006] Soft capsules can also benefit from the ability to adjust and / or control the release profile of the active agent from the filling composition of the soft capsule after the shell composition breaks / dissolves / disintegrates. Summary of the Invention

[0007] This invention relates to modified release soft capsules, such as dual-controlled release soft capsules. The modified release soft capsule comprises (a) a controlled release filling composition and (2) a pH-dependent shell composition encapsulating 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., glycerin, 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 of gelatin, pectin, dextrose, plasticizer, and binder.

[0008] In some embodiments, the modified release soft capsules do not require a separate pH-dependent coating (e.g., on a pH-dependent shell composition). Therefore, in some embodiments, the pH-dependent shell composition included in the modified release soft capsules does not require a separate pH-dependent coating, which also minimizes the risk of capsule damage 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 (d) a plasticizer, if appropriate. The pH-dependent shell composition (e.g., the amount of pectin, the amount of dextrose, the ratio of gelatin to pectin) and its preparation method (e.g., curing time, ribbon thickness) can be adjusted / regulated / modified to obtain the target pH solubility profile of the shell composition in various pH environments (e.g., the breakup / dissolution / disintegration time in acidic and buffered media).

[0010] The controlled-release filler composition includes at least one active agent and a controlled-release material. The active agent may be a pharmaceutical active ingredient or a pharmaceutical-like nutrient. The controlled-release material may be polyethylene oxide, a cellulose derivative, a gum, or a combination thereof. In some embodiments, the controlled-release filler composition further includes a hydrophilic carrier, such as a polyol (e.g., polyethylene glycol, polypropylene glycol) or water.

[0011] In one embodiment, the controlled-release filler composition (e.g., the type and amount of the active agent, the type and amount of the controlled-release material, and, where applicable, the type and amount of the hydrophilic carrier, and the ratio between these materials) and its preparation method (e.g., annealing duration) can be adjusted / regulated / modified to obtain a target release profile (e.g., zero-order release) of the active agent from the controlled-release filler composition. In some embodiments, the modified release soft capsules can be annealed. In one embodiment, the annealed modified release soft capsules comprise a controlled-release filler composition in the form of a matrix (solid or liquid) of controlled-release material encapsulated in a pH-dependent shell composition.

[0012] In some embodiments, a modified release soft capsule is disclosed, comprising a controlled release filler composition comprising: (i) at least one active agent; (ii) polyethylene oxide with a number average molecular weight of about 0.05 M Daltons to about 15 M Daltons; and (iii) a hydrophilic carrier, if applicable; and a pH-dependent shell composition encapsulating the controlled release filler composition, wherein the pH-dependent shell composition comprises gelatin, pectin, dextrose, and, if applicable, a plasticizer.

[0013] The modified release gel capsules described herein can also be called dual-controlled release soft capsules because they have two levels of controlled release. The first level of controlled release is due to the pH-dependent shell composition of the soft capsule. The second level of controlled release is due to the controlled release filling composition of the soft capsule.

[0014] This invention also relates to a method for preparing modified release soft capsules. In some embodiments, a method for preparing modified release soft capsules is disclosed, comprising: mixing at least one active agent with polyethylene oxide and, if applicable, a hydrophilic carrier to form a controlled release filler composition; encapsulating the controlled release filler composition in a pH-dependent shell composition comprising gelatin, pectin, dextrose, and, if applicable, a plasticizer; and annealing the encapsulated controlled release filler composition.

[0015] In some embodiments, the present invention also relates to a method for adjusting the levels of a dual controlled release mechanism of a soft capsule to facilitate targeted release of the active agent to a specific region within the gastrointestinal tract with a targeted active agent release profile. For example, in some embodiments, the modified release soft capsule described herein delivers the active agent to the lower gastrointestinal tract (e.g., near the colon) and releases the active agent in a controlled manner (e.g., a zero-order release lasting from about 2 hours to about 24 hours).

[0016] This invention also relates to a method of treating a condition by administering to an individual any of the delayed-release soft gel compositions described herein. Simple Explanation of the Diagram

[0017] The above and other features, properties and various advantages of the present invention will become more apparent when the following embodiments are considered in conjunction with the accompanying drawings, wherein:

[0018] Figure 1 illustrates the viscosity of shell compositions with amide-treated pectin and non-amide-treated pectin as a function of aging time.

[0019] Figure 2 illustrates the release profile of ibuprofen from self-modified release soft capsules according to the embodiments described herein, wherein the modified release soft capsules contain different concentrations of controlled release material in the controlled release filling composition.

[0020] Figure 3 illustrates the release profile of diphenhydramine from a self-modified release soft capsule according to one embodiment.

[0021] Figure 4 illustrates the release profile of acetaminophen from a self-modified release soft capsule according to one embodiment.

[0022] Figure 5 depicts an exemplary method for preparing modified release soft capsules according to one embodiment.

[0023] Figure 6 depicts the dissolution profile of the capsule obtained in an optical fiber dissolution test conducted at 37°C in 500 ml of water running at 100 RPM using the USP device II with a blade speed of 100 RPM.

[0024] Figure 7 depicts the dissolution profile of the capsule obtained in an optical fiber dissolution test conducted at 37°C in 500 ml of water using the USP device II with a blade speed of 50 RPM.

[0025] Figures 8A to 8D and Figures 9 to 10 show the residuals at 90% (hours) of the time for statistical analysis of the dissolved data in Examples 13 to 18.

[0026] Figure 8A shows the normal probability of 90% release time (hours).

[0027] Figure 8B is a comparative fitting plot of the time (in hours) to release 90%.

[0028] Figure 8C is a histogram of the time (in hours) for 90% release.

[0029] Figure 8D is a comparison chart of the time (in hours) for 90% release.

[0030] Figure 9 shows the interaction diagram for the release time (hours) of 90%.

[0031] Figure 10 shows the main effect after 90% of the time (hours) has been released.

[0032] Figure 11 depicts the dissolution profile of capsules filled with formulation 13 to 15 obtained in an optical fiber dissolution test conducted at 37°C in 500 ml of water using the USP device II with a blade speed of 100 RPM.

[0033] Figure 12 depicts the dissolution profile of the capsule obtained in an optical fiber dissolution test conducted at 37°C in 500 ml of water using the USP device II with a blade speed of 100 RPM.

[0034] Figure 13 depicts the dissolution profile of the capsule obtained in an optical fiber dissolution test conducted at 37°C in 500 ml of water using the USP device II with a blade speed of 50 RPM.

[0035] Figure 14 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.

[0036] Figure 15 shows the DSC curve of heat flow versus temperature for a capsule-filled composition containing an MC18-30 filler mixture.

[0037] Figure 16 shows the DSC curve of heat flow versus temperature for a capsule-filled composition containing polyethylene oxide with a number average molecular weight of 5,000,000 Da.

[0038] Figure 17 shows the DSC curve of heat flow versus temperature for a capsule-filled composition containing MC18-31 filler mixture.

[0039] Figure 18 shows the DSC curve of heat flow versus temperature for a capsule-filled composition containing polyethylene oxide with a number average molecular weight of 7,000,000 Da.

[0040] Figure 19 shows the DSC curve of heat flow versus temperature for a capsule-filled composition containing an MC18-32 filler mixture. Implementation

[0041] This invention advances current advanced technology by developing a dual-level controlled-release oral dosage form, specifically a modified-release soft capsule with two levels of controlled-release. The first level is attributed to a pH-dependent shell composition, which achieves the advantages associated with conventional delayed-release dosage forms without requiring 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 filler composition.

[0042] The pH-dependent shell composition of the modified release soft capsules described herein does not dissolve in the gastric environment of the stomach, but rather dissolves at a pH of about 3.5 or higher (e.g., in the duodenal region and / or the intestine). The solubility profile of the pH-dependent shell composition described herein can be adjusted by the composition and preparation method of the modified shell composition.

[0043] The controlled-release filling composition of the modified release soft capsules described herein can be adjusted by modifying the composition and preparation method. Among other factors, the controlled-release properties of the filling composition can be adjusted by incorporating controlled-release materials (such as polyethylene oxide, cellulose derivatives, gums, or a combination of two or more of these).

[0044] The dual-controlled release mechanism of the modified-release softgels described herein is beneficial for delivering active agents that may cause gastric irritation or bleeding (such as NSAIDs) or are sensitive to the acidic environment of the stomach (such as peptides and proteins / enzymes). This mechanism also helps reduce belching after taking capsules containing filling compositions that easily cause belching (such as fish oil, garlic oil, or krill oil). For example, belching often occurs when taking vitamins, minerals, supplements, and / or pharmaceutical products formulated to exhibit some (even very small) leakage in the stomach before reaching the intestines. Leakage can be particularly problematic when belching is associated with substances that have unpleasant sensations (such as fish oil and garlic oil, which are typically delivered in softgels). The modified-release softgels described herein are formulated to minimize and / or eliminate premature leakage (and therefore premature release of the capsule filling) in the gastric environment. The modified release soft capsules described in this article can also be used to deliver active agents (such as peptides and proteins) to the lower gastrointestinal tract and / or to the colon, where certain active agents are better absorbed. [definition] [ ]

[0045] As used herein, the term "pH-dependent" refers to the anti-dissolution or anti-disintegration properties of a substance such that dissolution or disintegration does not occur or is substantially absent in the gastric environment of the stomach for a period of time such as at least about 15 minutes, at least about 30 minutes, at least about one hour, at least about two hours, at least about three hours, at least about four hours, or at least about five hours. In some embodiments, the gastric environment of the stomach may be simulated here using 0.1 N HCl and, where appropriate, pepsin. It should be noted that pharmacological methods do not include pepsin; however, pepsin is added in the specific dissolution / disintegration tests described herein to better simulate / mimic in vivo conditions. Therefore, without being construed as limiting, in some embodiments, the compositions described herein are anti-dissolution / anti-disintegration even in a 0.1 N HCl environment including pepsin (assuming it is a more aggressive environment than 0.1 N HCl without pepsin) for the time as outlined above.

[0046] For example, the embodiments described herein include pH-dependent shell compositions that preferentially dissolve at a pH of about 3.5 or higher (e.g., in biological, artificial, or simulated duodenal environments and / or intestinal fluids) compared to biological, artificial, or simulated gastric fluids. In some embodiments, enteric environments can be simulated herein using pH 6.8 phosphate buffer with or without pancreatic enzymes. For example, the pH-dependent shell compositions described herein dissolve 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 in a pH of about 3.5 or higher (e.g., biological, artificial, or simulated duodenal environments and / or intestinal fluids, such as pH 6.8 phosphate buffer with pancreatic enzymes, if applicable). It should be noted that pharmacological methods do not include pancreatic enzymes; however, pancreatic enzymes are added in the specific dissolution / disintegration tests described herein to better simulate / mimic in vivo conditions. Therefore, without being construed as limiting, in some embodiments, the compositions described herein exhibit a similar dissolution / disintegration profile in a pH 6.8 buffer environment including trypsin (assuming it is a more corrosive environment than a pH 6.8 buffer environment without trypsin).

[0047] As used herein, "active pharmaceutical ingredient" and "active agent" refer to a drug or compound that can be used to diagnose, cure, alleviate, treat, or prevent a condition. In some embodiments, suitable "active agents" include pharmaceutical nutritional supplements such as vitamins, minerals, and supplements (VMS). Exemplary modified-release soft capsules may include, but are not limited to, capsules containing 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, easily abused drugs (e.g., opioids), less easily abused drugs, and similar products.

[0048] The term "condition" or "conditions" refers to medical conditions that can be treated or prevented by administering an effective amount of an active agent to an individual.

[0049] As used herein, the term "active agent" means any substance intended to produce a therapeutic, preventative, or other desired effect, whether or not it has been approved by a government agency for that purpose. With respect to a particular pharmaceutical preparation, this term includes pharmaceutical active agents and all pharmaceutically acceptable salts, solvates, and crystalline forms thereof, wherein the salts, solvates, and crystalline forms are pharmaceutically active.

[0050] Any pharmaceutically active ingredient, including both water-soluble and poorly soluble components, may be used for the purposes of this invention. Suitable pharmaceutical active ingredients include, but are not limited to, analgesics and anti-inflammatory agents (e.g., ibuprofen, naproxen sodium, aspirin), antacids, anthelmintics, antiarrhythmics, antibacterial agents, anticoagulants, antidepressants, antidiabetic agents, antidiabetic agents, antiepileptic agents, antifungal agents, antigout agents, antihypertensive agents, antimalarial agents, antimigraine agents, muscarinic agents, anti-hypertrophic agents and immunosuppressants, antiprotozoal agents, antirheumatic agents, antithyroid agents, antihistamines (e.g., diphenhydramine), antiviral agents, anxiolytics, sedatives, hypnotics and tranquilizers, beta-blockers, cardiotonics, corticosteroids, cough suppressants, cytotoxic agents, decongestants, diuretics, enzymes, and anti-Parkinson's agents. Agents, gastrointestinal agents, histamine receptor antagonists, lipid modulators, local anesthetics, myo-neurostimulants, nitrates and antianginal agents, nutritional agents, opioid analgesics, anticonvulsants (e.g., valproic acid), oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants and combinations thereof.

[0051] In some embodiments, the active pharmaceutical ingredient may be selected from, but is not limited to, the group consisting of: dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurine, asimadoline, beclomethasone, apremilast, sapacitabine, linsitinib, abiraterone. Biraterone, vitamin D analogs (e.g., calcifediol, calcitriol, paricalcitol, doxercalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, their pharmaceutically acceptable salts, and combinations thereof.

[0052] In some embodiments, the lipids in the dosage form may be selected from, but are not limited to, the group consisting of: almond oil, argan oil, avocado oil, borage seed oil, rapeseed oil, cashew oil, castor oil, hydrogenated castor oil, cocoa soybean oil, coconut oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp seed oil, hydroxylated lecithin, lecithin, flaxseed oil, Queensland longan 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 oil, soybean oil, sunflower seed oil, hydrogenated vegetable oil, walnut oil, and watermelon seed oil. Other oils and fats may include, but are not limited to, fish oil (Ω-3), krill oil, garlic oil, animal or vegetable fats (e.g., in their hydrogenated form), free fatty acids, and monoglycerides, diglycerides, and triglycerides of fatty acids having C8-, C10-, C12-, C14-, C16-, C18-, C20-, and C22-, such as fatty acid esters of EPA and DHA 3, and combinations thereof.

[0053] According to certain embodiments, the active agent may include lipid-lowering agents, including but not limited to statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), fibrates (e.g., clofibrate, ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil), niacin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, and pharmaceutically acceptable salts, hydrated solvates, and prodrugs thereof, mixtures thereof, and analogues thereof.

[0054] Suitable active ingredients for pharmaceutical-like nutritional supplements may include, but are not limited to, 5-hydroxytryptamine, acetyl-L-carnitine, alpha fatty acids, alpha-ketoglutarate, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristate, charcoal, polyglucosamine, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), dimethylaminoethanol, fumaric acid, germanium sesquioxide, glandular products, glucosamine hydrochloride, glucosamine sulfate, methyl butyrate, immunoglobulins, lactic acid, L-carnitine, liver products, malic acid, anhydrous maltose, mannose (d-mannose), methanesulfonylmethane, phytosterols, pyridine carboxylic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadium sulfate, and yeast.

[0055] Suitable active ingredients in nutritional supplements may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, or combinations thereof.

[0056] Suitable vitamin activators may include, but are not limited to, the following: ascorbic acid (vitamin C), vitamin B, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbic acid, mixed tocopherols, nicotinic acid (vitamin B3), orotic acid, para-aminobenzoic acid, pantothenate, pantothenic acid (vitamin B5), pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamethoxam (vitamin B1), ginsenosides, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oils, and oil-soluble vitamins.

[0057] Suitable active ingredients in herbal nutritional supplements may include, but are not limited to, the following: arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic oil, ginger root, ginkgo biloba, ginseng, goldenrod, hawthorn, kava-kava, licorice, milk thistle, psyllium, rauwolfia, senna, soybean, St. John's wort, saw palmetto, turmeric, and valerian.

[0058] Mineral activators may include, but are not limited to, the following: 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.

[0059] Other possible active agents include, but are not limited to: antihistamines (such as ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate). maleate), nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprafen, aminoprofen, fluprofen, bucloxic acid acid), indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamicacid), diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprin, azapropazone, benorilate, bromfenac, carprofen, magnesium choline salicylate, diflunisal, etoposide Etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid amino acid), metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, disalicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid (acid), tolmetin, its pharmaceutically acceptable salts and mixtures thereof) and acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., phenyloin, meprobmate, and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem, and nicardipine), antitussives and expectorants (e.g., codeine phosphate), antiasthmatics (e.g., theophylline), antacids, anticonvulsants (e.g., atropine, scopolamine), antidiabetic agents (e.g., insulin), diuretics (e.g., ethacrynic acid)Antihypertensive drugs include: phenylethylamine (bendrofluthiazide), antihypertensive drugs (e.g., propranolol, clonidine), antihypertensive drugs (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), and steroids (e.g., hydrocortisone, triamcinolone). Triamcinolone, prednisone, antibiotics (e.g., tetracycline), anti-hemorrhoid drugs, hypnotics, psychiatric drugs, antidiarrheals, mucolytics, sedatives, decongestants (e.g., pseudoephedrine), mild laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine), and cannabinoids, as well as their pharmaceutically acceptable salts, hydrates, solvents, and prodrugs.

[0060] The active agent may also be benzodiazepine, barbiturate, stimulant, or a mixture thereof. The term "benzodiazepine" refers to benzodiazepine and drugs that can inhibit the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlorodiazepam epoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, and their pharmaceutically acceptable salts, hydrates, solvents, prodrugs, and mixtures. Benzodiazepine antagonists that can be used as active agents include, but are not limited to, flumazenil and its pharmaceutically acceptable salts, hydrates, solvents and mixtures.

[0061] The term "barbiturates" refers to sedative-hypnotic drugs derived from barbituric acid (2,4,6,-trilateral-oxyhexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbital, butabarbital, butalbital, mesobarbital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures. Barbiturate antagonists that can be used as active agents include, but are not limited to, amphetamine, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0062] The term "stimulant" includes, but is not limited to, amphetamines, such as dextroamphetamine resin complexes, dextroamphetamine, methamphetamine, methylphenidate, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures. Stimulant antagonists that can be used as active agents include, but are not limited to, benzodiazepines and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0063] In one embodiment of the invention, the active pharmaceutical ingredient is an analgesic such as ibuprofen or an opioid. The term "opioid" refers to a neuroactive compound that works by binding to opioid receptors. Opioids are commonly used in the medical field due to their analgesic effects. It is believed that opioids are easily abused APIs. Examples of opioids include codeine, tramadol, anileridine, prodine, pethidine, hydrocodone, morphine, oxycodone, methadone, diamorphine, hydromorphone, oxymorphone, 7-hydroxymitragynine, buprenorphine, fentanyl, sufentanil, levorphanol, meperidine, tilidine, dihydrocodeine, dihydromorphine, and their medically acceptable salts.

[0064] Other examples of active pharmaceutical ingredients may include N-{1-[2-(4-ethyl-5-sideoxy-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidinyl}propionic acid; alfentanil; 5,5-diallyl barbituric acid; allobarbital; allylprodine; alphaprodine; 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolidine [4,3-a][1,4]-benzodiazepine; alprazolam; 2-diethylaminophenylacetone; amfepramone, (±)-α-methylphenethylamine; amphetamine; 2-(α-methylphenethylamino)-2-phenylacetonitrile; amphetamineil; 5-ethyl-5-isopentylbarbituric acid; amobarbital; anileridine; apoco deine); 5,5-diethylbarbituric acid; barbiturate; benzylmorphine; bezitramide; 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2(3H)-one; bromazepam; 2-bromo-4-(2-chlorophenyl)-9-methyl-1-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine; brotizolam, 17-cyclopropylmethyl-4,5a-epoxy-7a [(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-endo-bridged ethylmorphine-3-ol; butyl prophenine; 5-butyl-5-ethyl barbituric acid; butorphanol; (7-chloro-1,3-dihydro-1-methyl-2-sideoxy-5-phenyl-2H-1,4-benzodiazepine-3-yl)dimethylaminocarbamate; carbamazepam; (1S,2S) -2-amino-1-phenyl-1-propanol; cathine; d-norpseudoephedrine; 7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepine-2-yl-amine-4-oxide; clozapine, 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; clonitazene; 7-chloro-2,3-dihydro-2-sideoxy-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid; clozapine salt;5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazapine-2(3H)-one; clotiazepam; 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrozozono[3,2-d][1,4]benzodiazepine-6(5H)-one; cloxazolam; (-)-methyl-[3β-benzoyloxy-2β(1αH,5αH)-tropine carboxylate]; cocaine (c ocaine; (5α,6α)-7,8-disodehydro-4,5-epoxy-3-methoxy-17-methylmorphordin-6-ol; 4,5α-epoxy-3-methoxy-17-methyl-7-morphordin-6α-ol; codeine; 5-(1-cyclohexenyl)-5-ethylbarbituric acid; cyclobarbital; cyclorphan; cyprenorphine; 7-chloro-5-(2-chlorophenyl)-1H-1,4 -Benzadipine-2(3H)-one; delorazepam; desomorphine; dextromoramide; (+)-(1-phenylmethyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate; dextropropoxyphene; dezocine; diampromide; diamorphone ;7-Chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one; diazapine; 4,5α-epoxy-3-methoxy-17-methyl-6α-morphine; dihydrocodeine; 4,5α-epoxy-17-methyl-3,6a-morphinediol; dihydromorphine; dimenoxadol; dimephetamol; dimethylthiambutene; dioxaphetyl butyrate); dipipanone; (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]-octene-1-ol; dronabinol; eptazocine; 8-chloro-6-phenyl-4H-[1,2,4]-triazol[4,3-(a)][1,4]benzodiazepine; estazolam; ethoheptazine; ethyl[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-sideoxy-1H-1,4-benzodiazepine-3-carboxylic acid ester]; ethyl loflazepate4,5α-Epoxy-3-ethoxy-17-methyl-7-morphene-6α-ol; ethylmorphine; etonitazene; 4,5α-Epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-ethylene-bridged-morphene-3-ol; etorphine; N-ethyl-3-phenyl-8,9,10-trinorbornene-2-ylamine; fencamfamine; 7-[2- [α-Methylphenethylamino]ethyl theophylline; fenethylline; 3-(α-Methylphenethylamino)propionitrile; fenproporex; N-(1-phenylethyl-4-piperidinyl)propionylaniline; fentanyl; 7-chloro-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 unitrazepam); 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2(3H)-one; frazepam; 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepine-2(3H)-one; halazepam; 10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]azolyl[3,2-d][1,4]benzodiazepine-6(5H)-one; haloxazolam; heroin ;4,5α-epoxy-3-methoxy-17-methylmorphine; hydrocodone; 4,5α-epoxy-3-hydroxy-17-methyl-6-morphine; hydromorphine; hydroxypethidine; isomethadone; hydroxymethylmorphine; 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]benzo[3,2d][1,4]benzodiazepine-4,7(6H)-dione; ketazolam; 1- [4-(3-hydroxyphenyl)-1-methyl-4-piperidinyl]-1-propanone; ketobemidone; (3S,6S)-6-dimethylamino-4,4-diphenylhept-3-ester acetate; levacetylmethadol; LAAM; (-)-6-dimethylamino-4,4-diphenyl-3-heptanone; levomethadone; (-)-17-methyl-3-morphoneol; levphenoryl; levaminomethylmorphine; lofentanil;6-(2-chlorophenyl)-2-(4-methyl-1-piperazonylmethylene)-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; lormetazepam; 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; mefenorex; malidine; 2-methyl-2-propyltrimethylenediaminocarbamate; meprobamate; meptazinol; metazocine; methylmorphine; N,α-dimethylphenethylamine; metamphetamine; (±)-6-dimethylamino-4,4-diphenol-3-heptanone; methadone; 2-methyl-3-orthotolyl-4(3H)-quinazolinone; Methylphenidate; methyl[2-phenyl-2-(2-piperidinyl)acetate]; methylphenidate; 5-ethyl-1-methyl-5-phenylbarbituric acid; methylphenobarbital; 3,3-diethyl-5-methyl-2,4-piperidinidone; methylpyrrolidone; metopon; 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine; midazolam; 2-(benzylsulfinyl)acetamide; modafinil; (5α,6α)-7,8-didehydrogen -4,5-Epoxy-17-methyl-7-methylmorphine-3,6-diol; morphine; myrophine; (±)-trans-3-(1,1-dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]piperan-9(6αH)one; nabilone; nalbuphene; nalorphine; narceine; 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; Nordazepam; 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-tetrahydro-2-methyl-11b-phenyl Azo[3,2-d][1,4]benzodiazepine-6-(5H)-one; oxazolam; 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphine; oxycodone; oxymorphone; papaveretum; 2-imino-5-phenyl-azolidinone; pernoline; 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methylbridged-3-benzoazo-8-ol; pentazocine; 5-ethyl-5-(1-methylbutyl) )-Barbituric acid; Pentobarbital; (1-methyl-4-phenyl-4-piperidinecarboxylate); Pethidine; Phenadoxone; Phenomorphane; Phenazocine; Phenoperidine; Piminodine; Pholcodeine; 3-Methyl-2-phenylmorpholine; Phenmetrazine; 5-Ethyl-phenylbarbituric acid; Phenobarbital; α,α-Dimethylphenethylamine; Phenbutylamine; (R)-3-[-1-hydroxy-2-(methylamino)ethyl] Phenol; Phenylephrine, 7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepine-2(3H)-one; Pinazepam; α-(2-piperidinyl)diphenylmethylethanol; Pipravrol; 1'-(3-cyano-3,3-diphenylpropyl)[1,4'-bipiperidine]-4'-methylamine; Piritramide; 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one; Prazepam; Profadol; Proheptazine; Promedol;Properidine; propoxyphene; N-(1-methyl-2-N-piperidinylethyl)-N-(2-pyridyl)propionamine; {3-[4-methoxycarbonyl-4-(N-phenylpropionamine)N-piperidinyl]methyl propionate}; (S,S)-2-methylamino-1-phenylprop-1-ol; pseudoephedrine, remifentanil; 5- Secondary butyl-5-ethylbarbituric acid; isobutylbarbital; 5-allyl-5-(1-methylbutyl)-barbituric acid; secobarbital; N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidinyl}propionic acid; sufentanil; 7-chloro-2-hydroxymethyl-5-phenyl-1 H-1,4-benzodiazepine-2(3H)-one; temazepam; 7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one; tetrazepam; (2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylic acid ethyl ester; cis / trans-tiridine; tramadol; 8-chloro-6-(2-chlorophenyl)-1-methyl-4H -[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; triazolam; 5-(1-methylbutyl)-5-vinylbarbituric acid; vinylbital; (1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol; (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzoxy)-1-(m-methoxyphenyl)cyclohexanol;

[0065] In addition to the compounds mentioned above, active pharmaceutical ingredients also include any of these compounds as precursors. The term "precursor" refers to a compound that serves as a metabolic precursor to the active pharmaceutical ingredient. This precursor is converted in vivo to provide the active pharmaceutical ingredient with the desired therapeutic effect.

[0066] The dosage forms according to the present invention include various active agents and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts, such as hydrochlorides, hydrobroms, sulfates, phosphates and the like; organic acid salts, such as formates, acetates, trifluoroacetates, maleates, tartrates and the like; sulfonates, such as methanesulfonates, benzenesulfonates, p-toluenesulfonates and the like; amino acid salts, such as arginine salts, aspartic acid salts, glutamine salts and the like; metal salts, such as sodium salts, potassium salts, cesium salts and the like; alkaline earth metal salts, such as calcium salts, magnesium salts and the like; organic amine salts, such as triethylamine salts, pyridine salts, methylpyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-diphenylmethylethylenediamine salts and the like.

[0067] The phrase "medically acceptable" means that it is suitable for the preparation of pharmaceutical compositions that are generally safe, non-toxic, biologically or otherwise not undesirable, and acceptable for human medical use.

[0068] In addition to the compounds mentioned above, the active pharmaceutical ingredient also includes solvates of any of the compounds mentioned above. The term "solvate" refers to an aggregate comprising one or more active pharmaceutical ingredient molecules and one or more solvent molecules. 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 undissolved state. Alternatively, the solid particles of the suspended active pharmaceutical ingredient may contain a co-precipitated solvent.

[0069] As used herein, the terms “therapeutic effectiveness” and “effective dose” refer to the amount of active agent or the rate at which the active agent is administered to produce the desired therapeutic outcome.

[0070] As used herein, “shell” or “shell composition” refers to the outer shell or outer portion of a soft capsule of a capsule-filling composition.

[0071] Throughout this specification, the term "filling material" may be used interchangeably with the terms "filling composition" and "filling". These terms refer to the internal portion of a soft capsule encapsulated by the shell composition.

[0072] As used herein, "common pH-dependent polymers" refers to (but is not limited to) acrylic and methacrylic acid polymers, available under the trade name EUDRAGIT®, and other common acid-insoluble polymers, such as methyl methacrylate-methacrylic acid copolymers. Other common acid-insoluble polymers include, but are not limited to, cellulose acetate succinate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate (hydroxypropyl methyl cellulose succinate), polyvinyl acetate phthalate (PVAP), alginate (such as sodium alginate and potassium alginate), stearic acid, and shellac. Pectin and pectin derivatives are not considered common pH-dependent polymers. Glechoma hesperidin and its derivatives are also not considered common pH-dependent polymers. In some embodiments, the pH-dependent shell composition of the present invention does not include acid-insoluble polymers. In other words, in some embodiments, the pH-dependent shell composition and the pH-dependent soft capsule "do not contain or substantially do not contain common pH-dependent polymers".

[0073] As used herein, "free from or substantially free from" 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.%.

[0074] Unless otherwise specified, all references to "molecular weight" in this document refer to the average molecular weight.

[0075] As used in this article, the term "ambient temperature" refers to a temperature of approximately 20-35°C.

[0076] Throughout the specification and the scope of the claims, all references to wt.% refer to the weight of the component with reference to the weight of the entire composition of the invention, and may also refer to w / w unless otherwise expressly indicated.

[0077] As used herein, "delayed-release capsule," "delayed-release soft capsule," "pH-dependent capsule," or "pH-dependent soft capsule" refers to a capsule that, once the filling composition is encapsulated in a pH-dependent shell composition and dried, possesses delayed or pH-dependent properties. In some embodiments, these terms may refer to capsules that are also cured after drying. In some embodiments, no further processing steps are required after drying. In some embodiments, no further processing steps are required after curing. The term "curing" and its variations are used interchangeably with the term "annealing" and its variations.

[0078] As used herein, "modified release soft capsule" refers to a capsule in which a controlled release filling composition is encapsulated in a pH-dependent shell composition.

[0079] As used herein, the term "controlled release" refers to the release of an active agent over a period of time, for example, to provide a once-daily or twice-daily dosage form.

[0080] As used herein, “about” means any value within ±10% of the range, such that “about 10” would include 9 to 11. Unless otherwise specified, “a,” “an,” or “the” as used herein means one or more. Thus, by way of example, reference to “excipient” includes a single excipient and mixtures of two or more different excipients and the like.

[0081] Unless otherwise indicated, the description of ranges in this document is intended only as a shorthand for individually referring to each independent value belonging to that range, and each independent value is incorporated into this specification as if described separately herein. Unless otherwise specified herein or clearly contradicted, all methods described herein may be performed in any suitable order.

[0082] The use of any and all examples or illustrative language (such as "such as") provided herein is intended only to describe certain substances and methods and does not limit the scope. The language used in this specification should not be construed as indicating that any non-proposed element is essential to the practice of the disclosed substances and methods. [Controlled-release filling composition] [ ]

[0083] According to the embodiments, the filling composition of the modified release soft capsules described herein is a controlled release filling composition, which includes at least one active agent and a controlled release material.

[0084] The active agent may be any of the active agents described above, such as (but not limited to) pharmaceutical active ingredients or pharmaceutical-like nutritional supplements (e.g., vitamins, minerals, or supplements). Particularly suitable active agents are those that benefit from controlled release over an extended duration (e.g., 12 or 24 hours) when administered once or twice daily. Active agents that are unstable or that benefit from the low pH protection of gastric juices in the gastric region (such as peptides, proteins, enzymes, and analogues) may also be advantageously used with the soft capsules described herein. Additionally, active agents that can irritate or damage the gastric mucosa (e.g., NSAIDs) may be incorporated into the soft capsules described herein without requiring expensive tablet-making and coating processes. Generally, this document covers any active agent that benefits from the ability of soft capsules to promote targeted release of the active agent into a specific region within the gastrointestinal tract (GIT) and the ability of soft capsules to control the release of the active agent in a specific region within the GIT.

[0085] In one embodiment, the active agent includes fish oil, garlic oil, krill oil, or any other active agent that may cause an unpleasant sensation due to premature release of the active agent, such as belching.

[0086] In one embodiment, the active agent includes an NSAID such as ibuprofen, or any other active agent that can stimulate the gastric mucosa due to premature release of the active agent in the gastric region rather than later release in the gastric region.

[0087] In one embodiment, the active agent includes peptides, proteins, enzymes, or any other active agent that may be unstable in the acidic environment of the stomach and / or may be better absorbed closer to the colon.

[0088] In some embodiments, the active agent includes antihistamines (such as diphenhydramine) or acetaminophen.

[0089] In one embodiment, the active agent comprises a drug that is prone to abuse. In an alternative embodiment, the active agent is a drug that is not prone to abuse.

[0090] With regard to examples shown for a particular surfactant, such examples should not be regarded as limited to that surfactant, but rather as proof of concept applicable to a variety of surfactants.

[0091] In some embodiments, the active agent is present in the controlled-release filling composition in amounts 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 at most about 35 wt.%, at most about 40 wt.%, at most about 45 wt.%, at most about 50 wt.%, at most about 55 wt.%, or at most about 60 wt.%, based on the total weight of the controlled-release filling composition. In some embodiments, the controlled-release filling composition comprises 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.%, based on the total weight of the controlled-release filling composition. In one embodiment, the active agent is present in the controlled-release filler composition in an amount of about 5 wt.% to about 60 wt.% based on the total weight of the controlled-release filler composition. In another embodiment, the active agent is present in the controlled-release filler composition in an amount of about 10 wt.% to about 30 wt.% based on the total weight of the controlled-release filler composition. The concentration range of the active agent described herein may refer to the concentration of a single active agent (regardless of the number of active agents in the filler composition) or to the cumulative concentration of all active agents in the filler composition (if more than one active agent is present in the filler composition).

[0092] In some embodiments, the controlled-release material that may be incorporated into the controlled-release filler composition includes (but is not limited to) polyethylene oxide, cellulose derivatives, gums, or combinations thereof.

[0093] In embodiments, the available polyethylene oxide has a number-average molecular weight ranging from any one of about 0.05 M, about 0.5 M Dalton, about 1 M Dalton, about 2 M Dalton, about 3 M Dalton, or about 4 M Dalton to any one of about 5 M Dalton, about 7 M Dalton, about 10 M Dalton, about 12 M Dalton, about 15 M Dalton, or about 20 M Dalton, or any subrange or single value thereof. In one embodiment, the number-average molecular weight of the polyethylene oxide in the controlled-release filler composition ranges from about 0.05 M Dalton to about 15 M Dalton. In one embodiment, the number-average molecular weight of the polyethylene oxide in the controlled-release filler composition ranges from about 1 M Dalton to about 10 M Dalton. In one embodiment, the number-average molecular weight of the polyethylene oxide in the controlled-release filler composition ranges from about 2 M Dalton to about 5 M Dalton.

[0094] Suitable polyethylene oxides are typically nonionic, high molecular weight, water-soluble polyethylene oxide resins. An exemplary PEO resin of this type is the Polyox™ water-soluble resin available from DuPont Pharma Solutions. These PEO resins are commonly used as thickeners and rheology control agents. In this invention, these water-soluble PEO resins can be used to modify or control the release of active agents from self-filled compositions. If APIs are prone to misuse, PEO resins can also be used to fill compositions to prevent the misuse of APIs contained in the filled compositions.

[0095] A significant advantage of using polyethylene oxide as the rate control component in a filler composition is that it does not tend to be as viscous or sticky as other rate control polymers, thereby promoting the encapsulation process and ensuring a more uniform filler composition. While other additional rate control polymers may be used, the amount of such polymers must be carefully selected to prevent this viscosity or stickiness from causing problems during the encapsulation process that could lead to substandard products.

[0096] In the embodiments, the cellulose derivatives that can be used include microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or combinations thereof. In one embodiment, the cellulose derivative is hydroxypropyl methyl cellulose.

[0097] In the embodiments, the gums that may be used include tragacanth gum, gum arabic, agar, locust bean gum, galaya gum, galan gum, vegan gum, rhamnogalactan gum, guar gum, sage gum, locust bean gum, or combinations thereof. In one embodiment, the gum includes sage gum, locust bean gum, or combinations thereof. In one embodiment, the gum includes sage gum. In one embodiment, the gum includes locust bean gum.

[0098] Other release-controlled polymers that may be selected as appropriate may include pectin, starch, carbomer, sodium alginate, gelatin, casein, carrageenan, collagen, polydextrose, succinoglucon, polyvinyl alcohol clay, and combinations thereof.

[0099] In one embodiment, the controlled release material itself comprises any of the polyethylene oxides described herein. In some embodiments, the controlled release material comprises a combination of any of the polyethylene oxides described herein and any of the cellulose derivatives described herein. In some embodiments, the controlled release material comprises a combination of any of the polyethylene oxides described herein and any of the adhesives described herein.

[0100] In the embodiments, the amount of controlled-release material in the controlled-release filler composition, based on the total weight of the controlled-release filler composition, is 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.%, up to about 25 wt.%, up to about 35 wt.%, up to about 45 wt.%, up to about 55 wt.%, or up to about 65 wt.%, or a subrange thereof. In some embodiments, the controlled release filler composition comprises, by weight of the total controlled release filler composition, 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.

[0101] In one embodiment, a controlled-release filler material (e.g., PEO) is used in the controlled-release filler composition at an amount of at least 21.5 wt.% based on the total weight of the controlled-release filler composition. In one embodiment, a controlled-release filler material (e.g., PEO) is present in the controlled-release filler composition at an amount of about 10 wt.% to about 65 wt.% based on the total weight of the controlled-release filler composition. In one embodiment, a controlled-release filler material (e.g., PEO) is present in the controlled-release filler composition at an amount of about 25 wt.% to about 40 wt.% based on the total weight of the controlled-release filler composition.

[0102] In an alternative embodiment, PEO may be present in the controlled-release filler composition in any suitable amount, provided that the hydrophilic carrier is present in an amount of up to 65 wt.% of the total weight of the controlled-release filler composition. In this embodiment, the minimum amount of the hydrophilic carrier may be at least about 30 wt.%, at least about 40 wt.%, or at least about 55 wt.% of the total weight of the controlled-release filler composition. In these alternative embodiments, the amount of PEO in the controlled-release filler composition may be from about 5 wt.% to about 35 wt.% or about 20 wt.% of the total weight of the controlled-release filler composition.

[0103] The concentration range of controlled-release materials mentioned herein may refer to the concentration of a single controlled-release material (regardless of the number of controlled-release materials in the filler composition) or the cumulative concentration of all controlled-release materials in the filler composition (if more than one controlled-release material is present in the filler composition).

[0104] The concentration of the controlled-release material in the filler composition can be modified to obtain a target release profile of the surfactant. For example, as illustrated in Example 11 and Figure 2, in some embodiments, the amount of polyethylene oxide affects the release rate of the surfactant in the controlled-release filler composition. Polyethylene oxide having an average molecular weight of 4 M Daltons achieves a 12-hour release profile of the surfactant when incorporated into the filler composition at concentrations of approximately 12 wt.% and approximately 18 wt.% based on the total weight of the filler composition. In contrast, the same polyethylene oxide achieves a 24-hour zero-order release profile of the surfactant when incorporated into the filler composition at a concentration of approximately 24 wt.% based on the total weight of the filler composition.

[0105] Similarly, the weight ratio of the controlled-release material to other components of the filler composition (such as surfactants or hydrophilic carriers, if present) can be adjusted to obtain a targeted release profile of the surfactant. In some embodiments, the wt:wt ratio of the controlled-release material to the surfactant can be 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.

[0106] In some embodiments, the controlled-release material (e.g., PEO) and water and / or hydrophilic carrier may be present in any suitable amount in the controlled-release filler composition such that the weight ratio of the controlled-release material (e.g., PEO) to water and / or hydrophilic carrier (alone or cumulative) ranges 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, about 2:1 to about 1:2, about 10:1 to 1:3, about 8:1 to 1:3, about 5:1 to 1:3, about 3:1 to 1:3, about 2:1 to 1:3, about 1:1 to 1:3, about 10:1 to about 1:2, about 8:1 to about 1:2, about 5:1 to about 1:2, about 3:1 to about 1:2, about 1:1 to about 1:2, or any subrange or single weight ratio thereof. In one embodiment, the weight ratio of the controlled-release material (e.g., PEO) to water and / or a hydrophilic carrier (individually or cumulatively) is in the range of about 2:1 to about 1:2. In another embodiment, the weight ratio of the controlled-release material (e.g., PEO) to water and / or a hydrophilic carrier (individually or cumulatively) is in the range of about 3:1 to 1:3.

[0107] Other factors, such as (but not limited to) the type of release material and the molecular weight of the release material, can also affect the release rate of the active agent in the filler composition.

[0108] In one embodiment, the controlled-release filler composition may further include a hydrophilic carrier. The hydrophilic carrier may be a low molecular weight polyol, such as polyethylene glycol, polypropylene glycol, or combinations thereof. The hydrophilic carrier may also be water. Examples of additionally suitable hydrophilic carriers are hydrophilic solvents comprising polyethylene oxide derivatives of sorbitan esters, such as sorbitan monolaurate (polysorbate 20), polysorbate 80, polysorbate 60, polyethylene oxide 20 sorbitan trioleate (polysorbate 85), acetic acid, formic acid, other hydrophilic surfactants, and mixtures thereof.

[0109] In some embodiments, the controlled-release filler composition includes a hydrophilic carrier having a number-average molecular weight of any one of about 200 Daltons, about 400 Daltons, about 600 Daltons, about 800 Daltons, or about 1000 Daltons, or any subrange or single value of about 2000 Daltons, about 3000 Daltons, about 4000 Daltons, about 5000 Daltons, about 6000 Da, or about 7000 Da. Exemplary hydrophilic carriers that can be used in the controlled-release filler composition include polyethylene glycol 400, polyethylene glycol 600, water, or combinations thereof.

[0110] In some embodiments, the hydrophilic carrier in the filler composition comprises polyethylene glycol with a number average molecular weight of about 300 Daltons to about 7000 Daltons. In some embodiments, the hydrophilic carrier in the filler 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 some embodiments, the hydrophilic carrier may comprise compounds with a number average molecular weight of less than 200 Daltons.

[0111] In some embodiments, the hydrophilic carrier is present in the controlled release filler composition in an amount greater than 0 wt.%, at least about 15 wt.%, or at least about 30 wt.%, at most about 45 wt.%, at most about 60 wt.%, at most about 70 wt.%, or at most about 80 wt.% based on the total weight of the controlled release filler composition. In some embodiments, the controlled-release filler composition comprises, by weight of the total controlled-release filler composition, about 5 wt.% to about 15 wt.%, about 15 wt.% to about 28 wt.%, about 20 wt.% to about 32 wt.%, about 20 wt.% to about 42 wt.%, about 22 wt.% to about 45 wt.%, about 40 wt.% to about 45 wt.%, about 40 wt.% to about 55 wt.%, about 35 wt.% to about 55 wt.%, about 56 wt.% to about 77 wt.%, about 40 wt.% to about 79 wt.%, or about 29 wt.% to about 66 wt.% of a hydrophilic carrier.

[0112] In one embodiment, the hydrophilic carrier is included in the controlled-release filling composition in an amount of up to 65 wt.% based on the total weight of the controlled-release filling composition. In another embodiment, the hydrophilic carrier is included in the controlled-release filling composition in an amount of about 10 wt.% to about 75 wt.% or 30 wt.% to about 70 wt.% based on the total weight of the controlled-release filling composition. Preferably, the hydrophilic carrier is included in the controlled-release filling composition in an amount of about 40 wt.% to about 60 wt.% based on the total weight of the controlled-release filling composition.

[0113] In another embodiment, the hydrophilic carrier may be present in any amount in the controlled-release filler composition, provided that 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 filler 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 filler composition. The hydrophilic carrier is used to dissolve, disperse, and / or suspend other components of the liquid filler composition in the liquid, and may also be used to adjust the viscosity of the liquid filler composition to the required viscosity for the encapsulation step.

[0114] The concentration range of hydrophilic carriers mentioned in this article may refer to the concentration of a single hydrophilic carrier material (regardless of the number of hydrophilic carrier materials in the filler composition) or the cumulative concentration of all hydrophilic carrier materials in the filler composition (if more than one hydrophilic carrier material is present in the filler composition). In some embodiments, the filling composition is a liquid with a viscosity ranging from 1,000 cP to 100,000 cP, or 5,000 cP to 80,000 cP, or 10,000 cP to 60,000 cP when filled (or encapsulated) within a capsule shell composition. The viscosity of the liquid filling composition was determined at 20°C using a HAAKE RheoStress 600 rheometer equipped with a 40 mm flat geometry. The geometry oscillated at 1 Hz with a gap of 2 mm. A significant advantage of having a liquid filling composition during processing is that, unlike tablet dosage forms which typically require handling of powder throughout the dosage form preparation process, it avoids the need to handle powder during dosage form preparation, except in the initial mixing step. Furthermore, the processing of the liquid filling compositions described herein does not require the inclusion of flow enhancers or processing enhancers to facilitate processing. Similarly, since the filling composition is liquid at ambient temperature, it is not necessary to heat it before encapsulation, as heating may be harmful to heat-sensitive materials, such as those in the shell composition used in some soft capsules.

[0115] In some embodiments, based on fiber optic dissolution tests using a USP device II with a paddle speed of 50 rpm in a pH 6.8 phosphate buffer containing trypsin as appropriate, the release of the filler composition was controlled to release less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, or less than about 30% of the active agent after about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours.

[0116] In some embodiments, the controlled release of the filler composition at 37°C releases approximately 10 wt.% to approximately 30 wt.% of the active agent in 1 hour, approximately 15 wt.% to approximately 50 wt.% of the active agent in 2 hours, approximately 20 wt.% to approximately 80 wt.% of the active agent in 4 hours, approximately 40 wt.% to approximately 95 wt.% of the active agent in 8 hours, approximately 65 wt.% to approximately 100 wt.% of the active agent in 12 hours, and more than 90 wt.% of the active agent in 24 hours, as measured in each case by in vitro dissolution testing using a USP device II (blade) at 50 rpm.

[0117] In some embodiments, the release rate of the active agent from the release-filling composition is controlled such that, in an optical fiber dissolution test at 37°C using a USP device II with a blade speed of 100 RPM, less than 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, or less than about 30% of the active agent is released after about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours.

[0118] As will be described in further detail below, modified release soft capsules can be annealed at an annealing temperature for a specified duration. In some embodiments, annealing facilitates the formation of a matrix within the modified release soft capsule. For example, when the controlled release material is polyethylene oxide, annealing can promote the melting of the polyethylene oxide to form a matrix (liquid or solid) encapsulated within the pH-dependent shell composition.

[0119] Another embodiment relates to a method for preparing a controlled-release filler composition containing polyethylene oxide resin. This method is designed to accommodate soft capsule compositions that are incompatible with high encapsulation temperatures due to the relatively low melting point of the capsule shell composition. For example, gelatin-based soft gels can begin to melt at temperatures of 33-45°C, depending in part on the water content of the capsule shell material at the time of encapsulation. For such capsule shell materials with lower melting temperatures, methods have been designed to fill capsules with liquid filler compositions at lower temperatures. A significant advantage of this method is that it can be used for the final encapsulation of highly viscous liquid, semi-solid, or solid filler compositions. In this method, a solid solution or semi-solid filler is formed in situ within the capsule due to a heating step following encapsulation.

[0120] In this method, suspensions and dispersions can be used instead of solutions. After the encapsulation step, the soft capsule shell will typically contain up to 20 wt.% water by total weight of the capsule shell. During encapsulation and subsequent drying steps, most of the water in the capsule shell (i.e., up to about 70%) will migrate into the filler composition and dissolve solid components, such as PEO, in the suspension / dispersion of the filler composition, forming the desired solution in situ. Using this method, the dissolution of solid components (e.g., PEO) within the filler composition occurs in situ. Prior to encapsulation, the water content in the filler composition is low enough to limit or prevent the dissolution of at least some components of the filler composition (such as PEO) before the encapsulation and drying steps. Premature dissolution of certain components within the filler composition (i.e., before encapsulation and drying) may increase the viscosity of the filler composition and impair handleability. Typically, the initial filler composition will have a water content of about 2 wt.% to about 10 wt.% by total weight of the filler composition to avoid premature dissolution of the PEO component of the filler composition before encapsulation. Following the encapsulation and filling of the composition, a portion of the water from the soft capsule shell migrates into the filling composition, typically increasing the water content of the filling composition to approximately 15 wt.% to approximately 20 wt.% by weight of the total encapsulated and filled composition, thereby dissolving the PEO in the encapsulated and filled composition. During the subsequent drying process, the water is gradually removed until the water content of the encapsulated and dried filling composition is reduced to less than 10 wt.% by weight of the total encapsulated and dried filling composition. After a final heating step (also known as an annealing step), the water content of the final encapsulated and filled composition is further reduced to approximately 5 wt.% to approximately 8 wt.% by weight of the final encapsulated and filled composition. The final encapsulated and filled composition forms a solid solution of PEO in a hydrophilic carrier.

[0121] 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 within the filling composition. This uniform distribution of the API is a crucial feature for delivering high-efficiency and / or low-dose APIs, as such APIs should be delivered at a relatively constant rate over time to avoid overdosing or underdosing. In some embodiments, the uniform distribution of the API within the filling composition enables zero-order release of the API from the self-controlled release filling composition (whereby the API is delivered at a relatively constant rate over time, e.g., from about 2 hours to about 12 hours or from about 2 hours to about 24 hours).

[0122] In one embodiment, the controlled-release filler composition comprises, consists of, or is substantially composed of: at least one active agent (e.g., a pharmaceutical active ingredient, such as an NSAID (e.g., ibuprofen), an antihistamine (e.g., diphenhydramine), acetaminophen, a pharmaceutical nutritional supplement (e.g., garlic oil, fish oil, krill oil, or other vitamins, minerals, or supplements)), a controlled-release material (e.g., polyethylene oxide with a number average molecular weight of about 0.05 M Daltons to about 15 M Daltons, combined with a cellulose derivative (e.g., hydroxypropyl methylcellulose), or a gum (e.g., succinate)) and a hydrophilic carrier (e.g., polyethylene glycol with a number average molecular weight of about 200 Daltons to about 5000 Daltons, combined with water, as appropriate).

[0123] In some embodiments, the controlled-release filler composition may include additional filler components, such as flavoring agents, sweeteners, colorants, and fillers, or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides. [pH] [Dependency-dependent shell composition] [ ]

[0124] According to one embodiment, the pH-dependent shell composition includes gelatin, dextrose, a pH-dependent material (e.g., low-methoxyl pectin), and a plasticizer, if applicable. Preferably, the pH-dependent shell composition does not contain any additional pH-dependent polymers.

[0125] In one embodiment, the gelatin in the pH-dependent shell composition may include type A gelatin, type B gelatin, hide or skin gelatin (e.g., cowhide, pigskin), and / or bone gelatin (e.g., cow bone, pig bone), used alone or in combination. In one embodiment, the gelatin is a 250-Bloom gelatin. In one embodiment, the gelatin is a 150-Bloom gelatin. In another embodiment, only one type of gelatin is present. 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, based on the total weight of the dried capsule shell composition, is about 25 wt.% to about 85 wt.%, about 25 wt.% to about 80 wt.%, about 30 wt.% to about 85 wt.%, about 30 wt.% to about 75 wt.%, about 35 wt.% to about 70 wt.%, about 30 wt.% to about 65 wt.%, about 40 wt.% to about 65 wt.%, about 30 wt.% to about 55 wt.%, about 30 wt.% to about 40 wt.%, about 40 wt.% to about 80 wt.%, about 45 wt.% to about 65 wt.%, about 45 wt.% to about 60 wt.%, about 45 wt.% to about 75 wt.%, or about 50 wt.% to about 70 wt.%, or any single value or subrange thereof.

[0126] In one embodiment, the pH-dependent capsule shell composition comprises dextrose. In one embodiment, the amount of dextrose in the pH-dependent capsule shell composition, based on the total weight of the dried 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 subrange thereof. Dextran can be added to pH-dependent shell compositions to mitigate the potential reduction in gel strength. This should not be construed as limiting the belief that dextrose interacts with gelatin in the shell composition and causes the gelatin to crosslink. Examples further illustrate the effect of dextrose concentration on the solubility properties of the shell composition. The concentration of dextrose in the pH-dependent shell composition can be an amount that effectively improves gel strength, but not so high that it would interfere with capsule sealing, manufacturability, or product efficacy.

[0127] In some embodiments, the pH-dependent shell composition may comprise pectin, such as low-methoxyl pectin. In one embodiment, the pectin is low-methyl ester (LM) pectin with a degree of esterification less than 50. In some embodiments, the pectin is acetamipated pectin. In other embodiments, the low-methoxyl (LM) pectin is non-acetamipated pectin. In some embodiments, the pectin is a combination of acetamipated and non-acetamipated pectin. The addition of pectin contributes to the pH dependence of the shell composition. [ ]

[0128] Excessive pectin in the dosage form can reduce the gel strength of the shell composition, which in turn can adversely affect the sealing properties of the soft capsule. Excessive pectin in the pH-dependent shell composition can also increase the viscosity of the shell composition, making it challenging or impossible to process from a manufacturing point of view. [ ]

[0129] Therefore, pectin can be added to dosage forms at sufficiently high concentrations to form modified release soft capsules, while at the same time being low enough to mitigate the reduction in gel strength and the increase in viscosity to a level that would impede manufacturability. [ ]

[0130] In one embodiment, the amount of pectin in the pH-dependent shell composition, based on the total weight of the dried capsule shell composition, is about 2 wt.% to about 20 wt.%, about 3 wt.% to about 15 wt.%, about 3 wt.% to about 18 wt.%, about 5 wt.% to about 15 wt.%, about 3 wt.% to about 5.5 wt.%, about 3.5 wt.% to about 6.5 wt.%, about 2.5 wt.% to about 7 wt.%, about 4 wt.% to about 11 wt.%, about 7 wt.% to about 12 wt.%, about 8 wt.% to about 13 wt.%, or about 5 wt.% to about 10 wt.%, or a single value or subrange thereof. [ ]

[0131] The degree of esterification of pectin incorporated into the pH-dependent shell composition may be less than about 50%, or may be in the range of about 10% to about 50%, about 20% to about 40%, or about 25% to about 35%. Furthermore, the pectin may be acetaminated or unacetaminated. [ ]

[0132] In some embodiments, the pH-dependent shell composition comprises a stabilizer and / or a binder comprising guar gum. In some embodiments, the wt:wt ratio of pectin to stabilizer and / or binder (e.g., guar 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.

[0133] In some embodiments, the amount of stabilizer and / or binder (e.g., galvanic acid) in the pH-dependent shell composition, based on the total weight of the dried capsule 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.% stabilizer and / or binder (e.g., galvanic acid), or any single value or subrange thereof. [ ]

[0134] In some embodiments, the viscosity range of the pH-dependent shell composition may be between any one of about 20,000 cPs, about 30,000 cPs, about 40,000 cPs, about 50,000 cPs, about 60,000 cPs, or about 70,000 cPs, and up to about 80,000 cPs, about 90,000 cPs, about 100,000 cPs, about 110,000 cPs, about 120,000 cPs, about 130,000 cPs, about 140,000 cPs, about 150,000 cPs, about 160,000 cPs, or about 170,000 cPs, or any subrange or single value thereof. In one embodiment, the viscosity of the pH-dependent shell composition ranges from about 100,000 cPs to about 130,000 cPs, or from about 110,000 cPs to about 125,000 cPs, or about 115,000 cPs, or about 120,000 cPs. Viscosity is measured using a rheometer at 60°C, as described in further detail in the example associated with Figure 1. A gel block sample (e.g., any of the pH-dependent shell compositions described herein) is loaded onto the platform of the rheometer and maintained at 60°C. The disk rotates at a certain speed to provide a constant shear rate. Viscosity is obtained by measuring shear stress and shear rate. [ ]

[0135] In some embodiments, the pH-dependent shell composition retains a viscosity suitable for manufacturability even after heat aging for up to about 24 hours, up to about 48 hours, up to about 72 hours, up to about 96 hours, or up to about 1 week. In some embodiments, the viscosity of the pH-dependent shell composition after heat aging (lasting up to about 24 hours, up to about 48 hours, up to about 72 hours, up to about 96 hours, or up to about 1 week) may decrease (from the viscosity value of the composition before aging) by up to about 80%, up to about 70%, up to about 60%, up to about 50%, up to about 40%, up to about 35%, or up to about 30%. [ ]

[0136] 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, isomaltitol, maltitol, xylitol, erythritol, sennaol, eurythritol, pentaerythritol, or mannitol; or polyol plasticizers such as diglycerol, 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 include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyl groups, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, monoblock polymers, citrate-type plasticizers, and triacetin. Such plasticizers may include 1,2-butanediol, 2,3-butanediol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitan 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. [ ]

[0137] In one embodiment, the amount of plasticizer in the pH-dependent shell composition, based on the total weight of the dried capsule 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 subrange thereof.

[0138] In some embodiments, the amounts and ratios of various components (e.g., pectin, dextrose, gelatin, plasticizers) are adjusted to control the solubility and / or disintegration characteristics of the pH-dependent shell composition across a range of pH values ​​and accordingly promote the targeted release of the active agent into specific regions of the gastrointestinal tract.

[0139] For example, the gelatin to pectin w:w ratio in the pH-dependent shell composition can range from any of 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 subrange or single value thereof. In some 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, such as 0.1 N HCl with pepsin, if applicable) in an acidic medium, 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, such as 0.1 N HCl with pepsin, if applicable. The gelatin to pectin w:w ratio can be adjusted to achieve specific dissolution times of the soft capsules 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.).

[0140] The gelatin to plasticizer w:w ratio in the pH-dependent shell composition can also be adjusted to achieve a specific capsule hardness level, and the ratio range can be about 5:1 to about 1:5, about 5:1 to about 1:2, about 4:1 to about 1:4, about 4:1 to about 1:2, about 3:1 to about 1:3, about 3:1 to about 1:2, about 2:1 to about 1:2, about 1:1 or any single ratio value or subrange thereof.

[0141] In some embodiments, the hardness range of the pH-dependent shell composition described herein may be from any one of about 5 N, about 6 N, about 7 N, about 8 N, about 9 N, or about 10 N to any one of about 11 N, about 12 N, about 13 N, about 14 N, or about 15 N. Capsule hardness is determined using a hardness tester. Capsule hardness is defined as the force required to cause a 2.0 mm deformation of the capsule, expressed in Newtons.

[0142] In some embodiments, the shell moisture content of the pH-dependent shell composition described herein may range from any one of about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% to any one of about 11%, about 12%, about 13%, about 14%, or about 15%. The shell moisture content is determined by a loss on drying method. One to two grams of the pH-dependent capsule shell composition sample is placed in an oven at 105°C for 17 hours. The initial weight of the sample is recorded. After drying the sample in the 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 equation is defined as the shell moisture content:

[0143] In some embodiments, the equilibrium relative humidity range of the pH-dependent shell composition described herein may be any one of about 25%, about 28%, about 30%, about 32%, about 34%, or about 35% to any one of 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 constant humidity using a saturated salt solution.

[0144] In some embodiments, the burst strength of the pH-dependent shell composition described herein may range from any one of about 50 kg, about 60 kg, about 70 kg, about 80 kg, or about 90 kg to any one of about 100 kg, about 110 kg, about 120 kg, about 130 kg, about 140 kg, or about 150 kg. Bursting strength, an indicator of capsule robustness, is determined using a texture analyzer. The texture analyzer compresses the capsule until it bursts. The burst strength is defined as the force required to cause the capsule to burst, expressed in kilograms.

[0145] In one embodiment, the pH-dependent shell composition and pH-dependent soft capsule may be free of or substantially free of known pH-dependent polymers and / or free of pH-dependent coatings on the soft gel shell.

[0146] In one embodiment, the pH-dependent shell composition and pH-dependent soft capsule may include divalent cation salts, such as Ca++ (e.g., CaCl2) or Mg++ (e.g., MgCl2). In another embodiment, the pH-dependent shell composition and pH-dependent soft capsule may be free of or substantially free of divalent cation salts, such as Ca++ (e.g., CaCl2) or Mg++ (e.g., MgCl2). In yet another embodiment, the pH-dependent shell composition may not include the step of adding divalent cation salts other than a certain amount that may be present in other components, such as Ca++ (e.g., CaCl2) or Mg++ (e.g., MgCl2).

[0147] In one embodiment, the pH-dependent shell composition may include 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.

[0148] Suitable colorants for use in filling compositions and shell compositions may include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, purple, 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).

[0149] Suitable flavoring agents for use in filling compositions and shell compositions may include, but are not limited to, "flavor extracts" obtained by extracting a portion of a raw material (e.g., animal or plant material), typically using solvents such as ethanol or water; and natural flavorings obtained by extracting essential oils from flowers, fruits, roots, or whole plants.

[0150] Other exemplary flavoring agents used in the filling composition and the shell composition may include, but are not limited to, breath-freshening compounds such as menthol, spearmint and cinnamon, coffee beans, other flavorings or aromatherapy agents such as fruit flavorings (e.g., cherry, orange, grape, etc.), especially those for oral hygiene, and active agents for dental and oral cleaning, such as quaternary ammonium bases. Flavor enhancers (such as tartaric acid, citric acid, vanilla extract or analogues) may be used to enhance the effect of the flavoring agents.

[0151] Exemplary sweeteners used in filler compositions 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, such as potassium salts (available in Sunett® form), alitame, aspartame (available in NutraSweet® and Equal® form), aspartame-acesulfame salts (available in Twinsweet® form), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as sodium salts (available in Sweet'NLow® form), stevia, chlorinated derivatives of sucrose, such as sucralose (available in Kaltame® and Splenda® form), and mogroside. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizate (sold under the trade name MagnaSweet®); stevia (stevia glycosides); natural powerful sweeteners such as lo han guo (monk fruit); polyols such as sorbitol, mannitol, xylitol, erythritol and their analogues.

[0152] In some embodiments, the pH-dependent shell composition and / or pH-dependent soft capsules can be tested in a disintegration / dissolution test in an acidic medium of 0.1 N HCl (pH 1.2, with pepsin if applicable) at a USP device II with a paddle speed of 50 rpm, followed by a buffer medium (pH 6.8 phosphate buffer, with trypsin if applicable). The pH-dependent shell composition according to this embodiment can remain intact in an 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 can disintegrate in a buffer medium in about 60 minutes or less, in about 45 minutes or less, in about 30 minutes or less, in about 20 minutes or less, in about 15 minutes or less, in about 10 minutes or less, or in about 5 minutes or less.

[0153] Although the buffer medium for the two-stage dissolution / disintegration test has a pH of 6.8, it should be noted that similar dissolution / disintegration profiles can be obtained in buffer media with a pH of approximately 3.5 or higher (where trypsin may be present, if applicable). It should also be noted that the presence of pepsin (in acidic media) and trypsin (in buffer media) is not required for the pharmacopoeia method, but is used in some cases in this paper to simulate more aggressive environments that better mimic in vivo conditions.

[0154] In some embodiments, the pH-dependent shell composition described herein remains intact in an acidic environment (e.g., a gastric environment or a simulated gastric environment, such as simulated gastric juice, with pepsin in 0.1 N HCl, if applicable) 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, but ruptures / dissolves / disintegrates within a maximum of about 5 minutes, at most about 10 minutes, at most about 15 minutes, at most about 20 minutes, at most about 25 minutes, at most about 30 minutes, at most about 35 minutes, at most about 40 minutes, at most about 45 minutes, or at most about 60 minutes.

[0155] 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., glycerol, sorbitol, and combinations thereof), and (e) a stabilizer and / or binder (e.g., gellan gum), if appropriate. The amounts and wt:wt ratios of these components may be based on any of the values ​​or ranges described above.

[0156] In one embodiment, the pH-dependent shell composition comprises essentially the following: (a) gelatin, (b) dextrose, (c) a pH-dependent polymer (e.g., pectin, such as low-methoxyl pectin), (d) a plasticizer (e.g., glycerol, sorbitol, gellan gum, and combinations thereof), and, as appropriate, (e) a stabilizer and / or binder (e.g., gellan gum). The amounts and wt:wt ratios of these components may be based on any of the values ​​or ranges described above.

[0157] 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., glycerol, sorbitol, gellan gum, and combinations thereof), and, as appropriate, (e) a stabilizer and / or binder (e.g., gellan gum). The amounts and wt:wt ratios of these components may be based on any of the values ​​or ranges described above.

[0158] In one embodiment, the pH-dependent shell composition comprises / consistently consists of / consistently consists of: (a) about 25 wt.% to about 85 wt.%, about 25 wt.% to about 80 wt.%, about 30 wt.% to about 85 wt.%, about 30 wt.% to about 75 wt.%, about 35 wt.% to about 70 wt.%, about 30 wt.% to about 65 wt.%, about 40 wt.% to about 65 wt.%, about 30 wt.% to about 55 wt.%, about 30 wt.% to about 40 wt.%, about 40 wt.% to about 80 wt.%, about 45 wt.% to about 65 wt.%, about 45 wt.% to about 60 wt.%, about 45 wt.% to about 75 wt.%, or about 50 wt.% to about 70 wt.%, and (b) about 0.001 wt.% to about 1.0 wt.%. 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.% dextrose, (c) about 2 wt.% to about 20 wt.%, about 3 wt.% to about 15 wt.%, about 3 wt.% to about 18 wt.%, about 5 wt.% to about 15 wt.%, about 3 wt.% to about 5.5 wt.% wt.%, about 3.5 wt.% to about 6.5 wt.%, about 2.5 wt.% to about 7 wt.%, about 4 wt.% to about 11 wt.%, about 7 wt.% to about 12 wt.%, about 8 wt.% to about 13 wt.% or about 5 wt.% to about 10 wt.% pH-dependent polymers (e.g. pectin, such as low-methoxyl pectin), (d) 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.% wt.% plasticizer, and, as appropriate, (e) 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.%.% Stabilizers and / or binders (e.g., kerosene). All wt.% are based on the total weight of the dry, pH-dependent shell composition. [Method for preparing modified release soft capsules] [ ]

[0159] In some embodiments, the present invention covers a method for preparing any of the modified release soft capsules described herein, as shown in FIG5. Method 500 may include encapsulating any of the controlled-release filling compositions described herein within any of the pH-dependent shell compositions described herein (520). Encapsulation of the filling composition may be achieved in any known manner. As an example, rotational molding encapsulation may be used.

[0160] In some embodiments, the modified release soft capsule may be annealed (530) after encapsulation. Subsequently, the soft capsule may be annealed (or cured) at an annealing (or curing) temperature for a duration of annealing (or curing) time (540) to prepare the final modified release soft capsule (550).

[0161] Annealing temperatures may be in the range of about 25°C to about 80°C, about 30°C to about 70°C, or about 40°C to about 60°C, about 25°C to about 55°C, about 25°C to about 50°C, about 30°C to about 60°C, or about 35°C to about 50°C. If annealing occurs, the annealing temperature should be high enough to enhance the delayed-release properties of the pH-dependent shell composition and promote matrix formation within the pH-dependent shell composition, but not high enough to melt or degrade any component of the soft capsule, the pH-dependent shell composition, or the controlled-release filler composition.

[0162] The annealing duration can range from about 10 minutes to about 24 hours, from about 30 minutes to about 12 hours, from about 45 minutes to about 5 hours, or from about 60 minutes to about 3 hours. In some embodiments, the annealing duration can range from about 12 hours to about 168 hours, from about 18 hours to about 120 hours, from about 24 hours to about 72 hours, from about 24 hours, from about 48 hours, from about 72 hours, or any subrange or single value thereof.

[0163] In one embodiment, the annealing of the soft capsules may be carried out at a temperature of about 40°C for about 24 hours. In one embodiment, the annealing of the soft capsules may be carried out at a temperature of about 40°C for about 48 hours. In one embodiment, the annealing of the soft capsules may be carried out at a temperature of about 40°C for about 72 hours. In one embodiment, the annealing of the soft capsules may be carried out at a temperature of about 60°C for about 1 to 3 hours. In one embodiment, the annealing of the soft capsules may be carried out at a temperature of about 65°C for about 90 minutes.

[0164] In some embodiments, curing may occur in air (without any specific control over the nitrogen or oxygen content or humidity). In some embodiments, annealing may occur under inert conditions (e.g., in nitrogen).

[0165] In some embodiments, prior to encapsulation, method 500 may include preparing a controlled-release filler composition. The controlled-release filler composition may be prepared by combining (e.g., mixing) at least one active agent with a controlled-release material and, where appropriate, a hydrophilic carrier (if present). Any other component, such as a pharmaceutically acceptable excipient, may also be incorporated into the mixture to form the controlled-release filler composition. For example, in method 500 of FIG. 5, an active agent (referred to as drug substance 512) is mixed with a controlled-release material (e.g., polyethylene oxide 514), a hydrophilic carrier (e.g., polyethylene glycol 516), and other components (518).

[0166] In some embodiments, prior to encapsulation, method 500 may include preparing a pH-dependent shell composition (not shown in Figure 5). The pH-dependent soft capsule may be prepared by, for example, mixing gelatin, dextrose, pectin, plasticizers as needed, binders as needed (such as gellan gum), and any other ingredients as needed, such as pharmaceutically acceptable excipients. In preferred embodiments, the pH-dependent shell composition does not contain additional pH-dependent polymers (such as conventionally known pH-dependent synthetic polymers), and such additional pH-dependent polymers may not be added to the mixture when preparing the pH-dependent shell composition according to some embodiments.

[0167] The strip thickness of the pH-dependent shell composition can also be adjusted (e.g., during rotational molding) to control the pH-dependent dissolution profile of the final pH-dependent shell composition and to facilitate targeted release of the filler composition into specific areas within the GIT. The strip thickness of the pH-dependent shell composition can range from (but is not limited to) any one of about 0.02 inches, about 0.022 inches, about 0.024 inches, about 0.026 inches, about 0.028 inches, or about 0.030 inches to any one of about 0.032 inches, about 0.034 inches, about 0.036 inches, about 0.038 inches, about 0.04 inches, about 0.042 inches, about 0.044 inches, or about 0.050 inches, or any subrange or single value thereof.

[0168] In one embodiment, a method for preparing a pH-dependent soft capsule comprises, substantially comprises, or comprises the following: a) preparing any of the controlled-release filler compositions described herein; b) encapsulating the controlled-release filler composition from step a) in any of the pH-dependent shell compositions described herein (e.g., via spin-molding); c) drying the encapsulated pH-dependent soft capsule (e.g., by inverting or periodically drying in a basket without inverting); and, as appropriate, d) curing / annealing the pH-dependent soft capsule according to any of the curing / annealing conditions described herein.

[0169] In some embodiments, drying is performed at a relative humidity of about 5% to about 40%, about 10% to about 30%, or about 15% to about 25% at a temperature of about 10°C to about 50°C, about 15°C to about 40°C, or about 20°C to about 35°C.

[0170] In some embodiments, references to drying and curing / annealing should be distinguished herein. The purpose of drying the modified release soft capsules described herein is to remove excess water from the modified release soft capsule immediately after encapsulation. Therefore, the capsule will be physically stable. The purpose of curing / annealing the modified release soft capsules described herein is to enhance the delayed release characteristics of the modified release soft capsules. Therefore, the presence of a drying step is different from, and similarly, the presence of a curing / annealing step is different from, a drying step. [Stability of modified release soft capsules] [ ]

[0171] In some embodiments, the pH-dependent shell composition described herein is chemically and physically stable.

[0172] For example, its chemical stability can be demonstrated by the amount of active agent in the filler composition (e.g., the amount of fish oil component when the filler composition includes fish oil). In some embodiments, after storage for up to 12 months, up to 6 months, up to 3 months, or up to 1 month (either under ambient conditions or under stress conditions of 40°C and 75% relative humidity for any such duration), the content of the filler composition component is substantially similar to (or conforms to specifications) the original composition before storage.

[0173] In some embodiments, the physical stability of the modified release soft capsule and pH-dependent shell composition can be demonstrated by the solubility profile of the capsule in acidic and buffered media. In some embodiments, after storage for up to 12 months, up to 6 months, up to 3 months, or up to 1 month (under ambient conditions or under stress conditions of 40°C and 75% relative humidity for any such duration), the solubility profile of the capsule in acidic and buffered media is substantially similar (or conforms to specifications) to the solubility profile of the capsule before storage.

[0174] The term "substantially similar" can mean that a specific value is within approximately 30%, 25%, 20%, 15%, 10%, 5%, or 1% of the corresponding comparison value. The percentage is calculated based on the face value of the comparison value. For example, a dissolution time range of 27 to 33 minutes can be considered to be within 10% of a 30-minute comparison dissolution time.

[0175] In some embodiments, the invention may also relate to a method for stabilizing any modified release soft capsule described herein. This method may include protecting (e.g., from another potential source of oxidation or chemical degradation) any of the filler compositions described herein by encapsulating any of the filler compositions described herein (including at least one active agent) within any of the pH-dependent shell compositions described herein.

[0176] In some embodiments, the pH-dependent shell composition described herein produces robust modified-release soft capsules that release the filling composition prematurely in acidic environments (e.g., gastric environments). For example, based on the total weight of the filling composition, the modified-release soft capsules described herein can release up to about 10 wt.%, up to about 9 wt.%, up to about 8 wt.%, up to about 7 wt.%, up to about 6 wt.%, up to about 5 wt.%, up to about 4 wt.%, up to about 3 wt.%, up to about 1 wt.%, or 0 wt.% of the filling composition 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. The release time of the filler composition should not be confused with the release time of the surfactant in the filler composition, because the release profile of the surfactant from the filler composition will be specified by the components of the controlled release filler composition, as described in detail in the controlled release filler composition section.

[0177] In some embodiments, the cured / annealed modified release soft capsules described herein (i.e., capsules encapsulated with a pH-dependent shell composition) can reduce or eliminate any number of capsules exhibiting premature release in acidic environments. For example, the number of cured / annealed capsules exhibiting premature release in acidic environments (after exposure to acidic environments 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) can be up to about 30%, up to about 25%, up to about 20%, up to about 15%, up to about 10%, up to about 5%, up to about 3%, up to about 2%, up to about 1%, or 0% of the total number of capsules in the batch.

[0178] In contrast, without curing / annealing, the number of capsules (of the same composition) exhibiting premature release in an acidic environment (after exposure to an acidic environment for approximately 150 minutes, approximately 120 minutes, approximately 105 minutes, approximately 90 minutes, approximately 75 minutes, approximately 60 minutes, approximately 45 minutes, approximately 30 minutes, approximately 15 minutes, approximately 10 minutes, or approximately 5 minutes) can be greater than approximately 2%, greater than approximately 5%, greater than approximately 10%, greater than approximately 15%, greater than approximately 20%, greater than approximately 30%, greater than approximately 40%, greater than approximately 50%, greater than approximately 60%, greater than approximately 70%, greater than approximately 80%, or greater than approximately 90% of the total number of capsules in the batch.

[0179] In some embodiments, the curing / annealing modified release soft capsules described herein (i.e., capsules encapsulated with a pH-dependent shell composition) can reduce or eliminate the amount of filling composition released by capsules exhibiting premature release in acidic environments (e.g., after exposure to acidic environments 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).

[0180] For example, the amount of filling composition released from a cured / annealed capsule exhibiting 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) may be up to about 5 wt.%, up to about 4 wt.%, up to about 3 wt.%, up to about 2 wt.%, up to about 1 wt.%, or 0% of the total weight of the filling composition in the capsule.

[0181] In contrast, without curing, the amount of filling composition released from capsules (having the same composition) exhibiting premature release in an acidic environment (after exposure to an acidic environment for approximately 150 minutes, approximately 120 minutes, approximately 105 minutes, approximately 90 minutes, approximately 75 minutes, approximately 60 minutes, approximately 45 minutes, approximately 30 minutes, approximately 15 minutes, approximately 10 minutes, or approximately 5 minutes) can be greater than approximately 1 wt.%, greater than approximately 2 wt.%, greater than approximately 3 wt.%, greater than approximately 4 wt.%, greater than approximately 5 wt.%, greater than approximately 6 wt.%, greater than approximately 7 wt.%, greater than approximately 8 wt.%, greater than approximately 9 wt.%, greater than approximately 10 wt.%, greater than approximately 15 wt.%, or greater than approximately 20 wt.% of the total weight of the filling composition in the capsule. [Dual-Controlled Release Soft Capsules] [ ]

[0182] The soft capsules described herein comprise two levels of controlled release. The first level is defined by a pH-dependent shell composition, which facilitates targeted release of the filling composition within specific regions of the GIT. The second level is defined by a controlled-release filling composition, which facilitates controlled release profiles of the active agent within specific regions of the GIT.

[0183] In some embodiments, the present invention relates to a method for adjusting / regulating / controlling the dissolution location and dissolution profile of any of the delayed-release capsules (i.e., including controlled-release filler material encapsulated in a pH-dependent shell composition) described herein. The method includes adjusting at least one of i) to iv) to control the dissolution location of the pH-dependent shell composition along an individual gastrointestinal tract: i) the amount of at least one of pectin, gelatin, dextrose, and plasticizer in the pH-dependent shell composition; ii) the annealing temperature of the modified release soft capsule; iii) the annealing duration of the modified release soft capsule; or iv) the band thickness of the pH-dependent shell composition. The method further includes adjusting at least one of (v) to (vii) to obtain a target dissolution profile of at least one active agent: v) the amount of controlled-release material in the controlled-release filler composition; or vi) the annealing temperature of the modified release soft capsule; or vii) the annealing duration of the modified release soft capsule.

[0184] In some embodiments, the present invention also covers methods for treating conditions treatable by any of the modified release soft capsules described herein by administering the modified release soft capsule to an individual in need. [Example] [ ]

[0185] Specific embodiments of the present invention will now be described with reference to the following examples. It should be understood that these examples are merely for the purpose of illustrating the invention and should not be construed as limiting the scope of the invention in any way. [ ] Example 1 - Effect of dextrose concentration on the manufacture of pH-dependent shell compositions

[0186] pH-dependent shell compositions with different concentrations of dextrose were prepared to investigate the effect of dextrose concentration on the manufacturability of the compositions. The pH-dependent shell compositions are described in Table 1. [surface] [1-] [Dried shell composition] [Element] [1st] [Group] [No.] [2] [Group] [No.] [3] [Group] [No.] [4] [Group] [No.] [5] [Group] [wt.%] [wt.%] [wt.%] [wt.%] [wt.%] pectin 8-12 7-11 7-12 8-13 6-9 gelatin 45-65 38-58 38-58 38-58 38-58 glycerin 28-45 25-35 25-35 25-35 25-35 water 8-15 6-15 6-15 6-15 6-15 Dextrorotatory 0.02-0.10 0.01-0.06 0.10-0.20 0.10-0.30 none total 100 100 100 100 100 The effect of different amounts of dextrose in the pH-dependent shell composition on the rupture time at pH 6.8 is shown in Table 2. [surface] [2] [Group Number] [Dextrose (wt.%)] [T=0] [Results of Time-Based Dissolution] [T=6] [Dissolution results after one month] [Acid Phase] [(0.1N HCl)] [Buffer Phase] [(pH 6.8)] [Acid Phase] [(0.1N HCl)] [Buffer Phase] [(pH 6.8)] [1] 0.01 qualified (2-hour duration) qualified (Ruptured within 8 minutes) qualified (2-hour duration) It ruptured within 25 minutes. [2] 0.05 qualified (2-hour duration) qualified (Ruptured within 4 minutes) qualified (2-hour duration) No cracking for 60 minutes [3] 0.1 qualified (2-hour duration) qualified (Ruptured within 3 minutes) qualified (2-hour duration) No cracking for 60 minutes [4] 0.15 qualified (2-hour duration) qualified (Ruptured within 11 minutes) qualified (2-hour duration) No cracking for 60 minutes [5] [ ] none fail (Ruptured within 90 minutes) -- qualified (2-hour duration) ruptured within 28 minutes

[0187] Dextran is a reducing sugar and is thought to interact with gelatin by causing it to cross-link. When gelatin cross-links, its solubility decreases. This demonstrates that dextran can stabilize pectin soft capsules in acidic media (i.e., reduce leakage). Example 2 - The effect of solidification on capsule release characteristics

[0188] pH-dependent shell compositions were prepared to study the effect of curing on the release characteristics of capsules, as this is generally related to the filling composition (it should be noted that the release profile of the active agent in the self-filled composition is a second-level controlled release, which is not described in this specific example). The pH-dependent shell compositions are described in Table 3. [surface] [3-] [The gel block formulation inside the dried capsule shell, to] [wt.%] [count] [Element] [batch] [1] [batch] [2] [batch] [3] [Non-amided pectin] 7.0-12.0 8.0-12.0 8.0-12.0 [Dextrose] 0.02-0.10 0.10-1.0 0.10-1.0 [glycerin] 28-45 28-45 28-45 [gelatin] 45-65 45-65 45-65 [water] 8-15 8-15 8-15 [total] 100 100 100 [Additional Features] [Ratio of non-amided pectin to gelatin] 1:7 1:7.5 1:7.5 [Glycerin weight to gelatin weight ratio] 1:2 1:2 1:2 [Gel block viscosity] [(cPs)] 115,000 121,000 121,000 [Capsules that release prematurely before solidification] [%] [ ] 67% 42% 50%

[0189] Existing commercial products exhibit premature release in large quantities of capsules, with increased amounts of the filler composition also showing premature release, and in some cases, releasing almost 100 wt.% of the filler composition within a 10-minute duration in acidic media.

[0190] Coated soft capsules have been considered, but these capsules do not dissolve in buffered media for extended periods (longer than about 60 minutes and in some cases up to 120 minutes). This prolonged dissolution in buffered media suggests that coated soft capsules lack bioavailability. This, along with the challenges of two-step manufacturing methods, has spurred the exploration of pH-dependent shell compositions to form uncoated, modified-release soft capsules.

[0191] The pH-dependent shell composition described in Table 3 is used to form pectin soft gels, which to some extent reduces the occurrence of premature release and the amount of prematurely released filler composition (compared to existing commercial products).

[0192] However, prior to curing, a significant proportion of soft capsules in each batch continued to exhibit premature release of the filler composition in an acidic environment (e.g., 0.1 N HCl), as outlined in Table 3, "% of capsules exhibiting premature release prior to curing." Approximately 60 to 72 capsules from each batch were tested to assess the percentage of capsules exhibiting premature release prior to curing.

[0193] In some embodiments, approximately 10 wt.% of the filler composition is released from capsules exhibiting premature release prior to curing. In some embodiments, greater than 10 wt.% or less of the filler composition is released from capsules exhibiting premature release prior to curing.

[0194] As will be 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.

[0195] Pectin soft capsules were cured to enhance their stability in acidic environments (e.g., 0.1 N HCl). The pectin soft gels were packaged in cardboard boxes (for bulk packaging) or high-density polyethylene (HDPE) bottles 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 batches 1, 2, and 3 are summarized in Table 4 below. [surface] [4-] [Results of the Solidification Study] [sample] [Before curing] [Number of test capsules] [Dissolves after curing] [Capsules with premature release] [%] [Curing Time] [0.1N HCl] [Number of capsules with premature release] [(] [The total capsule of the test] [%) [pH 6.8] [Buffer solution] [(] [Time of breakage] [)] [batch] [1] 67% 12 24 hours 3 (25%) 8 minutes 36 48 hours none 7 minutes [batch] [2] 42% 60 48 hours 1 (1.7%) 7 minutes 72 72 hours none 9 minutes [batch] [3] 50% 60 48 hours none 7 minutes 60 72 hours none 7 minutes

[0196] The solubility of the pH-dependent shell composition after curing was evaluated according to the USP enteric coagulation test method applicable to two-stage enteric coagulation tests for uncoated enteric soft gels. Unless otherwise specified, the acidic media, buffer media, apparatus, and solubility test conditions for all dissolution / disintegration / rupture results and / or properties throughout this application are as described herein with respect to the two-stage enteric coagulation test.

[0197] The USP device II with blades is used at 37°C and a blade speed of 50 rpm. The acidic stage medium is 0.1 N HCl. The buffer stage medium is pH 6.8 phosphate buffer. For vitamin and mineral supplements and / or pharmaceutical nutritional products, enteric-coated capsules should remain intact in the acidic medium for at least 60 minutes to pass the first stage and rupture within 45 minutes in the buffer stage medium to pass the second stage. For pharmaceutical products, enteric-coated capsules should remain intact in the acidic medium for at least 120 minutes to pass the first stage and rupture within 45 minutes in the buffer stage medium to pass the second stage.

[0198] The curing of the soft capsules was evaluated at 24, 48, 72, 120, 168, and 288 hours. However, this article only presents data for up to 72 hours.

[0199] Table 5 depicts the amount of premature release of the filling composition from batch 3 pectin soft capsules in an acidic medium before and after curing, following USP enteric coating test guidelines at the end of 2 hours. The maximum amount of filling composition released was 5%. The pectin soft capsules in batch 3 contain fish oil in their filling composition, which includes docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). [surface] [5-] [batch] [3-] [follow] [USP] [Gut test guidelines in acidic media] [(0.1 N HCl)] [Amount of filler composition with premature release] [ ] [Container Number] [Before curing,] [2] [Hours later] [0.1 N HCl] [Dissolution in the Middle] [Cure]

[72] [Hours later,] [2] [Hours later] [0.1 N HCl] [Dissolution in the Middle] [%EPA] [% DHA] [%EPA] [% DHA] [V1] 5 4 0 0 [V2] 3 3 0 0 [V3] 3 3 0 0 [V4] 3 3 0 0 [V5] 1 1 0 0 [V6] 3 3 0 0

[0200] The curing data shows that curing significantly reduces or eliminates premature release of pectin capsules into the filler composition in acidic media, resulting in capsules with robust enteric properties and high-quality enteric products.

[0201] It should be noted that all pectin soft capsules tested in Table 5 dissolved in pH 6.8 buffer within 15 minutes. Example 3 - Intestinal solubility data in simulated gastric juice (SGF) containing pepsin

[0202] Cured pectin capsules with the gel block formulations outlined in Table 6A were subjected to enteric lysis tests using SGF (0.1 N HCl) and pepsin (simulating in vivo human conditions) for two-stage enteric lysis studies. [surface] [6A] [-] [The gel block formulation inside the dried capsule shell, to] [wt.%] [count] [Element] [batch] [4] [batch] [5] [Non-amided pectin] 7.0-11.0 8.0-13.0 [Dextrose] 0.02-0.08 0.02-0.08 [glycerin] 18-42 18-42 [gelatin] 45-65 45-65 [water] 8-15 8-15 [total] 100 100 [surface] [6B-] [surface] [6A] [Solubility of pectin soft capsules in acidic media with and without pepsin] [batch number] [0.1N HCl] [Contains pepsin] [0.1 N HCl] [ ] Batch 4 120 minutes in total 120 minutes in total Batch 5 120 minutes in total 120 minutes in total

[0203] When a suitable shell composition is used, such as an appropriate gelatin to pectin ratio, pepsin does not affect the solubility of the pectin shell in 0.1 N HCl medium. In batches 4 and 5, as illustrated in Tables 6A and 6B, the gelatin to pectin w:w ratio is 7:1. Without being construed as limiting, the Xianxin pectin softgel is robust and its gelatin-pectin network structure is strong enough to resist pepsin action, as demonstrated by the fact that the pectin softgels remained intact for 120 minutes in 0.1 N HCl even in the presence of pepsin, a biologically relevant medium (unlike pharmacopoeia methods excluding enzymes). Therefore, the Xianxin pectin softgels will also be sufficiently robust in vivo. Example 4 - Adjusting the breakup time of pectin capsules in the intestinal medium by changing the ratio of gelatin to pectin.

[0204] Pectin soft capsules with different gelatin-to-pectin ratios were prepared. The composition of different batches is summarized in Table 7B below. The rupture time of the pectin capsules in SGF (0.1 N HCl) containing pepsin varied with the gelatin-to-pectin ratio, as summarized in Table 7A below. [surface] [7A] batch number [gelatin] [-] [Pectin Ratio] 0.1 N HCl containing pepsin Batch 6 18:1 It broke at 12 minutes. Batch 7 12:1 It broke at 36 minutes. Batch 8 8:1 120 minutes in total Batch 1 7:1 120 minutes in total [Table 7B-] [Used in gelatin] [Pectin Ratio Study: Gel Block Formulation Based on Dry Shell Composition (wt.%)] [Element] [batch] [6] [batch] [7] [batch] [8] [batch] [1] pectin Non-acidified pectin 3.0-8.0 Acidified pectin 6.0-10.0 Non-acidified pectin 8.0-15.0 Non-acidified pectin 7.0-12.0 Dextrorotatory 0 0 0.02-0.10 0.02-0.10 glycerin 8-15 21-41 8-15 28-45 Sorbitol 21-32 0 21-32 0 gelatin 44-65 42-61 44-65 45-65 water 8-15 8-15 8-15 8-15 [total] [100.0] [100.0] [100.0] [100.0]

[0205] All pectin soft capsules from Table 7A ruptured within 45 minutes in a pH 6.8 buffer solution. Table 7A illustrates that the rupture time of pectin soft capsules in acidic media can be adjusted by changing the gelatin to pectin ratio. Example 5 - The effect of the thickness of the soft gel strip on the enteric coating efficiency of pectin soft capsules

[0206] Pectin soft capsules with different strip thicknesses were prepared. The composition of the batches of dried pH-dependent shell compositions with different strip thicknesses is summarized in Table 8A below. The solubility of pectin capsules with different strip thicknesses in SGF (0.1 N HCl) and in pH 6.8 buffer was evaluated after approximately 72 to 96 hours of curing. The results are summarized in Table 8B below. [Table 8A] [-] [Gel block formulation based on dried shell composition, studied using strip thickness] [(wt.%] [)] [Element] [batch] [9] [batch]

[10] [Batch 11] [Batch 12] [Batch 13] [Batch 14] [Pectin] [Amination-treated pectin] [ ] [6.5-10.0] [Non-amided pectin] [8.0-12.0] [Amination-treated pectin] [ ] [6.5-10.0] [Non-amided pectin] [7.0-11.0] [Non-amided pectin] [8.0-12.0] [Non-amided pectin] [8.0-13.0] [Dextrose] [none] [0.020-0.15] [none] [0.02-0.06] [0.020-0.15] [0.02-0.10] [glycerin] [22-40] [21-41] [22-40] [18-42] [21-41] [18-42] [gelatin] [42-58] [44-61] [42-58] [45-65] [44-61] [45-65] [water] [8-15] [8-15] [8-15] [8-15] [8-15] [8-15] [total] [100.0] [100.0] [100.0] [100.0] [100.0] [100.0] [surface] [8B-] Dissolution of cured soft gel pectin capsules with different strip thicknesses [batch number] [Thickness of the strip] [(] [inch] [)] [Regarding the dissolution of cured pectin soft capsules] [0.1N HCl] [(]

[0120] [minute] [)] [pH 6.8] [Buffer solution] [(] [Break Time,] [min] [ ] [)] Batch 9 0.028 whole 7 Batch 10 0.030 whole 1 Batch 11 0.032 whole 8 Batch 12 0.034 whole 5 Batch 13 0.036 whole 3 Batch 14 0.038 whole 7

[0207] The dissolution results depicted in Table 8B demonstrate that pectin soft capsules with a strip thickness ranging from 0.028 inches to 0.038 inches exhibit robustness after curing and demonstrate compliance with enteric coating guidelines for pharmaceutical and VMS (vitamin, mineral, and supplement) products. This thickness range should not be construed as limiting. In some embodiments, thicker or thinner strips may also be used. Example 6 - pH-dependent viscosity of shell composition after aging

[0208] Pectin and gelatin interact to form a network structure, which contributes to a significant increase in the viscosity of the gel block shown in Figure 1. The interaction between pectin and gelatin contributes to the delayed-release properties of the capsule shell composition. However, as seen in Figure 1, the viscosity of the pH-dependent shell composition gel block decreases over time. Viscosity and the percentage decrease are summarized in Table 9 below.

[0209] The viscosity in this example, and throughout this specification, was measured using a rheometer (Thermo Fisher Rheostress 6000) at 60°C. The test was conducted under ambient conditions. A gel block sample was loaded onto the platform of the rheometer, which was maintained at 60°C. A 40 mm disk was oscillated at a frequency of 0.1 Hz to provide a constant shear rate. Viscosity was obtained by measuring shear stress and shear rate. [surface] [9-] [aging] [pH] [Viscosity of the dependent shell composition] Aging time (hours) Viscosity (cPs) viscosity reduction % after 0 hours of aging Non-acidified pectin 0 140,000 N / A 24 hours at 60℃ 90,000 Approximately 36% 48 hours at 60℃ 90,000 Approximately 36% 72 hours at 60℃ 75,000 Approximately 46% 96 hours at 60℃ 75,000 Approximately 46% Acidified pectin 0 105,000 N / A 24 hours at 60℃ 70,000 Approximately 33% 48 hours at 60℃ 55,000 Approximately 48% 72 hours at 60℃ 35,000 Approximately 67% 96 hours at 60℃ 40,000 Approximately 62%

[0210] As can be seen from Table 9, after aging at 60°C for 48 hours, 72 hours, and 96 hours, the viscosity of non-amided pectin decreased by a smaller percentage compared to that of amided pectin.

[0211] The decrease in viscosity is caused by the thermal degradation of the molecular chain lengths of pectin and gelatin. Despite this viscosity reduction, the gel block of the pH-dependent shell composition retains a viscosity suitable for manufacturability and processability even after heating the composition at 60°C for 4 days. Furthermore, soft capsules made from the aged gel still exhibit satisfactory pH-dependent delayed release properties. Example 7 - Chemical Stability of Pectin Soft Capsules

[0212] Table 10 below depicts the chemical stability of fish oil encapsulated in a pectin pH-dependent shell composition according to the embodiments described herein after 6 months of storage 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-methoxyaniline ≤ 20, a dissolution time exceeding 120 minutes in 0.1 N HCl (pH 1.2), and a dissolution time of up to 45 minutes in a buffer medium (pH 6.8 phosphate buffer). The values ​​of these parameters for the control (fish oil raw material), delayed-release softgel pectin capsules stored under ambient conditions for 6 months, and delayed-release pectin soft capsules stored at 40°C and 75% RH for 6 months are summarized in Table 10. [surface] [10-] [Chemical stability of modified release soft capsules] [sample] [Batch 10] [EPA TG] [(] [≥ 160 mg / g] [DHA TG] [(] [≥ 100 mg / g] [peroxide] [(] [≤ 5 meq O, 2, / kg)] [p-Methoxyaniline] [(] [≤ 20)] [Dissolve] 0.1N HCl pH 1.2 pH 6.8 phosphate buffer [Fish oil ingredients] 172 124 0.9 11.0 N / A N / A [exist] [T=6] [At one month old, environment] 174 123 2.4 12.9 Pass (120 minutes or more complete) 15 minutes [exist] [T=6] [At one month,]

[40] [℃] [75% RH] 174 123 2.5 14.8 Pass (120 minutes or more complete) 25 minutes

[0213] Accelerated stability data (summarized in Table 10) show that the pH-tolerant pectin shell composition according to the examples protects the filler composition (e.g., fish oil component) from oxidation, as evidenced by the non-significant / substantial similarity in peroxide and p-methoxyaniline values ​​and EPA and DHA assays compared to the raw material after 6 months (under ambient conditions and under stress conditions of 40°C and 75% RH). Example 8 - Valproic acid pectin soft capsules

[0214] Table 11A below depicts the stability of valproic acid encapsulated in a pectin pH-dependent shell composition (the gel formulation of the dried shell composition is summarized in Table 11B) according to the embodiments described herein after storage at T=0, 40°C and 75% relative humidity (RH) for 3 months (T=3 months), and after storage at 40°C and 75% RH for 6 months (T=6 months). As demonstrated in Table 11A, after storage at 40°C and 75% RH for 3 months and after storage at 40°C and 75% RH for 6 months, the solubility profile of the pH-dependent shell composition remains substantially similar to that at T=0. [surface] [11A-] [Encapsulated in pectin] [pH] [Dissolution of valproic acid in the dependent shell composition] [batch number] [Filling Composition] [T = 0] [T=3] [months]

[40] [℃ / 75% RH] [T=6] [months]

[40] [℃ / 75% RH] [Acid Phase] [(0.1N HCl] [,pH 1.2)] [Buffer Phase] [(pH 6.8)] [Phosphate buffer] [Acid Phase] [(0.1N HCl] [,pH 1.2)] [Buffer Phase] [(pH 6.8)] [Phosphate buffer] [Acid Phase] [(0.1N HCl] [,pH 1.2)] [Buffer Phase] [(pH 6.8)] [Phosphate buffer] [Batch 15] valproic acid Full movie (120 minutes) qualified (9 min) Full movie (120 minutes) qualified (12 min) Full movie (120 minutes) qualified (11 min) [surface] [11B] - Gel mass formulation in the dried capsule shell, expressed in wt.% [Element] [batch]

[15] [Amination-treated pectin] 6.5-8.0 [Dextrose] none [glycerin] 20-45 [gelatin] 42-56 [water] 8-15 [total] 100 Example 9 - Physical Properties of Pectin Soft Capsules

[0215] Modified release soft capsules with the pH-dependent shell composition described herein are robust, as demonstrated by the physical properties outlined in Table 12 below. [surface] [12-] [Modify the physical properties of the release soft capsule] [parameter] [Typical Specifications] [Shell moisture] [(%) 6-15 [hardness] [(] [Newton] [)] 7-14 [Balanced relative humidity] [(%) ] 30-45 [Tear strength] [(kg)] 60-120

[0216] The moisture content of the capsule shell was determined by the loss on drying method. A sample of 1 to 2 grams of the pH-dependent capsule shell composition was placed in an oven at 105°C for 17 hours. The initial weight of the sample was recorded. After drying the sample in the oven at 105°C for 17 hours, the final weight of the sample was recorded. The percentage of weight loss calculated according to the following equation was defined as the moisture content of the capsule shell:

[0217] Capsule hardness is determined using a hardness tester. Capsule hardness is defined as the force required to deform a capsule by 2.0 mm, expressed in Newtons.

[0218] Equilibrium relative humidity (%) is defined as the humidity condition under which the capsule maintains a constant total weight. It is determined using an environmental chamber maintained at constant humidity using a saturated salt solution.

[0219] Rupture strength is determined using a texture analyzer. The texture analyzer compresses the capsule until it ruptures. The force required to rupture the capsule, expressed in kilograms, is defined as the rupture strength. Example 10 - An exemplary composition for pectin and gellan gum modified release soft capsules

[0220] Modified release soft capsules comprising a combination of pectin and gellan gum were prepared. Formulations based on the dried shell composition are summarized in Table 13 below. [surface]

[13] [-] [Gel block formulation in the dried capsule shell, as] [wt.%] [count] [Element] [batch]

[15] [Pectin] 7.0-10.5 [Dextrose] 0.02-0.5 [glycerin] 15-25, [gelatin] 35-50 [Sorbitol solution] 25-32 [Gel] 0.1-2.0 [water] 6-15 [total] 100

[0221] Examples 1 to 10 illustrate the first-level controlled release in the dual-level controlled release soft capsules described herein. The first level is a pH-dependent shell composition. Examples 11 and 12 illustrate dual-level controlled release, wherein the first level is attributable to the pH-dependent shell composition and the second level is attributable to the controlled release filling composition. Example 11 - An exemplary composition of a pectin and gellan gum modified release soft capsule having a controlled release filling composition

[0222] Prepare dual controlled-release soft capsules comprising the pH-dependent shell composition described in Table 14 and the controlled-release filling composition described in Table 15. [surface] [14-] [The gel block formulation inside the dried capsule shell, to] [wt.%] [Unit] [Element] [wt.%] [scope] [gelatin] 28-50 [Sorbitol solution] 15-35 [Pectin] 2.5-7.0 [Gel] 0.1-2.0 [Dextrose] 0.005-0.5 [purification] [water] 25-45 [total] 100.0 [surface] [15-] [contain] [Polyox, TM ] [Controlled-release filling composition] [Element] [Filling material] [-1] [ (%) [Filling material] [-2] [ (%) [Filling material] [-3] [ (%) [water] 1.0-4.0 1.5-5.0 2.0-6.0 Potassium hydroxide 1.0-3.0 1.5-4.0 2.0-5.0 Polyethylene glycol

[0600] 15.0-28.0 20.0-42.0 22.0-45.0 [Ibuprofen] 12.0-18.0 19.0-25.0 24.0-32.0 Polyethylene glycol

[0400] 40.0-45.0 20.0-32.0 5.0-15.0 [Polyethylene oxide] 8.0-15.0 16.0-20.0 22.0-28.0 [total] 100.0 100.0 100.0

[0223] The polyethylene oxide polymer grade used in the controlled-release filler compositions summarized in Table 15 is POLYOX™ WSR 301. POLYOX™ WSR 301 is a water-soluble polymer. It is based on a long-chain nonionic polyethylene oxide polymer. POLYOX™ WSR 301 has a high molecular weight of 4,000,000 Daltons, with a viscosity ranging from 1650 to 5500 cPs.

[0224] Modified release soft capsules were prepared by encapsulating each of the controlled release filling compositions from Table 15 into the pH-dependent shell compositions from Table 14. After encapsulation, the modified release soft 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 promoted the melting of the polyethylene oxide polymer to form a solid matrix inside the capsule.

[0225] Dissolution tests were performed on the resulting capsules. A USP II device with paddles was used at a speed of 50 rpm. 0.1 N HCl was used as the dissolution medium for the first 120 minutes. Phosphate buffer was then added to adjust the pH to 6.8. Drug release profiles were monitored using a fiber optic probe for up to 24 hours. Figure 2 illustrates the release profile of ibuprofen from the capsules.

[0226] As shown in Figure 2, no ibuprofen was released during the first two hours in 0.1 N HCl medium, indicating the robust enteric properties of the pH-dependent shell composition. Notably, according to the pharmacopoeia, release of up to 10% is permitted in acidic media. When the pH was adjusted to pH 6.8, ibuprofen was gradually released from the polyethylene oxide polymer matrix (i.e., the self-controlled release filler composition).

[0227] The amount of polyethylene oxide polymer (PEP) affects the ibuprofen release rate. Higher PEP amounts result in slower ibuprofen release. Formulation filler-3, containing 24 wt.% PEP, achieved a zero-order release profile over a 24-hour period. Formulation fillers-1 and-2, containing 12 wt.% and 18 wt.% PEP, respectively, achieved a 12-hour release profile.

[0228] This data shows that the drug release profile can be adjusted by changing the filling composition. Example 12 - An exemplary composition of a pectin-modified release soft capsule having a controlled-release filling composition

[0229] A dual controlled-release soft capsule was prepared comprising 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 composition was encapsulated in the pH-dependent shell composition and then the capsule was dried. [surface] [16-] [The gel block formulation inside the dried capsule shell, to] [wt.%] [count] [Element] [%] [,w / w] [Function] [Amination-treated pectin] 3.5-6.5 Enteric polymers [glycerin] 12.0-21.0 plasticizers [Dextrose] 0.005-0.4 enhancer [gelatin] 28.0-45.0 Film-forming agent [water] 33.0-51.0 solvent [total] 100.0 [surface] [17-] [Controlled-release filler composition containing diphenhydramine] [Element] [Filling material] -4 (%) Polyethylene glycol

[0400] 40.0-55.0 [Polyethylene oxide] [(POLYOX™ WSR 301)] 15.0-30.0 [water] 3.0-7.0 [Sanxian Glue] 5.0-12.0 [Diphenhydramine] 4.0-10.0 [total] 100.0 [surface] [18-] [Controlled-release filler composition containing acetaminophen] [Element] [Filling material] [-5(%)] Polyethylene glycol

[0400] 35.0-55.0 [Polyethylene oxide] [(POLYOX™ WSR 301)] 10.0-35.0 Hydroxypropyl methylcellulose 1.0-5.5 [Acetaminophen] 25.0-42.0 [total] 100.0

[0230] Each diphenhydramine capsule contains 50 mg of diphenhydramine. Each acetaminophen capsule contains 325 mg of acetaminophen.

[0231] The filled capsules were then placed in a 65°C oven for 90 minutes to anneal them. After annealing, a two-stage dissolution test was performed. The impeller speed was set to 50 RPM. 0.1 N HCl was used as the dissolution medium for the first 120 minutes. Phosphate buffer was then added to adjust the pH to 6.8. Drug release profiles were monitored using a fiber optic probe for up to 12 hours. Figures 3 and 4 show the release of diphenhydramine and acetaminophen from the capsules, respectively.

[0232] In summary, the combination of pectin in the shell composition and Polyox™ polymer in the filler composition creates a novel drug delivery platform that may be used for colonic drug delivery and other drug delivery applications. [Example] [13-18] [Solubility Overview of the Filler Composition]

[0233] A 2×3 full-factor design, repeated twice, was used to design the six (6) filler compositions used in Samples 1–12, as shown in Table 19 below. Each composition was prepared twice to allow for evaluation of composition variability. Diphenhydramine hydrochloride was used as a model drug for the active pharmaceutical ingredient in the filler compositions. "PEG 400" is an abbreviation for polyethylene glycol with a number average molecular weight of 400, "PEO" is an abbreviation for polyethylene oxide, "M" stands for "million," "HCl" is an abbreviation for hydrochloric acid, and "Mn" is an abbreviation for number average molecular weight. All PEOs used in Samples 1–12 were nonionic, water-soluble, and were Polyox™ products available from DuPont Pharma Solutions. [surface]

[19] [Filling Composition] [ ] [sample] [PEG 400] [(g)] [PEO Polyox™] [grade] [PEO (g)] [water] [(g)] [Diphenhydramine hydrochloride] [(g)] 1 14.0 Mn 5M Yes 4.0 2.0 2.0 2 14.0 Mn 0.9M Yes 4.0 2.0 2.0 3 14.0 Mn 0.1M Yes 4.0 2.0 2.0 4 14.0 Mn 5M Yes 4.0 2.0 2.0 5 10.0 Mn 5M Yes 8.0 2.0 2.0 6 10.0 Mn 0.1M Yes 8.0 2.0 2.0 7 10.0 Mn 5M Yes 8.0 2.0 2.0 8 14.0 Mn 0.9M Yes 4.0 2.0 2.0 9 10.0 Mn 0.1M Yes 8.0 2.0 2.0 10 10.0 Mn 0.9M Da 8.0 2.0 2.0 11 10.0 Mn 0.9M Da 8.0 2.0 2.0 12 14.0 Mn 0.1M Da 4.0 2.0 2.0

[0234] Diphenhydramine capsules of samples 1-12 were prepared using the filling compositions shown in Table 19 as follows. First, the filling compositions were prepared by dissolving diphenhydramine hydrochloride (DHP) in 2 ml of water and mixing PEG 400 and PEO to form two components. Then, the DHP aqueous solution was added to the PEG / PEO mixture. Each capsule No. 0 was filled with 0.55 g of the filling composition to provide a dose of 50 mg diphenhydramine / capsule. The capsules were then annealed in an oven at 60°C for one (1) hour.

[0235] Dissolution studies were conducted using pre-filled No. 0 gelatin hard-shell capsules containing the filling composition, performed via optical fiber dissolution in 500 ml of water at 37°C using a USP apparatus II at paddle speeds of 50 rpm and 100 rpm. The filling composition used in the dissolution studies is shown in Table 20. [surface] [20.] [Filling composition for dissolution studies] [ ] [Ingredients] [PEG 400 (g)] [PEO] [Polyox™] [grade] [PEO (g)] [Diphenhydramine] [(g)] [water] [(g)] 1 (Example 13) 10.0 Mn 5M Da 8.0 2.0 2.0 2 (Example 14) 14.0 Mn 5M Da 4.0 2.0 2.0 3 (Example 15) 10.0 Mn 0.9M Da 8.0 2.0 2.0 4 (Example 16) 14.0 Mn 0.9M Da 4.0 2.0 2.0 5 (Example 17) 10.0 Mn 0.1M Da 8.0 2.0 2.0 6 (Example 18) 14.0 Mn 0.1M Da 4.0 2.0 2.0

[0236] The solubility profiles of the six (6) filler compositions listed in Table 20 at a blade speed of 100 RPM are shown in Figure 6. The solubility profiles of the six (6) filler compositions listed in Table 20 at a blade speed of 50 RPM are shown in Figure 7.

[0237] The solubility profiles of the various filler compositions were similar at blade speeds of 50 RPM and 100 RPM, indicating that the drug release mechanism is primarily diffusion. The solubility results showed that higher molecular weight PEO and higher PEO concentrations each resulted in slower drug release. Filler compositions 5 and 6, prepared from 0.1 M PEO, exhibited immediate release profiles, while all other filler compositions showed variable drug release rates, as shown in Figures 6 and 7.

[0238] Minitab 16 software package was used to analyze the collected dissolution dataset. The time to 90% drug release was used as the dependent variable. The general linear model module in Minitab 16 software package was used to analyze the effects of PEO content and PEO molecular weight on the dependent variable. The results are summarized in Tables 21-22 and 24 below. [surface] [twenty one.] [General Linear Model] [:] [release] [90% DHP] [Time Pair] [PEO%] [,] [PEO Mn(MDa)] [ ] [factor] [type] [grade] [value] [ ] [ ] PEO % fixed 2 18.182 36.364 PEO Mn (MDa) fixed 3 0.1 0.9 5.0 [surface] [twenty two.] [time] [90% (h)] [Variation Analysis] [,] [Usage Adjustment] [SS] [conduct] [test] [ ] source [DF] [Seq SS] [Adj SS] [Adj MS] [F] [P] PEO % 1 29.482 29.482 29.482 22.14 0.000 PEO Mn (MDa) 2 116.323 116.323 58.162 43.68 0.000 PEO %*PEO Mn (MDa) 2 22.703 22.703 11.352 8.52 0.002 error 18 23.970 23.970 1.332 total twenty three 192.478 S=1.15398 R-Sq=87.55% R-Sq(adj) = 84.09% [surface] [twenty three.] [Using Turkic methods] [(] [Tukey Method] [and] [95.0%] [Trust level groups information] [ ] [PEO%] [N] [average value] [Grouping] 36.364 12 4.1500 A 18.182 12 1.9333 B The average values ​​for those that do not share a single letter are significantly different. [ ] [ ] [surface] [twenty four] [.] [Use of Turkic methods and] [95.0%] [Trust level groups information] [ ] [PEO Mn (MDa)] [N] [average value] [Grouping] 5.0 8 5.9500 A 0.9 8 2.5500 B 0.1 8 0.6250 C The average values ​​of groups that do not share a single letter are significantly different.

[0239] The following abbreviations are used in the aforementioned table: DF - Degrees of Freedom Seq SS - continuous sum of squares, which is a measure of the variation of different components of the model. The adjusted sum of squares of the Adj SS-term is the increase in the regression sum of squares compared to a model with only the other terms. Adj MS - Adjusted mean squared value measurement or model explains how much variation. The FF value is a test statistic used to determine whether the model is missing a higher-order term that includes the predicted values ​​in the current model. P - probability. P < 0.05 indicates a significant result; otherwise, it is not significant. N - Number of data points

[0240] Figures 8A-8D show the residuals at 90% release time (hours). Figure 8A is the normal probability plot, Figure 8B is the relative fit, Figure 8C is the histogram, and Figure 8D is the relative order. Figure 9 shows the interaction plot at 90% release time (hours). Figure 10 shows the main effects plot at 90% release time (hours).

[0241] Based on these statistical analyses, there is an interaction between release time and PEO molecular weight and concentration. The higher the PEO molecular weight and the higher the PEO concentration, the slower the API release. Example 19 - Immediate-release composition of PEO polymer, high-Mn polyethylene glycol and HPMC polymer

[0242] Immediate-release compositions based on PEO resin, high molecular weight polyethylene glycol (1000-5000 Daltons), and low-viscosity hydroxypropyl methylcellulose (HPMC) have been developed for potential use in abuse prevention soft capsules. Three formulations (3) shown in Table 25 below were prepared. Formulation 13 contains PEO and PEG 3350 with a number average molecular weight of 100,000 Da. Formulation 14 contains PEO and HPMC. Formulation 15 contains PEO, PEG 3350, and HPMC. [ ] [surface] [25.] [contain] [PEG 3350] [and] [HPMC] [The ingredients] [ ] 13 ingredients [ (g)] [Wt.%] 14 ingredients [ (g)] [Wt.%] Formula 15 [ (g)] [Wt.%] PEO (Mn=100,000 Da) 6.0 30.0 6.0 30.0 4.0 20.0 PEG 400 10 50.0 10 50.0 10.0 50.0 PEG 3350 1.0 5.0 - - 2.0 10.0 HPMC METHOCEL™ VLV - - 1.0 5 1.0 5.0 water 2.0 10.0 2.0 10.0 2.0 10.0 diphenhydramine 1.0 5.0 1.0 5.0 1.0 5.0 Total (g) 20.0 100.0 20.0 100.0 20.0 100.0

[0243] Diphenhydramine (DPH) capsules of type 0 were prepared by mixing PEG 400 with PEO and PEG 3350 and / or HPMC. DPH dissolved in water and a 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 diphenhydramine / capsule). Finally, the capsules were annealed in an oven at 60°C for one (1) hour.

[0244] For the dissolution study, the optical fiber was dissolved in 500 ml of water at 37°C using a USP apparatus II with a blade speed of 100 RPM. The dissolution profile of formulations 13-15 is shown in Figure 11.

[0245] Formulations 13-15 were demonstrated as immediate-release formulations. Diphenhydramine was released to 100% from these formulations in approximately one (1) hour. Of the three formulations, formulation 15 had the fastest drug release rate. This is not theoretically required, but is believed to be due to the higher amount of PEG 3350 in formulation 15. Examples 20-22: Controlled Release PEO Soft Capsules

[0246] Three batches of soft capsules were manufactured using a soft capsule encapsulation machine, containing filler compositions made from PEO resins having various number-average molecular weights (900,000 Da, 5,000,000 Da, and 7,000,000 Da). The filler compositions used for batch manufacturing are shown in Tables 26-28 below. [surface] [26.] [Example]

[20] [Filling Formula] [(18MC-30)] [ ] [ mg / ] [capsule] [Project Description] 25.0 Diphenhydramine hydrochloride, USP 300.0 Polyethylene glycol 400, NF 175.0 Polyoxyethylene-Mn 900,000 Da (Polyox™ WSR 1105) total 500.0 [surface] [27.] [Example] [twenty one] [Filling Formula] [(18MC-31)] [ ] [ mg / ] [capsule] [Project Description] 25.0 Diphenhydramine hydrochloride, USP 300.0 Polyethylene glycol 400, NF 175.0 Polyoxyethylene-Mn 5,000,000 Da (Polyox™ WSR Coagulant) total 500.0 [surface] [28.] [Example] [twenty two] [Filling Formula] [(18MC-32)] [ ] [ mg / ] [capsule] [Project Description] 25.0 Diphenhydramine hydrochloride, USP 300.0 Polyethylene glycol 400, NF 175.0 Polyethylene oxide-Mn 7,000,000 Da (Polyox™ WSR-303) total 500.0

[0247] After encapsulation, the soft capsule was sealed in an aluminum package for five (5) days to allow moisture to migrate from the moist capsule shell into the filler. This moisture migration dissolves the PEO in the filler composition and forms a gel to provide a sustained release profile. After five (5) days, the filler moisture content in each capsule was tested, and the results are shown in Table 29 below. [surface] [29.] [Softgels to replenish moisture] [ ] [Example] [Replenish moisture,] [wt.%] [water] [sample] [1] [sample] [2] [average] 20 (18MC-30) 19.3 16.2 17.3 21 (18MC-31) 17.1 16.2 16.7 22 (18MC-32) 17.2 17.3 17.3

[0248] Despite a sufficiently high moisture content, the results showed that the PEO resin particles within the soft capsules were not fully dissolved. Unbound from theory, it appears that PEG 400 binds to the moisture content, preventing complete dissolution of the PEO resin particles. Therefore, the soft capsules were annealed in an oven at 60°C for one hour (1 hour) to melt and dissolve the PEO resin particles. The annealed soft capsules were then subjected to a dissolution test.

[0249] The in vitro drug release rate was evaluated using an optical fiber dissolution system conducted at 37°C and 500 ml of water at paddle speeds of 50 RPM and 100 RPM using a USP device II. Comparative dissolution results of capsules prepared with three (3) PEO resins of different number average molecular weights are shown in Figures 12-13.

[0250] At a blade speed of 100 RPM, capsules containing PEO with a number average molecular weight of 900,000 Da exhibited 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 a number average molecular weight of 5,000,000 and 7,000,000 Da exhibited similar drug release rates. At 50 RPM, the solubility profiles of all three capsules in Examples 20-22 were similar.

[0251] Differential scanning colorimetric analysis (DSC) was performed on the PEO resin and filler compositions used for soft gel encapsulation, as shown in Figures 14-19. The blue curve represents the initial heating at 10°C / min. The green curve represents the cooling at 10°C / min. The red curve represents the second heating at 10°C / min. During the initial heating cycle, all three PEO resins had melting temperatures below 60°C. Without being bound by theory, it is believed that this reduced melting temperature of the filler compositions is attributed to the plasticizing effect of PEG 400 on the PEO resin. DSC analysis can be used to select appropriate processing and annealing temperatures for specific filler compositions.

[0252] A controlled-release soft gel filler composition based on polyethylene oxide resin was developed based on experimental design. The effects of PEO concentration and molecular weight on drug release rate were investigated. The drug release rate was significantly affected by both PEO molecular weight and PEO polymer concentration. The higher the PEO molecular weight or PEO polymer concentration, the slower the drug release rate. The same composition showed similar dissolution profiles at impeller speeds of 50 rpm and 100 rpm, indicating that the drug release mechanism is mainly attributed to diffusion via the polymer matrix.

[0253] We have also developed compositions containing low molecular weight PEO, PEG 3350, and low viscosity HPMC for immediate-release soft capsules. These compositions exhibited immediate-release profiles when dissolution studies were conducted.

[0254] Three batches of soft capsules containing various Mn PEO resins were manufactured. The soft capsules were then subjected to a dissolution test. All three batches of soft capsules exhibited prolonged release profiles. DSC analysis was performed on the PEO resins and the three compositions. PEG 400 in the compositions appears to act as a plasticizer for the PEO resins, resulting in a lower melting temperature (<60°C) for the PEO resins, which is beneficial for product manufacturing. Example 23 - Viscosity Adjustment of Filler Compositions Using Polyoxyethylene

[0255] Three compositions containing only polyethylene oxide (Polyox™) and polyethylene glycol 400 were prepared to demonstrate how the viscosity of a filled composition can be controlled by varying the amounts of polyethylene oxide and polyethylene glycol in the filled composition. The filled compositions and their viscosities are shown in Table 30 below. [surface]

[30] [Viscosity Adjustment] [ ] [PEO (wt.%)] [PEG 400 wt.%] [Viscosity] [(cP)] 10 90 229 30 70 2374 40 60 18190

[0256] For the sake of simplicity, embodiments of the method of the present invention are depicted and described as a series of actions. However, the actions according to the invention may occur in various orders and / or simultaneously, and other actions are not presented or described herein. Furthermore, implementing the method according to the disclosed subject matter does not require all the actions described. In addition, those skilled in the art will understand and appreciate that the method may alternatively be represented as a series of related states via state diagrams or events.

[0257] In the foregoing description, numerous specific details, such as particular materials, dimensions, and process parameters, are set forth to provide a thorough understanding of the invention. In one or more embodiments, particular features, structures, materials, or characteristics may be combined in any suitable manner. The terms "example" or "illustrative" are used herein to mean serving as an example, illustration, or description. No form or design described herein as "example" or "illustrative" should be construed as superior or advantageous to other forms or designs. Indeed, the use of the terms "example" or "illustrative" is intended to present concepts in a concrete manner. As used in this application, the term "or" is intended to mean inclusive "or" rather than exclusive "or." That is, unless otherwise specified or apparent from the context, "X includes A or B" is intended to mean naturally inclusive of either of the 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 foregoing cases. Throughout this specification, references to "embodiment," "certain embodiments," or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Therefore, the phrases "embodiment," "certain embodiments," or "one embodiment" appearing throughout this specification do not necessarily refer to the same embodiment.

[0258] The invention has been described with reference to specific exemplary embodiments thereof. Therefore, the specification and drawings should be viewed in an illustrative rather than restrictive sense. In addition to what has been shown and described herein, various modifications to the invention will be apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

[0259] 500: Methods 510: Mixed 512: Raw materials for pharmaceuticals 514: Polyethylene oxide 516: Polyethylene glycol 518: Other ingredients 520: Encapsulation 530: Drying 540: Heating / Annealing 550: Soft Capsules

Claims

1. A modified release soft capsule comprising: (a) a controlled-release filling composition comprising: (i) at least one active agent; and (ii) a controlled-release material; and (b) a pH-dependent shell composition encapsulating the filling composition, wherein the pH-dependent shell composition comprises 45 wt.% to 65 wt.% gelatin, 5 wt.% to 15 wt.% pectin and 0.05 wt.% to 0.2 wt.% dextrose.

2. The modified release soft capsule of claim 1, wherein the controlled release material is selected from polyethylene oxide, cellulose derivatives, gums or combinations thereof.

3. The modified release soft capsule of claim 2, wherein the controlled release material comprises polyethylene oxide having a content of about 0.05 M Daltons to about 15 M Daltons.

4. The modified release soft capsule of any one of claims 2 to 3, wherein the controlled release material comprises a cellulose derivative selected from microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and combinations thereof.

5. The modified release soft capsule of any one of claims 2 to 3, wherein the controlled release material comprises gum selected from tragacanth gum, gum arabic, guar gum, saffron gum, locust bean gum, or combinations thereof.

6. The modified release soft capsule of any one of claims 2 to 3, wherein the controlled release material is present in the controlled release filling composition in an amount of at least about 8 wt.% and at most about 65 wt.% based on the total weight of the controlled release filling composition.

7. The modified release soft capsule of any one of claims 1 to 3, 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 soft capsule of claim 1, wherein the controlled release filling composition further comprises a hydrophilic carrier comprising polyethylene glycol, propylene glycol, water, or a combination thereof.

9. The modified release soft capsule of claim 7, wherein the hydrophilic carrier is present in the controlled release filling composition in an amount greater than 0 wt.% and up to about 70 wt.% based on the total weight of the controlled release filling composition.

10. The modified release soft capsule of any one of claims 1 to 3, wherein the at least one active agent is present in the controlled release filling composition in an amount of about 5 wt.% to about 60 wt.% based on the total weight of the controlled release filling composition.

11. The modified release soft capsule of any of claims 1 to 3, wherein less than about 85% of the active agent is released after 0.5 hours at 37°C, based on an optical fiber dissolution test using apparatus II at a paddle speed of 50 rpm in a pH 6.8 phosphate buffer solution containing trypsin, as appropriate.

12. The modified release soft capsule of any one of claims 1 to 3, wherein the modified release soft capsule is annealed.

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

14. The modified release soft capsule of claim 13, wherein the matrix is ​​a solid or a liquid.

15. The modified release soft capsule of any one of claims 1 to 3, wherein the pH-dependent shell composition further comprises a plasticizer.

16. The modified release soft capsule of any one of claims 1 to 3, wherein the pectin is low-methoxyl pectin.

17. The modified release soft capsule of any one of claims 1 to 3, wherein the pectin is selected from the group consisting of amide-treated pectin, non-amide-treated pectin, and combinations thereof.

18. The modified release soft capsule of any one of claims 1 to 3, wherein the pH-dependent shell composition comprises about 45 wt.% to about 60 wt.% gelatin based on the weight of the dried pH-dependent shell composition.

19. The modified release soft capsule of any one of claims 1 to 3, wherein the pH-dependent shell composition comprises about 0.1 wt.% to about 0.2 wt.% dextrose based on the weight of the dried pH-dependent shell composition.

20. The modified release soft capsule of claim 15, wherein the pH-dependent shell composition contains about 10 wt.% to about 40 wt.% plasticizer based on the weight of the dried pH-dependent shell composition.

21. The modified release soft capsule of any one of claims 1 to 3, wherein the gelatin is selected from the group consisting of type A gelatin, type B gelatin and mixtures thereof.

22. The modified release soft capsule of any one of claims 1 to 3, wherein the gelatin is selected from the group consisting of fish gelatin, animal skin gelatin, bone gelatin and mixtures thereof.

23. The modified release soft capsule of any one of claims 1 to 3, wherein the pectin is non-amided pectin.

24. The modified release soft capsule of claim 15, wherein the plasticizer is selected from glycerin, sorbitol and combinations thereof.

25. The modified release soft capsule of claim 24, wherein the plasticizer is glycerin.

26. The modified release soft capsule of any of claims 1 to 3, wherein, based on a dissolution / disintegration test performed in a USP device II at a paddle speed of 50 rpm in a pH 6.8 phosphate buffer with pancreatic enzymes present, the pH-dependent shell composition dissolves / disintegrates in an intestinal environment in less than about 60 minutes.

27. The modified release soft capsule of any of claims 1 to 3, wherein the pH-dependent shell composition dissolves / disintegrates in an acidic medium for at least about 15 minutes based on a dissolution / disintegration test performed in 0.1N HCl with pepsin, if applicable, at a paddle speed of 50 rpm in a USP device II.

28. The modified release soft capsules of any of claims 1 to 3 are free of additional pH-dependent polymers.

29. The modified release soft capsule of any one of claims 1 to 3, wherein the viscosity of the pH-dependent shell composition is in the range of about 110,000 cPs to about 125,000 cPs.

30. The modified release soft capsule of any one of claims 1 to 3, wherein the gelatin to pectin w:w ratio of the pH-dependent shell composition is in the range of about 2:1 to about 20:

1.

31. The modified release soft capsule of claim 15, wherein the plasticizer to gelatin w:w ratio of the pH-dependent shell composition is in the range of about 5:1 to about 1:

5.

32. The modified release soft capsule of any one of claims 1 to 3, wherein the w:w ratio of the controlled release material to the at least one active agent in the controlled release filling composition is in the range of about 10:1 to about 1:

10.

33. A modified release soft capsule as claimed in any of claims 1 to 3, wherein the at least one active agent is selected from pharmaceutical active ingredients, pharmaceutical nutritional products, and combinations thereof.

34. The modified release soft capsule of claim 33, wherein the active agent comprises at least one pharmaceutically active ingredient selected from nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, antihistamines, and combinations thereof.

35. The modified release soft capsule of claim 33, wherein the active agent comprises vitamins, minerals, supplements, and combinations thereof.

36. The modified release soft capsule of claim 35, wherein the active agent comprises fish oil, garlic oil, krill oil, or a combination thereof.

37. A method for preparing a modified release soft capsule as claimed in any one of claims 1 to 36, comprising the steps of: (a) preparing the controlled release filling composition; and (b) encapsulating the controlled release filling composition with the pH-dependent shell composition.

38. The method of claim 37, further comprising drying the encapsulated modified release soft capsule.

39. The method of any one of claims 37 to 38, further comprising annealing the modified release soft capsule.

40. The method of claim 39, wherein the annealing occurs at a temperature ranging from about 25°C to about 80°C.

41. The method of any of claims 39, wherein the duration of the annealing occurs is in the range of about 10 minutes to about 24 hours.

42. The method of any one of claims 37 to 38, wherein (a) comprises mixing the at least one active agent with the controlled release material and, where appropriate, with a hydrophilic carrier.

43. The method of any one of claims 37 to 38, further comprising preparing the pH-dependent shell composition.

44. The method of claim 43, wherein the preparation comprises mixing gelatin, dextrose, pectin and, where appropriate, a plasticizer to form the pH-dependent shell composition strip.

45. The method of claim 44, wherein the thickness of the pH-dependent shell composition strip is in the range of about 0.020 inches to about 0.050 inches.

46. ​​A method for adjusting the dissolution position and profile of a modified release soft capsule composed of a controlled-release filling composition encapsulated in a pH-dependent shell composition, the method comprising: adjusting at least one of i) to iv) to control the dissolution position of the pH-dependent shell composition along the gastrointestinal tract of an individual: i) the amount of at least one of pectin, gelatin, dextrose, and plasticizer in the pH-dependent shell composition, wherein the pH-dependent shell composition comprises 45 wt.% to 65 wt.% gelatin, 5 wt.% to 15 wt.% pectin, and 0.05 wt.% to 0.2 wt.% dextrose; ii) the annealing temperature of the modified release soft capsule; iii) the annealing duration of the modified release soft capsule; or iv) the band thickness of the pH-dependent shell composition; and adjusting at least one of (v) to (vii) to obtain a target dissolution profile of the at least one active agent: v) the amount of controlled-release material in the controlled-release filling composition, or vi) The modification releases the annealing temperature of the soft capsule; or vii) the modification releases the annealing duration of the soft capsule.

47. Use of a modified release soft capsule as claimed in any one of claims 1 to 37, for use in preparing a delayed-release soft capsule composition for administration to an individual in need of treatment of a condition.

48. A modified release soft capsule comprising: (a) a controlled release filling composition comprising: (i) at least one active agent; and (ii) polyethylene oxide with a number average molecular weight of about 0.05 M Daltons to about 15 M Daltons; and (iii) a hydrophilic carrier, if applicable; and (b) a pH-dependent shell composition encapsulating the controlled release filling composition, wherein the pH-dependent shell composition comprises 45 wt.% to 65 wt.% gelatin, 5 wt.% to 15 wt.% pectin, 0.05 wt.% to 0.2 wt.% dextrose, and, if applicable, a plasticizer.

49. A method for preparing modified release soft capsules, comprising: mixing at least one active agent with polyethylene oxide and, if applicable, a hydrophilic carrier to form a controlled release filling composition; encapsulating the controlled release filling composition in a pH-dependent shell composition comprising 45 wt.% to 65 wt.% gelatin, 5 wt.% to 15 wt.% pectin, 0.05 wt.% to 0.2 wt.% dextrose and, if applicable, a plasticizer; and annealing the encapsulated controlled release filling composition.

50. The modified release soft capsule of claim 48 or the modified release soft capsule prepared by the method of claim 49, wherein the delayed release capsule exhibits a zero-order release of the active agent for a duration of about 2 hours to about 24 hours.

51. The modified release soft capsule of claim 48 or the modified release soft capsule prepared by the method of claim 49, wherein, based on a dissolution / disintegration test performed in a USP device II at a paddle speed of 50 rpm in a pH 6.8 phosphate buffer with pancreatic enzymes, if applicable, the pH-dependent shell composition dissolves / disintegrates in an intestinal environment in less than about 60 minutes; and wherein, based on a dissolution / disintegration test performed in a USP device II at a paddle speed of 50 rpm in 0.1N HCl with pepsin, if applicable, the pH-dependent shell composition dissolves / disintegrates in an acidic medium in at least about 15 minutes.

52. The modified release soft capsule of claim 51, wherein less than about 85% of the active agent is released after 0.5 hours in the second pH 6.8 phosphate buffer stage of the two-stage fiber optic dissolution test using device II at a blade speed of 50 rpm.

53. A modified release soft capsule comprising: (a) a controlled release filling composition comprising: (i) at least one active agent; and (ii) a controlled release material; and (b) a pH-dependent shell composition encapsulating the controlled release filling composition, wherein the pH-dependent shell composition comprises 0.05 wt.% to 0.2 wt.% dextrose.

54. The modified release soft capsule of claim 53, wherein the pH-dependent shell composition comprises gelatin.

55. The modified release soft capsule of any one of claims 53 to 54, wherein the pH-dependent shell composition comprises a pH-dependent release material.

56. The modified release soft capsule of claim 55, wherein the pH-dependent release material comprises pectin.

57. The modified release soft capsule of any one of claims 53 to 54, wherein the pH-dependent shell composition comprises a plasticizer.

58. A modified release soft capsule as claimed in any of claims 53 to 54, wherein the modified release soft capsule is annealed.

59. The modified release soft capsule of claim 58, wherein the annealed soft capsule comprises a controlled release filler composition in the form of a matrix of the controlled release material encapsulated in the pH-dependent shell composition.

60. A modified release soft capsule as claimed in any of claims 53 to 54, wherein the at least one active agent is selected from pharmaceutical active ingredients, pharmaceutical nutritional products, and combinations thereof.

61. The modified release soft capsule of claim 60, wherein the active agent comprises at least one pharmaceutically active ingredient selected from nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, antihistamines, and combinations thereof.

62. The modified release soft capsule of claim 60, wherein the active agent comprises vitamins, minerals, supplements, and combinations thereof.

63. The modified release soft capsule of claim 62, wherein the active agent comprises fish oil, garlic oil, krill oil, or a combination thereof.

64. A modified release soft capsule as claimed in any of claims 53 to 54, wherein the active agent is a pharmaceutically active ingredient that is not easily abused.

65. A modified release soft capsule as claimed in any of claims 53 to 54, wherein the controlled release material comprises polyethylene oxide.

66. The modified release soft capsule of claim 65, wherein the polyethylene oxide has a number average molecular weight of about 0.05 M Daltons to about 15 M Daltons.

67. The modified release soft capsule of any one of claims 53 to 54, wherein the controlled release material further comprises a hydrophilic carrier.

68. The modified release soft capsule of claim 67, wherein the hydrophilic carrier comprises polyethylene glycol having a number average molecular weight of about 200 Daltons to about 7,000 Daltons.

69. The modified release soft capsule of claim 67, 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.

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