Soft gel capsules with delayed release.

Description

Soft gel capsules with delayed release. Divided from BR112023008881-0, filed on November 10, 2021. CROSS-REFERENCE TO RELATED REQUESTS

[001] This application claims priority over U.S. Provisional Application 63 / 112,453, filed November 11, 2020, the content of which is incorporated in its entirety herein. FIELD OF INVENTION

[002] The present invention relates to delayed-release softgel capsules. In certain embodiments, the gelatin-based shell compositions have delayed-release properties with the inclusion of a small amount of synthetic polymer, an organic acid, or a combination thereof. BACKGROUND OF THE INVENTION

[003] Soft gel capsules, in particular gelatin soft gel capsules (or soft gel capsules), provide a dosage form that is more readily accepted by patients, since the capsules are easy to swallow and do not need to be flavored to mask any unpleasant taste of the active agent. Encapsulating drugs in soft gel capsules also provides the potential to improve the bioavailability of pharmaceutical agents. For example, the active ingredients can be rapidly released in liquid form as soon as the gelatin shell breaks.

[004] Efforts have been made to create delayed-release dosage forms. Delayed-release dosage forms are designed to protect the contents of the dosage forms from gastric conditions. For example, delayed-release dosage forms can be produced by adding a pH-dependent coating to the surface of a manufactured dosage form such as a tablet or capsule. Such coatings can IPaçãto887nBSí®2204S!,dfe Wfffiam.niüg. W87 2 / 70 can be applied by spraying the dosage form, followed by drying the dosage form, usually at elevated temperatures. This method of coating a capsule with a pH-dependent coating can lead to disadvantages in terms of performance 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 flaking off the dosage form. Furthermore, the process of applying a pH-dependent coating is very inefficient.

[005] Other delayed-release dosage forms 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 can lead to capsules that are leak-prone due to insufficient sealing or that are brittle (i.e., like eggshells) due to the inclusion of a large amount of polymer.

[006] Improving the pH-dependent shell compositions of soft gel capsules is an ongoing endeavor. SUMMARY OF THE INVENTION

[007] The present invention relates to delayed-release soft gel capsules. The delayed-release soft gel capsules comprise (a) a filling material and (2) a pH-dependent shell composition. The delayed-release soft gel capsules according to the present invention do not require a pH-dependent coating. By eliminating the need to add a pH-dependent coating to the soft gel capsule, the risk of damaging the capsules during the coating process is also minimized.

[008] In certain embodiments, the pH-dependent shell composition comprises: (a) a gelatin, (b) dextrose, (c) a pec IPaiçãto887nBSí®2204S!,dfe 1(00^20¾]}¾ 1S7E577 3 / 70 tin such as a low methoxyl pectin, (d) from about 0.5% by weight to about 10% by weight of a polymer, based on the total weight of the dry pH-dependent shell composition.

[009] In certain embodiments, the pH-dependent shell composition comprises: (a) a film former and (b) from about 0.5% by weight to about 10% by weight of a synthetic polymer, based on the total weight of the pH-dependent dry shell composition.

[0010] In certain embodiments, the pH-dependent shell composition comprises: (a) a gelatin, (b) dextrose, (c) a pectin such as a low methoxyl pectin and (d) an organic acid.

[0011] In certain embodiments, the pH-dependent coating composition comprises: (a) a film former and (b) an organic acid.

[0012] This disclosure also applies to a manufacturing process for any of the delayed-release softgel capsules described herein.

[0013] In certain embodiments, the present disclosure also refers to a method of treating a condition by administering to a subject in need any of the delayed-release softgel capsule compositions described herein.

[0014] The soft gel capsule shells described herein, the pH-dependent shell compositions described herein and their preparation process (e.g., existence or non-existence of a curing step and its conditions, washing with organic acid and so forth) can be tuned / adjusted / modified to achieve a target pH dissolution / disintegration profile of the shell composition in various pH environments (e.g., rupture / dissolution / disintegration time in acidic medium and in buffer medium4 / 70).

[0015] In certain embodiments, the present disclosure is directed to methods of inhibiting the premature release of a filler material (and correspondingly of an active agent present in the filler material) in the early gastrointestinal tract.

[0016] In certain embodiments, the present disclosure is directed to methods of inhibiting the occurrence of eructation due to the premature release of a filler material (and correspondingly of an active agent present in the filler material) in the early gastrointestinal tract. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention advances the state of the art by developing delayed-release oral dosage forms, in particular, delayed-release soft gel capsules, which achieve the advantages associated with conventional delayed-release dosage forms without the need to apply a pH-dependent coating. The delayed-release soft gel capsules of the present invention do not dissolve / disintegrate in a gastric environment of the stomach, but rather dissolve at a target pH, for example, above about 1.2, above about 2, above about 3, above about 3.5, above about 4, above about 5, above about 6 or above about 6.8. The dissolution profile of the delayed-release soft gel capsules described in this document can be adjusted by modifying the composition of the soft gel capsule shell.

[0018] This mechanism is beneficial for the delivery of active ingredients that may cause stomach irritation or are sensitive to the acidic environment of the stomach. This mechanism is also beneficial for reducing belching after consuming capsules that encapsulate filler materials that tend to contribute to belching. By Petition 870260022436, dated 06 / 03 / 2026, page 20 / 287 5 / 70 For example, belching commonly occurs when consuming vitamins, minerals, supplements, and / or pharmaceuticals that are formulated in dosage forms exhibiting some leakage (even in a very small amount) into the stomach before reaching the intestines. Leakage can be particularly problematic when belching is associated with substances that have a perceived harmful effect, such as fish oil and garlic, which are commonly administered in softgel capsules. The delayed-release softgel capsules described herein can be formulated in a way that minimizes and / or eliminates premature leakage (and consequently premature release of the capsule filling) into the gastric environment of the stomach. Definitions

[0019] As used in this document, the term pH-dependent is used to refer to the property of a substance that is resistant to dissolution or disintegration, such that dissolution or disintegration does not occur or does not occur substantially in a gastric environment of the stomach, for example, for a time period of 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 certain embodiments, the gastric environment of the stomach may be simulated herein with 0.1 N HCl and optionally with the addition of pepsin adjusted to a pH of 1.2, 2, 3, 4, 5, or 6 with a buffer, such as phosphate-buffered solution, sodium hydroxide solution, or potassium hydroxide solution.It should be noted that pharmacopoeial methods do not include pepsin; however, pepsin has been added in certain dissolution / disintegration tests described herein to better simulate / mimic in vivo conditions. Therefore, without being interpreted as limiting, in certain embodiments, the... Petition 870260022436, dated 06 / 03 / 2026, p. 21 / 287 6 / 70 of the compositions described herein are resistant to dissolution / disintegration for the durations described above, even in 0.1 N HCl environments that include Pepsin (which is presumed to be a more aggressive environment than 0.1 N HCl without Pepsin).

[0020] For example, the embodiments described herein include a pH-dependent shell composition that preferentially dissolves at a pH of about 3.5 or higher, 4 or higher, 5 or higher, or 6 or higher (e.g., in a biological, artificial, or simulated duodenal environment and / or intestinal fluid) compared to biological, artificial, or simulated gastric fluid. In certain embodiments, the intestinal environment may be simulated herein with pH 6.8 phosphate buffer with or without pancreatin. For example, the pH-dependent shell composition described herein dissolves at a pH of about 3.5 or higher, 4 or higher, 5 or higher, or 6 or higher (e.g., in a biological, artificial, or simulated duodenal environment and / or intestinal fluid, such as pH 6.8 phosphate buffer optionally with pancreatin) in less than about 60 minutes, less than about 45 minutes, less than about 30 minutes, less than about 20 minutes, less than about 10 minutes, or less than about 5 minutes.It should be noted that the pharmacopoeial methods do not include pancreatin; however, pancreatin has been added in certain dissolution / disintegration tests described herein to better simulate / mimic in vivo conditions. Therefore, without being interpreted as limiting, in certain embodiments, the compositions described herein exhibit similar dissolution / disintegration profiles in pH of approximately 3.5 or higher, 4 or higher, 5 or higher, 6 or higher, or 6.8 buffer environments that include pancreatin (which is presumed to be a more aggressive environment than the pH 6.8 buffer environment without pancreatin).

[0021] As used in this document, pharmaceutically active ingredient, active agents refers to a drug or compound. Petition 870260022436, dated 06 / 03 / 2026, page 23 / 287 7 / 70 which can be used in the diagnosis, cure, mitigation, treatment, or prevention of a condition. In certain modalities, suitable active agents include nutraceuticals such as vitamins, minerals, and supplements (VMS). Exemplary delayed-release softgel capsules may include, without limitation, capsules containing lactic acid bacteria, probiotics, fish oil capsules, valproic acid, garlic, peppermint oil, polyethylene glycol, ibuprofen solution or suspension, proton pump inhibitors, aspirin, and similar products.

[0022] 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 a subject.

[0023] As used herein, the term active ingredient refers to any material intended to produce a therapeutic, prophylactic or other intended effect, whether or not approved by a government agency for that purpose. This term in relation to a specific agent includes the pharmaceutically active agent and all its pharmaceutically acceptable salts, solvates and crystalline forms, where the salts, solvates and crystalline forms are pharmaceutically active.

[0024] Any pharmaceutically active ingredient may be used for the purposes of the present invention, including both those that are water-soluble and those that are poorly water-soluble. Suitable pharmaceutically active ingredients include, without limitation, analgesics and anti-inflammatory agents (e.g., ibuprofen, naproxen sodium, aspirin), antacids, anthelmintics, antiarrhythmic agents, antibacterial agents, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarials, antimigraine agents, antimuscarinics, antineoplastics and immunosuppressants, antiprotozoals, antirheumatics, antithyroid agents, antivirals, anxiolytics, sedatives Petition 870260022436, dated 06 / 03 / 2026, page 23 / 287 8 / 70 vos, hypnotics and neuroleptics, beta-blockers, cardiac inotropic agents, corticosteroids, antitussives, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, lipid-regulating agents, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritional agents, opioid analgesics, anticonvulsant agents (e.g., valproic acid), oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants and their combinations.

[0025] In some embodiments, the active pharmaceutical ingredient may be selected, without limitation, from the group consisting of dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurin, asimadoline, beclomethasone, apremilast, sapacitabine, linsitinib, abiraterone, vitamin D analogues (e.g., calcifediol, calcitriol, paricalcitol, doxercalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, their pharmaceutically acceptable salts and combinations thereof.

[0026] In some embodiments, the lipids in dosage form may be selected, without limitation, from the group consisting of almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, peppermint oil, rice bran oil, safflower oil, ger oil Petition 870260022436, dated 06 / 03 / 2026, page 24 / 287 9 / 70 gellin, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, walnut oil, and watermelon seed oil. Other oils and fats may include, among others, fish oil (omega-3), krill oil, animal or vegetable fats, for example, in their hydrogenated form, free fatty acids and mono-, di- and triglycerides with fatty acids C8-, C10-, C12-, C14-, C16-, C18-, C20- and C22-, fatty acid esters such as EPA and DHA 3 and their combinations.

[0027] According to certain embodiments, the active agents 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 their salts, hydrates, solvates, and pharmaceutically acceptable prodrugs, mixtures of any of the foregoing and the like.

[0028] Suitable active nutraceutical agents may include, but are not limited to, 5-hydroxytryptophan, acetyl L-carnitine, alpha-lipoic acid, alpha-ketoglutarates, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), dimethylaminoethanol, fumaric acid, germanium sequioxide, glandular products, glucosamine HCl, glucosamine sulfate, hydroxymethylbutyrate, immunoglobulin, lactic acid, L-carnitine, liver products. Malic acid, anhydrous maltose, mannose (d-mannose), methylsulfonylmethane, phytosterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadium sulfate and yeast.

[0029] Active ingredients in appropriate nutritional supplements may include vitamins, minerals, fiber, fatty acids, amino acids, Petition 870260022436, dated 06 / 03 / 2026, page 26 / 287 10 / 70 herbal supplements or a combination thereof.

[0030] Suitable vitamin active agents may include, but are not limited to, the following: ascorbic acid (vitamin C), B vitamins, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbates, mixed tocopherols, niacin (vitamin B3), orotic acid, para-aminobenzoic acid, pantothenates, pantothenic acid (vitamin B5), pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamine (vitamin B1), tocotrienols, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oils, and oil-soluble vitamins.

[0031] Suitable active ingredients in herbal 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, rauowolfia, senna, soy, St. John's wort, saw palmetto, saffron, valerian.

[0032] Active mineral agents may include, but are not limited to, the following: boron, calcium, chelated minerals, chloride, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvate, zinc, and other minerals.

[0033] Examples of other possible active agents include, but are not limited to, antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), nonsteroidal anti-inflammatory agents (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, ami Petition 870260022436, dated 06 / 03 / 2026, page 26 / 287 11 / 70 noprofen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidomethacin, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprin, azapropazone, benorilate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicylate, sulindac, sulfinpyrazone, tenoxicam, thiaprophenic acid.tolmetin, pharmaceutically acceptable salts thereof and mixtures thereof) and acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., phenylalanine, meprobmate and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardipine), antitussives and expectorants (e.g., codeine phosphate), antiasthmatics (e.g., theophylline), antacids, antispasmodics (e.g., atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluthiazide), antihypertensives (e.g., propranolol, clonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidal drugs, hypnotics, psychotropic drugs.Antidiarrheals, mucolytics, sedatives, decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine) and cannabinoids, as well as pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof.

[0034] The active agent may also be a benzodiazepine, Petition 870260022436, dated 06 / 03 / 2026, p. 28 / 287 12 / 70 barbiturates, stimulants, or mixtures thereof. The term “benzodiazepines” refers to benzodiazepines and benzodiazepine-derived medications that are capable of depressing the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, cetazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Benzodiazepine antagonists that can be used as active agents include, but are not limited to, flumazenil, as well as pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0035] The term “barbiturates” refers to sedative-hypnotic drugs derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mefobarbital, metarbital, pentobarbital, phenobarbital, secobarbital, as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and mixtures thereof. Barbiturate antagonists that may be used as active agents include, but are not limited to, amphetamines, as well as pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.

[0036] The term stimulants includes, but is not limited to, amphetamines, such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, as well as pharmaceutically acceptable salts, hydrates and solvates and mixtures thereof. Stimulant antagonists that may be used as active agents include, but are not limited to, benzodiazepines, as well as pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.

[0037] Dosage forms according to disclosure include Petition 870260022436, dated 06 / 03 / 2026, p. 28 / 287 13 / 70 in various active agents and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, but are not limited to, salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate and the like; salts of organic acids such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; salts of amino acids such as arginate, asparaginate, glutamate and the like, and metallic salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like.

[0038] As used in this document, the terms therapeutically effective and an effective amount refer to the amount of active agent or the rate at which it is administered that is necessary to produce a desired therapeutic result.

[0039] As used in this document, shell or shell composition refers to the shell of a soft gel capsule that encapsulates a filler material.

[0040] As used in this document, free or substantially free refers to a composition comprising less than about 1% by weight, less than about 0.5% by weight, less than about 0.25% by weight, less than about 0.1% by weight, less than about 0.05% by weight, less than about 0.01% by weight, or 0% by weight of said component.

[0041] All references to % by weight throughout the specifications and claims refer to the weight of the component relative to the weight of the entire composition in question and may also be designated as w / w. Petition 870260022436, dated 06 / 03 / 2026, p. 39 / 287 14 / 70

[0042] As used in this document, filler material or filler refers to the composition that is encapsulated by the pH-dependent capsule shell and contains at least one pharmaceutically active ingredient.

[0043] As used in this document, delayed-release capsules or delayed-release capsules or pH-dependent capsules or pH-dependent capsule capsules refer to capsules that exhibit delayed or pH-dependent properties once the filler material is encapsulated in the shell, and the capsules are dried. In certain embodiments, these terms may refer to capsules that have also been cured after drying. In certain embodiments, no further processing step after drying is required. In certain embodiments, no further processing step after curing is required.

[0044] As used in this document, approximately refers to any values ​​that are within a range of ± 10%, so approximately 10 includes 9 to 11. As used in this document, a, an or the refers to one or more, unless otherwise specified. Thus, for example, reference to an excipient includes a single excipient as well as a mixture of two or more different and similar excipients.

[0045] The citation of value ranges in this document is intended only as a shorthand method of referring individually to each separate value within the range, unless otherwise indicated in this document, and each separate value is incorporated into the descriptive report as if it were recited individually in this document. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by the context. Petition 870260022436, dated 06 / 03 / 2026, page 20 / 287 15 / 70

[0046] The use of any and all examples or exemplary language (e.g., “as”) provided herein is intended only to illuminate certain materials and methods and does not represent a limitation of scope. No language in the descriptive report should be interpreted as indicating any element not claimed as essential to the practice of the materials and methods disclosed. Soft gel capsule dosage form.

[0047] According to a first embodiment, a pH-dependent soft gel capsule comprises (a) a filler material and (b) a pH-dependent shell composition, wherein the filler material comprises at least one active agent, wherein the pH-dependent shell composition comprises a gelatin, dextrose, a pH-dependent material (e.g., a low-methoxyl pectin), a synthetic polymer and, optionally, a plasticizer. Preferably, the synthetic polymer is present in the pH-dependent shell composition in an amount of about 0.5% by weight to about 10% by weight, based on the total weight of the dry pH-dependent shell composition.

[0048] According to certain embodiments, a pH-dependent soft gel capsule comprises (a) a filler material and (b) a pH-dependent shell composition, wherein the filler material comprises at least one active agent, wherein the pH-dependent shell composition comprises a film former and a synthetic polymer. Preferably, the synthetic polymer is present in the pH-dependent shell composition in an amount of about 0.5% by weight to about 10% by weight, based on the total weight of the dry pH-dependent shell composition. The pH-dependent shell composition may further include at least one of pectin, dextrose or Petition 870260022436, dated 06 / 03 / 2026, page 21 / 287 16 / 70 gelatin.

[0049] According to alternative embodiments, a pH-dependent soft gel capsule comprises (a) a filler material and (b) a pH-dependent shell composition, wherein the filler material comprises at least one active agent, wherein the pH-dependent shell composition comprises a gelatin, dextrose, a pH-dependent material (e.g., a low methoxyl pectin), an organic acid and, optionally, a plasticizer.

[0050] According to alternative embodiments, a pH-dependent soft gel capsule comprises (a) a filler material and (b) a pH-dependent shell composition, wherein the filler material comprises at least one active agent, wherein the pH-dependent shell composition comprises a film former and an organic acid. The pH-dependent shell composition may further include at least one of pectin, dextrose or gelatin.

[0051] According to certain embodiments, a pH-dependent soft gel capsule comprises (a) a filler material and (b) a pH-dependent shell composition, wherein the filler material comprises at least one pharmaceutically active ingredient, wherein the pH-dependent shell composition comprises a gelatin, dextrose, a pH-dependent material (e.g., a low methoxyl pectin), an organic acid, a synthetic polymer and, optionally, a plasticizer. Preferably, the synthetic polymer is present in the pH-dependent shell composition in an amount of about 0.5% by weight to about 10% by weight, based on the total weight of the dry pH-dependent shell composition.

[0052] According to certain embodiments, a capsule of capsules Petition 870260022436, dated 06 / 03 / 2026, page 23 / 287 17 / 70 pH-dependent soft gel composition comprises (a) a filler material and (b) a pH-dependent shell composition, wherein the filler material comprises at least one pharmaceutically active ingredient, wherein the pH-dependent shell composition comprises a film former, an organic acid and a synthetic polymer. Preferably, the synthetic polymer is present in the pH-dependent shell composition in an amount of about 0.5% by weight to about 10% by weight, based on the total weight of the dry pH-dependent shell composition. The pH-dependent shell composition may further include at least one of pectin, dextrose or gelatin.

[0053] Suitable fillers comprise at least one pharmaceutically active ingredient and can be produced according to known methods. In addition to at least one pharmaceutically active ingredient, suitable fillers may comprise additional filler components such as flavoring agents, sweetening agents, coloring agents, and fillers or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides. Suitable amounts of pharmaceutically active ingredient and pharmaceutically acceptable excipients can be easily determined by one skilled in the art.

[0054] In one embodiment, the gelatin in the pH-dependent shell composition may include Type A gelatin, Type B gelatin, a skin or skin gelatin (e.g., calf skin, pig skin) and / or a bone gelatin (e.g., bovine bone, pig bone) used alone or in combination. In one embodiment, the gelatin is a 250 Bloom gelatin. In another embodiment, there is only one type of gelatin. In yet another embodiment, the gelatin is a combination of at least two types of gelatin. In one embodiment Petition 870260022436, dated 06 / 03 / 2026, page 23 / 287 18 / 70 of, the amount of gelatin in the pH-dependent shell composition is from about 30% by weight to about 85% by weight, from about 30% by weight to about 75% by weight, from about 30% by weight to about 65% by weight, from about 30% by weight to about 55% by weight, from about 30% by weight to about 40% by weight, from about 40% by weight to about 80% by weight, from about 45% by weight to about 65% by weight, from about 45% by weight to about 75% by weight, or from about 50% by weight to about 70% by weight, or any single value or subrange, based on the total dry weight of the capsule shell composition.

[0055] In certain embodiments, the pH-dependent shell composition may include, instead of or in addition to at least one of: gelatin, pectin or dextrose, a film former that is a gelling agent not derived from animals. Suitable non-animal-derived gelling agents include, without limitation, carrageenan, starch, pregelatinized starch, xanthan gum, agar-agar, pectin, alginate, sugar, high molecular weight polyethylene glycol, sugar-derived alcohol, a cellulose derivative, a cellulosic polymer, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, aluminum magnesium silicate, carbomer, carbopol, silicon dioxide, curdlan, furcelleran, albumin, soy protein, chitosan, or a combination thereof.

[0056] Carrageenan can be at least one of iota carrageenan, kappa carrageenan, and lambda carrageenan.

[0057] Starch can be modified starch or native starch, sweet potato starch, potato starch, corn starch, tapioca starch, pea starch, hydroxypropyl starch, hydroxyalkylated starch, acid-treated starch, dextrin, unmodified high-amylose corn starch, waxy modified corn starch, non- Petition 870260022436, dated 06 / 03 / 2026, page 24 / 287 19 / 70 granular, high-amylose modified corn starch, pregelatinized rice flour, and a combination thereof. As used herein and in the claims, the term modified starch includes starches such as hydroxypropyl starches, acid-diluted starches, and the like. In general, modified starches are products prepared by chemical treatment of starches, for example, acid-treated starches, enzymatically treated starches, oxidized starches, cross-linked starches, and other starch derivatives. It is preferable that the modified starches be derivatives in which the side chains are modified with hydrophilic or hydrophobic groups to form a more complex structure with a strong interaction between the side chains.

[0058] In certain embodiments, the non-animal gelling agent is in the composition of the casing in an amount, for example, of about 2% by weight to about 20% by weight, about 2% by weight to about 15% by weight, about 2% by weight to about 40% by weight, about 10% by weight to about 80% by weight, or about 15% by weight to about 75% by weight, or about 20% by weight to about 70% by weight, or about 25% by weight to about 60% by weight, or about 25% by weight to about 45% by weight, or about 20% by weight to about 35% by weight, or about 30% by weight to about 40% by weight, or about 32% by weight, or about 35% by weight, or about 38% by weight, or any subrange or single concentration value therein, with all % by weight being based on the total weight of the shell composition. In one embodiment, the non-animal gelling agent includes carrageenan and does not include starch (or modified starch).In one embodiment, the composition of the soft gel capsule shell is substantially starch-free or starch-free (or modified starch-free).

[0059] In one embodiment, the composition of the capsule shell Petition 870260022436, dated 06 / 03 / 2026, p. 26 / 287 20 / 70 pH-dependent formula includes dextrose. In one embodiment, the pH-dependent amount of dextrose in the capsule shell composition is from about 0.001% by weight to about 1.0% by weight, from about 0.002% by weight to about 0.008% by weight, from about 0.005% by weight or about 0.01% by weight to about 4% by weight, from about 0.1% by weight or about 0.15% by weight to about 3% by weight, from about 0.1% by weight to about 1% by weight, from about 0.1% or about 0.15% by weight or about 0.2% by weight or about 0.25% by weight to about 2% by weight, from about 0.1% by weight to about 0.2% by weight, from about 0.1% by weight to about 0.4% by weight, or any value single or subrange, based on the total weight of the dry capsule shell composition. Dextrose may be added to the delayed-release capsule shell to mitigate the potential reduction in gel strength.Without being interpreted as limiting, it is believed that dextrose interacts with the gelatin in the shell composition and causes gelatin cross-linking. The pH-dependent concentration of dextrose in the shell composition may be at an effective level to improve gel strength, but not so high as to interfere with capsule sealing, manufacturability, or product performance.

[0060] In some embodiments, the pH-dependent shell composition may comprise pectin, for example, a low-methoxyl pectin. In one embodiment, the pectin is low-methyl ester (LM) pectin with a Degree of Esterification of less than 50. In some embodiments, the pectin is amidated pectin. In certain embodiments, the amidated pectin may have a Degree of Amidation of less than 25, 5 to 25, 10 to 20, or 15 to 25. In other embodiments, the low-methoxyl pectin (LM) is non-amidated pectin. In certain embodiments, the pectin is a combination of amidated pectin and non-amidated pectin. The addition of pectin contributes to the pH-dependent nature of the composition. Petition 870260022436, dated 06 / 03 / 2026, p. 26 / 287 21 / 70 pH of the dosage form.

[0061] Too much pectin in the dosage form can reduce the gel strength of the soft gel capsule, which in turn can adversely affect the sealing capacity of the soft gel capsule. Too much 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 standpoint. Therefore, pectin can be added to the dosage form at a concentration high enough to form a delayed-release dosage form, while simultaneously being low enough to mitigate the reduction in gel strength and mitigate the increase in viscosity.

[0062] In one embodiment, the amount of pectin in the pH-dependent shell composition is from about 2% by weight to about 20% by weight, from about 3% by weight to about 15% by weight, from about 3% by weight to about 5.5% by weight, from about 4% by weight to about 11% by weight, from about 7% by weight to about 12% by weight, from about 8% by weight to about 13% by weight, or from about 5% by weight to about 10% by weight, or any single value or subrange thereof, based on the total weight of the dry capsule shell composition.

[0063] The pH-dependent degree of esterification of the pectin incorporated into the casing composition may be less than about 50%, or may range from about 10% to about 50%, from about 20% to about 40%, or from about 25% to about 35%. In addition, the pectin may be amidated or non-amidated.

[0064] In certain embodiments, the pH-dependent shell composition comprises a stabilizer and / or a binder comprising gellan gum. In certain embodiments, the amount of stabilizer and / or binder (e.g., gellan gum) in the composition Petition 870260022436, dated 06 / 03 / 2026, p. 28 / 287 22 / 70 pH-dependent shell composition is from about 0.05% by weight to about 5% by weight, from about 0.1% by weight to about 3% by weight, or from about 0.2% by weight to about 2% by weight of stabilizer and / or binder (e.g., gellan gum), or any single value or subrange, based on the total weight of the dry composition of the capsule shell.

[0065] In certain embodiments, the pH-dependent shell composition may have a viscosity ranging from 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 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 or about 150,000 cPs, or any subrange or single value therein. In one embodiment, the pH-dependent shell composition exhibits a viscosity ranging 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. A gel mass sample (e.g., of any of the pH-dependent shell compositions described herein) is loaded onto the rheometer platform, maintained at 60°C.A disc rotates at a certain speed to provide a fixed shear rate. Viscosity is obtained by measuring the shear stress and the shear rate.

[0066] In certain embodiments, the pH-dependent shell composition can maintain a viscosity suitable for manufacturing even after being heat-aged 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 certain embodiments, the viscosity of the pH-dependent shell composition, after heat aging (for up to about 24 hours, up to about 48 hours, up to Petition 870260022436, dated 06 / 03 / 2026, page 28 / 287 23 / 70 (approximately 72 hours, up to approximately 96 hours, or up to approximately 1 week) can reduce (the viscosity value of the composition before aging) by up to approximately 80%, up to approximately 70%, up to approximately 60%, up to approximately 50%, up to approximately 40%, up to approximately 35%, or up to approximately 30%.

[0067] In one embodiment, the plasticizer in the pH-dependent shell composition may include glycerin, sorbitol, or a solution of sorbitol and sorbitan and combinations thereof. Other suitable plasticizers may include, but are not limited to, sugar alcohol plasticizers such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers such as diglycerin, dipropylene glycol, a polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, a polyether polyol, ethanolamines; and mixtures thereof. Other exemplary plasticizers may also include, without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyl groups, ester-type plasticizers, glycol ethers, poly(propylene glycol).Multiblock polymers, single-block polymers, citrate ester and triacetin type plasticizers. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyltributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyltriethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.

[0068] In one embodiment, the amount of plasticizer in the pH-dependent casing composition is from about 15% by weight to about 45% by weight, from about 15% by weight to about 40% by weight. Petition 870260022436, dated 06 / 03 / 2026, page 49 / 287 24 / 70 weight, from about 18% by weight to about 45% by weight, from about 18% by weight to about 42% by weight, from about 20% by weight to about 35% by weight, from about 25% by weight to about 30% by weight, or any single value or subrange, based on the total weight of the dry capsule shell composition.

[0069] In certain embodiments, any of the pH-dependent shell compositions described herein may further include a synthetic polymer. Suitable synthetic polymers include, without limitation, acrylic and methacrylic acid polymers, which may be available under the trade name EUDRAGIT®, methacrylic acid-ethyl acrylate copolymer, which may be available under the trade name Kollicoat®, and other conventional acid-insoluble polymers, for example, methyl acrylate-methacrylic acid copolymers. Other suitable acid-insoluble polymers include, without limitation, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate (hypermellose acetate succinate), polyvinyl acetate phthalate (PVAP), salts of algenic acids such as sodium alginate and potassium alginate, stearic acid and shellac.

[0070] In certain embodiments, suitable synthetic polymers are insoluble in water, such as methacrylic acid-ethyl acrylate copolymer. Adding a water-insoluble polymer to the pH-dependent shell composition is believed to make the pH-dependent shell composition more hydrophobic. When the pH-dependent shell composition becomes more hydrophobic (compared to the pH-dependent shell composition that does not include the synthetic polymer), it is believed to reduce the amount of water that migrates from the filler material to the shell composition. This, in turn, increases the robustness of the shell composition. Petition 870260022436, dated 06 / 03 / 2026, page 40 / 287 25 / 70 and allows the shell composition to retain its mechanical strength. It is also believed that this allows for the inhibition of premature release of soft gel capsules (which include the aforementioned pH-dependent coating composition) without having to subject the soft gel capsule to prolonged curing (e.g., at about 40°C for 4-5 days). This benefit can be observed even in soft gel capsules where the pH-dependent shell composition includes non-amidated pectin. This benefit can also be seen in soft gel capsules where the pH-dependent shell composition does not include a stabilizer / binder, such as gellan gum.It is also believed that methacrylic acid-ethyl acrylate copolymers (and other suitable acrylate polymers as appreciated by those skilled in the art) in combination with pectin extend the pH-dependent performance of the shell composition and correspondingly of the soft gel capsule (e.g., by extending the durability of soft gel capsules at higher pH values ​​and allowing targeted release of the filling material at a target site within the gastrointestinal tract).

[0071] In one embodiment, the synthetic polymer is Kollicoat MAE100P, which is a methacrylic acid-ethyl acrylate copolymer (1:1). This synthetic polymer can be chosen, in certain embodiments, provided that it is already pre-neutralized and does not require the addition of a base (such as ammonia) to neutralize or solubilize the polymer during processing.

[0072] In certain embodiments, the amount of synthetic polymer in the pH-dependent shell compositions described herein is from about 0.5% by weight to about 10% by weight, from about 1% by weight to about 5% by weight, from about 1.5% by weight to about 4% by weight, or from about 2% by weight to about 3% by weight, or Petition 870260022436, dated 06 / 03 / 2026, p. 41 / 287 26 / 70 any single value, or subrange thereof, based on the total weight of the dry capsule shell composition.

[0073] The synthetic polymer is believed to function as a sealant, without being interpreted as limiting, to stop / inhibit the infiltration of a capsule sealing filler material.

[0074] In certain embodiments, any of the pH-dependent shell compositions described herein may further include an organic acid. Suitable organic acids include lactic acid, tannic acid, citric acid, acetic acid, or a combination thereof. In one embodiment, the organic acid in the pH-dependent shell composition comprises lactic acid. In one embodiment, the organic acid in the pH-dependent shell composition comprises tannic acid. In one embodiment, the organic acid in the pH-dependent shell composition comprises both lactic acid and tannic acid.

[0075] In certain embodiments, the amount of organic acid in the pH-dependent shell compositions described herein is from about 0.1% by weight to about 8% by weight, from about 0.2% by weight to about 5% by weight, or from about 0.2% by weight to about 2% by weight, or any single value, or subrange, based on the total weight of the dry capsule shell composition.

[0076] It is believed that the organic acid(s), without being interpreted as limiting, facilitate the interaction between gelatin and pectin to form a more robust soft gel capsule.

[0077] In certain embodiments, the quantity of the various components (e.g., pectin, dextrose, gelatin, synthetic polymer, plasticizer, stabilizer / binder) and the ratio of the various components are adjusted to control the dissolution and / or disintegration properties of the soft gel capsule over various pH ranges.

[0078] For example, the gelatin to pectin ratio p:p in Petition 870260022436, dated 06 / 03 / 2026, page 42 / 287 27 / 70 pH-dependent casing composition can vary from about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1 or about 9:1 to any of 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 therein.In certain embodiments, lower w:w gelatin to pectin ratios provide a pH-dependent shell composition that is more stable (dissolves / disintegrates more slowly, if at all) in an acidic medium (e.g., 0.1 N HCl optionally with pepsin, pH adjusted with phosphate buffer, sodium hydroxide, or potassium hydroxide), while higher w:w gelatin to pectin ratios provide a pH-dependent shell composition that is less stable (dissolves / disintegrates more rapidly) in an acidic medium (e.g., 0.1 N HCl optionally with pepsin, pH adjusted with phosphate buffer, sodium hydroxide, or potassium hydroxide). The w:w gelatin to pectin ratio can be adjusted to achieve a specific dissolution / disintegration time for the soft gel capsule in an acidic medium with a certain pH (e.g., at least about 15 minutes, at least about 30 minutes, at least about 45 minutes).at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes at a pH of 1.2, 2, 3, 4, 5, 6 or a subrange, and so on) and / or a particular dissolution / disintegration time for the soft gel capsule in buffered medium with a given pH (for example, up to about 5 minutes, up to about 10 minutes, up to about 20 minutes, up to about 30 minutes, up to about 45 minutes, or up to about 60 minutes in a biological, artificial or simulated duodenal environment and / or intestinal fluid, such as pH 6.8 phosphate buffer, sodium hydroxide buffer or potassium hydroxide buffer, optionally with PancreaPetition 870260022436, dated 06 / 03 / 2026, page. 28 / 70 tub.

[0079] The w:w ratio of gelatin to plasticizer in the pH-dependent shell composition can also be adjusted to achieve a given level of capsule hardness and can vary from about 5:1 to about 1:5, from about 4:1 to about 1:4, from about 3:1 to about 1:3, from about 2:1 to about 1:2, about 1:1, or any single ratio value or subrange.

[0080] In certain embodiments, the w:w ratio of pectin to stabilizer and / or binder (e.g., gellan gum) is from about 1:10 to about 50:1; from about 1:5 to about 40:1; from about 1:1 to about 25:1 or from about 10:1 to about 24:1, or any single ratio value or subrange.

[0081] In certain embodiments, the w:w ratio of synthetic polymer to pectin in the pH-dependent shell composition is from about 3:1 to about 1:20, from about 3:1 to about 1:15, from about 3:1 to about 1:10, from about 2:1 to about 1:5, from about 2:1 to about 1:3, about 1:1 or any single ratio value or subrange therein.

[0082] In certain embodiments, the w:w ratio of synthetic polymer to gelatin in the pH-dependent shell composition is from about 1:3 to about 1:100, from about 1:3 to about 1:50, from about 1:3 to about 1:25, from about 1:3 to about 1:20, from about 1:3 to about 1:15, from about 1:3 to about 1:10, or from about 1:3 to about 1:5, or any single ratio value or subrange.

[0083] In certain embodiments, the w:w ratio of organic acid to pectin in the pH-dependent envelope composition is from about 2:1 to about 1:60, from about 2:1 to about 1:40, from about 2:1 to about 1:20, from about 2:1 to about 1:15, from about 2:1 to about 1:10, from about 1:1 to about 1:5, or any single ratio value or subrange contained therein. Petition 870260022436, dated 06 / 03 / 2026, p. 44 / 287 29 / 70

[0084] In certain embodiments, the w:w ratio of organic acid to gelatin in the pH-dependent shell composition is about 1:15 to about 1:250, about 1:15 to about 1:200, about 1:15 to about 1:150, about 1:15 to about 1:100, about 1:20 to about 1:75, about 1:20 to about 1:50, or about 1:30 to about 1:50, or any single ratio value or subrange.

[0085] In certain embodiments, soft gel capsules made using the pH-dependent shell compositions described herein may have a hardness ranging from about 5 N, about 6 N, about 7 N, about 8 N, about 9 N, or about 10 N to any 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. The force required to cause a 2.0 mm deformation of the capsule in Newtons is defined as the capsule hardness.

[0086] In certain embodiments, soft gel capsules made using the pH-dependent shell compositions described herein may have a shell moisture content ranging from about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% to about 11%, about 12%, about 13%, about 14%, or about 15%. The shell moisture content is determined by loss in the drying method. A 1-2 gram sample of pH-dependent capsule shell composition is placed in an oven at 105°C for 17 hours. The initial weight of the sample is recorded. After drying the sample in 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 equation below, is defined as the shell moisture content: % loss of (initial weight) (final weight) weight=-------------------------- 100% (initial weight)

[0087] In certain embodiments, the casing compositions of Petition 8702600204.30, dated 6 / 03 / 2026, p. 36 / 287 The pH 30 / 70 pendants described herein may have an equilibrium relative humidity ranging from about 25%, about 28%, about 30%, about 32%, about 34%, or about 35% to about 38%, about 40%, about 42%, about 45%, or about 50%. Equilibrium Relative Humidity (%) is defined as the humidity condition in which the capsule maintained a constant total weight. It is determined using environmental chambers maintained at constant humidity using saturated saline solutions.

[0088] In certain embodiments, soft gel capsules made using the pH-dependent shell compositions described herein may have a burst strength ranging from about 50 kg, about 60 kg, about 70 kg, about 80 kg or about 90 kg to about 100 kg, about 110 kg, about 120 kg, about 130 kg, about 140 kg or about 150 kg. The burst strength is determined using a texture analyzer. The texture analyzer compressed the capsule until the capsule burst. The force, in kilograms, required to make the capsule burst is defined as the burst strength.

[0089] In one embodiment, the pH-dependent shell composition and the pH-dependent soft gel capsule may be free or substantially free of a pH-dependent top coating on the soft gel capsule shell.

[0090] In one embodiment, the pH-dependent shell composition and the pH-dependent soft gel capsule may include divalent cationic salts, such as Ca++ (e.g., CaCl2) or Mg++ (e.g., MgCl2). In another embodiment, the pH-dependent shell composition and the pH-dependent soft gel capsule may be free or substantially free of divalent cationic 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 cationic salts. Petition 870260022436, dated 06 / 03 / 2026, page 46 / 287 31 / 70 as Ca++ (e.g., CaCl2) or Mg++ (e.g., MgCl2) in addition to a quantity of divalent cationic salts that may be present in other components.

[0091] In one embodiment, the pH-dependent shell composition may optionally comprise additional agents such as stabilizers or binders (e.g., gellan gum), coloring agents, flavoring agents, sweetening agents, fillers, antioxidants, diluents, pH modifiers, or other pharmaceutically acceptable excipients or additives such as synthetic colorants and mineral oxides.

[0092] Examples of suitable coloring agents may include, but are not limited to, colors such as, for example, white, black, yellow, blue, green, pink, red, orange, violet, indigo, and brown. In specific embodiments, the color of the dosage form may indicate the content (e.g., one or more active ingredients) contained therein.

[0093] Suitable flavoring agents may include, but are not limited to, flavor extracts obtained by extracting a portion of a raw material, for example, animal or vegetable material, generally using a solvent such as ethanol or water; natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from whole plants.

[0094] Additional exemplary flavoring agents that may be in dosage form may include, but are not limited to, breath-freshening compounds such as menthol, peppermint and cinnamon, coffee beans, other flavors or fragrances such as fruit flavors (e.g., cherry, orange, grape, etc.), especially those used for oral hygiene, as well as actives used in dental and oral hygiene, such as quaternary ammonium bases. The effect of the flavors may be enhanced by using flavor enhancers such as tartaric acid, Petition 870260022436, dated 06 / 03 / 2026, page 48 / 287 32 / 70 of citrus, vanillin or similar.

[0095] Examples of sweetening agents may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof. Artificial sweeteners include, for example, acesulfame and its various salts, such as the potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salt (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as the sodium salt (available as Sweet'N Low®), stevia, chlorine derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®), and mogrosides.Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); Stevia rebaudiana (Stevioside), natural intensive sweeteners such as Lo Han Kuo, polyols such as sorbitol, or sorbitan solution, mannitol, xylitol, erythritol and the like.

[0096] In one embodiment, the pH-dependent shell composition comprises: (a) gelatin, (b) dextrose, (c) a pH-dependent polymer (e.g., pectin, such as a low-methoxyl pectin), (d) from about 0.5% by weight to about 10% by weight of a synthetic polymer, based on the total weight of the dry pH-dependent shell composition, (e) optionally an organic acid, (f) optionally a plasticizer (e.g., glycerin, sorbitol or sorbitol sorbitan solution and combinations thereof), and optionally (g) a stabilizer and / or binder (e.g., gellan gum). The amounts and w / w ratios of these components may conform to any of the values ​​or ranges described above.

[0097] In one embodiment, the composition of the enclosure depends Petition 870260022436, dated 06 / 03 / 2026, page 48 / 287 33 / 70 pH dependent shell composition consists essentially of: (a) gelatin, (b) dextrose, (c) a pH dependent polymer (e.g., pectin, such as a low methoxyl pectin), (d) from about 0.5% by weight to about 10% by weight of a synthetic polymer, based on the total weight of the dry pH dependent shell composition, (e) optionally an organic acid, (f) optionally a plasticizer (e.g., glycerin, sorbitol or sorbitol sorbitan solution and combinations thereof) and optionally (g) a stabilizer and / or binder (e.g., gellan gum). The amounts and w / w ratios of these components may conform to any of the values ​​or ranges described above.

[0098] In one embodiment, the pH-dependent shell composition consists of: (a) gelatin, (b) dextrose, (c) a pH-dependent polymer (e.g., pectin, such as a low-methoxyl pectin), (d) from about 0.5% by weight to about 10% by weight of a synthetic polymer, based on the total weight of the dry pH-dependent shell composition, (e) optionally an organic acid, (f) optionally a plasticizer (e.g., glycerin, sorbitol or sorbitol sorbitan solution and combinations thereof), and optionally (g) a stabilizer and / or binder (e.g., gellan gum). The amounts and w / w ratios of these components may conform to any of the values ​​or ranges described above. Dissolution and Disintegration

[0099] Reference to a dissolution or dissolution test throughout this disclosure refers to results of tests performed with a USP II Apparatus with paddles from about 50 RPM to about 250 RPM, from about 500 mL to any of about 900 mL of 0.1 N HCl acid medium adjusted to pH 1.2, 2.0, 3.0, 4.0, 5.0 and 6.0 with phosphate buffer solution, sodium hydroxide solution or potassium hydroxide solution (also referred to as “Stage Petition 870260022436, dated 06 / 03 / 2026, p. 39 / 287 34 / 70 (Acid). After two hours, phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution is added to adjust the pH to 6.8 (also known as “pH 6.8 buffer”). The term dissolve in relation to the performance of the soft gel capsule and / or shell composition in a two-stage dissolution test may be used interchangeably with the term rupture. The two-stage dissolution test may also be referred to herein as a two-stage enteric dissolution test or as an enteric dissolution test.

[00100] Reference to a disintegration or disintegration test throughout this disclosure refers to test results performed with a USP disintegration apparatus of approximately 500 mL to approximately 900 mL of 0.1 N HCl acid medium adjusted to pH 1.2, 2.0, 3.0, 4.0, 5.0, and 6.0 phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution (also referred to as the “Acid Stage”). After two hours, phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution is added to adjust the pH to 6.8 (also known as the “pH 6.8 buffer”). The term disintegrate in relation to the performance of the soft gel capsule and / or shell composition in a two-stage disintegration test may be used interchangeably with the term rupture. The two-stage disintegration test may also be referred to in this document as a two-stage enteric disintegration test or simply as an enteric disintegration test.

[00101] In certain embodiments, the casing composition does not dissolve at a pH of 1.2 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP II apparatus with paddles at any one time from about 50 RPM to any one time from about 250 RPM at any one time from about Petition 870260022436, dated 06 / 03 / 2026, p. 40 / 287 35 / 70 of 500 mL to any of approximately 900 mL of acidic medium (0.1 N HCl adjusted to pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00102] In certain embodiments, the shell composition does not dissolve at a pH of 1.2 for a period of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP II apparatus with paddles at about 50 RPM to about 250 RPM from about 500 mL to about 900 mL of pH-adjusted 0.1N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00103] In certain embodiments, the composition of the casing does not dissolve at a pH of 1.2 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP II Apparatus with paddles at about 50 RPM to about 250 RPM from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00104] In certain embodiments, the shell composition does not disintegrate at a pH of 1.2 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00105] In certain embodiments, the composition of the envelope does not disintegrate at a pH of 1.2 for a period of at least about 15 minutes, at least about 30 minutes, at least about 45 Petition 870260022436, dated 06 / 03 / 2026, p. 41 / 287 36 / 70 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of 0.1 N HCl acid medium adjusted for pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00106] In certain embodiments, the shell composition does not disintegrate at a pH of 1.2 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP disintegration apparatus from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00107] In certain embodiments, the composition of the casing does not dissolve at a pH between 1.2 and 2 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP II apparatus with paddles at any one speed from about 50 RPM to any one speed from about 250 RPM in any one speed from about 500 mL to any one speed from about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00108] In certain embodiments, the shell composition does not dissolve at a pH between 1.2 and 2 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., when measured with a USP II Apparatus with paddles from about 50 RPM to about 250 RPM in any of about 500 mL to any of about 900 mL 0.1N HCl acidic medium adjusted pa Petition 870260022436, dated 06 / 03 / 2026, p. 43 / 287 37 / 70 pH with phosphate buffered solution, sodium hydroxide solution, or potassium hydroxide solution).

[00109] In certain embodiments, the shell composition does not dissolve at a pH between 1.2 and 2 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP II Apparatus with paddles at either about 50 RPM to either about 250 RPM in either about 500 mL to either about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00110] In certain embodiments, the shell composition does not disintegrate at a pH between 1.2 and 2 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to any of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00111] In certain embodiments, the shell composition does not disintegrate at a pH between 1.2 and 2 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00112] In certain embodiments, the composition of the envelope does not disintegrate at a pH between 1.2 and 2 for a period of approximately 15 minutes. Petition 870260022436, dated 06 / 03 / 2026, p. 43 / 287 38 / 70 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of 0.1 N HCl acid medium adjusted for pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00113] In certain embodiments, the composition of the casing does not dissolve at a pH every 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP II apparatus with paddles at any one from about 50 RPM to any one from about 250 RPM in any one from about 500 mL to any one from about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00114] In certain embodiments, the composition of the casing does not dissolve at a pH of 2 for a period of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP II apparatus with paddles at about 50 RPM to about 250 RPM from about 500 mL to about 900 mL of pH-adjusted 0.1N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00115] In certain embodiments, the composition of the casing does not dissolve at a pH of 2 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP II Apparatus with paddles at about 50 RPM to about 250 RPM from about 500 mL to about 900 mL of acidic medium 0.1 N HCl adjusted to pH with phosphate buffer solution, solution of hyPetition 870260022436, 06 / 03 / 2026, p. 39 / 70 sodium hydroxide or potassium hydroxide solution).

[00116] In certain embodiments, the composition of the shell does not disintegrate at a pH every 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to about 900 mL of acidic 0.1 N HCl medium adjusted to pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00117] In certain embodiments, the shell composition does not disintegrate at a pH of 2 for a period of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00118] In certain embodiments, the shell composition does not disintegrate at a pH of 2 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP disintegration apparatus from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00119] In certain embodiments, the casing composition does not dissolve at a pH between 2 and 3 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (e.g., when measured with a USP II apparatus with paddles at any one of about 50 RPM to any one of about 250 RPM at any one of about Petition 870260022436, dated 06 / 03 / 2026, p. 46 / 287 40 / 70 of 500 mL to any of about 900 mL of acidic medium (0.1 N HCl adjusted to pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00120] In certain embodiments, the shell composition does not dissolve at a pH between 2 and 3 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP II Apparatus with paddles at about 50 RPM to about 250 RPM in any of about 500 mL to any of about 900 mL of pH-adjusted 0.1N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00121] In certain embodiments, the shell composition does not dissolve at a pH between 2 and 3 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP II Apparatus with paddles at either about 50 RPM to either about 250 RPM in either about 500 mL to either about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00122] In certain embodiments, the shell composition does not disintegrate at a pH between 2 and 3 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to any of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00123] In certain forms, the composition of the casing does not Petition 870260022436, dated 06 / 03 / 2026, p. 46 / 287 41 / 70 disintegrates at a pH between 2 and 3 over a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate-buffered solution, sodium hydroxide solution, or potassium hydroxide solution).

[00124] In certain embodiments, the shell composition does not disintegrate at a pH between 2 and 3 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to any of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00125] In certain embodiments, the composition of the casing does not dissolve at a pH every 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP II apparatus with paddles at any one from about 50 RPM to any one from about 250 RPM in any one from about 500 mL to any one from about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00126] In certain embodiments, the composition of the casing does not dissolve at a pH of 3 for a period of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured Petition 870260022436, dated 06 / 03 / 2026, p. 47 / 287 42 / 70 of a USP II apparatus with paddles from approximately 50 RPM to approximately 250 RPM, from approximately 500 mL to approximately 900 mL of acidic medium (0.1 N HCl) adjusted for pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00127] In certain embodiments, the composition of the casing does not dissolve at a pH of 3 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP II Apparatus with paddles at about 50 RPM to about 250 RPM from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00128] In certain embodiments, the composition of the shell does not disintegrate at a pH every 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to about 900 mL of acidic 0.1 N HCl medium adjusted to pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00129] In certain embodiments, the shell composition does not disintegrate at a pH of 3 for a period of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00130] In certain embodiments, the composition of the envelope does not disintegrate at a pH of 3 for a period of approximately 15 minutes. Petition 870260022436, dated 06 / 03 / 2026, p. 48 / 287 43 / 70 approximately 360 minutes, approximately 30 minutes to approximately 240 minutes, or approximately 45 minutes to approximately 180 minutes (for example, when measured with a USP disintegration apparatus from approximately 500 mL to approximately 900 mL of 0.1 N HCl acid medium adjusted for pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00131] In certain embodiments, the composition of the casing does not dissolve at a pH between 3 and 4 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP II apparatus with paddles at any one from about 50 RPM to any one from about 250 RPM in any one from about 500 mL to any one from about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00132] In certain embodiments, the shell composition does not dissolve at a pH of 1.2 for a period of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP II apparatus with paddles at about 50 RPM to about 250 RPM from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00133] In certain embodiments, the shell composition does not dissolve at a pH between 3 and 4 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (e.g., when measured with a USP II Apparatus with paddles at either about 50 RPM to either about 250 RPM in either about 500 mL to either about 900 mL of acidic medium). Petition 870260022436, dated 06 / 03 / 2026, p. 49 / 287 44 / 70 0.1 N HCl adjusted to pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution.

[00134] In certain embodiments, the shell composition does not disintegrate at a pH between 3 and 4 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to any of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00135] In certain embodiments, the shell composition does not disintegrate at a pH between 3 and 4 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00136] In certain embodiments, the shell composition does not disintegrate at a pH between 3 and 4 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00137] In certain embodiments, the composition of the casing does not dissolve at a pH every 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes or 120 minutes (for example, when measured with Petition 870260022436, dated 06 / 03 / 2026, p. 60 / 287 45 / 70 a USP II apparatus with paddles at either about 50 RPM to either about 250 RPM in either about 500 mL to either about 900 mL of acidic medium (0.1 N HCl adjusted for pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00138] In certain embodiments, the composition of the casing does not dissolve at a pH of 4 for a period of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP II apparatus with paddles at about 50 RPM to about 250 RPM from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00139] In certain embodiments, the composition of the casing does not dissolve at a pH of 4 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP II Apparatus with paddles at about 50 RPM to about 250 RPM from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00140] In certain embodiments, the composition of the shell does not disintegrate at a pH every 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to about 900 mL of acidic 0.1 N HCl medium adjusted to pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00141] In certain forms, the composition of the casing does not Petition 870260022436, dated 06 / 03 / 2026, p. 61 / 287 46 / 70 disintegrates at a pH of 4 over a period of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate-buffered solution, sodium hydroxide solution, or potassium hydroxide solution).

[00142] In certain embodiments, the shell composition does not disintegrate at a pH of 4 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP disintegration apparatus from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00143] In certain embodiments, the composition of the casing does not dissolve at a pH between 4 and 5 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP II apparatus with paddles at any one from about 50 RPM to any one from about 250 RPM in any one from about 500 mL to any one from about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00144] In certain embodiments, the shell composition does not dissolve at a pH between 4 and 5 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., when measured with a USP II apparatus with paddles of about 50 Petition 870260022436, dated 06 / 03 / 2026, p. 62 / 287 47 / 70 RPM at approximately 250 RPM in either approximately 500 mL to approximately 900 mL of 0.1N HCl acidic medium adjusted to pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution.

[00145] In certain embodiments, the shell composition does not dissolve at a pH between 4 and 5 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP II Apparatus with paddles at either about 50 RPM to either about 250 RPM in either about 500 mL to either about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00146] In certain embodiments, the shell composition does not disintegrate at a pH between 4 and 5 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to any of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00147] In certain embodiments, the shell composition does not disintegrate at a pH between 4 and 5 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution). Petition 870260022436, dated 06 / 03 / 2026, p. 63 / 287 48 / 70

[00148] In certain embodiments, the shell composition does not disintegrate at a pH between 4 and 5 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00149] In certain embodiments, the shell composition does not dissolve at a pH of 5 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP II apparatus with paddles at any of about 50 RPM to any of about 250 RPM in any of about 500 mL to any of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00150] In certain embodiments, the shell composition does not dissolve at a pH of 5 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP II Apparatus with paddles at about 50 RPM to about 250 RPM from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00151] In certain embodiments, the composition of the casing does not dissolve at a pH of 5 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (e.g., when measured with a USP II apparatus with paddles at about 50 RPM to about 250 Petition 870260022436, dated 06 / 03 / 2026, p. 64 / 287 49 / 70 RPM of approximately 500 mL to approximately 900 mL of acidic medium (0.1 N HCl) adjusted for pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution.

[00152] In certain embodiments, the shell composition does not disintegrate at a pH every 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00153] In certain embodiments, the shell composition does not disintegrate at a pH of 5 for a period of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00154] In certain embodiments, the shell composition does not disintegrate at a pH of 5 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP disintegration apparatus from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00155] In certain embodiments, the composition of the casing does not dissolve at a pH between 5 and 6 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes or 120 minutes (for example, when measured Petition 870260022436, dated 06 / 03 / 2026, p. 66 / 287 50 / 70 with a USP II apparatus with paddles at either of about 50 RPM to either of about 250 RPM in either of about 500 mL to either of about 900 mL of acidic medium (0.1 N HCl adjusted for pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00156] In certain embodiments, the shell composition does not dissolve at a pH between 5 and 6 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP II Apparatus with paddles from about 50 RPM to about 250 RPM in any of about 500 mL to any of about 900 mL 0.1N HCl acidic medium adjusted to pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00157] In certain embodiments, the shell composition does not dissolve at a pH between 5 and 6 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP II Apparatus with paddles at either about 50 RPM to either about 250 RPM in either about 500 mL to either about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00158] In certain embodiments, the shell composition does not disintegrate at a pH between 5 and 6 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to any of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate-buffered solution, solu Petition 870260022436, dated 06 / 03 / 2026, p. 66 / 287 51 / 70 (sodium hydroxide or potassium hydroxide solution).

[00159] In certain embodiments, the shell composition does not disintegrate at a pH between 5 and 6 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00160] In certain embodiments, the shell composition does not disintegrate at a pH between 5 and 6 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00161] In certain embodiments, the shell composition does not dissolve at a pH of 6 in 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP II apparatus with paddles at any of about 50 RPM to any of about 250 RPM in any of about 500 mL to any of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00162] In certain embodiments, the composition of the casing does not dissolve at a pH of 6 for a period of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes. Petition 870260022436, dated 06 / 03 / 2026, p. 68 / 287 52 / 70 tos, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP II apparatus with paddles from about 50 RPM to about 250 RPM from about 500 mL to about 900 mL of 0.1N HCl acid medium adjusted for pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00163] In certain embodiments, the composition of the casing does not dissolve at a pH of 6 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP II Apparatus with paddles at about 50 RPM to about 250 RPM from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00164] In certain embodiments, the composition of the shell does not disintegrate at a pH every 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to about 900 mL of acidic 0.1 N HCl medium adjusted to pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00165] In certain embodiments, the shell composition does not disintegrate at a pH of 6 for a period of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (for example, when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution). Petition 870260022436, dated 06 / 03 / 2026, p. 68 / 287 53 / 70

[00166] In certain embodiments, the shell composition does not disintegrate at a pH of 6 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP disintegration apparatus from about 500 mL to about 900 mL of pH-adjusted 0.1 N HCl acid medium with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00167] In certain embodiments, the composition of the envelope does not dissolve at a lower pH. 8.1, less than 8.0, less 7.6, less than 7.5, less 7.1, less than 7.0, less than 8.4, less than8.3, to 7.9, less than7.8, to 7.4, less than7.3, to 6.9, less than6.8, less than 8.2, less than less than 7.7, less than less than 7.2, less than less than 6.7, less than 6.6, less than 6.5, less than 6.4, less than 6.3, less than 6.2, less than6.1, less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5, less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, less than 4.8, less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, less than 4.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3 or less than 1.2 for a period of time of at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes or at least 120 minutes (for example,when measured with a USP II apparatus with paddles at either of about 50 RPM to either of about 250 RPM at either of, Petition 870260022436, dated 06 / 03 / 2026, p. 59 / 287 54 / 70 approximately 500 mL to any of approximately 900 mL of acidic medium (0.1 N HCl adjusted to pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00168] In certain embodiments, the composition of the envelope does not dissolve at a lower pH. 8.1, less than 8.0, less 7.6, less than 7.5, less 7.1, less than 7.0, less than 8.4, less than8.3, to 7.9, less than7.8, to 7.4, less than7.3, to 6.9, less than6.8, less than 8.2, less than less than 7.7, less than less than 7.2, less than less than 6.7, less than 6.6, less than 6.5, less than 6.4, less than 6.3, less than 6.2, less than 6.1, less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5, less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, less than 4.8, less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, less than 4.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, or less than 1.2 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example,when measured with a USP II apparatus with paddles of any speed from about 50 RPM to any speed of about 250 RPM in any volume from about 500 mL to any volume of about 900 mL of acidic medium (0.1 N HCl adjusted for pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00169] In certain embodiments, the composition of the casing does not disintegrate at a pH lower than 8.4, lower than 8.3, lower than 8.2, lower than 8.1, lower than 8.0, lower than 7.9, lower than 7.8, lower than 7.7, lower than Petition 870260022436, dated 00 / 03 / 2026, p. 60 / 287 55 / 70 7.6, less than 7.5, less than 7.4, less than 7.3, less than 7.2, less than 7.1, less than 7.0, less than 6.9, less than 6.8, less than 6.7, less than 6.6, less than 6.5, less than 6.4, less than 6.3, less than 6.2, less than 6.1, less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5, less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, less than 4.8, less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, less than 4.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, or less than 1.2 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., when measured with a USP disintegration apparatus in any one of about 500 mL to any one of about 900 mL of acidic medium). 0.1 N HCl adjusted to pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution.

[00170] In certain embodiments, the composition of the envelope does not disintegrate at a pH lower than 8.4, lower than 8.3, lower than 8.2, lower than 8.1, less than 7.6, less than 7.1, less than 8.0, less than 7.5, less than 7.0, less than 7.9, less than 7.4, less than 6.9, less than 7.8, less than 7.3, less than 6.8, less than 7.7, less than 7.2, less than 6.7, less than 6.6, less than 6.5, less than 6.4, less than 6.3, less than 6.2, less than 6.1, less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5, less than 5.4, less than 5.3, less than 5.2, less than 5.1. less than 5.0, less than 4.9, less than 4.8, less than 4.7, Petition 870260022436, dated 06 / 03 / 2026, page 61 / 287 56 / 70 less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, less than 4.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less of 1.4, less than 1.3 or less than 1.2 for a period of about 15 minutes to about 360 minutes, about 30 minutes to about 240 minutes, or about 45 minutes to about 180 minutes (for example, when measured with a USP disintegration apparatus in any of about 500 mL to about 900 mL of 0.1 N HCl acid medium adjusted for pH with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution).

[00171] By virtue of the present invention, the appropriate pH for dissolving and / or disintegrating and / or breaking down the shell composition and releasing the filler material can be selected to program the release of the active agent to inhibit premature release of the active agent in acidic portions of the gastrointestinal tract (e.g., gastric environment where the pH is between 1.2 and 3.5) and instead release the active agent in the intended portion of the gastrointestinal tract. For example, the duodenum has a typical pH ranging from 7.0 to 8.5; the small and large intestines typically have a pH of 4.0 to 7.0; the colon has a typical pH of 6.5 and the jejunum has a typical pH of 6.1 to 7.2. In one embodiment, the shell composition can be adjusted to direct the release of the active agent in the duodenum at a pH of about 7.0 to about 8.5.In one embodiment, the composition of the shell can be adjusted to direct the release of the active agent into the small and large intestines at a pH of about 4.0 to about 7.0. In another embodiment, the composition of the shell can... Petition 870260022436, dated 06 / 03 / 2026, page 63 / 287 57 / 70 can be adjusted to direct the release of the active agent in the colon at a pH of approximately 6.5. In one embodiment, the composition of the shell can be adjusted to direct the release of the active agent in the jejunum at a pH of approximately 6.1 to approximately 7.2.

[00172] In certain embodiments, the combination of pectin and methyl acrylic copolymer in pH-dependent shell compositions increases the capsule rupture threshold to pH 7.5 to 8.5, providing a means to distribute the active agent in the small intestine. Preparation method

[00173] The encapsulation of the filling material can be carried out in any conventional manner. As an example, a rotary die encapsulation can be used.

[00174] According to one embodiment, a pH-dependent soft gel capsule is prepared by a process comprising the steps of: (a) preparing the filling material, said filling material comprising at least one active agent; and (b) encapsulating the filling material of step (a) in a pH-dependent shell composition. The encapsulation process according to step (b) may further comprise a substep of preparing the pH-dependent shell composition, for example, by mixing a gelatin, dextrose, pectin, a synthetic polymer, optionally a plasticizer and optionally a stabilizer / binder. In one embodiment, the substep of preparing the pH-dependent shell composition includes, for example, mixing a gelatin, dextrose, pectin, an organic acid, optionally a plasticizer and optionally a stabilizer / binder.In one embodiment, the pH-dependent shell composition preparation substep includes, for example, mixing a gelatin, dextrose, pectin, a synthetic polymer, an organic acid, optionally a plasticizer, and optionally a... Petition 870260022436, dated 06 / 03 / 2026, page 63 / 287 58 / 70 stabilizer / binder.

[00175] The thickness of the pH-dependent wrapping composition tape (as used, for example, during rotary die encapsulation) can also be adjusted to control the pH-dependent dissolution profile of the final pH-dependent soft gel capsule. The thickness of the pH-dependent wrapping composition tape can vary, without limitation, from 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 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 therein.

[00176] In certain embodiments, the pH-dependent soft gel capsule (e.g., after encapsulation) may be dried and optionally cured. Curing of the soft gel capsule may be carried out at a temperature ranging from about 25°C to about 75°C, from about 25°C to about 70°C, from about 30°C to about 60°C, or from about 35°C to 50°C. The curing temperature should be high enough to enhance the delayed-release properties of the soft gel capsules, but not so high as to melt the soft gel capsule.

[00177] The curing time can vary from about 12 hours to about 168 hours, from about 18 hours to about 120 hours, from about 24 hours to about 72 hours, about 24 hours, about 48 hours, about 72 hours, or any subrange or single values ​​contained therein. In one embodiment, the curing of the soft gel capsule can be carried out at a temperature of about 40°C for about 24 hours. In one embodiment, the curing of the soft gel capsule can be carried out at a temperature of about 40°C for about 48 hours. In one embodiment, the curing of the soft gel capsule can be carried out at Petition 870260022436, dated 06 / 03 / 2026, p. 64 / 287 59 / 70 at a temperature of about 40°C for about 72 hours. In certain embodiments, curing can occur in the air (without any specific control as to nitrogen, oxygen or humidity content). In certain embodiments, curing can occur under inert conditions (e.g., in nitrogen).

[00178] In one embodiment, the process for preparing a pH-dependent soft gel capsule comprises, essentially consists of, or consists of a) preparing any of the filling materials described herein; b) encapsulating the filling material from step a) in any of the pH-dependent shell compositions described herein (e.g., via rotary die encapsulation); c) drying the encapsulated pH-dependent soft gel capsules (e.g., by drum drying or regular drying in a drumless basket); and optionally d) curing the pH-dependent soft gel capsule according to any of the curing conditions described herein.

[00179] In certain embodiments, drying is carried out at about 10°C to about 50°C, about 15°C to about 40°C, or about 20°C to about 35°C at a relative humidity of about 5% to about 40%, about 10% to about 30%, or about 15% to about 25%.

[00180] In certain embodiments, the reference to drying and curing must be distinguished here. The purpose of drying the delayed-release capsules described herein is to remove excess water from the delayed-release capsule immediately after encapsulation. Thus, the capsules will become physically stable. The purpose of curing the delayed-release soft gel capsules described herein is to enhance the delayed-release property of the delayed-release soft gel capsule. Therefore, the presence of a drying step is not the same as a curing step, and similarly, the presence of a curing step is not the same as a curing step. Petition 870260022436, dated 06 / 03 / 2026, page 66 / 287 60 / 70 of a curing step is not the same as a drying step.

[00181] In certain embodiments, the pH-dependent shell compositions described herein exhibit any of the delayed-release properties described herein (e.g., according to any of the dissolution or disintegration profiles described herein) without being cured. For example, in certain embodiments, the inclusion of the synthetic polymer may enhance the delayed-release properties of the soft gel capsule without the need for further curing of the soft gel capsule.

[00182] In certain embodiments, the process for preparing the soft gel capsules described herein may further include washing the soft gel capsule with an organic acid. Suitable organic acids include, without limitation, lactic acid, tannic acid, citric acid, acetic acid, or a combination thereof. In certain embodiments, washing the soft gel capsule with an organic acid further enhances the robustness of the soft gel capsule and its delayed-release properties (as evidenced by obtaining, for example, any one or more of the dissolution or disintegration release profiles described herein). Stability of the soft gel capsule

[00183] In certain embodiments, the delayed-release soft gel capsules with the pH-dependent shell compositions described herein are chemically and physically stable.

[00184] For example, its chemical stability can be evidenced by the content of the active agent in the filler material (e.g., content of fish oil constituents when the filler material includes fish oil). In certain embodiments, the content of the constituents of the filler material is substantially similar (or within specifications) after storage for up to 12 months, up to 6 months, up to 3 months, or up to 1 month (in Petition 870260022436, dated 06 / 03 / 2026, page 66 / 287 61 / 70 environmental conditions or under stress conditions of 40°C and 75% relative humidity for any of these durations) compared to the raw material before storage for the said duration.

[00185] In certain embodiments, the physical stability of delayed-release soft gel capsules can be evidenced by the capsule dissolution profile in acidic and buffered media. For example, the capsule dissolution profile in acidic and buffered media is substantially similar (or within specifications) 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 of these durations) compared to the capsule dissolution profile before storage.

[00186] The term substantially similar may refer to a particular value within about 30%, within about 25%, within about 20%, within about 15%, within about 10%, within about 5%, or within about 1% of a corresponding comparative value. The percentage being calculated based on the nominal value of the comparative value. For example, a dissolution time interval of 27 minutes to 33 minutes may be considered within 10% of the comparative dissolution time of 30 minutes.

[00187] In certain embodiments, the pH-dependent shell composition described herein produces a robust delayed-release soft gel capsule that exhibits little or no premature release of the filler material in an acidic environment (e.g., stomach environment). For example, the delayed-release soft gel capsules described in this document may release up to about 10% by weight, up to about 9% by weight, up to about 8% by weight, up to about 7% by weight, up to about 6% by weight, up to about Petition 870260022436, dated 06 / 03 / 2026, page 67 / 287 62 / 70 from 5% by weight, up to about 4% by weight, up to about 3% by weight, up to about 1% by weight or 0% by weight of the filler material based on the total weight of the filler material in the acid stage after exposure to the acid stage (e.g., as defined for the dissolution tests or disintegration tests described herein) for 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. EXAMPLES

[00188] The specific embodiments of the invention will now be demonstrated by reference to the following examples. It should be understood that these examples are disclosed only to illustrate the invention and should not be taken in any way to limit the scope of the present invention. EXAMPLE 1 - Addition of Synthetic Polymer Sealant to Wet Gel Mass to Inhibit Premature Release in Acid Stage

[00189] A pH-dependent shell composition having the dry shell composition of Table 1 was prepared. Table 1 - Dry casing composition of a pH-dependent casing composition including a synthetic polymer (compositions from batches 20MC-59A and 20MC-59B) INGREDIENT by weight (based on the total weight of the dry casing composition) Gelatin 40 - 65 Glycerin 25 - 55 Pectin 6 - 15 Synthetic Polymer (Kollicoat MAE100P) 0.5 - 10 Gellan gum 0.1 - 2 Dextrose 0.01- 0.5 Water 6-15 Total 100 Petition 870260022436, dated 06 / 03 / 2026, page 68 / 287 63 / 70 [000190] The synthetic polymer used in this example, Kollicoat MAE100P, an ethyl methacrylate copolymer (1:1), functioned as a sealant to prevent the seepage of filler materials from the capsule seals. [000191] Fish oil and polyethylene glycol 400 were encapsulated in pH-dependent shell compositions having the dry shell composition of Table 1 and dried. After drying, the soft gel capsules were subjected to a two-stage dissolution test performed in a USP II apparatus with a paddle at 50 RPM, where in the first stage, the soft gel capsules were in an acidic stage (0.1 N HCl) for two hours (120 minutes), and in the second stage, the soft gel capsules were in a buffer stage (pH 6.8 buffer). The results are summarized in Table 2. Table 2 - Results of the Two-Stage Dissolution Test on Soft Gel Capsules with pH-Dependent Shell Composition from Table 1 Not much Filling Dissolution T0 @ 50 RPM 0.1 N HCl Buffer pH 6.8 20MC-59A Fish oil Intact for 120 minutes (no premature releases) Rupture in 4 minutes 20MC-59B Polyethylene glycol 400 Intact for 120 minutes (no premature releases) Rupture in 8 minutes [000192] Fish oil soft gel capsules (Lot No. 20MC59A), before aging (T0) and after aging for 3 months at 40°C and 75% relative humidity (T3), were also subjected to two-stage dissolution with a rowing speed of 100 RPM (all other dissolution test conditions being the same as the results described in Table 2). The gel capsules Petition 870260022436, dated 06 / 03 / 2026, p. 69 / 287 64 / 70 soft cells also remained intact for 120 minutes in 0.1 N HCl and broke down in pH 6.8 buffer (Table 3). Table 3 - Two-Stage Dissolution Test Result in Soft Gel Capsules with pH-Dependent Shell Composition from Table 1 with Fish Oil (Lot 20MC-59A) Not very filling. Dissolution T0 at 100 RPM 0.1 N HCl pH 6.8 buffer 20MC-59A Fish oil Intact for 120 minutes (no premature releases) Rupture in 4 minutes. Dissolution T3 (40 °C / 75% RH) at 100 RPM 0.1 N HCl pH 6.8 buffer Intact for 120 minutes (no premature releases) Rupture in 8 minutes. [000193] Fish oil soft gel capsules (Lot No. 20MC59A), after aging for 3 months at 40°C and 75% relative humidity (T3), were also subjected to a two-stage disintegration test using a USP disintegration apparatus, where in the first stage, the soft gel capsules were in an acidic stage (0.1 N HCl) for one hour (60 minutes), and in the second stage, the soft gel capsules were in a buffer stage (pH 6.8 buffer). In the disintegration test, the capsules remained intact for 60 minutes and broke down in pH 6.8 buffer in 5 minutes (Table 4). Petition 870260022436, dated 06 / 03 / 2026, page 70 / 287 65 / 70 Table 4 - Result of the two-stage disintegration test on soft gel capsules with pH-dependent shell composition from Table 1 with fish oil filling (lot 20MC-59A), after aging for 3 months at 40°C / 75% RH (T3) Not very filling. Disintegration. 0.1 N HCl buffer pH 6.8. 20MC-59A fish oil. Intact for 60 minutes (no premature releases). Rupture in 5 minutes. [000194] In summary, pH-dependent shell compositions containing methacrylic acid-ethyl acrylate copolymer inhibited premature releases of filler materials during acid-stage dissolution, even without curing soft gel capsule shells. EXAMPLE 2 - Addition of Organic Acids in pH-Dependent Shell Composition [000195] Organic acids were added to wet gel masses of pH-dependent shell composition to facilitate the interaction between pectin and gelatin. Examples of organic acids that were tested were lactic acid and tannic acid. Table 5 shows a wet gel composition for a pH-dependent shell composition containing lactic acid. Table 5 - Dry casing composition of a pH-dependent casing composition including lactic acid (compositions from batches 20MC-58A and 20MC-58B) INGREDIENT by weight (based on the total weight of the dry wrapper composition) Gelatin 40 - 70 Glycerin 20 - 55 Pectin 6 - 16 Petition 870260022436, dated 06 / 03 / 2026, page 71 / 287 66 / 70 Lactic acid 0.2 - 2.0 Gellan gum 0.1 - 2 Dextrose 0.02- 2.0 Water 6-15 Total 100 [000196] Fish oil and polyethylene glycol 400 were encapsulated in pH-dependent shell compositions having the dry shell composition of Table 5 and dried. After drying, the soft gel capsules were subjected to a two-stage dissolution test performed in a USP II apparatus with a paddle at 50 RPM, where in the first stage, the soft gel capsules were in an acidic stage (0.1 N HCl) for two hours (120 minutes), and in the second stage, the soft gel capsules were in a buffer stage (pH 6.8 buffer). The results are summarized in Table 6. Table 6 - Results of the Two-Stage Dissolution Test on Soft Gel Capsules with pH-Dependent Shell Composition from Table 5 Not much filling. Dissolution. T0 @ 50 RPM. 0.1 N HCl. Buffer pH 6.8. 20MC-58a Fish oil. Premature release observed - capsules survived for 120 minutes. Rupture in 5 minutes. 20MC-58B Polyethylene glycol 400. Premature release observed - capsules survived for 120 minutes. Rupture in 6 minutes. [000197] Table 7 shows a dry casing composition for a pH-dependent casing composition containing tannic acid. Petition 870260022436, dated 06 / 03 / 2026, page 72 / 287 67 / 70 Table 7 - Dry casing composition of a pH-dependent casing composition including tannic acid (compositions from batches 20MC-65A and 20MC-65B) INGREDIENT by weight (based on the total weight of the dry wrapper composition) Gelatin 40 - 75 Glycerin 20 - 45 Pectin 6 - 16 Lactic acid 0.2 - 5 Gellan gum 0.3 - 2.5 Dextrose 0.01 - 2.0 Water 6-15 Total 100 [000198] Fish oil and polyethylene glycol 400 were encapsulated in pH-dependent shell compositions with the dry shell mass composition shown in Table 7 and dried. After drying, the soft gel capsules were subjected to a two-stage dissolution test performed in a USP II apparatus with a paddle at 50 RPM, where in the first stage, the soft gel capsules were in an acidic stage (0.1 N HCl) for two hours (120 minutes), and in the second stage, the soft gel capsules were in a buffer stage (pH 6.8 buffer). The results are summarized in Table 8. Table 8 - Results of the Two-Stage Dissolution Test on Soft Gel Capsules with pH-Dependent Shell Composition from Table 7 Not much filling. Dissolution T0 @ 50 RPM. 0.1 N HCl. Buffer pH 6.8. 20MC-65A Fish oil. Premature release observed - capsules survived for 120 minutes. Rupture in 3 minutes. Petition 870260022436, dated 06 / 03 / 2026, page 73 / 287 68 / 70 20MC-65B Polyethylene glycol 400 Premature release observed - capsules survived for 120 minutes Rupture in 4 minutes [000199] The addition of organic acids to pH-dependent shell compositions improved the robustness of the shell compositions and, correspondingly, of the soft gel capsule capsules. EXAMPLE 3 - pH-Dependent Washing of the Shell Composition with Organic Acids [000200] Newly manufactured fish oil capsules encapsulated using the gel mass shown in Table 5 were washed with lactic acid and allowed to dry. [000201] After drying, the capsules were subjected to two-stage dissolution tests performed on a USP Apparatus II with a paddle at 50 RPM, where in the first stage the soft gel capsules were in an acidic state (0.1 N HCl) for two hours (120 minutes), and in the second stage, the soft gel capsules were in a buffer state (pH 6.8 buffer). The results are summarized in Table 9. Table 9 - Results of the Two-Stage Dissolution Test on Soft Gel Capsules with pH-Dependent Shell Composition from Table 5 and Washed with Lactic Acid Not very filling. Dissolution T0 @ 50 RPM 0.1 N HCl Buffer pH 6.8 20MC-58A* Fish oil. Intact for 120 minutes (no premature release). Disrupted in 8 minutes. [000202] Treatment of pH-dependent shell compositions with organic acids facilitated the interaction between pectin and gelatin and inhibited its premature release. [000203] To simplify the explanation, the modalities of the methods of this disclosure are represented and described as a series of acts. However, acts in accordance with this disclosure may occur Petition 870260022436, dated 06 / 03 / 2026, p. 74 / 287 69 / 70 in various orders and / or simultaneously, and with other acts not presented and described herein. Furthermore, not all of the illustrated acts may be necessary to implement the methods according to the disclosed subject matter. Additionally, those skilled in the art will understand and appreciate that the methods can alternatively be represented as a series of interrelated states by means of a state or event diagram. [000204] In the preceding description, numerous specific details are presented, such as specific materials, dimensions, process parameters, etc., to provide a complete understanding of the present invention. The particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The words example or exemplar are used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as an example or exemplar should not necessarily be interpreted as preferential or advantageous in relation to other aspects or designs. Rather, the use of the words “example” or “exemplary” is intended to present concepts in a concrete manner. As used in this application, the term “or” is intended to mean an inclusive “or” rather than an exclusive “or.”That is, unless otherwise specified, or clear from the context, “X includes A or B” is intended to mean any of the natural inclusive permutations. 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 preceding instances. The reference throughout this descriptive report to a modality, certain modalities, or a modality means that a given feature, structure, or characteristic described in connection with the modality is included in at least one modality. Thus, the phrase “a modality,” “certain modalities,” or a modality appears in several places throughout this. Petition 870260022436, dated 06 / 03 / 2026, p. 76 / 287 70 / 70 descriptive reports do not necessarily refer to the same modality. [000205] The present invention has been described with reference to specific exemplary embodiments thereof. The descriptive report and drawings should therefore be considered in an illustrative and not restrictive sense. Various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

1. Delayed-release soft gel capsule, characterized in that it comprises: (a) a filling material; and (b) a pH-dependent shell composition; wherein the filling material comprises at least one active agent; wherein the pH-dependent shell composition comprises gelatin, pectin, dextrose and from 0.5% by weight to 10% by weight of a synthetic polymer, based on the total weight of the pH-dependent dry shell composition; and wherein the pH-dependent shell composition has a gelatin to pectin ratio w:w ranging from 6:1 to 20:

1.

2. Delayed-release soft gel capsule, characterized in that it comprises: (a) a filling material; and (b) a pH-dependent shell composition; wherein the filling material comprises at least one active agent; wherein the pH-dependent shell composition comprises gelatin, pectin, dextrose and an organic acid; and wherein the pH-dependent shell composition has a gelatin to pectin ratio w:w ranging from 6:1 to 20:

1.

3. Delayed-release soft gel capsule according to claim 1 or 2, characterized in that the pH-dependent shell composition further comprises a plasticizer.

4. Soft gel capsule with delayed release, according to Petition 870260022436, dated 06 / 03 / 2026, page 77 / 287 2 / 10, with any of claims 1 to 3, characterized in that the pectin is low methoxyl pectin.

5. Soft gel capsule with delayed release, according to any one of claims 1 to 4, characterized in that the pectin is selected from the group consisting of amidated pectin, non-amidated pectin and combinations thereof.

6. Delayed-release soft gel capsule according to any one of claims 1 to 5, characterized in that the pH-dependent shell composition comprises from 40% to 80% by weight, from 45% to 75% by weight, or from 45% to 65% by weight of a gelatin, based on the weight of the dry pH-dependent shell composition.

7. Delayed-release soft gel capsule according to any one of claims 1 to 6, characterized in that the pH-dependent shell composition comprises from 2% to 20% by weight, from 3% to 15% by weight, or from 7% to 15% by weight of pectin, based on the dry weight of the pH-dependent shell composition.

8. Delayed-release soft gel capsule according to any one of claims 1 to 7, characterized in that the pH-dependent shell composition comprises from 0.01% by weight to 4% by weight, from 0.05% by weight to 0.5% by weight, or from 0.1% by weight to 0.2% by weight of dextrose, based on the weight of the dry pH-dependent shell composition.

9. Delayed-release soft gel capsule according to claim 3, characterized in that the pH-dependent shell composition comprises from 15% to 40% by weight, from 20% to 35% by weight, or from 25% to 30% by weight of a plasticizer, based on the weight of the dry pH-dependent shell composition. Petition 870260022436, dated 06 / 03 / 2026, p. 78 / 287 3 / 10 10. Delayed-release soft gel capsule according to any one of claims 1 to 9, characterized in that the gelatin is selected from the group consisting of Type A gelatin, Type B gelatin and mixtures thereof.

11. Delayed-release soft gel capsule according to any one of claims 1 to 10, characterized in that the gelatin is selected from the group consisting of fish gelatin, skin gelatin, bone gelatin and mixtures thereof.

12. Soft gel capsule with delayed release, according to any one of claims 1 to 11, characterized in that the pectin is non-amidated pectin.

13. Delayed-release soft gel capsule according to claim 3, characterized in that the plasticizer is selected from the group consisting of glycerin, sorbitol and combinations thereof.

14. Delayed-release soft gel capsule according to claim 1, characterized in that the pH-dependent shell composition comprises from 1% by weight to 5% by weight, from 1.5% by weight to 4% by weight, or from 2% by weight to 3% by weight of a synthetic polymer, based on the weight of the dry pH-dependent shell composition.

15. Delayed-release soft gel capsule according to any one of claims 1 to 14, characterized in that the pH-dependent shell composition: does not dissolve in an acidic pH of 1.2, 2.0, 3.0, 4.0, 5.0, 6.0, or a subrange thereof, for at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, or at least 120 minutes, when measured with a USP II apparatus with paddles of about 50 RPM to 250 RPM, from 500 mL to 900 mL 0.1 N HCl, adjusted to the pH of the acidic stage. Petition 870260022436, dated 06 / 03 / 2026, p.70 / 287 4 / 10 with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution; and dissolves in a buffer pH above 6.5, above 6.8, above 7.0, above 7.5, above 8.0, or above 8.5 in up to 60 minutes, up to 45 minutes, up to 30 minutes, up to 15 minutes, or up to 10 minutes, when measured with a USP II apparatus with paddles of about 50 RPM to 250 RPM, from 500 mL to 900 mL of phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, adjusted to buffer pH.

16. Delayed-release soft gel capsule according to any one of claims 1 to 15, characterized in that the pH-dependent shell composition: does not disintegrate in an acidic pH stage of 1.2, 2.0, 3.0, 4.0, 5.0, 6.0 or a subrange thereof, for at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes or at least 120 minutes when measured with a USP disintegration apparatus from 500 mL to 900 mL of 0.1 N HCl, adjusted to the acidic pH stage with phosphate buffer solution, sodium hydroxide solution or potassium hydroxide solution;and disintegrates in a buffer pH above 6.5, above 6.8, above 7.0, above 7.5, above 8.0, or above 8.5 in up to 60 minutes, up to 45 minutes, up to 30 minutes, up to 15 minutes, or up to 10 minutes when measured with a USP disintegration apparatus, from 500 mL to 900 mL of phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, adjusted to the buffer pH.

17. Delayed-release soft gel capsule, according to any one of claims 1 to 16, characterized in that the pH-dependent shell composition presents a gelatin to pectin p:p ratio ranging from 6:1 to 18:

1.

18. Delayed-release soft gel capsule according to any one of claims 1 to 16, characterized in that the pH-dependent shell composition has a plasticizer to gelatin ratio p:p ranging from 5:1 to 1:

5.

19. Soft gel capsule with delayed release, according to any one of claims 1 to 18, characterized in that it reduces the incidence of belching.

20. Delayed-release soft gel capsule according to claim 2, characterized in that it further comprises a synthetic polymer of 1% to 5% by weight, 1.5% to 4% by weight, or 2% to 3% by weight of a synthetic polymer, based on the pH-dependent dry weight of the capsule composition.

21. Delayed-release soft gel capsule according to claim 20, characterized in that the synthetic polymer comprises a methacrylic acid-ethyl acrylate copolymer.

22. Delayed-release soft gel capsule according to claim 2, characterized in that the organic acid comprises at least one of the following: lactic acid, tannic acid, or a combination thereof.

23. Delayed-release soft gel capsule according to claim 2, characterized in that the organic acid is present in the pH-dependent shell composition in an amount of 0.1% to 8% by weight, 0.2% to 5% by weight, or 0.2% to 2% by weight, based on the total dry weight of the pH-dependent shell composition.

24. Delayed-release soft gel capsule, characterized by the fact that it comprises: (a) a filler material; and (b) a pH-dependent shell composition; wherein the filler material comprises at least one active agent; wherein the pH-dependent shell composition comprises a film former and from 0.5% by weight to 10% by weight of a synthetic polymer comprising a methacrylic acid-ethyl acrylate copolymer, based on the total weight of the dry pH-dependent shell composition; wherein the pH-dependent shell composition further comprises gelatin and dextrose; wherein the pH-dependent shell composition has a w:w ratio of gelatin to pectin ranging from 6:1 to 20:

1.

25. Delayed-release soft gel capsule according to claim 24, characterized in that the film former further comprises a gelling agent of non-animal origin comprising carrageenan, starch, pregelatinized starch, xanthan gum, agar, pectin, alginate, sugar, high molecular weight polyethylene glycol, sugar-derived alcohol, cellulose derivative, cellulosic polymer, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, silicon dioxide, curdlan, furcelleran, albumin, soy protein, chitosan or a combination thereof.

26. Delayed-release soft gel capsule according to claim 24 or 25, characterized in that the pH-dependent shell composition comprises the synthetic polymer Petition 870260022436, dated 06 / 03 / 2026, page 83 / 287 7 / 10 in an amount of 1% by weight to 5% by weight, 1.5% by weight to 4% by weight, or 2% by weight to 3% by weight, based on the weight of the dry pH-dependent shell composition.

27. Delayed-release soft gel capsule according to any one of claims 24 to 26, characterized in that it does not disintegrate in an acidic pH stage of 1.2, 2.0, 3.0, 4.0, 5.0, 6.0, or a subrange thereof, for at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, or at least 120 minutes, when measured with a USP disintegration apparatus from 500 mL to 900 mL of 0.1 N HCl, adjusted to the acidic pH stage with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution;and disintegrate at a buffer pH above about 6.5, above 6.8, above 7.0, above 7.5, above 8.0, or above 8.5 in up to 60 minutes, up to 45 minutes, up to 30 minutes, up to 15 minutes, or up to 10 minutes, when measured with a USP disintegration apparatus, from 500 mL to 900 mL of phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, adjusted to buffer pH.

28. Delayed-release soft gel capsule according to any one of claims 24 to 27, characterized in that: it does not dissolve in an acidic pH of 1.2, 2.0, 3.0, 4.0, 5.0, 6.0, or a subrange thereof, for at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, or at least 120 minutes when measured with a USP II apparatus, with paddles at 50 RPM to 250 RPM, from 500 mL to 900 mL of 0.1 N HCl, adjusted to acidic pH with phosphate buffer solution, sodium hydroxide solution or Petition 870260022436, dated 06 / 03 / 2026, p.83 / 287 8 / 10 potassium hydroxide; and dissolves in a buffer pH above 6.5, above 6.8, above 7.0, above 7.5, above 8.0 or above 8.5 in up to 60 minutes, up to 45 minutes, up to 30 minutes, up to 15 minutes, or up to 10 minutes, when measured with a USP II Apparatus, with paddles of about 50 RPM to 250 RPM, from 500 mL to 900 mL of phosphate buffer solution, sodium hydroxide solution or potassium hydroxide solution, adjusted to buffer pH.

29. Delayed-release soft gel capsule, characterized in that it comprises: (a) a filling material; and (b) a pH-dependent shell composition, wherein the filling material comprises at least one active agent; wherein the pH-dependent shell composition comprises an organic acid, gelatin, dextrose, and a film former comprising pectin; wherein the pH-dependent shell composition has a w:w ratio of gelatin to pectin ranging from 6:1 to 20:

1.

30. Delayed-release soft gel capsule according to claim 29, characterized in that the pH-dependent shell composition further comprises a synthetic polymer.

31. Delayed-release soft gel capsule, according to claim 29 or 30, characterized in that the film former further comprises a gelling agent of non-animal origin comprising carrageenan, starch, pregelatinized starch, xanthan gum, agar, pectin, alginate, sugar, high molecular weight polyethylene glycol, sugar-derived alcohol, derived from Petition 870260022436, dated 06 / 03 / 2026, page. 84 / 287 9 / 10 cellulose, cellulosic polymer, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, microcrystalline cellulose, attapulgite, bentonite, dextrin, alginate, kaolin, lecithin, aluminum magnesium silicate, carbomer, carbopol, silicon dioxide, curdlan, furcelleran, albumin, soy protein, chitosan or a combination thereof.

32. Delayed-release soft gel capsule according to any one of claims 29 to 31, characterized in that the organic acid comprises at least one of lactic acid, tannic acid, acetic acid, citric acid, or a combination thereof.

33. Delayed-release soft gel capsule according to any one of claims 29 to 32, characterized in that the organic acid is present in the pH-dependent shell composition in an amount of 0.1% by weight to 8% by weight, 0.2% by weight to 5% by weight, or 0.2% by weight to 2% by weight, based on the total weight of the pH-dependent dry shell composition.

34. Delayed-release soft gel capsule according to any one of claims 29 to 33, characterized in that the delayed-release soft gel capsule: does not disintegrate in an acidic pH stage of 1.2, 2.0, 3.0, 4.0, 5.0, 6.0, or a subrange thereof, for at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, or at least 120 minutes when measured with a USP disintegration apparatus from 500 mL to 900 mL of 0.1 N HCl, adjusted to the acidic pH stage with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution; and disintegrates at a buffer pH above 6.5, above Petition 870260022436, dated 06 / 03 / 2026, page.86 / 287 10 / 10 6.8, above 7.0, above 7.5, above 8.0, or above 8.5 in up to 60 minutes, up to 45 minutes, up to 30 minutes, up to 15 minutes, or up to 10 minutes, when measured with a USP disintegration apparatus, from 500 mL to 900 mL of phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, adjusted to buffer pH.

35. Delayed-release soft gel capsule according to any one of claims 29 to 34, characterized in that the delayed-release soft gel capsule: does not dissolve in an acidic pH stage of 1.2, 2.0, 3.0, 4.0, 5.0, 6.0, or a subrange thereof, for at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, or at least 120 minutes when measured with a USP II apparatus, with paddles from 50 RPM to 250 RPM, from 500 mL to 900 mL of 0.1 N HCl, adjusted to the acidic pH stage with phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution;and dissolves in a buffer pH above 6.5, above 6.8, above 7.0, above 7.5, above 8.0, or above 8.5 in up to 60 minutes, up to 45 minutes, up to 30 minutes, up to 15 minutes, or up to 10 minutes when measured with a USP II apparatus, with paddles from 50 RPM to 250 RPM, from 500 mL to 900 mL of phosphate buffer solution, sodium hydroxide solution, or potassium hydroxide solution, adjusted to the buffer pH.