RU2844033C1 - Delayed-release capsules of soft gelatine - Google Patents

Abstract

FIELD: medical science.

SUBSTANCE: invention refers to delayed-release capsules of soft gelatine. Proposed capsule of delayed release of soft gelatine is intended for use in a method of treating a colonic disease. Capsule contains a filling material and a composition dependent on pH of the shell. Filling material contains at least one pharmaceutically active ingredient. PH-dependent coating composition contains, in terms of the total dry weight of the pH-dependent coating composition, 45-65 wt. % gelatine, 7-15 wt. % pectin and 0.1-2 wt. % dextrose. PH-dependent coating composition dissolves or disintegrates or breaks down in the colonic medium.

EFFECT: invention aims at preparing the capsules suitable for initiating the release of the active agent on the target area in the colonic medium.

12 cl, 1 dwg, 17 tbl, 12 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to delayed-release soft gelatin capsules, wherein the gelatin-based shell compositions have delayed-release characteristics without the need for pH-dependent coatings or the addition of conventional pH-dependent synthetic polymers. The delayed-release soft gelatin capsules described in the present invention are particularly suitable for delivery to the colon.

LEVEL OF TECHNOLOGY

Soft capsules, particularly soft gelatin capsules (or soft gelatin capsules), are a dosage form that is readily accepted by patients because the capsules are easy to swallow and do not require flavoring to mask the unpleasant taste of the active ingredient. Encapsulation of drugs in soft capsules also provides the opportunity to improve the bioavailability of pharmaceuticals. For example, the active ingredients can be easily released in liquid form after the gelatin shell is broken.

Attempts have been made to create sustained release dosage forms. Sustained release dosage forms are intended to provide protection of the contents of the dosage forms from the effects of gastric juices. For example, sustained release dosage forms can be prepared by applying a pH-dependent coating to the surface of a manufactured dosage form, such as a tablet or capsule. Such coatings can be applied by spraying them onto the dosage form and then drying the dosage form, usually at elevated temperatures. This technique of applying a pH-dependent coating to a capsule can lead to disadvantages such as deterioration in potency and appearance. For example, the capsule may appear rough, the coating may be unevenly applied, and/or the coating may be prone to cracking or peeling off from the dosage form. In addition, the technique of applying a pH-dependent coating is extremely inefficient.

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 result in capsules that are prone to leakage due to inadequate sealing.

Accordingly, there is currently a need for a delayed release soft gelatin capsule that does not require either a pH-dependent coating or the addition of conventional pH-dependent polymers to the shell.

SUMMARY OF THE INVENTION

The present invention relates to delayed-release soft gelatin capsules. The delayed-release soft gelatin capsules comprise (a) a filler material and (b) a pH-dependent shell composition. The delayed-release soft gelatin capsules of the present invention do not require either a pH-dependent coating or an added conventional pH-dependent polymer. Accordingly, the pH-dependent shell composition eliminates the need for applying a pH-dependent coating, which also reduces the likelihood of damage to the capsules during the coating procedure. The delayed-release soft gelatin capsules described in the present invention are particularly suitable for delivery to the colon.

In one embodiment, the pH-dependent shell composition comprises: (a) gelatin, (b) dextrose, (c) pectin, such as low methoxylated pectin, and optionally (d) a plasticizer. The composition of the pH-dependent shell composition (e.g., amount of pectin, amount of dextrose, ratio of gelatin to pectin) and the method of its preparation (e.g., curing time, tape thickness) can be adjusted/changed/modified to provide a target pH-dependent dissolution profile of the shell composition in environments having different pH values (e.g., disruption/dissolution/disintegration times in an acidic environment and in a buffered environment). The present invention also relates to a method of making delayed-release capsules from soft gelatin. In particular, the amount of dextrose contained in the pH-dependent shell composition described in the present invention can be adjusted to provide a delay in the release of the active agent until it reaches the colonic environment of a human subject.

The present invention also relates to a method of treating a pathological condition (e.g., a colon disease or other pathological condition that is treatable by targeted administration of an active agent to the colon) carried out by administering to a subject any of the soft gelatin delayed release capsule compositions described in the present invention. The delivery can be for the treatment of a disease or pathological condition of the colon and it can also be used to treat a systemic pathological condition using a drug that is suitable for absorption in the colon.

The present invention also relates to a method of delivering an active agent to the colon of a patient, carried out by orally administering any of the soft gelatin delayed release capsule compositions described in the present invention. In some embodiments, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the active agent is delivered to the colon of the patient.

BRIEF DESCRIPTION OF DRAWINGS

The above and other features of the present invention, their nature and various advantages will become more apparent upon consideration of the following detailed description together with the accompanying drawings, where:

Fig. 1 shows the dependence of the viscosity of the shell compositions containing amidated pectin and not containing amidated pectin on the duration of aging.

DETAILED DESCRIPTION OF THE INVENTION

The present invention improves the prior art by providing oral delayed release dosage forms, in particular delayed release soft gelatin capsules, which have the advantages of conventional delayed release dosage forms without the need for a pH-dependent coating or the addition of a conventional pH-dependent synthetic polymer to the capsule shell. The delayed release soft gelatin capsules of the present invention do not dissolve in the stomach environment but dissolve in the intestine, in particular the colon, of a human subject. The dissolution profile of the delayed release soft gelatin capsules described in the present invention can be controlled by varying the composition of the soft gelatin capsule shells.

This mechanism is advantageous for the delivery of active ingredients that may cause gastric irritation or are sensitive to the acidic environment of the stomach. This mechanism is also advantageous for reducing belching after ingestion of capsules that encapsulate filler materials that tend to promote belching. For example, belching often occurs after ingestion of vitamins, minerals, dietary supplements, and/or pharmaceutical products that are formulated in dosage forms that are characterized by some leakage (even extremely small amounts) in the stomach before reaching the intestine. Leakage can be especially problematic when the belching is associated with substances that cause an unpleasant sensation, such as fish oil and garlic, which are usually delivered using soft gelatin capsules. The soft gelatin delayed release capsules described in the present invention can be formulated to minimize and/or eliminate premature leakage (and thus premature release of the capsule fill material) in the stomach environment and any other portion of the gastrointestinal tract prior to the colon.

As used herein, the term "pH dependent" means a characteristic of the stability of a compound to dissolution or disintegration such that the substance does not, or substantially does not, dissolve or disintegrate in the stomach environment and any other portion of the gastrointestinal tract prior to the colon, such as for a period of at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours. In some embodiments, the stomach environment can be simulated using 0.1 N HCl and optionally with the addition of pepsin. It should be noted that pepsin is not used in pharmacopoeial procedures, but pepsin is added in some of the dissolution/disintegration studies described herein to better simulate/mimicker in vivo conditions. Therefore, without limiting the invention, in some embodiments, the compositions described herein are stable and do not dissolve/degrade over the time periods described above, even in 0.1 N HCl environments that contain the enzyme pepsin (which are considered more aggressive environments than 0.1 N HCl without added pepsin).

For example, embodiments described herein include a pH-dependent coating composition that preferably dissolves at a pH of about 3.5 or greater (e.g., in a biological, synthetic, or artificial colonic environment and/or biological, synthetic, or artificial intestinal juice) rather than in a biological, synthetic, or artificial gastric juice. For example, the pH-dependent coating composition of the present invention dissolves at a pH of about 3.5 or greater (e.g., in a biological, synthetic, or artificial colonic environment and/or a biological, synthetic, or artificial intestinal juice) after a period of at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, or after a period of time ranging from any of about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, or about 30 minutes, up to any of about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 75 minutes, or about 90 minutes, or after a period of time that is any single value or a value within any subrange specified in the present invention. In some embodiments, the colonic environment or intestinal juice may be simulated in the present invention using a phosphate buffer having a pH of 6.8, optionally with the addition of pancreatin. It should be noted that pancreatin is not used in pharmacopoeial methods, but in some of the dissolution/disintegration studies described in the present invention, pancreatin is added to better simulate/mimicker in vivo conditions. Therefore, without limiting this, in some embodiments, the compositions described in the present invention have similar dissolution/disintegration profiles in buffered media having a pH of 6.8 that contain pancreatin (which are considered more aggressive environments than a buffered medium having a pH of 6.8 without the addition of pancreatin).

As used herein, the terms "pharmaceutically active ingredient", "active agents" mean a drug or compound that can be used to diagnose, cure, alleviate, treat or prevent a pathological condition. In some embodiments, suitable "active agents" include nutraceuticals such as vitamins, minerals and nutritional supplements (VMPD). Typical delayed release soft gelatin capsules may include, but are not limited to, capsules containing lactic acid bacteria, probiotics, capsules containing fish oil, valproic acid, garlic, peppermint oil, polyethylene glycol, ibuprofen solution or suspension, proton pump inhibitors, aspirin, and similar products.

The term "pathological condition" or "pathological conditions" means those pathological conditions that can be treated or prevented by administering to a subject an active agent in an effective amount.

As used herein, the term "active ingredient" means any substance that is intended to provide a therapeutic, prophylactic or other desired effect, whether or not approved by a governmental agency for use for that purpose. This term, when used in relation to a particular agent, includes a pharmaceutically active agent and all pharmaceutically acceptable salts, solvates and crystalline forms thereof, wherein the salts, solvates and crystalline forms are pharmaceutically active.

For the purposes of the present invention, any pharmaceutically active ingredient can be used, including those that are soluble in water and those that are poorly soluble in water. Suitable pharmaceutically active ingredients include, but are not limited to, analgesics and anti-inflammatory agents (e.g., ibuprofen, naproxen sodium, aspirin), antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarial agents, antimigraine agents, antimuscarinics, antineoplastic agents and immunosuppressants, antiprotozoals, antirheumatic agents, antithyroid agents, antivirals, tranquilizers, sedatives, hypnotics and neuroleptics, beta blockers, cardiac inotropic agents, corticosteroids, cough suppressants, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, lipid regulators, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritional supplements, opioid analgesics, anticonvulsants (eg, valproic acid), oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants and combinations thereof.

In some embodiments, the active agent contained in the capsule may be any pharmaceutically or therapeutically active agent that is desirable for delivery to the small intestine, such as pancreatin and other proteolytic enzymes, diclofenac, naproxen, aspirin, indomethacin, omeprazole, cardiac glycosides, electrolyte preparations containing sodium, potassium and magnesium salts, as well as preparations containing calcium and iron, preparations containing bisacodyl, and valproic acid.

In some embodiments, the active agent may be a drug that is desirable for delivery to the colon, including drugs intended for the treatment of colon disease, for example, 5-SAC (5-aminosalicylic acid); steroids such as hydrocortisone, budesonide; laxatives; octreotide; cisapride; anticholinergics; calcium channel blockers, 5HT3 antagonists such as ondansetron, and peptides such as insulin.

In some embodiments, active agents that are suitable for delivery to the colon are, without limitation, one or more of the following: anti-infective agents such as antibiotics and antiviral agents; analgesics and analgesic combinations; appetite suppressants; anthelmintics; anti-arthritic agents; anti-asthmatic agents; anticonvulsants; antidepressants; antidiabetic agents, antidiarrheal agents; antihistamines; anti-inflammatory agents; anti-migraine agents; antiemetics; antineoplastic agents; antiparkinsonian drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular drugs including potassium and calcium channel blockers, beta blockers, alpha blockers and antiarrhythmic agents; antihypertensive agents; Diuretics and antidiuretics; vasodilators; including those for the common coronary, peripheral, and cerebral arteries; central nervous system stimulants; vasoconstrictors; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressants; muscle relaxants; parasympatholytics; psychostimulants; sedatives and tranquilizers; probiotics; anticancer agents (eg, specific agents for colon cancer or agents for other types of cancer that can be treated systemically with an anticancer agent suitable for absorption in the colon).

Examples of colorectal cancer agents include, but are not limited to, the following: Avastin (bevacizumab), Bevacizumab, Camptosar (irinotecan hydrochloride), Capecitabine, Cetuximab, Cyramza (ramucirumab), Eloxanthin (oxaliplatin), Erbutux (cetuximab), 5-FU (fluorouracil injection), Fluorouracil injection, Ipilimumab, Irinotecan hydrochloride, Keytruda (pembrolizumab), Leucovorin calcium, Lonsurf (trifluridine and tipiracil hydrochloride), Mvazi (bevacizumab), Nivolumab, Opdivo (nivolumab), Oxaliplatin, Panitumumab, Pembrolizumab, Ramucirumab, Regorafenib, Stivarga (regorafenib), Trifluridine and tipiracil hydrochloride, vectibix (panitumumab), xeloda (capecitabine), ervoy (ipilimumab), zaltrap (ziv-aflibercept), ziv-aflibercept, and any combinations thereof.

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

In some embodiments, the lipids contained in the dosage form may be selected from the group consisting of, but not limited to, the following: almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew nut oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hempseed oil, hydroxylated lecithin, lecithin, flaxseed oil, macadamia nut oil, mango butter, manila hemp oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, peppermint oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, nut oil and watermelon oil. Other oils and fats may include, but are not limited to, fish oil (omega-3), krill oil, animal or vegetable fats such as those in their hydrogenated form, free fatty acids and mono-, di- and triglycerides of _C8 , _C10 , _C12 , _C14 , _C16 , _C16 , _C20 and _C22 fatty acids, fatty acid esters such as EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), and combinations thereof.

In some 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 pharmaceutically acceptable salts, hydrates, solvates, and prodrugs, mixtures of any of the foregoing, and the like.

Suitable nutritional actives 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 sesquioxide, glandular products, glucosamine HCI, glucosamine sulfate, hydroxymethylbutyrate, immunoglobulin, lactic acid, L-carnitine, liver-derived products, malic acid, maltose anhydrous, mannose (d-mannose), methylsulfonylmethane, phytosterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium-containing yeast, shark cartilage, theobromine, vanadyl sulfate and yeast.

Suitable nutritionally active additives may include vitamins, minerals, fiber, fatty acids, amino acids, herbal remedies, or a combination thereof.

Suitable vitamin actives 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-containing oils and oil soluble vitamins.

Suitable herbal actives 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, plantain, rauwolfia, senna, soybean, St. John's wort, saw palmetto, turmeric, valerian.

Mineral actives may include, but are not limited to, the following: boron, calcium, chelating 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.

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

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

The term "barbiturates" means sedative-hypnotic drugs formed from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbital, butabarbital, butalbital, methohexital, mephobarbital, metarbital, pentobarbital, phenobarbital, secobarbital, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists that can be used as the active agent include, but are not limited to, amphetamines, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

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

The dosage forms provided in the present invention include various active agents and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; salts derived from organic acids such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; salts derived from amino acids such as arginate, aspartate, glutamate, etc.; and metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dichlorhexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

As used herein, the terms "therapeutically effective amount" and "effective amount" mean the amount of active agent or the rate of administration thereof that is necessary to provide the desired therapeutic result.

As used herein, "shell," "shell composition," or "pH-dependent shell composition" means a soft gelatin capsule shell in which a fill material is encapsulated.

As used herein, the term "conventional pH dependent polymers" includes, but is not limited to, acrylic and methacrylic acid polymers sold under the trade name EUDRAGIT®, and other conventional acid insoluble polymers such as methyl acrylate/methacrylic acid copolymers. Other conventional acid insoluble polymers include, but are not limited to, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), alginic acid salts such as sodium alginate and potassium alginate, stearic acid, and shellac. Pectin and pectin derivatives are not considered to be conventional pH-dependent polymers. In some embodiments, the pH-dependent shell composition of the present invention does not contain an acid-insoluble polymer. In other words, in some embodiments, the pH-dependent shell composition and the pH-dependent soft gelatin capsule are "free or substantially free of conventional pH-dependent polymers."

As used herein, "free or substantially free" means that the composition contains less than about 1 wt.%, less than about 0.5 wt.%, less than about 0.25 wt.%, less than about 0.1 wt.%, less than about 0.05 wt.%, less than about 0.01 wt.%, or 0 wt.% of the specified component.

Throughout the present description and in the claims, all values indicated in wt.% mean the weight of the component based on the weight of the entire composition proposed in the present invention, and they can also be designated as wt./wt.

As used herein, the term "fill material" or "filling material" means a composition that is encapsulated in a pH-dependent shell and contains at least one pharmaceutically active ingredient.

As used herein, the terms "delayed release capsules" or "soft gelatin delayed release capsules" or "pH-dependent capsules" or "pH-dependent soft gelatin capsules" mean capsules that have delayed release characteristics or pH-dependent characteristics after the fill material is encapsulated in the shell and the capsules are dried. In some embodiments, these terms may mean capsules that are also cured after drying. In some embodiments, no additional processing steps are required after drying. In some embodiments, no additional processing steps are required after curing.

As used in the present invention, the term "about" means any value equal to that value within ±10%, thus a value of "about 10" includes values of 9 to 11.

As used in the present invention, the terms "a" or "an" in the singular or plural mean one or more, unless otherwise indicated. For example, reference to "an inert filler" includes reference to a single inert filler as well as a mixture of two or more different inert fillers, etc.

The indication of ranges of values in the present invention is used only to briefly indicate specifically all individual values within that range, unless otherwise indicated in the present invention, and each individual value is included in the description as if it were specifically indicated in the present invention. All methods described in the present invention can be performed in any suitable order, unless otherwise indicated in the present invention or otherwise clearly contradicted by context.

The use of any and all examples or indications of typical values (e.g., "such as") in the present invention is intended merely to describe particular materials and methods and does not impose a limitation on the scope of the present invention. No expression in the description should be construed as indicating any unstated element important to the practice of the disclosed materials and methods.

In a first embodiment, a pH-dependent soft gelatin 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 gelatin, dextrose, a pH-dependent material (e.g. low methoxylated pectin) and optionally a plasticizer. Preferably, the pH-dependent composition does not contain additional pH-dependent polymers. In some embodiments, the pH-dependent soft gelatin capsule or pH-dependent shell composition is formulated to remain intact in an acidic environment, such as the stomach environment or the simulated gastric fluid environment (e.g., for a period of at least about 5 hours, at least about 4 hours, at least about 3 hours, at least about 2 hours, at least about 1 hour, etc.), and to dissolve/disintegrate in the colon (or the simulated intestinal fluid environment) after a target period of time (e.g., after a period of at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, or after a period of time ranging from any value greater than 0 minutes, about 5 min, about 10 min, about 15 min, about 20 min, about 25 min, or about 30 min, up to any value of about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 60 min, about 75 min, or about 90 min, or after a period of time that is any single value or a value within any subrange specified in the present invention).

Suitable filler materials contain at least one pharmaceutically active ingredient and can be prepared by known methods. In addition to at least one pharmaceutically active ingredient, suitable filler materials may contain additional filler components such as flavoring agents, sweeteners, coloring agents and fillers, or other pharmaceutically acceptable excipients or additives such as synthetic dyes and inorganic oxides. A person of ordinary skill in the art can easily determine suitable amounts of the pharmaceutically active ingredient and pharmaceutically acceptable excipients.

In one embodiment, the gelatin contained in the pH-dependent shell composition may comprise gelatin type A, gelatin type B, skin or dermal gelatin (e.g., calf skin, pig skin) and/or bone gelatin (e.g., calf bone, pig bone), used alone or in combination. In one embodiment, the gelatin is gelatin having a Bloom strength of 250 degrees. In another embodiment, only one type of gelatin is contained. In yet another embodiment, the gelatin is a combination of at least two types of gelatin. In one embodiment, the amount of gelatin contained in the pH-dependent shell composition is from about 30 to about 85 wt. %, from about 30 to about 75 wt. %, from about 30 to about 65 wt. %, from about 30 to about 55 wt. %, from about 30 to about 40 wt. %, from about 40 to about 80 wt. %, from about 45 to about 65 wt. %, from about 45 to about 75 wt. %, or from about 50 to about 70 wt. %, based on the total dry weight of the capsule shell composition, or it is any single amount or amount within any subrange specified in the present invention.

In one embodiment, the pH-dependent capsule shell composition comprises dextrose. In one embodiment, the amount of dextrose contained in the pH-dependent capsule shell composition is from about 0.001 to about 1.0 wt. %, from about 0.002 to about 0.008 wt. %, from about 0.005 or about 0.01 wt. % to about 4 wt. %, from about 0.1 or about 0.15 wt. % to about 3 wt. %, from about 0.1 to about 1 wt. %, from about 0.1 or about 0.15, or about 0.2, or about 0.25 wt. % to about 2 wt. %, from about 0.1 to about 0.2 wt. %, from about 0.05 or about 0.1 wt. % to about 0.4 wt. %, or up to about 0.5 wt. % based on the total weight of the dry capsule shell composition, or it is any single amount or amount within any subrange specified in the present invention.

Dextrose can be added to the delayed release capsule shell to provide a reduction in possible decrease in gel strength. The amount of dextrose contained in the pH-dependent shell composition can also be adjusted to provide a targeted dissolution profile of the delayed release soft gelatin capsule, for example, to provide dissolution/disintegration of the delayed release soft gelatin capsule at a specific location in the gastrointestinal tract (e.g., in the colon). In one embodiment, the amount of dextrose contained in the pH-dependent shell composition is adjusted to provide a delay in dissolution of the delayed release soft gelatin capsule before it reaches the colon and to provide a targeted dissolution profile in the colon. For example, the amount of dextrose contained in the pH-dependent coating composition can be adjusted to prevent premature dissolution/degradation in an acidic medium (e.g., 0.1 N HCl, optionally with the addition of pepsin) while adjusting the dissolution/disintegration/degradation time in a buffered medium (e.g., phosphate buffer having a pH of 6.8, optionally with the addition of pancreatin, used to simulate the colonic environment of a human subject). The dissolution/disintegration/degradation time in the buffer step can be adjusted to provide dissolution/disintegration/degradation occurring after a time period of at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, or a time period ranging from any value of about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, or about 30 minutes to any value of about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 75 minutes, or about 90 minutes, or a time period that is any single value or a value within any subrange specified in the present invention. The dissolution/disintegration/degradation time in an acidic environment can be adjusted to maintain the soft gelatin delayed release capsule intact for 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, at least about 120 minutes, or at least about 150 minutes.

Without imposing limitations, it can be assumed that in the shell composition, dextrose interacts with gelatin and causes cross-linking of the gelatin. The effect of the amount of dextrose on the dissolution characteristics of the shell composition is further illustrated in the examples. The concentration of dextrose contained in the pH-dependent shell composition can be effective to improve gel strength, but not so high that the capsule seal or the processability or performance of the product are impaired.

In some embodiments, the pH-dependent coating composition may comprise a pectin, such as a low methoxylated pectin. In one embodiment, the pectin is a low methoxylated (LMW) pectin having a degree of esterification of less than 50. In some embodiments, the pectin is an amidated pectin. In other embodiments, the low methoxylated (LMW) pectin is a non-amidated pectin. In some embodiments, the pectin is a combination of amidated pectin and non-amidated pectin. The addition of pectin helps provide the pH-dependent characteristics of the dosage form.

Excessive amounts of pectin in a dosage form may reduce the gel strength of a soft gelatin capsule, which in turn may adversely affect the sealability of the soft gelatin capsule. Excessive amounts of pectin in a pH-dependent shell composition may also increase the viscosity of the shell composition, making processing difficult or impossible during manufacture.

Therefore, pectin can be added to the dosage form at a concentration that is high enough to provide a delayed release dosage form, and at the same time low enough to provide a reduction in gel strength and a reduction in viscosity increase.

In one embodiment, the amount of pectin contained in the pH-dependent shell composition is from about 2 to about 20 wt.%, from about 3 to about 15 wt.%, from about 3 to about 5.5 wt.%, from about 4 to about 11 wt.%, from about 7 to about 12 wt.%, from about 8 to about 13 wt.%, or from about 5 to about 10 wt.%, based on the total dry weight of the capsule shell composition, or any single amount or amount within any subrange specified herein.

The degree of esterification of the pectin contained in the pH-dependent shell composition may be less than about 50% or it may be in the range of 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.

In some embodiments, the pH-dependent coating composition comprises a stabilizer and/or a binder comprising gellan gum. In some embodiments, the 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.

In some embodiments, the amount of stabilizer and/or binder (e.g., gellan gum) contained in the pH-dependent shell composition is from about 0.05 to about 5 wt. %, from about 0.1 to about 3 wt. %, or from about 0.2 to about 2 wt. % of stabilizer and/or binder (e.g., gellan gum) based on the total dry weight of the capsule shell composition, or any single amount or amount within any subrange specified herein.

In some embodiments, the pH-dependent coating composition may have a viscosity in a range of from any of about 20,000 cP, about 30,000 cP, about 40,000 cP, about 50,000 cP, about 60,000 cP, or about 70,000 cP to any of about 80,000 cP, about 90,000 cP, about 100,000 cP, about 110,000 cP, about 120,000 cP, about 130,000 cP, about 140,000 cP, or about 150,000 cP, or any subrange therein, or any individual viscosity value described herein. In one embodiment, the pH-dependent coating composition has a viscosity in the range of about 100,000 to about 130,000 cP, or about 110,000 to about 125,000 cP, or about 115,000 cP, or about 120,000 cP. The viscosity is determined using a rheometer at 60°C, as described in more detail in the examples with respect to Fig. 1.

A sample of the gel mass (e.g., any of the pH-dependent shell compositions described in the present invention) is placed on a rheometer platform, the temperature of which is maintained at 60°C. The disk is rotated at a certain speed and a constant shear rate is provided. Viscosity is determined by measuring the shear stress and the shear rate.

In some embodiments, the pH-dependent shell composition may maintain a viscosity that is suitable for processability even after heat aging for up to about 24 hours, up to about 48 hours, up to about 72 hours, up to about 96 hours, or up to about 1 week. In some embodiments, the viscosity of the pH-dependent shell composition after heat aging (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) may decrease (compared to the viscosity value of the composition before aging) by up to about 80%, up to about 70%, up to about 60%, up to about 50%, up to about 40%, up to about 35%, or up to about 30%.

In one embodiment, the plasticizer contained in the pH-dependent coating composition may include glycerol, sorbitol, and combinations thereof. Other suitable plasticizers may include, but are not limited to, a hydroxy sugar plasticizer such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or a polyol plasticizer such as diglycerol, dipropylene glycol, polyethylene glycol having a MW (molecular weight) of up to 10,000, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyol, ethanolamines; and mixtures thereof. Other typical plasticizers may also include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols containing aliphatic hydroxy groups, ester plasticizers, glycol ethers, poly(propylene glycol), multiblock copolymers, monoblock polymers, ester plasticizers - citrates and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof

In one embodiment, the amount of plasticizer contained in the pH-dependent shell composition is from about 15 to about 45 wt.%, from about 15 to about 40 wt.%, from about 18 to about 45 wt.%, from about 18 to about 42 wt.%, from about 20 to about 35 wt.%, from about 25 to about 30 wt.%, based on the total dry weight of the capsule shell composition, or it is any single amount or an amount within any subrange specified in the present invention.

In some embodiments, the amounts of various components (e.g., pectin, dextrose, gelatin, plasticizer) and the ratios of the amounts of the various components are adjusted to control the dissolution and/or disintegration characteristics of the soft gelatin capsule in different pH ranges.

For example, the weight ratio of gelatin to pectin in the pH-dependent shell composition may be in the range of any value of about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, or about 9:1, to any value 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 it may be in any subrange, or any individual value, specified herein. In some embodiments, lower gelatin to pectin weight ratios provide a pH-dependent shell composition that is more stable (dissolves more slowly, if at all) in an acidic medium (e.g., 0.1 N HCl, optionally with added pepsin), whereas higher gelatin to pectin weight ratios provide a pH-dependent shell composition that is less stable (dissolves more quickly) in an acidic medium (e.g., 0.1 N HCl, optionally with added pepsin). The gelatin to pectin weight ratio can be adjusted to provide a specific dissolution time for the soft gelatin capsule in an acidic medium (e.g., about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or any subrange thereof, etc.).

The weight ratio of gelatin to plasticizer in the pH-dependent shell composition can also be adjusted to provide a certain hardness of the capsule and can be in the range of 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 it can be any single ratio value or a ratio value within any subrange specified in the present invention.

In some embodiments, the pH-dependent coating compositions described in the present invention may have a hardness in the range of any value of about 5 N, about 6 N, about 7 N, about 8 N, about 9 N, or about 10 N, to any value of about 11 N, about 12 N, about 13 N, about 14 N, or about 15 N. The hardness of the capsule is determined using a hardness testing device. The force, expressed in Newtons, required to compress the capsule by 2.0 mm is determined as the hardness of the capsule.

In some embodiments, the pH-dependent shell compositions described herein may have a shell moisture content in a range of from any of about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% to any of about 11%, about 12%, about 13%, about 14%, or about 15%. The shell moisture content is determined using a loss on drying technique. A sample of the pH-dependent capsule shell composition weighing from 1 to 2 g is kept in an oven at 105°C for 17 hours. The initial weight of the sample is recorded. After drying the sample in an oven at 105°C for 17 hours, the final weight of the sample is recorded. The percent weight loss, calculated according to the equation below, is defined as the shell moisture content:

In some embodiments, the pH-dependent shell compositions described herein may have an equilibrium relative humidity in the range of any of about 25%, about 28%, about 30%, about 32%, about 34%, or about 35%, to any of about 38%, about 40%, about 42%, about 45%, or about 50%. Equilibrium relative humidity (%) is defined as the humidity at which the capsule maintains a constant total mass. It is determined using environmental chambers in which constant humidity is maintained using saturated salt solutions.

In some embodiments, the pH-dependent coating compositions described in the present invention may have a crushing strength in the range of any of about 50 kg, about 60 kg, about 70 kg, about 80 kg, or about 90 kg, to any of about 100 kg, about 110 kg, about 120 kg, about 130 kg, about 140 kg, or about 150 kg. The crushing strength is determined using a Texture Analyzer. Using the Texture Analyzer, the capsule is compressed until it breaks. The force, expressed in kilograms, required to break the capsule is determined as the crushing strength.

In one embodiment, the pH-dependent shell composition and the pH-dependent soft gelatin capsule may be free or substantially free of conventional pH-dependent polymers and/or may be free of a pH-dependent outer coating applied to the soft gelatin shell.

In one embodiment, the pH-dependent shell composition and the pH-dependent soft gelatin capsule may comprise salts formed with divalent cations such as Ca ⁺⁺ (e.g., _CaCl2 ) or Mg ⁺⁺ (e.g., _MgCl2 ). In another embodiment, the pH-dependent shell composition and the pH-dependent soft gelatin capsule may be free or substantially free of salts formed with divalent cations such as Ca ⁺⁺ (e.g., _CaCl2 ) or Mg ⁺⁺ (e.g., _MgCl2 ). In another embodiment, the formation of the pH-dependent shell composition may not include the step of adding salts formed with divalent cations such as Ca ⁺⁺ (e.g., _CaCl2 ) or Mg ⁺⁺ (e.g., _MgCl2 ), different from the salts formed with divalent cations that may be present in certain amounts in other components.

In one embodiment, the pH-dependent coating composition may optionally contain additional agents such as stabilizers or binders (e.g., gellan gum), coloring agents, flavoring agents, sweeteners, fillers, antioxidants, diluents, pH modifiers, or other pharmaceutically acceptable excipients or additives such as synthetic dyes and inorganic oxides.

Typical suitable coloring agents may include, but are not limited to, those providing colors such as, for example, white, black, yellow, blue, green, pink, red, orange, purple, dark blue, and brown. In preferred embodiments, the color of the dosage form may indicate the components contained therein (e.g., one or more active ingredients).

Typical suitable flavoring agents may include, but are not limited to, "aromatic extract" obtained by extracting a portion of a source material, such as animal or plant material, often using a solvent such as ethanol or water; natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from whole plants.

Additional typical flavoring agents that may be contained in the dosage form may include, but are not limited to, breath freshening compounds such as menthol, mint and cinnamon, coffee beans, other flavorings or aromas such as fruit flavors (e.g., cherry, orange, grape, etc.), especially those used for oral hygiene, as well as active substances used for cleaning teeth and cleaning the oral cavity, such as quaternary ammonium bases. The effect of flavorings can be enhanced by using flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

Typical sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof. Artificial sweeteners include, for example, acesulfame and its various salts such as the potassium salt (sold under the name Sunett®), alitame, aspartame (sold under the name NutraSweet® and Equal®), aspartame-acesulfame salt (sold under the name Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts such as the sodium salt (sold under the name Sweet'N Low®), stevia, chlorinated sucrose derivatives such as sucralose (sold under the name 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 (stevioside), natural intense sweeteners such as monk fruit, polyols such as sorbitol, mannitol, xylitol, erythritol, etc.

In some embodiments, the pH-dependent shell composition and/or the pH-dependent soft gelatin capsule can be tested using a dissolution/disintegration test using a USP II apparatus with paddles at a stirring speed of 50 rpm in an acidic medium (pH=1.2 (0.1 N HCl solution), optionally with the addition of pepsin) and then in a buffered medium to simulate the colonic environment and/or intestinal juice (e.g., a phosphate buffer having a pH=6.8, optionally with the addition of pancreatin, e.g., 1% pancreatin). In this embodiment, the pH-dependent soft gelatin capsule may remain intact in an acidic environment for at least about 10 minutes, at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours, and may disintegrate in intestinal juice and/or in a colonic environment and/or in an artificial intestinal juice (such as a buffer medium) after a period of time of at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, or after a period of time comprising any value of about 10 minutes, about 15 minutes, about 20 minutes, about 25 min or about 30 min, to any value of about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 60 min, about 75 min, or about 90 min, or after a time interval that is any single value or a value within any subrange specified in the present invention.

Although the buffer medium used for the two-phase dissolution/disintegration test has a pH of 6.8, it should be noted that a similar dissolution/disintegration profile can be achieved by using a buffer medium having a pH of about 3.5 or more (optionally with the addition of pancreatin). It should also be noted that according to pharmacopoeial procedures, the presence of pepsin (in an acidic medium) and pancreatin (in a buffered medium) is not necessary, but they are used in the present invention in some cases to simulate more aggressive environments that better mimic in vivo conditions.

In some embodiments, the two-phase dissolution/disintegration test (including both an acidic medium and a buffered medium) can be conducted for a total of about 420 minutes, about 360 minutes, about 300 minutes, about 240 minutes, about 210 minutes, about 180 minutes, about 150 minutes, about 120 minutes, about 105 minutes, about 90 minutes, about 75 minutes, about 60 minutes, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, or about 5 minutes.

The encapsulation of the filling material can be carried out using any conventional method. For example, encapsulation using a rotary stamp can be used.

In one embodiment, a pH-dependent soft gelatin capsule is produced by a process comprising the steps of: (a) providing a fill material, said fill material comprising at least one pharmaceutically active ingredient; and (b) encapsulating the fill material obtained in step (a) using a pH-dependent shell composition. The encapsulation procedure carried out in step (b) may further comprise a sub-step of obtaining a pH-dependent shell composition by, for example, mixing gelatin, dextrose, pectin and optionally a plasticizer. Preferably, the pH-dependent shell composition does not contain additional pH-dependent polymers (such as conventional pH-dependent synthetic polymers).

The thickness of the pH-dependent shell composition tape (used, for example, in rotary die encapsulation) can also be adjusted to adjust the pH-dependent dissolution profile of the final pH-dependent soft gelatin capsule. The thickness of the tape of the pH dependent coating composition, without limitation, can be in a range of from any value of about 0.02 inches, about 0.022 inches, about 0.024 inches, about 0.026 inches, about 0.028 inches, or about 0.030 inches, to any value of about 0.032 inches, about 0.034 inches, about 0.036 inches, about 0.038 inches, about 0.04 inches, about 0.042 inches, about 0.044 inches, or about 0.050 inches, or it can be in any subrange, or have any individual value, specified in the present invention.

In some embodiments, the pH-dependent soft gelatin capsule (e.g., after encapsulation) can be dried and optionally cured. The curing of the soft gelatin capsule can be carried out at a temperature in the range of from about 25 to about 75°C, from about 25 to about 70°C, from about 30 to about 60°C, or from about 35 to 50°C. The curing temperature should be high enough to improve the delayed release characteristics of the soft gelatin capsules, but not so high that the soft gelatin capsules melt.

The curing time may be in the range of about 12 to about 168 hours, about 18 to about 120 hours, about 24 to about 72 hours, about 24 hours, about 48 hours, about 72 hours, or any subrange thereof, or any single value specified herein. In one embodiment, the curing of the soft gelatin capsule may be carried out at a temperature of about 40°C for about 24 hours. In one embodiment, the curing of the soft gelatin capsule may be carried out at a temperature of about 40°C for about 48 hours. In one embodiment, the curing of the soft gelatin capsule may be carried out at a temperature of about 40°C for about 72 hours. In some embodiments, the curing may be carried out in air (without any particular adjustment of nitrogen or oxygen content or humidity). In some embodiments, curing may be performed under inert conditions (e.g., under a nitrogen atmosphere).

In one embodiment, a method for producing a pH-dependent soft gelatin capsule comprises the following steps, essentially consists of or consists of the following steps: a) providing any of the fill materials described in the present invention; b) encapsulating the fill material obtained in step a) using any of the pH-dependent shell compositions described in the present invention (e.g., by encapsulation using a rotary die); c) drying the pH-dependent soft gelatin capsules obtained after encapsulation (e.g., by inversion drying or by conventional basket drying without inversion); and optionally d) curing the pH-dependent soft gelatin capsules in accordance with any curing conditions described in the present invention.

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

In some embodiments, the present invention should distinguish between drying and curing. The purpose of drying the soft gelatin delayed-release capsules described in the present invention is to remove excess water from the soft gelatin delayed-release capsule immediately after encapsulation. In this way, the capsules become physically stable. The purpose of curing the soft gelatin delayed-release capsules described in the present invention is to improve the delayed-release characteristics of the soft gelatin delayed-release capsule. Therefore, having a drying step does not mean the same as having a curing step, and, similarly, having a curing step does not mean the same as having a drying step.

In some embodiments, delayed release soft gelatin capsules containing the pH dependent shell compositions described herein are chemically and physically stable.

For example, their chemical stability can be confirmed by determining the content of the active agent contained in the filler material (e.g., the content of fish oil components, if the filler material includes fish oil). In some embodiments, the content of the components of the filler material is substantially the same (or meets 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 using stringent conditions - at 40 ° C and a relative humidity of 75%, for any of these periods of time), as the content in the original material before storage.

In some embodiments, the physical stability of the soft gelatin delayed release capsules can be confirmed by determining the dissolution profile of the capsule in an acidic medium and in a buffered medium. For example, the dissolution profile of the capsule in an acidic medium and in a buffered medium is substantially the same (or meets 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 using stringent conditions of 40°C and 75% relative humidity for any of these periods of time) as the dissolution profile of the capsule before storage.

The term "substantially the same" may mean a specific value that differs from the corresponding comparative value by about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, or about 1%. Values expressed as percentages are calculated based on the nominal value of the comparative value. Thus, for example, a dissolution time value in the range of 27 to 33 minutes may be considered to differ by 10% from a comparative dissolution time value of 30 minutes.

In some embodiments, the present invention may also relate to a method of stabilizing any of the soft gelatin delayed release capsules described in the present invention. The method may include protecting (e.g., from oxidation or other possible cause of chemical degradation) any of the fill materials described in the present invention by encapsulating any of the fill materials described in the present invention (including at least one active agent) using any of the pH-dependent shell compositions described in the present invention.

In some embodiments, use of the pH-dependent shell composition described herein provides a durable, delayed-release soft gelatin capsule that exhibits little or no premature release of fill material in an acidic environment (e.g., in the stomach or an artificial gastric environment such as artificial gastric juice, 0.1 N HCl, optionally with added pepsin) for at least about 10 minutes, at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours. For example, the delayed-release soft gelatin capsules described herein can release up to about 10 wt. %, up to about 9 wt. %, up to about 8 wt. %, up to about 7 wt. %, up to about 6 wt. %, up to about 5 wt. %, up to about 4 wt. %, up to about 3 wt. %, up to about 1 wt. % or 0 wt. % of the filler material, based on the total weight of the filler material after being kept in an acidic medium for up to about 150 min, up to about 120 min, up to about 105 min, up to about 90 min, up to about 75 min, up to about 60 min, up to about 45 min, up to about 30 min, up to about 15 min, up to about 10 min or up to about 5 min.

In some embodiments, hardening the delayed release soft gelatin capsules described herein (i.e., which are encapsulated using a pH-dependent shell composition) can provide for a reduction in the number of capsules or no capsules that exhibit premature release of any amount in an acidic environment, after a time period of about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours, or any subrange thereof. For example, the amount of hardened capsules characterized by premature release in an acidic environment (after keeping in an acidic environment for up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 150 minutes, up to about 120 minutes, up to about 105 minutes, up to about 90 minutes, up to about 75 minutes, up to about 60 minutes, up to about 45 minutes, up to about 30 minutes, up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes) can be up to about 30%, up to about 25%, up to about 20%, up to about 15%, up to about 10%, up to about 5%, up to about 3%, up to about 2%, up to about 1%, or 0%, based on the total number of capsules in the batch.

In contrast, without curing, the amount of capsules (having the same composition) characterized by premature release in an acidic environment (after keeping in an acidic environment for up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 150 minutes, up to about 120 minutes, up to about 105 minutes, up to about 90 minutes, up to about 75 minutes, up to about 60 minutes, up to about 45 minutes, up to about 30 minutes, up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes) can be greater than about 2%, greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, or greater than about 90% in recalculated to the total number of capsules in the batch.

In some embodiments, hardening the delayed release soft gelatin capsules described herein (i.e., which are encapsulated using a pH-dependent shell composition) can provide a reduction in the amount of fill material released from capsules that are characterized by premature release of some amount in an acidic environment, or no such release (e.g., after incubation in an acidic environment for up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 150 minutes, up to about 120 minutes, up to about 105 minutes, up to about 90 minutes, up to about 75 minutes, up to about 60 minutes, up to about 45 minutes, up to about 30 minutes, up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes).

For example, the amount of fill material released from hardened capsules characterized by the premature release of some amount in an acidic environment (e.g., after keeping in an acidic environment for up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 150 minutes, up to about 120 minutes, up to about 105 minutes, up to about 90 minutes, up to about 75 minutes, up to about 60 minutes, up to about 45 minutes, up to about 30 minutes, up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes) can be up to about 5 wt. %, up to about 4 wt. %, up to about 3 wt. %, up to about 2 wt. %, up to about 1 wt. %, or 0%, based on the total weight of the fill material contained in the capsule.

In contrast, without curing, the amount of filler material released from capsules (having the same composition) characterized by premature release in an acidic environment (e.g., after keeping in an acidic environment for up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 150 minutes, up to about 120 minutes, up to about 105 minutes, up to about 90 minutes, up to about 75 minutes, up to about 60 minutes, up to about 45 minutes, up to about 30 minutes, up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes) can be greater than about 1 wt. %, greater than about 2 wt. %, greater than about 3 wt. %, greater than about 4 wt. %, greater than about 5 wt. %, greater than about 6 wt. %, greater than about 7 wt. %, greater than about 8 wt. %, more than about 9 wt. %, more than about 10 wt. %, more than about 15 wt. %, or more than about 20 wt. %, based on the total weight of the filler material contained in the capsule.

In some embodiments, use of the pH-dependent shell composition described in the present invention provides a durable, delayed-release soft gelatin capsule that remains intact in an acidic environment (e.g., in the stomach environment or an artificial stomach environment such as artificial gastric juice, 0.1 N HCl solution, optionally with the addition of pepsin) for at least about 10 minutes, at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours, but releases at least about 50 wt. %, at least about 60 wt. %, at least about 70 wt. %, at least about 80 wt. %, at least about 90 wt. %, at least about 95 wt. %, at least about 96 wt. %, at least about 97 wt. %, at least about 98 wt. %, or at least about 98 wt. % of the filling material based on the total weight of the filling material in the colonic medium (or artificial colonic media, such as a buffered medium having a pH of 6.8, optionally with the addition of pancreatin) after a period of time of at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, or after a period of time ranging from any of about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, or about 30 minutes, up to any of about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 75 minutes, or about 90 minutes, or after a period of time, (representing any single value or a value within any subrange specified in the present invention) when maintained in such a colonic environment or artificial colonic environment.

In one embodiment, the pH-dependent coating composition comprises: (a) gelatin, (b) dextrose, (c) a pH-dependent polymer (e.g., pectin, such as low methoxylated pectin), (d) a plasticizer (e.g., glycerol, sorbitol, and combinations thereof), and optionally (e) a stabilizer and/or binder (e.g., gellan gum). The amounts and weight ratios of these components may correspond to any of the values or ranges described above in the present invention.

In one embodiment, the pH-dependent coating composition consists essentially of: (a) gelatin, (b) dextrose, (c) a pH-dependent polymer (e.g., pectin, such as low methoxylated pectin), (d) a plasticizer (e.g., glycerin, sorbitol, gellan gum, and combinations thereof), and optionally (e) a stabilizer and/or binder (e.g., gellan gum). The amounts and weight ratios of these components may correspond to any of the values or ranges described above in the present invention.

In one embodiment, the pH-dependent coating composition comprises: (a) gelatin, (b) dextrose, (c) a pH-dependent polymer (e.g., pectin, such as low methoxylated pectin), (d) a plasticizer (e.g., glycerin, sorbitol, gellan gum, and combinations thereof), and optionally (e) a stabilizer and/or binder (e.g., gellan gum). The amounts and weight ratios of these components may correspond to any of the values or ranges described above in the present invention.

In one embodiment, the pH-dependent shell composition comprises: (a) from about 30 to about 85 wt. %, from about 30 to about 75 wt. %, from about 30 to about 65 wt. %, from about 30 to about 55 wt. %, from about 30 to about 40 wt. %, from about 40 to about 80 wt. %, from about 45 to about 65 wt. %, from about 45 to about 75 wt. %, or from about 50 to about 70 wt. % gelatin, (b) from about 0.01 to about 4 wt. %, or from about 0.1 to about 3 wt. %, from about 0.2 to about 2 wt. %, or from about 0.01 to about 0.1 wt. %, or from about 0.05 to about 0.5 wt. %, or from about 0.1 to about 0.2 wt. %, or from about 0.15 to about 0.25 wt. %, or from about 0.2 to about 0.4 wt. % dextrose, (c) from about 2 to about 20 wt. %, from about 3 to about 15 wt. %, from about 7 to about 15 wt. %, from about 3 to about 5.5 wt. %, or from about 7 to about 12 wt. % a pH-dependent polymer (e.g., a pectin, such as a low methoxylated pectin), (d) from about 15 to about 45 wt. %, from about 15 to about 40 wt. %, from about 20 to about 35 wt. %, or from about 25 to about 30 wt. % a plasticizer, and optionally (e) from about 0.05 to about 5 wt. %, about 0.1 to about 3 wt. %, or from about 0.2 to about 2 wt. % stabilizer and/or binder (e.g. gellan gum). All values expressed in wt. % are based on the total weight of the dry composition of the pH-dependent shell.

In one embodiment, the pH-dependent shell composition consists essentially of: (a) from about 30 to about 85 wt. %, from about 30 to about 75 wt. %, from about 30 to about 65 wt. %, from about 30 to about 55 wt. %, from about 30 to about 40 wt. %, from about 40 to about 80 wt. %, from about 45 to about 65 wt. %, from about 45 to about 75 wt. %, or from about 50 to about 70 wt. % gelatin, (b) from about 0.01 to about 4 wt. %, or from about 0.1 to about 3 wt. %, or from about 0.2 to about 2 wt. %, or from about 0.01 to about 0.1 wt. %, or from about 0.05 to about 0.5 wt. %, or from about 0.1 to about 0.2 wt. %, or from about 0.15 to about 0.25 wt. %, or from about 0.2 to about 0.4 wt. % dextrose, (c) from about 2 to about 20 wt. %, from about 3 to about 15 wt. %, from about 7 to about 15 wt. %, or from about 3 to about 5.5 wt. %, or from about 7 to about 12 wt. % a pH-dependent polymer (e.g., a pectin, such as low methoxylated pectin), (d) from about 15 to about 45 wt. %, from about 15 to about 40 wt. %, from about 20 to about 35 wt. %, or from about 25 to about 30 wt. % a plasticizer, and optionally (e) from about 0.05 to about 5 wt. %, from about 0.1 to about 3 wt. %, or from about 0.2 to about 2 wt. % of a stabilizer and/or binder (e.g., gellan gum). All values expressed in wt. % are based on the total dry weight of the pH-dependent coating composition.

In one embodiment, the pH-dependent shell composition comprises: (a) from about 30 to about 85 wt. %, from about 30 to about 75 wt. %, from about 30 to about 65 wt. %, from about 30 to about 55 wt. %, from about 30 to about 40 wt. %, from about 40 to about 80 wt. %, from about 45 to about 65 wt. %, from about 45 to about 75 wt. %, or from about 50 to about 70 wt. % gelatin, (b) from about 0.01 to about 4 wt. %, or from about 0.1 to about 3 wt. %, or from about 0.2 to about 2 wt. %, or from about 0.01 to about 0.1 wt. %, or from about 0.05 to about 0.5 wt. %, or from about 0.1 to about 0.2 wt. %, or from about 0.15 to about 0.25 wt. %, or from about 0.2 to about 0.4 wt. % dextrose, (c) from about 2 to about 20 wt. %, from about 3 to about 15 wt. %, from about 7 to about 15 wt. %, or from about 3 to about 5.5 wt. %, or from about 7 to about 12 wt. % a pH-dependent polymer (e.g., a pectin, such as a low methoxylated pectin), (d) from about 15 to about 45 wt. %, from about 15 to about 40 wt. %, from about 20 to about 35 wt. %, or from about 25 to about 30 wt. % a plasticizer, and optionally (e) from about 0.05 to about 5 wt. %, from about 0.1 to about 3 wt. %, or from about 0.2 to about 2 wt. % stabilizer and/or binder (e.g. gellan gum). All values expressed in wt. % are based on the total weight of the dry composition of the pH-dependent shell.

EXAMPLES

Specific embodiments of the present invention will be described with reference to the following examples. It should be understood that these examples are provided solely to illustrate the present invention and should not be considered as limiting the scope of the present invention in any way.

EXAMPLE 1 - Effect of Dextrose Concentration on Formulation Processability

pH-dependent coating compositions having different dextrose concentrations were prepared to study the effect of dextrose concentration on the processing properties of the composition. The pH-dependent coating compositions are shown in Table 1.

The effect of changing the amount of dextrose contained in the pH-dependent coating composition on the disintegration time at a pH of 6.8 is presented in Table 2.

Dextrose is a reducing sugar and is thought to interact with gelatin to cause cross-linking of the gelatin. If the gelatin is cross-linked, its solubility is reduced. Dextrose has been shown to stabilize (i.e. reduce leakage) a pectin-containing soft gelatin capsule in an acidic environment. Dextrose can also affect the amount of active agent (vitamins, minerals, food additives or pharmaceutical ingredients) released in a buffered environment, as well as the dissolution time of the active agent in the buffered environment. This is illustrated in Example 7 below using samples from Groups 3 and 4 of Table 2.

Although Table 2 shows that some capsules (e.g., those in Groups 2, 3, and 4) do not disintegrate in a phosphate buffer with a pH of 6.8 within 60 min, when pancreatin is added to the buffer medium (which is believed to better simulate in vivo conditions), the shell composition dissolves in less than 45 min, as shown in Example 7 below.

EXAMPLE 2 - Effect of curing on capsule release characteristics

The pH-dependent coating compositions were prepared to study the curing properties of the capsules. The pH-dependent coating compositions are shown in Table 3.

In the case of existing commercially available products, a large number of capsules exhibit premature release, increased amounts of filler material are released prematurely, and in some cases almost 100 wt.% of the filler material is released in an acidic environment within 10 min.

Soft gelatin capsules containing a coating were examined, but they did not dissolve in the buffer medium for an extended period of time (for more than about 60 minutes and in some cases for up to 120 minutes). It was believed that the prolonged dissolution in the buffer medium indicated that the soft gelatin capsules containing a coating did not provide bioavailability. This fact, as well as the difficult two-step manufacturing process, prompted studies of pH-dependent coating compositions for the preparation of delayed-release soft gelatin capsules without the application of a separate coating.

The pH-dependent shell compositions shown in Table 3 were used to prepare pectin-containing soft gelatin capsules that provided a reduction in the incidence of premature release of fill material and a slight reduction in the amount of fill material that was prematurely released (compared to existing commercially available products).

However, prior to curing, a significant proportion of soft gelatin capsules in each lot still exhibited premature release of some fill material in an acidic environment (e.g., 0.1 N HCl), as shown in Table 3 under "% of capsules exhibiting premature release prior to curing." About 60 to about 72 capsules from each lot were tested to determine the % of capsules exhibiting premature release prior to curing.

In some embodiments, about 10 wt. % of the fill material was released from the capsules characterized by premature release before curing. In some embodiments, more than 10 wt. % of the fill material was released from the capsules characterized by premature release before curing, or less than 10 wt. % of the fill material was released from the capsules characterized by premature release before curing.

As shown in the following examples, curing provides a reduction in the incidence of premature release, a reduction in the amount of filler material released if premature release occurs, and in some cases no premature release at all.

The pectin-containing soft gelatin capsules were cured to improve their stability in an acidic environment (e.g., 0.1 N HCl). The pectin-containing soft gelatin capsules were packed in cardboard boxes (in case of large quantities) or in high-density polyethylene (HDPE) bottles and placed in an oven heated to 40°C. Humidity control was not used. The only variable parameter for the samples was the curing time. The results of the curing studies for capsules of lots 1, 2, and 3 are shown in Table 4 below.

Dissolution after curing was tested according to the USP enteric coating test method using a two-stage dissolution test for enteric coating materials applicable to uncoated soft gelatin enteric capsules. Unless otherwise stated, throughout this specification, the acidic environment, buffer environment, apparatus, and dissolution test conditions used to conduct all dissolution tests were as described herein with respect to the two-stage dissolution test for enteric coating materials.

A USP II apparatus with paddles was used, with a paddle speed of 50 rpm and a temperature of 37°C. In the acid stage, the medium was 0.1 N HCl. In the buffer stage, the medium was phosphate buffer with a pH of 6.8. For a vitamin, mineral, food supplement, and/or nutraceutical, in order for the enteric capsules to pass the first stage test, they must remain intact in the acid medium for at least 60 min, and in order for them to pass the second stage test, they must disintegrate in the buffer medium within 45 min. In the case of pharmaceutical products, for enteric-coated capsules to pass the first stage test, they must remain intact in an acidic environment for at least 120 minutes, and for them to pass the second stage test, they must disintegrate in a buffered environment within 45 minutes.

Soft gelatin capsules cured for 24 hours, 48 hours, 72 hours, 120 hours, 168 hours and 288 hours were tested. However, the present invention presents results obtained with curing for only up to 72 hours.

Table 5 shows the results for the amount of fill material prematurely released from pectin-containing soft gelatin capsules of batch 3 in an acidic environment before and after curing, obtained in accordance with the USP test criteria for enteric coating materials, after 2 hours. The maximum amount of fill material released was 5%. The fill material for the pectin-containing soft gelatin capsules of batch 3 included fish oil (which contains docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)).

The results of the curing study show that curing provides a significant reduction in the amount of premature release of the filling material from pectin-containing capsules in an acidic environment or ensures the absence of premature release, and provides capsules with stable enteric-coating characteristics and a high-quality enteric-coating product.

It should be noted that all pectin-containing soft gelatin capsules listed in Table 5 were dissolved in a buffer with a pH of 6.8 within 15 min.

EXAMPLE 3 - Results of a study on the dissolution of enteric-coated capsules in artificial gastric juice (AGJ) with the addition of pepsin

A disintegration study was conducted on enteric-coated hardened pectin-containing capsules with the gel mass compositions shown in Table 6A using 0.1 N HCl with the addition of pepsin (to simulate in vivo conditions in humans) to conduct a two-stage dissolution study of the enteric-coated material.

Pepsin does not affect the dissolution of pectin-containing shells in 0.1 N HCl when a suitable shell composition is used, such as a suitable gelatin to pectin weight ratio. In the capsules of lots 4 and 5 shown in Tables 6A and 6B, the gelatin to pectin weight ratio was 7:1. Without imposing limitations, it can be assumed that the pectin-containing soft gelatin capsules are strong and that the gelatin-pectin networks are strong enough to resist the attack of pepsin, this is confirmed by the fact that pectin-containing soft gelatin capsules remain intact for 120 min in 0.1 N HCl even in the presence of pepsin, this medium is a biorelevant medium, in contrast to the medium used in the pharmacopoeial method, which does not contain the enzyme. Thus, it can be expected that pectin-containing soft gelatin capsules will also be sufficiently robust in vivo.

EXAMPLE 4 - Modulation of the degradation time of pectin-containing capsules in enteric media by varying the gelatin to pectin mass ratio

Pectin-containing soft gelatin capsules with different gelatin-to-pectin ratios were prepared. The compositions of the capsules from different batches are shown in Table 7B below. The disintegration time of the pectin-containing capsules in IZHS (0.1 N HCl) with added pepsin varied with the gelatin-to-pectin ratio, as shown in Table 7A below.

All pectin-containing soft gelatin capsules listed in Table 7A were disintegrated in a buffer having a pH of 6.8 within 45 min. Table 7A shows that the disintegration time of pectin-containing soft gelatin capsules in an acidic medium can be modulated by changing the gelatin to pectin mass ratio.

EXAMPLE 5 - Effect of Softgelatin Tape Thickness on Enteric Properties of Pectin-Containing Softgelatin Capsules

Pectin-containing soft gelatin capsules were prepared using tapes of varying thickness. The dry compositions of the pH-dependent shells used to prepare batches of capsules using tapes of varying thickness are shown in Table 8A below. The dissolution of pectin-containing capsules prepared using tapes of varying thickness was studied after curing for approximately 72 to 96 h in IHS (0.1 N HCl) and a buffer having a pH of 6.8. The results are shown in Table 8B below.

The results of the dissolution study presented in Table 8B show that pectin-containing soft gelatin capsules made from a tape having a thickness in the range of 0.028 to 0.038 inches are strong after curing and meet the requirements for enteric pharmaceutical products and VMS (vitamin, mineral, dietary supplement) products. This thickness range should not be considered limiting. In some embodiments, thicker tapes or thinner tapes can also be used.

EXAMPLE 6 - Viscosity of a pH-dependent shell composition after aging

Pectin and gelatin interact with each other to form networks that contribute to a significant increase in the viscosity of the gel mass, as shown in Fig. 1. It can be assumed that the interaction between pectin and gelatin contributes to the delayed release characteristics of the capsule shell composition. However, as shown in Fig. 1, the viscosity of the gel mass of the pH-dependent shell composition decreases over time. The viscosity values and the decrease expressed in % are presented in Table 9 below.

In this example and in all cases in this description, the viscosity was determined using a rheometer (HAAKE Rheostress 6000, Thermo Fisher) at 60°C. The studies were conducted under ambient conditions. The gel mass samples were placed on the rheometer platform, which was maintained at 60°C. The 40 mm diameter disk was oscillated at a frequency of 0.1 Hz and the shear rate was maintained constant. The viscosity was determined by measuring the shear stress and the shear rate.

As can be seen from Table 9, after aging at 60°C for 48 h, after aging at 60°C for 72 h, and after aging at 60°C for 96 h, the non-amidated pectin exhibited a smaller percentage decrease in viscosity than the amidated pectin.

It can be assumed that the decrease in viscosity is caused by thermal decomposition of the long molecular chains of pectin and gelatin. Despite this decrease in viscosity, the gel masses of the pH-dependent shell compositions retain a viscosity suitable for manufacturing and processing, even after maintaining the composition under heating at 60 °C for 4 days. In addition, soft gelatin capsules made using aged gel still have satisfactory pH-dependent delayed release characteristics.

EXAMPLE 7 - Effect of adding dextrose on dissolution time in a buffered medium in the presence of pancreatin

The dissolution of pectin-containing soft gelatin capsules containing different amounts of dextrose in a pH-dependent shell composition was studied in an acidic medium (0.1 N HCl, pH 1.2) and in a buffered medium (phosphate buffer, pH 6.8, with the addition of 1% pancreatin). The dissolution of these pectin-containing soft gelatin capsules was studied in accordance with the two-stage dissolution study of enteric materials described in Example 2 above. The results are shown in Table 10 below.

Three samples from groups 3 and 4 listed in Tables 1 and 2 (Example 1) above were tested and the average value was determined. As can be seen from the results in Table 10, the samples from group 3 (0.1 wt.% dextrose in the pH-dependent coating composition) remained intact in an acidic medium (0.1 N HCl, pH 1.2) for 120 min and were destroyed in a buffer medium (phosphate buffer, pH 6.8, with the addition of 1% pancreatin) after approximately 25.7 min (on average). Group 4 samples (0.15 wt% dextrose in a pH-dependent coating composition) remained intact in an acidic medium (0.1 N HCl, pH 1.2) for 120 min and were destroyed in a buffered medium (phosphate buffer, pH 6.8, with the addition of 1% pancreatin) after approximately 39.0 min (on average).

Thus, as shown in Table 10, the amount of dextrose contained in the pH-dependent coating composition can be adjusted to ensure a targeted dissolution/disintegration/degradation time in a buffered medium with the addition of pancreatin. This is applicable to ensure targeted delivery of active agents such as vitamins, minerals, food additives or pharmaceutical ingredients to the colon.

EXAMPLE 8 - Chemical stability of a pectin-containing soft gelatin capsule

Table 11 below shows the results of a chemical stability study of capsules containing fish oil encapsulated using a pectin-containing pH-dependent shell composition according to the embodiments described in the present invention, after storage for 6 months under ambient conditions and at 40°C and at a relative humidity (RH) of 75%. Acceptable capsules should have the following characteristics: EPA-TG (triglycerides) ≥ 160 mg/g, DHA-TG ≥ 100 mg/g, peroxide ≤ 5 mEq _O2 /kg, p-anisidine ≤ 20, dissolution time in 0.1 N HCl solution (pH = 1.2): more than 120 min, and dissolution time in a buffered medium (phosphate buffer, pH = 6.8): up to 45 min. The values of these parameters are given in Table 11 for the control sample (fish oil starting material), for the pectin-containing delayed-release soft gelatin capsule stored at ambient conditions for 6 months, and for the pectin-containing delayed-release soft gelatin capsule stored at 40°C and 75% RH for 6 months.

The results of the accelerated stability study (shown in Table 11) indicate that the pectin-containing pH-stable shell composition according to the embodiments provides protection of the filling material (e.g., fish oil components) from oxidation, as evidenced by the minor difference/significant similarity in the values for peroxide and p-anisidine, and the results of the EPA and DHA analysis obtained after 6 months (after storage at ambient conditions, as well as under the harsh conditions of 40°C and 75% RH), when compared with the results obtained for the starting material.

EXAMPLE 9 - Pectin-containing soft gelatin capsule with incorporated valproic acid

Table 12A below illustrates the stability of the dissolution profile of capsules containing valproic acid encapsulated using a pectin-containing pH-dependent shell composition (the gel composition at levels indicated based on the weight of the dry shell composition is presented in Table 12B) according to the embodiments described in the present invention, at T=0, after storage for 3 months (T=3 months) at 40°C and at a relative humidity (RH) of 75%, and after storage for 6 months (T=6 months) at 40°C and at a RH of 75%. As can be seen from Table 12A, the dissolution profile of the pH-dependent shell composition after storage for 3 months at 40°C and at a RH of 75%, and after storage for 6 months at 40°C and at a RH of 75%, remains substantially the same as the dissolution profile at T=0.

EXAMPLE 10 - Physical characteristics of soft gelatin capsules containing pectin

The delayed release soft gelatin capsules containing the pH dependent shell composition described in the present invention are strong as evidenced by their physical characteristics shown in Table 13 below.

The moisture content of the shell was determined using the loss on drying method. A sample of the pH-dependent capsule shell composition weighing 1 to 2 g was kept in an oven at 105°C for 17 h. The initial weight of the sample was recorded. After drying the sample in an oven at 105°C for 17 h, the final weight of the sample was recorded. The percentage loss in weight, calculated according to the equation below, was determined as the moisture content of the shell:

The hardness of the capsule was determined using a hardness testing device. The force, expressed in Newtons, required to compress the capsule by 2.0 mm was defined as the hardness of the capsule.

Equilibrium relative humidity (%) was defined as the humidity at which the capsule retains a constant total mass. It was determined using artificial climate chambers in which constant humidity was maintained using saturated salt solutions.

The crushing strength was determined using Texture Analyzer. Using Texture Analyzer, the capsule was compressed until it broke. The force, expressed in kilograms, required to break the capsule was determined as the crushing strength.

EXAMPLE 11 - Illustrative Delayed Release Soft Gelatin Capsule Composition Containing Pectin and Gellan Gum

A delayed-release soft gelatin capsule was prepared that contained a combination of pectin and gellan gum. The composition is shown in Table 14 below, the contents of the components are given based on the weight of the dry shell composition.

EXAMPLE 12 - Stability Study of Gel Mass Compositions Corresponding to Embodiments Described in the Present Invention

The stability of gel mass compositions corresponding to embodiments described in the present invention was studied. Three gel masses having different dextrose concentrations were prepared. Soft gelatin capsules containing 1000 mg of fish oil were prepared from the gel masses. The soft gelatin capsules were dried and packed in HDPE bottles, then the bottles were sealed by induction sealing. The composition of each gel mass (calculated on the weight of the dry shell) is given in Table 15. As shown in Table 15, the basic composition of the gel mass was the same and the amount of dextrose was varied, which was 0.05 wt. %, 0.10 wt. % and 0.15 wt. %.

Soft gelatin capsules from all three lots, packaged in HDPE bottles, were placed in stability chambers under the following conditions: 40°C/relative humidity=75%. At the 3 and 6 month time points, samples were removed and analyzed. During the stability study, enzyme was added before the buffer steps. The results of the stability study are shown in Tables 16A-16D. The results indicate that compositions containing dextrose in amounts of about 0.05 to about 0.10 wt.% are stable under accelerated conditions for about 6 months. In the case of pancreatin addition, compositions containing 0.15 wt.% were good stable under accelerated conditions for 6 months.

Table 17 shows the results of a stability study of soft gelatin capsules stored at ambient conditions for 2 years.

As shown in Table 17, the compositions containing from about 0.05 to about 0.1 wt. % had good stability under room temperature conditions for 2 years. In conclusion, it should be noted that the addition of different amounts of dextrose improves the stability of the enteric properties of pectin-containing soft gelatin capsules, which allows for the delivery of certain drug molecules to the colon.

For ease of explanation, embodiments of the methods of the present invention are shown and described as a sequence of actions. However, the actions of the present invention can be performed in any order and/or simultaneously and together with other actions not shown and described herein. In addition, not all illustrated events may be required to perform the methods corresponding to the claimed subject matter. In addition, it should be understood and obvious to those skilled in the art that the methods can alternatively be represented as a series of interrelated states in the form of a state diagram or events.

In order to provide a thorough understanding of the present invention, numerous specific features are set forth in the foregoing description, such as specific materials, dimensions, process parameters, and the like. Specific features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The words "example" or "typical" are used herein to indicate an example, instance, or illustration. Any feature or design described herein as "example" or "typical" is not necessarily preferred or advantageous over other features or designs. Rather, the use of the words "example" or "typical" is intended to describe representations in a particular manner. As used in this application, the term "or" is meant to be an inclusive "or" rather than an exclusive "or." This means that unless otherwise indicated or obvious from context, "X includes A or B" means any conventional inclusive permutation. This means that if X includes A; X includes B; or X includes both A and B, then "X includes A or B" means any of the above. In the present invention, reference to the expressions "an embodiment," "some embodiments," or "one embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, all the expressions "an embodiment," "some embodiments," or "one embodiment" in different parts of the present specification do not necessarily mean the same embodiment.

The present invention has been described with reference to specific exemplary embodiments thereof. Accordingly, the description and drawings are to be considered as illustrative and not restrictive. Various modifications of the present invention in addition to those shown and described herein will be apparent to those skilled in the art and are intended to be within the scope of the appended claims.

Claims (17)

1. A delayed release soft gelatin capsule for use in a method of treating a disease of the colon, comprising: (a) filling material and (b) a pH dependent shell composition, wherein the filling material comprises at least one pharmaceutically active ingredient, wherein the pH-dependent shell composition comprises, based on the total weight of the dry pH-dependent shell composition , from 45 to 65 wt.% gelatin, from 7 to 15 wt.% pectin and from 0.1 to 2 wt.% dextrose and where the pH dependent coating composition dissolves/disintegrates/degrades in the colonic environment. 2. A delayed release soft gelatin capsule according to claim 1, wherein the pH-dependent shell composition further comprises a plasticizer. 3. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the pectin is low methoxylated pectin or a pectin selected from the group consisting of amidated pectin, non-amidated pectin and combinations thereof, preferably the pectin is non-amidated pectin. 4. A delayed release soft gelatin capsule according to any one of claims 2, 3, wherein the pH-dependent shell composition comprises from 15 to 40 wt.%, preferably from 20 to 35 wt.%, more preferably from 25 to 30 wt.% of a plasticizer, based on the weight of the dry pH-dependent shell composition. 5. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the gelatin is selected from the group consisting of: gelatin type A, gelatin type B and mixtures thereof, or is selected from the group consisting of: fish gelatin, skin gelatin, bone gelatin and mixtures thereof. 6. A delayed release soft gelatin capsule according to any one of claims 2 to 5, wherein the plasticizer is selected from the group consisting of glycerol, sorbitol and combinations thereof, preferably glycerol. 7. A delayed release soft gelatin capsule according to any one of claims 1-6, wherein, according to the dissolution/disintegration test carried out using a USP II apparatus with paddles at a stirring speed of 50 rpm, in a phosphate buffer having a pH of 6.8, optionally with the addition of pancreatin, the capsule dissolves/disintegrates in the intestinal medium after a time period of at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, or after a time period comprising any value of 10 minutes, 15 minutes, 20 minutes, 25 minutes or 30 minutes up to any value of 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 75 minutes or 90 minutes. 8. A delayed release soft gelatin capsule according to any one of claims 1 to 7, wherein the capsule dissolves/disintegrates in an acidic medium in at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, or at least 5 hours, as determined by a dissolution/disintegration test using a USP II apparatus with paddles at a stirring speed of 50 rpm in 0.1 N HCl, optionally with the addition of pepsin. 9. A delayed release soft gelatin capsule according to any one of the preceding claims, which does not contain additional pH dependent polymers. 10. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the pH dependent shell composition has a viscosity in the range of from 110,000 to 125,000 cP. 11. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the pH-dependent shell composition has a weight ratio of gelatin to weight of pectin in the range of from 2:1 to 20:1 or from 6:1 to 18:1, or wherein the pH-dependent shell composition has a weight ratio of plasticizer to weight of gelatin in the range of from 5:1 to 1:5. 12. A delayed release soft gelatin capsule according to any one of claims 1 to 11, further comprising less than 1 wt.% of conventional pH-dependent polymers.