RU2828673C1 - DELAYED-RELEASE SOFT GELATIN CAPSULES IN MEDIUM WITH HIGHER pH VALUE - Google Patents

Abstract

FIELD: biotechnology; pharmaceutics.

SUBSTANCE: disclosed are soft gelatine sustained-release capsules containing a filling material and a shell composition, wherein the filling material contains at least one active agent, and the coating composition contains gelatine, dextrose and a pH-dependent polymer containing pectin and gellan gum. Described also are methods of producing such capsules and a method for controlling the pH-dependent dissolution profile of a sustained-release soft gelatine capsule and a method of delivering an active agent to a target site in the gastrointestinal tract by administering a sustained-release soft gelatine capsule to a subject.

EFFECT: group of inventions enables to stabilize and reduce the flow of a pH-dependent polymer, such as pectin, soft gelatine capsules in an acidic medium with dextrose content.

29 cl, 11 tbl

Description

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 62/926,681, filed October 28, 2019, which is incorporated herein by reference in its entirety.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to delayed release soft gelatin capsules, wherein the gelatin-based shell compositions comprise pectin and gellan gum.

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 form 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 the coating onto the dosage form and then drying the dosage form, typically 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 pH-dependent coating technique 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.

The release of active agents from typical delayed release preparations may occur at a pH that is only slightly above the normal pH of the stomach. This is problematic due to changes in the pH of the patient's stomach and may cause problems with the stability of the active agent and unintended release of the active agent at a higher position in the gastrointestinal tract than desired.

Accordingly, what is currently needed is a delayed-release soft gelatin capsule from which the active agent is not released or is substantially not released at certain pH values that exceed the pH value in the stomach.

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 (2) a pH-dependent shell composition.

In one embodiment, the pH-dependent shell composition comprises: (a) gelatin, (b) gellan gum, and (c) pectin, such as low methoxylated pectin, and optionally (d) a plasticizer and (e) dextrose. The present invention also relates to a method for making delayed-release capsules from soft gelatin.

In some embodiments, the soft gelatin delayed release 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 a pH-dependent coating, which also reduces the likelihood of damage to the capsules during the coating procedure.

In some embodiments, the present invention also relates to a method of treating a pathological condition carried out by administering to a subject in need thereof any of the soft gelatin delayed release capsule compositions disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention improves the prior art by providing oral dosage forms of delayed release, in particular delayed release soft gelatin capsules, from which the active agent is not released or is not substantially released at a pH that exceeds the pH of typical gastric juice, equal to 1.2, and from which the active agent is released at a target site located in the gastrointestinal tract, having a target pH (e.g., a pH of 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more). The dissolution profile of the delayed release capsules described in the present invention can be controlled by changing the composition of the soft gelatin capsule shell compositions.

This mechanism is advantageous for the delivery of active agents 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, food supplements, and/or pharmaceutical products that are formulated in dosage forms that exhibit some leakage (even extremely small amounts) in the stomach before reaching the intestine. Leakage can be particularly problematic when the belching is associated with substances that cause an unpleasant sensation, such as fish oil and garlic, which are typically 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 gastric juice. In addition, the soft gelatin delayed release capsules described in the present invention can provide these benefits in different subjects, including those subjects whose pH values in different parts of the gastrointestinal tract differ from "standard" or "average" pH values due to, for example, different diets.

In some embodiments, a soft gelatin delayed release capsule comprises (a) a fill material and (b) a shell composition, wherein the fill material comprises at least one active agent, and wherein the shell composition comprises gelatin and a pH-dependent polymer comprising pectin and gellan gum.

In some embodiments, the coating composition does not degrade at a pH of 5 for 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (e.g., as measured by a USP II paddle stirrer at 50 rpm using an acidic medium, 750-900 mL of 0.1 N HCl adjusted to the desired pH with phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 5 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., as measured by a test using a USP II apparatus with paddles at a stirring speed of from about 50 to about 250 rpm, using an acidic medium of from about 500 to about 900 ml of a 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 5 for a period of time of from about 15 minutes to about 360 minutes, from about 30 minutes to about 240 minutes, or from about 45 minutes to about 180 minutes (e.g., as measured by a test using a USP II apparatus with paddles at a stirring speed of from about 50 to about 250 rpm using an acidic medium of from about 500 to about 900 ml of a 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 5 to 6 for 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (e.g., as measured by a USP II paddle test at 50 rpm using an acidic medium, 750-900 mL of 0.1 N HCl adjusted to the desired pH with phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 5 to 6 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., as measured by a test using a USP II apparatus with paddles at a stirring speed of about 50 to about 250 rpm using an acidic medium of about 500 to about 900 ml of a 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 5 to 6 for a period of time of from about 15 to about 360 minutes, from about 30 to about 240 minutes, or from about 45 to about 180 minutes (e.g., as determined by testing using a USP II apparatus with paddles at a stirring speed of from about 50 to about 250 rpm using an acidic medium of from about 500 to about 900 ml of a 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 6 to 7 for 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (e.g., as measured by a USP II paddle test at 50 rpm using an acidic medium, 750-900 mL of 0.1 N HCl adjusted to the desired pH with phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 6 to 7 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., as measured by a test using a USP II apparatus with paddles at a stirring speed of about 50 to about 250 rpm using an acidic medium of about 500 to about 900 ml of a 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 6 to 7 for a period of time of from about 15 to about 360 minutes, from about 30 to about 240 minutes, or from about 45 to about 180 minutes (e.g., as measured by a test using a USP II apparatus with paddles at a stirring speed of from about 50 to about 250 rpm using an acidic medium of from about 500 to about 900 ml of a 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 7 to 8 for 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (e.g., as measured by a USP II paddle test at 50 rpm using an acidic medium, 750-900 mL of 0.1 N HCl adjusted to the desired pH with phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 7 to 8 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., as measured by a test using a USP II apparatus with paddles at a stirring speed of about 50 to about 250 rpm using an acidic medium of about 500 to about 900 mL of a 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 7 to 8 for a period of time of from about 15 to about 360 minutes, from about 30 to about 240 minutes, or from about 45 minutes to about 180 minutes (e.g., as measured by a test using a USP II apparatus with paddles at a stirring speed of from about 50 to about 250 rpm using an acidic medium of from about 500 to about 900 ml of a 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 8 to 8.4 for 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 120 minutes (e.g., as measured by a USP II paddle test at 50 rpm using an acidic medium, 750-900 mL of 0.1 N HCl adjusted to the desired pH with phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 8 to 8.4 for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes (e.g., as measured by a test using a USP II apparatus with paddles at a stirring speed of about 50 to about 250 rpm using an acidic medium of about 500 to about 900 ml of a 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of 8 to 8.4 for a period of time of about 15 to about 360 minutes, about 30 to about 240 minutes, or about 45 to about 180 minutes (e.g., as measured by a test using a USP II apparatus with paddles at a stirring speed of about 50 to about 250 rpm using an acidic medium of about 500 to about 900 ml of a 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of less than 8.4, less than 8.3, less than 8.2, less than 8.1, less than 8.0, less than 7.9, less than 7.8, less than 7.7, less than 7.6, less than 7.5, less than 7.4, less than 7.3, less than 7.2, less than 7.1, less than 7.0, less than 6.9, less than 6.8, less than 6.7, less than 6.6, less than 6.5, less than 6.4, less than 6.3, less than 6.2, less than 6.1, less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5, less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, less than 4.8, less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, less than 4.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, or less than 1.2, for a period of time equal to 15 min, 30 min, 45 min, 60 min, 90 min, or 120 min (e.g., based on a test using a USP II apparatus with paddles at a stirring speed of 50 rpm, using an acidic medium, 750-900 ml of 0.1 N HCl solution adjusted to the required pH with phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of less than 8.4, less than 8.3, less than 8.2, less than 8.1, less than 8.0, less than 7.9, less than 7.8, less than 7.7, less than 7.6, less than 7.5, less than 7.4, less than 7.3, less than 7.2, less than 7.1, less than 7.0, less than 6.9, less than 6.8, less than 6.7, less than 6.6, less than 6.5, less than 6.4, less than 6.3, less than 6.2, less than 6.1, less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5, less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, less than 4.8, less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, less than 4.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, or less than 1.2, for a period of time of at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 min, not less than about 90 min, or not less than about 120 min (e.g., as determined by testing using a USP II apparatus with paddles at a stirring speed of from about 50 to about 250 rpm, using an acidic medium, from about 500 to about 900 ml of a 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer, sodium hydroxide, or potassium hydroxide).

In some embodiments, the coating composition does not degrade at a pH of less than 8.4, less than 8.3, less than 8.2, less than 8.1, less than 8.0, less than 7.9, less than 7.8, less than 7.7, less than 7.6, less than 7.5, less than 7.4, less than 7.3, less than 7.2, less than 7.1, less than 7.0, less than 6.9, less than 6.8, less than 6.7, less than 6.6, less than 6.5, less than 6.4, less than 6.3, less than 6.2, less than 6.1, less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5, less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, less than 4.8, less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, less than 4.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, or less than 1.2, for a period of time equal to from about 15 to about 360 minutes, from about 30 to about 240 minutes, or from about 45 to about 180 min (e.g., as determined by testing using a USP II apparatus with paddles at a stirring speed of about 50 to about 250 rpm, using an acidic medium, about 500 to about 900 ml of 0.1 N HCl solution adjusted to the desired pH with phosphate buffer, sodium hydroxide, or potassium hydroxide).

With the present invention, it is possible to select a pH value that is suitable for the rupture of the coating composition and the release of the active agent, in order to program the release of the active agent in the desired area of the gastrointestinal tract. For example, a typical pH value in the duodenum is in the range of 7.0 to 8.5; the pH value in the small and large intestine is usually from 4.0 to 7.0; a typical pH value in the colon is 6.5 and a typical pH value in the jejunum is from 6.1 to 7.2. In one embodiment, the coating composition can be adapted to target the release of the active agent in the duodenum at a pH of from about 7.0 to about 8.5. In one embodiment, the coating composition can be adapted to target the release of the active agent in the small and large intestine at a pH of from about 4.0 to about 7.0. In one embodiment, the coating composition may be adapted to target the release of the active agent in the colon at a pH of about 6.5. In one embodiment, the coating composition may be adapted to target the release of the active agent in the jejunum at a pH of about 6.1 to about 7.2.

In some embodiments, the weight ratio of pectin to 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.

As used herein, the term "pH dependent" means a characteristic of the stability of a substance to dissolution or disintegration such that, in some embodiments, the substance does not or substantially does not dissolve or disintegrate in gastric fluid, or, in alternative embodiments, the substance does not or substantially does not dissolve or disintegrate in the pH ranges disclosed herein, such as within a period of time 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. For example, embodiments described herein include a pH dependent coating composition that preferentially dissolves in a biological, synthetic, or artificial intestinal fluid rather than in a biological, synthetic, or artificial gastric fluid.

As used herein, the terms "pharmaceutically active ingredient," "active agent," or "pharmaceutically active agent" mean a drug or compound that can be used to diagnose, cure, alleviate, treat, or prevent a pathological condition, and/or a 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. These terms, when used in reference to a particular agent, include a pharmaceutically active agent and all pharmaceutically acceptable salts, solvates, and crystalline forms thereof, wherein the salts, solvates, and crystalline forms are pharmaceutically active. In some embodiments, suitable "active agents" include nutraceuticals such as vitamins, minerals, and nutritional supplements (VMS). 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. Typical, non-limiting examples of pathological conditions for which delayed release soft gelatin capsules may be useful may include those pathological conditions that can be treated or prevented, without limitation, by administering capsules containing mesalamine, lactic acid bacteria, fish oil, dietary supplements, proton pump inhibitors, aspirin and similar products.

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 slightly soluble in water. Suitable pharmaceutically active ingredients include, but are not limited to, analgesics and anti-inflammatory agents, 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 modulating agents, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritional agents, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants and their combinations.

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 fatty acids _C8 , _C10 , _C12 , _C14 , _C16 , _C16 , _C20 and _C22 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 HCl, 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, ginger root, ginkgo biloba, ginseng, goldenrod, hawthorn, kava kava, licorice, milk thistle, plantain, rauwolfia, senna, soybean, St. John's wort, saw palmetto, turmeric, valerian.

Suitable 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 can 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" and "effective amount" mean the amount of active agent or the rate of administration thereof that is necessary to provide the desired therapeutic result.

The terms "treatment" and "treat" include the administration of an active agent with the aim of alleviating the severity of a pathological condition.

The terms "prevention" and "prevent" include the prevention of the occurrence of a pathological condition by prophylactic administration of an active agent.

The term "subject" means a human or animal who exhibits (clinical or otherwise) a pathological condition and is suspected of needing treatment with any of the active agents described herein.

As used herein, "shell" or "shell composition" means a soft gelatin capsule shell in which a fill material is encapsulated. In some embodiments, these terms and the term "pH-dependent shell composition" are also used interchangeably.

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. Gellan gum and gellan gum 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, based on the total weight of the composition.

Throughout this description and in the claims, all values indicated in wt.% mean the mass of the component based on the mass of the entire composition 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 capsule shell and contains at least one active agent.

As used in the present invention, the terms "delayed release capsules" or "delayed release soft gelatin 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. No additional processing steps are required.

As used herein, the term "about" means any value equal to that value within ±10%, so that a value of "about 10" includes values of 9 to 11. As used herein, singular or plural terms mean one or more unless otherwise indicated. For example, a reference to an "inert filler" includes a 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 specifically indicate 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 carried out in any suitable order, unless otherwise indicated in the present invention and unless clearly contradicted by the 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, the 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 active agent, wherein the pH-dependent shell composition comprises gelatin, gellan gum, pectin and optionally a plasticizer and/or dextrose. Preferably, the pH-dependent composition does not contain or is substantially free of additional pH-dependent polymers (e.g. conventional pH-dependent polymers).

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

In one embodiment, the gelatin contained in the pH-dependent shell composition may comprise gelatin type A, gelatin type B, hide or skin gelatin (e.g., from calf skin, pig skin) and/or bone gelatin (e.g., from 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 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 75 wt. %, or from about 50 to about 70 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.

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 wt. %, or from about 0.01 to about 2 wt. %, or up to about 4 wt. %, from about 0.1 wt. %, or from about 0.15 to about 3 wt. %, from about 0.1 to about 1 wt. %, from about 0.1 or from about 0.15 wt. %, or from about 0.2 wt. %, or from about 0.25 to about 2 wt. %, from about 0.1 to about 0.2 wt. %, or from about 0.1 to about 0.4 wt. % based on the total weight of the dry composition of the capsule shell, or 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 mitigation of a possible decrease in the gel strength of the shell composition. The concentration of dextrose contained in the pH-dependent shell composition can be effective to improve the gel strength of the shell composition, but not so high that the capsule seal, the processability of the capsule or shell composition, or the performance of the soft gelatin capsule 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 for a reduction in the decrease in the gel strength of the shell composition and a reduction in the increase in the viscosity of the shell composition.

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, any of the pH-dependent coating compositions described herein further comprises gellan gum. In some embodiments, the weight ratio of pectin to 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 ratio of pectin to gellan gum can be adjusted to provide a desired pH-dependent dissolution/disintegration profile of the coating composition.

In one embodiment, the amount of gellan gum contained in the pH dependent shell composition is from about 0.1 to about 10 wt.%, from about 0.2 to about 8 wt.%, from about 0.4 to about 5 wt.%, from about 0.05 to about 5 wt.%, from about 0.1 to about 3 wt.%, from about 0.2 to about 2 wt.%, from about 0.2 to about 0.8 wt.%, or from about 0.3 to about 0.7 wt.%, based on the total dry weight of the capsule shell composition, or any single amount or amount within any subrange specified herein.

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, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 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, 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.%, or 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, gellan gum, plasticizer) and the ratios of the amounts of the various components are adjusted to adjust the dissolution and/or disintegration characteristics of the soft gelatin capsule over 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 environment (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 environment (e.g., 0.1 N HCl, optionally with added pepsin). The gelatin to pectin weight ratio can be adjusted to provide a specific duration of dissolution of the soft gelatin capsule at a specific pH, as described herein.

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, can be about 1:1, or it is any single ratio value or a ratio value located in any subrange specified in the present invention.

In some embodiments, the pH-dependent coating compositions described herein 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 10 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 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 shell 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 up to about 115,000 cP, or up to about 120,000 cP. The viscosity is determined using a rheometer at 60°C. 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 maintained at 60°C. The disk is rotated at a specific speed and a constant shear rate is provided. The viscosity is determined by measuring the shear stress and the shear rate.

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 preparation 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 ), other than 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 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 disintegration test conducted using a USP disintegration test apparatus. In this embodiment, the pH-dependent soft gelatin capsule may remain intact in an acidic environment (e.g., in a biological, synthetic, or artificial intestinal juice, such as one having a pH of 1.2 (0.1 N HCl), optionally with the addition of pepsin, or at a pH of 2.0, or at a pH of 3.0, or at a pH of 4.0, or at a pH of 5.0, or at any subrange of pH, or at any individual pH value specified in the present invention)) for at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours, and may disintegrate in a biological, synthetic, or artificial intestinal juice (e.g., in phosphate buffer having a pH of 6.8, optionally with the addition of pepsin, or at a higher pH such as a pH of 7, a pH of 8, or a pH of 8.4) for about 120 minutes or less, for about 60 minutes or less, for about 30 minutes or less, for about 20 minutes or less, for about 10 minutes or less, or for about 5 minutes or less.

In some embodiments, the disintegration test (including both an acidic environment and a buffered environment) can be conducted for about 420 minutes, about 360 minutes, about 300 minutes, about 240 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 method comprising the steps of: (a) providing a fill material, said fill material comprising at least one active agent; 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 preparing a pH-dependent shell composition, carried out, for example, by mixing gelatin, dextrose, pectin and optionally a plasticizer. In this method, the shell composition, using which the fill material is encapsulated, may have any of the compositions and/or any of the dissolution profiles described above in the present invention.

The encapsulation procedure carried out in step (b) may further comprise a substep of preparing a pH-dependent shell composition, carried out, for example, by mixing gelatin, gellan gum, pectin and optionally a plasticizer and/or dextrose to obtain a wet gel mass. Preferably, the pH-dependent shell composition does not contain or is substantially free of additional pH-dependent polymers (such as conventional pH-dependent polymers).

In some embodiments, the concentrations of the various components contained in the wet gel mass may be the following: (a) from about 20 to about 60 wt. %, from about 25 to about 55 wt. %, or from about 27 to about 45 wt. % gelatin, (b) from about 0.01 to about 5 wt. %, from about 0.1 to about 5 wt. %, or from about 0.1 to about 0.5 wt. % gellan gum, (c) from about 1 to about 10 wt. %, from about 2 to about 10 wt. %, or from about 3 to about 8 wt. % pectin, such as low methoxylated pectin, (d) from about 5 to about 40 wt. %, from about 8 to about 35 wt. %, or from about 10 to about 32 wt. % plasticizer and optionally (e) from about 0.01 to about 4 wt. %, from about 0.01 to about 3 wt. %, or from about 0.01 to about 2.5 wt. % dextrose, all wt. % values being based on the total weight of the wet gel mass, the remainder being water to provide 100 wt. %

In some embodiments, the method may further comprise forming a tape of the shell composition from the wet gel mass. The thickness of the tape of the pH-dependent shell composition (used, for example, in rotary die encapsulation) may also be adjusted to adjust the pH-dependent dissolution profile of the final pH-dependent soft gelatin capsule.

The thickness of the tape comprising the pH dependent coating composition may, without limitation, 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 may 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 provide improved delayed release characteristics of the soft gelatin capsules, but not so high that the soft gelatin capsules melt.

The curing time, if included in the method, may be in the range of from about 12 to about 168 hours, from about 18 to about 120 hours, from about 24 to about 72 hours, may be about 24 hours, about 48 hours, about 72 hours, or it may be in any subrange, or have any individual value, specified in the present invention. In one embodiment, the curing of the soft gelatin capsule can be carried out at a temperature of about 40°C for about 24 hours. In one embodiment, the curing of the soft gelatin capsule can be carried out at a temperature of about 40°C for about 48 hours. In one embodiment, the curing of the soft gelatin capsule can be carried out at a temperature of about 40°C for about 72 hours. In some embodiments, the curing can be carried out in air (without any special adjustment of nitrogen or oxygen content or humidity). In some embodiments, the curing can be carried out 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 stability can be demonstrated by the fact that the pH-dependent dissolution/disintegration profile of the soft gelatin delayed release capsules after storage (e.g., for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, or about 18 months under conditions ranging from ambient temperature to 40°C and at a relative humidity of 75%) is the same as the pH-dependent dissolution/disintegration profile of the soft gelatin delayed release capsules before storage. In some embodiments, the pH-dependent dissolution/disintegration profile of the soft gelatin delayed release capsule after storage for up to 18 months, 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) is substantially the same as (or meets specifications) the pH-dependent dissolution/disintegration profile of the soft gelatin delayed release capsule prior to 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 one embodiment, the pH-dependent coating composition of the finished dosage form comprises: (a) gelatin, (b) gellan gum, (c) pectin, such as low methoxylated pectin, (d) a plasticizer, and optionally (e) dextrose.

In one embodiment, the pH-dependent coating composition of the finished dosage form consists essentially of: (a) gelatin, (b) gellan gum, (c) pectin, such as low methoxylated pectin, (d) a plasticizer, and optionally (e) dextrose.

In one embodiment, the pH dependent coating composition comprises: (a) gelatin, (b) gellan gum, (c) pectin, such as low methoxylated pectin, (d) a plasticizer, and optionally (e) dextrose.

In one embodiment, the pH-dependent coating composition of the finished dosage form 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 5 wt. %, from about 0.01 to about 2 wt. %, or up to about 4 wt. %, from about 0.1 to about 3 wt. %, about 0.2 to about 2 wt. %, from about 0.01 to about 0.1 wt. %, about 0.05 to about 0.5 wt. %, about 0.1 to about 0.2 wt. % dextrose, (c) about 2 to about 20 wt. %, about 3 to about 15 wt. %, about 7 to about 15 wt. %, about 3 to about 5.5 wt. %, or about 7 to about 12 wt. % pectin, such as low methoxylated pectin, (d) about 0.1 to about 10 wt. %, about 0.2 to about 8 wt. %, about 0.4 to about 5 wt. %, about 0.05 to about 5 wt. %, about 0.1 to about 3 wt. %, or about 0.2 to about 2 wt. % gellan gum, and (e) 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. % of a plasticizer. All values expressed in wt. % are based on the total dry weight of the pH-dependent shell composition.

In one embodiment, the pH-dependent coating composition of the final dosage form 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 5 wt. %, from about 0.01 to about 2 wt. %, or up to about 4 wt. %, from about 0.1 to about 3 wt. %, from about 0.2 to about 2 wt. %, from about 0.01 to about 0.1 wt. %, about 0.05 to about 0.5 wt. %, about 0.1 to about 0.2 wt. % dextrose, (c) about 2 to about 20 wt. %, about 3 to about 15 wt. %, about 7 to about 15 wt. %, about 3 to about 5.5 wt. %, or about 7 to about 12 wt. % pectin, such as low methoxylated pectin, (d) about 0.1 to about 10 wt. %, about 0.2 to about 8 wt. %, about 0.4 to about 5 wt. %, about 0.05 to about 5 wt. %, about 0.1 to about 3 wt. %, or about 0.2 to about 2 wt. % gellan gum, and (e) 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. % of a plasticizer. All values expressed in wt. % are based on the total dry weight of the pH-dependent shell composition.

In one embodiment, the pH-dependent coating composition of the final dosage form 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 5 wt. %, from about 0.01 to about 2 wt. %, or up to about 4 wt. %, from about 0.1 to about 3 wt. %, from about 0.2 to about 2 wt. %, from about 0.01 to about 0.1 wt. %, about 0.05 to about 0.5 wt. %, about 0.1 to about 0.2 wt. % dextrose, (c) about 2 to about 20 wt. %, about 3 to about 15 wt. %, about 7 to about 15 wt. %, about 3 to about 5.5 wt. %, or about 7 to about 12 wt. % pectin, such as low methoxylated pectin, (d) about 0.1 to about 10 wt. %, about 0.2 to about 8 wt. %, about 0.4 to about 5 wt. %, about 0.05 to about 5 wt. %, about 0.1 to about 3 wt. %, or about 0.2 to about 2 wt. % gellan gum, and (e) 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. % of a plasticizer. All values expressed in wt. % are based on the total dry weight of the pH-dependent shell composition.

In some embodiments, the present invention relates to a method of adjusting the pH-dependent dissolution profile of any of the soft gelatin delayed release capsules described herein by adjusting the amount of at least one of the following: gelatin, pectin, and gellan gum (and optionally dextrose and/or plasticizer, if present) contained in the shell composition in order to provide a target pH-dependent dissolution profile at a pH in the range of from about 1.2 to about 8.4 (e.g., at one or more of pH values equal to 1.2, 2.0, 3.0, 4.0, 5.0, 6.0, 6.8, 7.0, 8.0, 8.4, or at a pH value in any subrange or at any individual pH value specified herein).

In some embodiments, the present invention relates to a method of treating, preventing or ameliorating a pathological condition by administering to a subject in need thereof any of the soft gelatin delayed release capsules described herein (which contains an active agent that can provide treatment, prevention or amelioration of said pathological condition).

In some embodiments, the present invention relates to a method of delivering an active agent to a target site located in the gastrointestinal tract (e.g., the colon, the duodenum, the small intestine, the large intestine, or the jejunum) by administering to a subject any of the soft gelatin delayed release capsules described herein, wherein the soft gelatin delayed release capsule shell composition dissolves/disintegrates at a pH at the target site for up to about 120 minutes, for up to about 90 minutes, for up to about 60 minutes, for up to about 30 minutes, or for up to about 15 minutes, and wherein the soft gelatin delayed release capsule shell composition does not dissolve/disintegrate or substantially does not dissolve/disintegrate at a pH that is lower than the pH at the target site for up to about 120 min, for up to about 90 min, for up to about 60 min, for up to about 30 min, or for up to about 15 min.

EXAMPLES

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

Brief description of dissolution studies of delayed release soft gelatin capsules at different pH values

Pectin-based soft gelatin delayed-release capsules made using only pectin and gelatin could remain intact for an extended period of time (120 min) only at a pH of 2.0 or less, which is a standard in vitro test for enteric coating materials. When using a medium with a pH of 3.0 or greater, pectin-based soft gelatin capsules disintegrated within 5-7 min and completely dissolved, becoming immediate-release capsules (Table 1A). This may result in premature disintegration of soft gelatin capsules in the upper gastrointestinal tract in humans due to diet-induced pH changes. Premature disintegration of soft gelatin capsules may result in adverse effects observed in patients and may reduce the bioavailability of some drug products. The tests were carried out using a USP II apparatus with paddles at a stirring speed of 50 rpm using an acidic medium, 750-900 ml of 0.1 N HCl solution, the pH of which was adjusted to 1.2, 2.0, 3.0, 4.0 and 5.0 with phosphate buffer. After 2 h, 250 ml of phosphate buffer solution was added to adjust the pH to 6.8.

The composition of the shell for batch No. 19MS-03 is presented in Table 1B.

Using the present invention, when gellan gum was added to pectin-containing gel masses (Table 2A - wet mass; Table 2B - dry shell composition composition), the resulting delayed release soft gelatin capsules remained intact for 120 minutes in environments with a pH value of up to 3.0, and they remained intact for 60 minutes in environments with a pH value of 3 to 5 (Table 3). This wider pH range, in which the soft gelatin delayed release capsules remain intact, allows the soft gelatin capsules to pass through the stomach intact and release the drug in the intestine, thereby providing the desired therapeutic benefits at the target site, preventing or minimizing adverse effects associated with premature drug release, and protecting the active agent from exposure to a low pH environment that may occur in the upper gastrointestinal tract, such as due to changes in the patient's diet. In the dry shell composition, the pectin to gellan gum weight ratio is in the range of 10:1 to 24:1.

The inventive stability samples containing the coating composition shown in Table 2B were stored at 40°C and 75% relative humidity for 6 months. The comparative stability samples containing the coating composition shown in Table 4 were also stored at 40°C and 75% relative humidity for 6 months. Dissolution tests were performed on the comparative and inventive stability samples at a pH of 5, with and without pepsin. The results of the dissolution tests are shown in Table 5 below. The tests were performed using a USP II apparatus with paddles at a stirring speed of 100 rpm, using an acidic medium of 750-900 ml of 0.1 N HCl. HCl solution, with pepsin added (if specified), and adjusted to pH 5.0 with phosphate buffer (also referred to as the "acid step"). After 2 h, 250 ml of phosphate buffer solution were added to adjust the pH to 6.8, with pancreatin added (if specified) (also referred to as the "buffer step, pH 6.8", or "buffer step"). Capsules that disintegrated within 2 h of the acid step were not tested with the buffer having a pH of 6.8.

According to the results in Table 5, the addition of gellan gum slows down the dissolution of the soft gelatin shell/capsule composition (or causes the soft gelatin shell/capsule composition to remain intact for a longer period of time) in environments having a higher pH value compared to the soft gelatin shell/capsule compositions not containing gellan gum. This is true even if pepsin is added in the acid step, such an environment is considered to be a more aggressive environment than 0.1 N HCl solution without the addition of pepsin.

The effect of gellan gum concentration on the dissolution of the shell composition was further investigated by comparing the stability samples of the present invention containing 0.5 wt. % gellan gum (based on the total dry shell composition weight) and 0.3 wt. % gellan gum (based on the total dry shell composition weight). The stability samples were stored at 40°C and 75% relative humidity for 6 months. The results of the dissolution tests are shown in Table 6 below. The tests were conducted using a USP II apparatus with paddles at a stir rate of 100 rpm using an acidic medium, 750-900 mL of 0.1 N HCl solution, the pH of which was adjusted to 5.0 with a phosphate buffer (also referred to as the "acid step"). After 2 hours, 250 ml of phosphate buffer solution was added to adjust the pH to 6.8, with pancreatin (if specified) added (also referred to as the "pH 6.8 buffer step" or "buffer step"). Capsules that failed within 2 hours of the acid step were not tested with the pH 6.8 buffer.

According to the results presented in Table 6, the use of a higher concentration of gellan gum produces capsules that are stronger than capsules containing a lower amount of gellan gum.

The effect of gellan gum on the dissolution of uncured soft gelatin capsules stored at ambient conditions (i.e., room temperature and without humidity control) for 18 months was studied. The results of the dissolution tests are shown in Table 8 below. The tests were conducted using a USP II apparatus with paddles at a stirring speed of 100 rpm, then 50 rpm, using an acidic medium of 750-900 mL of 0.1 N HCl adjusted to pH 3.0, 4.0, and 5.0 with phosphate buffer, 0.2 M sodium phosphate (also referred to as the "acid step"). After 2 h, 250 ml of phosphate buffer solution was added to adjust the pH to 6.8 (also referred to as the "pH 6.8 buffer step" or "buffer step"). Capsules that failed within 2 h of the acid step were not tested with the pH 6.8 buffer.

Uncured capsules containing gellan gum consistently remained intact in an acidic environment for a longer period of time than capsules without gellan gum.

The effect of gellan gum on the dissolution of soft gelatin capsules cured at 40°C for 96 h was studied. The results of the dissolution tests are shown in Table 9 below. The tests were conducted using a USP II apparatus with paddles at a stirring speed of 100 rpm, then 50 rpm, using an acidic medium, 750-900 ml of 0.1 N HCl solution, the pH of which was adjusted to 4.0 and 5.0 with phosphate buffer, 0.2 M sodium phosphate solution (also called "acid step"). After 2 h, 250 ml of phosphate buffer solution was added to adjust the pH to 6.8 (also called "buffer step, pH=6.8" or "buffer step"). Capsules that failed within 2 hours during the acid test step were not tested using a buffer having a pH of 6.8.

Hardened capsules containing gellan gum remained intact for a longer period of time than capsules without gellan gum.

Disintegration tests were conducted on the stability tested samples of the present invention containing the coating composition shown in Table 2B and stored at 40°C and 75% relative humidity for 6 months in environments with different pH values. The results of the disintegration tests are shown in Table 11 below. The disintegration tests were conducted using a USP disintegration apparatus using an acidic environment, 750-900 mL of 0.1 N HCl adjusted to pH 4.0 and 5.0 with phosphate buffer (also referred to as the "acid step"). After 2 hours, 250 mL of phosphate buffer solution was added to adjust the pH to 6.8 (also referred to as the "buffer step, pH 6.8" or "buffer step").

Capsules containing gellan gum remained intact in disintegration tests at pH 4 and pH 5 for 120 minutes; capsules without gellan gum did not survive the full duration of the acid stage of the test.

For ease of explanation, the embodiments and 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 actions may be required to perform the methods according 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 sequence of interrelated states via a state diagram or events.

In order to provide a thorough understanding of the present invention, numerous specific features, such as specific materials, dimensions, process parameters, and the like, are set forth in the foregoing description. The 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 (30)

1. A delayed release soft gelatin capsule comprising: (a) a fill material; and (b) a shell composition, wherein the fill material comprises at least one active agent, and wherein the shell composition comprises gelatin, dextrose and a pH dependent polymer comprising pectin and gellan gum, wherein the shell composition does not degrade at a pH of at least 4 and less than 6.0 for 15 minutes, 30 minutes, 45 minutes or 60 minutes, when tested using a USP II paddle apparatus at a stirring speed of 50 rpm using an acidic medium, 900 ml of 0.1 N HCl solution adjusted to the desired pH with a phosphate buffer. 2. A delayed release soft gelatin capsule according to claim 1, wherein, according to a test conducted using a USP II apparatus with paddles at a stirring speed of 50 rpm, using an acidic medium, 900 ml of a 0.1 N HCl solution, the pH of which is adjusted to the required value using a phosphate buffer, the shell composition does not degrade at a pH of 5 for 15 minutes, 30 minutes, 45 minutes or 60 minutes. 3. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the coating composition does not degrade at a pH of 5 to 6 for 15 minutes, 30 minutes, 45 minutes, or 60 minutes, when tested using a USP II apparatus with paddles at a stirring speed of 50 rpm using an acidic medium, 900 ml of 0.1 N HCl solution adjusted to the desired pH with phosphate buffer. 4. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the shell composition obtained from the wet mass comprises from 0.1 to 5% gellan gum. 5. The delayed release soft gelatin capsule of claim 4, wherein the wet mass further comprises from about 2 to about 10% pectin. 6. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the shell composition further comprises a plasticizer. 7. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the pectin is low methoxylated pectin. 8. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the shell composition comprises from about 40 to about 80% by weight of gelatin, based on the total dry weight of the shell composition. 9. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the shell composition comprises from about 0.1 to about 10% by weight or from about 0.4 to about 5% by weight of gellan gum, based on the total dry weight of the shell composition. 10. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the shell composition comprises from about 0.1 to about 10% by weight or about 2 to about 20% by weight pectin, based on the total dry weight of the shell composition. 11. The delayed release soft gelatin capsule of claim 1, wherein the shell composition comprises from about 0.01 to about 2% by weight of dextrose based on the total dry weight of the shell composition. 12. The delayed release soft gelatin capsule of claim 6, wherein the shell composition comprises from about 15 to about 40% by weight of a plasticizer based on the total dry weight of the shell composition. 13. 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. 14. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the gelatin is selected from the group consisting of fish gelatin, skin gelatin, bone gelatin and mixtures thereof. 15. The delayed release soft gelatin capsule of claim 7, wherein the low methoxylated pectin is selected from the group consisting of amidated pectin, non-amidated pectin, and combinations thereof. 16. A delayed release soft gelatin capsule according to any one of claims 6 or 12, wherein the plasticizer is glycerol, sorbitol or combinations thereof. 17. A delayed release soft gelatin capsule according to any one of the preceding claims, wherein the weight ratio of pectin to 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. 18. A delayed release soft gelatin capsule comprising: (a) a fill material; and (b) a shell composition, wherein the fill material comprises at least one active agent, and wherein the shell composition comprises gelatin, dextrose, and a pH dependent polymer comprising pectin and gellan gum, wherein, in a USP II paddle test at a stirring speed of 50 rpm using an acidic medium, 900 ml of 0.1 N HCl solution, the pH of which is adjusted to the required value using a phosphate buffer, sodium hydroxide or potassium hydroxide, the coating composition does not deteriorate at a pH of less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5, less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, less than 4.8, less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, less than 4.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, or 2.0, for a period of time equal to 15 min, 30 min, 45 min, 60 min, 90 min, or 120 min. 19. A method for producing a delayed release soft gelatin capsule according to any one of claims 1 to 17, comprising the steps of: providing a fill material containing an active agent; and encapsulating the fill material using a shell composition, wherein the shell composition comprises gelatin, dextrose and a pH-dependent polymer comprising pectin and gellan gum, wherein, in a test carried out using a USP II apparatus with paddles at a stirring speed of 50 rpm, using an acidic medium, 900 ml of a 0.1 N HCl solution, the pH of which is adjusted to the required value with a phosphate buffer, the shell composition does not degrade at a pH of at least 4 and less than 6.0 for 15 minutes, 30 minutes, 45 min or 60 min. 20. A method for making a delayed release soft gelatin capsule according to claim 18, comprising the steps of: providing a fill material containing an active agent; and encapsulating the fill material using a shell composition, wherein the shell composition comprises gelatin, dextrose, and a pH-dependent polymer comprising pectin and gellan gum, wherein, according to a test conducted using a USP II apparatus with paddles at a stirring speed of 50 rpm, using an acidic medium, 900 ml of 0.1 N HCl solution, the pH of which is brought to the required value using a phosphate buffer, the composition of the shell is not destroyed at a pH of less than 6.0, less than 5.9, less than 5.8, less than 5.7, less than 5.6, less than 5.5, less than 5.4, less than 5.3, less than 5.2, less than 5.1, less than 5.0, less than 4.9, less than 4.8, less than 4.7, less than 4.6, less than 4.5, less than 4.4, less than 4.3, less than 4.2, less than 4.1, less than 4.0, less than 3.9, less than 3.8, less than 3.7, less than 3.6, less than 3.5, less than 3.4, less than 3.3, less than 3.2, less than 3.1, less than 3.0, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1 or 2.0, for 15 min, 30 min, 45 min or 60 min. 21. The method of claim 19 or 20, wherein, according to a test conducted using a USP II apparatus with paddles at a stirring speed of 50 rpm, using an acidic medium, 900 ml of a 0.1 N HCl solution, the pH of which is adjusted to the required value using a phosphate buffer, the coating composition does not degrade at a pH of 5 for 15 minutes, 30 minutes, 45 minutes or 60 minutes. 22. The method of any one of claims 19 to 21, wherein, according to a test conducted using a USP II apparatus with paddles at a stirring speed of 50 rpm, using an acidic medium, 900 ml of a 0.1 N HCl solution, the pH of which is adjusted to the required value using a phosphate buffer, the coating composition does not degrade at a pH of 5 to 6 for 15 minutes, 30 minutes, 45 minutes or 60 minutes. 23. The method according to any one of paragraphs. 19-22, further comprising obtaining a shell composition. 24. The method according to claim 23, wherein the production comprises mixing gelatin, pectin and gellan gum to produce a wet gel mass. 25. The method according to claim 24, wherein the production additionally includes production of a shell composition in the form of a tape from a wet gel mass. 26. The method of claim 25, wherein the tape-shaped sheath composition has a thickness in the range of from about 0.020 to about 0.050 inches. 27. The method according to any one of claims 19-26, further comprising drying the delayed release soft gelatin capsule. 28. A method for adjusting the pH-dependent dissolution profile of a delayed release soft gelatin capsule comprising a fill material encapsulated using a shell composition according to any one of claims 1 to 18, the method comprising adjusting the amount of at least one of the following: gelatin, pectin and gellan gum contained in the shell composition by adding at least one of the following: gelatin, pectin and gellan gum in order to provide a target pH-dependent dissolution profile at a pH value in the range of from about 1.2 to about 6.0. 29. A method for delivering an active agent to a target site located in the gastrointestinal tract, the method comprising administering to the subject a soft gelatin delayed release capsule according to any one of claims 1-18 or a soft gelatin delayed release capsule manufactured by the method according to any one of claims 19-27, wherein the soft gelatin delayed release capsule shell composition dissolves/disintegrates at a pH at the target site for up to about 120 minutes, for up to about 90 minutes, for up to about 60 minutes, for up to about 30 minutes, or for up to about 15 minutes, and wherein the soft gelatin delayed release capsule shell composition does not dissolve/disintegrate or substantially does not dissolve/disintegrate at a pH that is lower than the pH at the target site for up to about 120 minutes, for up to about 90 minutes, for up to about 60 minutes, for up to about 30 minutes, or for up to about 15 minutes.