阅读说明：本技术 肠溶性软明胶胶囊 (Enteric soft gelatin capsule ) 是由 T.冈山 M.高桥 T.藤井 于 2019-03-15 设计创作，主要内容包括：本发明提供了肠溶性软明胶胶囊,其包括填充材料和肠溶性壳组合物,其特征在于所述胶囊的肠溶性质无需肠溶衣或外加的常规肠溶聚合物就可以获得。(The present invention provides enteric soft gelatin capsules comprising a fill material and an enteric shell composition, characterized in that the enteric properties of the capsules are obtained without the need for an enteric coating or an added conventional enteric polymer.)

1. An enteric soft gelatin capsule comprising:

(a) a filler material; and

(b) the composition of the shell is such that,

wherein the filling material comprises at least one pharmaceutically active ingredient, and

wherein the shell composition comprises about 40 wt% to about 80 wt% gelatin, about 2.0 wt% to about 20 wt% low methoxyl pectin, about 0.15 wt% to about 4.0 wt% cellulose derivative, about 15 wt% to about 40 wt% plasticizer.

2. The enteric soft gelatin capsule of claim 1 wherein the gelatin is selected from the group consisting of type a gelatin, type B gelatin, and mixtures thereof.

3. The enteric soft gelatin capsule of claim 1 wherein the gelatin is selected from the group consisting of fish gelatin, skin gelatin, bone gelatin, and mixtures thereof.

4. The enteric soft gelatin capsule of any of claims 1 to 3 wherein the low methoxyl pectin is selected from the group consisting of LM pectin (P-25), LM pectin (445C), LM pectin (100C), and combinations thereof.

5. The enteric soft gelatin capsule of any of claims 1 to 4 wherein the plasticizer is selected from the group consisting of glycerol, glycerin, sorbitol and combinations thereof.

6. The enteric soft gelatin capsule of claim 5 wherein the plasticizer is glycerol.

7. The enteric soft gelatin capsule of any of claims 1 to 6 wherein the cellulose derivative is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and combinations thereof.

8. The enteric soft gelatin capsule of claim 7 wherein the cellulose derivative is hydroxypropyl methylcellulose.

9. The enteric soft gelatin capsule of any of claims 1 to 8 wherein the shell composition comprises from about 45 wt% to about 75 wt% gelatin.

10. The enteric soft gelatin capsule of claim 9, wherein the shell composition comprises from about 50% to about 70% by weight gelatin.

11. The enteric soft gelatin capsule of any of claims 1 to 10 wherein the shell composition comprises about 3 wt% to about 15 wt% pectin.

12. The enteric soft gelatin capsule of claim 11, wherein the shell composition comprises about 3 wt% to about 5.5 wt% pectin.

13. The enteric soft gelatin capsule of any of claims 1 to 12 wherein the shell composition comprises from about 20 wt% to about 35 wt% plasticizer.

14. The enteric soft gelatin capsule of claim 13, wherein the shell composition comprises from about 25 wt% to about 30 wt% plasticizer.

15. The enteric soft gelatin capsule of any of claims 1 to 14 wherein the shell composition comprises from about 0.20 wt% to about 2.0 wt% of the cellulose derivative.

16. The enteric soft gelatin capsule of claim 15 wherein the shell composition comprises from about 0.25 wt% to about 1.4 wt% of the cellulose derivative.

17. The enteric soft gelatin capsule of any of claims 1 to 6, wherein the capsule disintegrates in an enteric environment in less than about 30 minutes, less than about 20 minutes, less than about 10 minutes, or less than about 5 minutes in a disintegration test based on a basket assembly NT-40H model instrument placed in a 1000mL beaker at a test temperature of about 37 ℃ ± 2 ℃.

18. The enteric soft gelatin capsule of any of claims 1 to 17, wherein the capsule disintegrates in acidic media within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, which is a disintegration test based on a basket assembly NT-40H model instrument placed in a 1000mL beaker at a test temperature of about 37 ℃ ± 2 ℃.

19. A process for the preparation of an enteric soft gelatin capsule according to any of claims 1 to 18 comprising the steps of:

(a) Preparing the filling material; and

(b) the filling material is sealed with an enteric shell composition.

20. The method according to claim 19, further comprising preparing an enteric shell composition by mixing gelatin, hydroxypropyl methylcellulose, low methoxyl pectin, and a plasticizer, wherein the enteric shell composition is free of enteric polymer.

Technical Field

The present invention relates to enteric soft gelatin capsules wherein the gelatin-based shell composition has enteric properties without the use of an enteric coating or the addition of an enteric polymer.

Background

Soft gelatin capsules, particularly soft gelatin capsules and/or soft gelatin capsules, provide a more acceptable dosage form for patients because the capsules are easier to swallow and do not require flavoring to mask the unpleasant taste of the active agent. Soft gelatin encapsulation of the drug provides a potential for further enhancing the bioavailability of the pharmaceutical ingredients. For example, when the gelatin shell is broken, the active ingredient is rapidly released in liquid form.

Efforts have been made by those skilled in the art to create enteric dosage forms. Enteric dosage forms are designed to protect the dosage form ingredients from the gastric environment. For example, enteric dosage forms may be prepared by adding an enteric coating to the surface of the dosage form being manufactured (e.g., a tablet or capsule). Such coating may be achieved by spraying the dosage form and then drying the dosage form (typically at elevated temperature). This method of coating the capsules with an enteric coating can result in a compromise in their performance and appearance. For example, capsules may have a rough feel, coatings may be unevenly applied, and/or enteric coatings are prone to cracking or flaking from the dosage form. In addition, the efficiency of the enteric coating process is low.

Other enteric dosage forms have also been developed which incorporate conventional enteric polymers (e.g., acid-insoluble polymers) in their capsule shells. However, the addition of such conventional enteric polymers can result in capsules that are prone to leakage due to inadequate sealing.

Thus, there is a need for enteric soft gelatin capsules that do not require the use of an enteric coating or the addition of conventional enteric polymers to the shell.

It has been surprisingly found that the gelatin-based shell composition of the present invention has satisfactory enteric properties without the use of an enteric coating or the incorporation of conventional enteric polymers.

Disclosure of Invention

The invention relates to an enteric soft gelatin capsule. The enteric soft gelatin capsule comprises (a) a fill material and (2) an enteric shell composition. The enteric soft gelatin capsules of the present invention do not contain an enteric coating or an added conventional enteric polymer. Thus, the enteric shell composition eliminates the need for adding an enteric coating while minimizing the risk of damaging the capsule during coating.

In some embodiments, the enteric shell composition comprises: (a) gelatin, (b) cellulose derivatives (e.g. hydroxypropylmethylcellulose, HPMC), (c) pectin (e.g. low methoxyl pectin) and (d) plasticizers. The invention also relates to a process for the preparation of enteric soft gelatin capsules.

Detailed description of the embodiments

The present invention advances the art by developing enteric oral dosage forms, particularly enteric soft gelatin capsules, that can achieve the advantages of conventional enteric dosage forms without the need to apply an enteric coating or add conventional enteric polymers to the capsule shell. The enteric soft gelatin capsule of the present invention does not dissolve in the environment of the stomach but dissolves in the intestine. This mechanism facilitates the delivery of active ingredients that may cause gastric irritation or be sensitive to the acidic environment of the stomach. The enteric soft gelatin capsules of the present invention do not dissolve in the environment of the stomach, but rather dissolve in the intestine. This mechanism facilitates the delivery of active ingredients that may cause gastric irritation or be sensitive to the acidic environment of the stomach.

As used herein, the term "enteric" refers to the dissolution or disintegration resistant properties of a material such that the conditions are met such that it does not dissolve or disintegrate in the gastric environment. For example, described embodiments of the invention include enteric shell compositions that are soluble in biological, artificial or simulated intestinal fluid, but not in biological, artificial or simulated gastric fluid. As used herein, the term "pharmaceutically active ingredient" refers to a drug or compound that can be used to diagnose, cure, alleviate, treat or prevent a condition. The term "symptoms" refers to those medical conditions that can be treated or prevented by administering an effective amount of the active ingredient to a subject. Non-limiting exemplary conditions that may benefit from enteric soft gelatin capsules include, but are not limited to, capsules containing lactic acid bacteria, fish oil capsules, proton pump inhibitors, aspirin, and similar products.

As used herein, the term "active ingredient" refers to any substance intended to produce a therapeutic, prophylactic or other desired effect, whether or not it has been approved by a governmental agency for such purpose. The term with respect to a particular ingredient includes a pharmaceutically active ingredient, and all pharmaceutically acceptable salts, solvates, and crystal forms thereof, wherein the salts, solvates, and crystal forms are pharmaceutically active.

Any pharmaceutically active ingredient may be used for the purposes of the present invention, including those that are water soluble and those that are poorly 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 drugs, antihypertensive drugs, antimalarials, antimigraine drugs, antimuscarinics, antineoplastics and immunosuppressants, antiprotozoals, antirheumatics, antithyroids, antivirals, anxiolytics, sedatives, hypnotics and antipsychotics, beta-receptor blockers, cardiac inotropic drugs, corticosteroids, antitussives, cytotoxins, decongestants, diuretics, enzymes, antiparkinsonian drugs, gastrointestinal drugs, histamine receptor antagonists, lipid regulators, local anesthetics, neuromuscular drugs, nitrates and antianginals, nutritional agents, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, Spermicides, stimulants, and combinations thereof.

In some embodiments, the active pharmaceutical ingredient may be selected from, but is not limited to: dabigatran, dronedarone, ticagrelor, iloritone, ivacaptan, midostaurin, asimadoline, beclomethasone, aprilat, sabatidine, lincetitinib, abiraterone, vitamin D analogues (e.g., calcifediol, calcitriol, paricalcitol, doxercalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, robipratropium, pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the lipid in the dosage form may be selected from, but is not limited to: almond oil, argan oil, avocado oil, borage seed oil, canola oil (canola oil), cashew oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hydroxylated lecithin, linseed oil, macadamia oil, mango butter, manila oil, Mongolian nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla seed oil, pine seed oil, pistachio nut oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, walnut oil, and watermelon oil. Other oils and fats may include, but are not limited to, fish oil (omega-3), krill oil, animal and vegetable fats (e.g., hydrogenated versions thereof), free fatty acids, and mono-, di-, and triglycerides having C8, C10, C12, C14, C16, C18, C20, and C22 fatty acids, and combinations thereof.

According to certain embodiments, the active ingredient 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, lomitacin, phytosterols, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof, mixtures of any of them, and the like.

Suitable nutraceutical active ingredients may include, but are not limited to: 5-hydroxytryptophan, acetyl L-carnitine, alpha lipoic acid, alpha-ketoglutarate, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamine (vitamin 812), dimethylaminoethanol, fumaric acid, germanium sesquioxide, glandular products, glucosamine hydrochloride, glucosamine sulfate, hydroxymethyl butyrate, immunoglobulin, lactic acid, L-carnitine, liver products, malic acid, anhydrous maltose, mannose (d-mannose), methylsulfonylmethane, phytosterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate and yeast.

Suitable nutritional supplement active ingredients may include: vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, and combinations thereof.

Suitable vitamin active ingredients may include, but are not limited to: ascorbic acid (vitamin C), B vitamins, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbate, mixed tocopherols, niacin (vitamin B3), orotic acid, p-aminobenzoic acid, pantothenate, pantothenic acid (vitamin B5), pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamine (vitamin B1), tocotrienols, vitamin a, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oil, and oil-soluble vitamins.

Suitable herbal supplement actives may include, but are not limited to, the following: arnica, bilberry, black cohosh, ternate buttercup root, chamomile, echinacea, evening primrose oil, fenugreek, linseed, feverfew, garlic, ginger root, ginkgo leaf, ginseng, compositae, hawthorn, kava, licorice, silybum marianum, plantain seed, rauwolfia, senna leaf, soybean, st john's wort, serenoa repens, turmeric, valerian.

Mineral actives may include, but are not limited to, the following: boron, calcium, chelated minerals, chlorides, chromium, coated minerals, cobalt, copper, limestone, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvic acid, zinc, and other minerals.

Examples of other possible active agents include, but are not limited to: antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and chlorpheniramine maleate), non-steroidal anti-inflammatory drugs (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofene, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, carprofen, oxaprozin, prolofen, moloprofen, trioxolafen, suprofen, aminoprofen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, thiacloprid, zidomethacin, acemetacin, fenzake, clinacard, oxepin, mefenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenamic acid, bromfenac, oxypheniramine, alfapx, benzoate, benzofenamic acid, fenamic acid, chlorpheniramine maleate, fluroxypheniramine, fluroxyp, Carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faxamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, analgin, methylsalicylic acid, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicylate, sulindac, sulphoxipyrazine, tenoxicam, tiaprofenic acid, tolmetin (pharmaceutically acceptable salts thereof and mixtures thereof) and acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., phenytoin, meprobamate and nitro-tranquilizers (e.g., nifedipine, papaverine, diltiazepine and nicardipine), antitussives and codeine phosphates (e.g., codeine phosphate), Anti-asthmatics (e.g., theophylline), antacids, anti-spasmodics (e.g., atropine, hyoscyamine), anti-diabetic drugs (e.g., insulin), diuretics (e.g., diuretic acid, bendroflumethiazide), pressants (e.g., propranolol, clonidine), hypotensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., cortisol, triamcinolone, prednisone), antibiotics (e.g., tetracycline), hemorrhoid remedies, hypnotics, psychotropic drugs, antidiarrheal drugs, expectorants, sedatives, decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine), and cannabinoids, and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof.

The active agent may also be a benzodiazepine drug, a barbiturate drug, an agonist, or a mixture thereof. The term "benzodiazepine drug" refers to benzodiazepines and derivatives of benzodiazepines that inhibit the central nervous system; benzodiazepines include, but are not limited to: alprazolam, bromoazepam, chlordiazepam, dipotassium chloride, diazepam, estazolam, flurazepam, halazepam, ketozolam, lorazepam, nitrazepam, oxazepam, pramipepam, quazepam, temazepam, triazolam, ritalin, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Benzodiazepine antagonists useful as active ingredients include, but are not limited to, flumazenil and pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.

The term "barbiturates" refers to sedative-hypnotic agents derived from barbituric acid (2,4, 6-trioxyhydropyrimidine). Barbiturates include, but are not limited to, amobarbital, alprenbital, sec-barbital, butabarbital, methohexital, promethanamine, methamphetal, pentobarbital, phenobarbital, secobarbital, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists useful as active agents include, but are not limited to, amphetamine and pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.

The term "stimulant" includes, but is not limited to, amphetamines (e.g., dextroamphetamine resin complex, dextroamphetamine, methamphetamine, ritalin), and pharmaceutically acceptable salts, hydrates, and solvates thereof, and mixtures thereof. Agonist antagonists that may be used as active agents include, but are not limited to, benzodiazepines, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

The dosage forms of the present invention comprise a variety of active agents and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, but are not limited to: inorganic acid salts (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); organic acid salts (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, etc.); sulfonates (e.g., methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); amino acid salts (e.g., arginine salt, aspartic acid salt, glutamic acid salt, etc.) and metal salts (e.g., sodium salt, potassium salt, cesium salt, etc.); alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.); organic amine salts (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, etc.).

As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount or rate of administration of an active agent required to produce a desired therapeutic result.

As used herein, "shell" or "shell composition" refers to the shell of a soft gelatin capsule that encapsulates a fill material within the capsule.

As used herein, "conventional enteric polymers" means, but is not limited to, acrylic and methacrylic polymers, which are trademarkedAnd other conventional acid-insoluble polymers (e.g., 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 methyl cellulose phthalate, hydroxypropyl methyl acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), alginates (e.g., sodium alginate and potassium alginate), stearic acid, and shellac. In some embodiments, the enteric shell compositions of the invention do not include an acid insoluble polymer. In other words, the enteric shell composition and enteric soft gelatin capsule are "free or substantially free of conventional enteric polymers".

As used herein, "free or substantially free" means that the composition comprises 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 recited ingredients.

Throughout the description and claims all references to wt% refer to the weight of the ingredient compared to the weight of the entire composition and may also be expressed as w/w.

As used herein, "fill material" or "fill" refers to a composition that is encapsulated by an enteric capsule shell and that contains at least one pharmaceutically active ingredient.

As used herein, "enteric capsule" or "enteric soft gelatin capsule" refers to a capsule having enteric properties which is dried once the fill material is encapsulated in a shell. No further processing steps are required.

As used herein, "about" refers to any value within a variation range of ± 10%, e.g., "about 10" includes 9 to 11. As used herein, unless otherwise specified, "a" and "an" and "the" mean one or more. Thus, for example, reference to "an excipient" includes a single excipient as well as mixtures of two or more different excipients, and the like.

Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate certain materials and methods and does not pose a limitation on the scope unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the disclosed materials and methods.

According to a first embodiment, an enteric soft gelatin capsule comprises: (a) a filling material and (b) an enteric shell composition, said filling material comprising at least one pharmaceutically active ingredient, wherein said enteric shell composition comprises gelatin, a cellulose derivative (such as hydroxypropylmethylcellulose HPMC), a low methoxyl pectin and a plasticizer, and wherein said enteric shell composition is free of conventional enteric polymers.

Suitable filling materials comprise at least one pharmaceutically active ingredient, which can be manufactured according to known methods. Suitable filling materials may include, in addition to at least one of the pharmaceutically active ingredients, other filling components such as flavoring agents, sweetening agents, coloring agents and fillers or other pharmaceutically acceptable excipients or additives such as synthetic dyes and inorganic oxides. Suitable amounts of pharmaceutically active ingredient and pharmaceutically acceptable excipients can be readily determined by one of ordinary skill in the art.

In one embodiment, the gelatin in the enteric shell composition may include the use of type a gelatin, type B gelatin, and/or bone gelatin, alone or in combination. In one embodiment, the gelatin is a 250-kinetic gelatin. In another embodiment, the gelatin is of only one type. In another embodiment, the gelatin is a combination of at least two gelatins. In one embodiment, the gelatin amount of the enteric capsule shell composition is from about 40 wt% to about 80 wt%, more preferably, from about 45 wt% to about 75 wt%, and most preferably, from about 50 wt% to about 70 wt%.

In one embodiment, the enteric capsule shell composition comprises HPMC. In one embodiment, the amount of cellulose derivative (e.g., HPMC) in the enteric capsule shell composition is about 0.15 wt% to about 4.0 wt%, more preferably, about 0.2 wt% to about 2.0 wt%, most preferably, about 0.25 wt% to about 1.4 wt%. In some embodiments, the enteric capsule shell composition may comprise HPMC, Methylcellulose (MC), Hydroxypropylcellulose (HPC), or a combination thereof. Cellulose derivatives may be added to enteric capsule shells to mitigate potential gum strength reduction. The concentration of the cellulose derivative in the enteric capsule shell composition may be an effective amount to increase the strength of the gum without interfering with sealing.

In some embodiments, the enteric shell composition may include pectin (e.g., low methoxyl pectin). In some embodiments, the low methoxyl pectin may be LM pectin (P-25), LM pectin (445C), LM pectin (100C), or a combination thereof. The addition of pectin facilitates enteric solubility of the dosage form. However, excessive pectin in the dosage form may reduce the gel strength of the soft gelatin capsule, which in turn affects the sealability of the soft gelatin capsule. Thus, the pectin concentration added to the dosage form is high enough to form an enteric dosage form, while low enough to slow the decrease in gum strength. In some embodiments, the amount of low methoxyl pectin in the enteric shell composition is about 2 wt% to about 20 wt%, about 3 wt% to about 15 wt%, about 3 wt% to about 5.5 wt%, and about 5 wt% to about 10 wt%. The degree of esterification of the pectin incorporated into the enteric capsule shell composition may be less than about 50%, or in the range of about 10% to about 50%, about 20% to about 40%, or about 25% to about 35%. In some embodiments, the plasticizer in the enteric shell composition may include glycerin, glycerol, sorbitol, and combinations thereof. Other suitable plasticizers may include, but are not limited to, sugar alcohol plasticizers (e.g., isomalt, maltitol, xylitol, erythritol, adonitol, galactitol, pentaerythritol, or mannitol); or polyol plasticizers (e.g., diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000MW, neopentyl glycol, propylene glycol, 1, 3-propanediol, 2-methyl-1, 3-propanediol, trimethylolpropane, polyether polyols, ethanolamine, and mixtures thereof). Other exemplary plasticizers may also include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small molecule organics, low molecular weight polyols having aliphatic hydroxyl groups, ester-type plasticizers, glycol ethers, polypropylene glycols, multi-block polymers, mono-block polymers, citrate-type plasticizers, and triacetin. Plasticizers such as these may include 1, 2-butanediol, 2, 3-butanediol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactic acid, 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 some embodiments, the amount of plasticizer in the enteric shell composition is from about 15 wt% to about 40 wt%, more preferably, from about 20 wt% to about 35 wt%, and most preferably, from about 25 wt% to about 30 wt%.

In some embodiments, the enteric shell composition and enteric soft gelatin capsule may be free or substantially free of conventional enteric polymers.

In some embodiments, the enteric shell composition and enteric soft gelatin capsule may be free or substantially free of divalent cations, such as Ca²⁺(e.g. CaCl)₂) Or Mg²⁺(e.g. MgCl)₂)。

In some embodiments, the enteric shell composition may optionally include additives such as colorants, flavors, sweeteners, fillers, antioxidants, diluents, pH adjusters, or other pharmaceutically acceptable excipients or additives (e.g., synthetic dyes and inorganic oxides).

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

Exemplary suitable flavoring agents can include, but are not limited to, "spice extracts," which are obtained by extracting a portion of a raw material (e.g., an animal or plant material), which is typically obtained by using a solvent (e.g., ethanol or water); natural essence, which is obtained by extracting essential oil from flowers, fruits, roots, etc. or the whole plant.

Other exemplary flavoring agents in the dosage form can include, but are not limited to, breath freshening compounds (such as menthol, spearmint, and cinnamon), coffee beans, other flavors or fragrances (e.g., fruit flavors-cherry, orange, grape, etc.), flavors particularly for oral hygiene, and actives for dental and oral cleaning (e.g., quaternary ammonium salt bases). Taste enhancers (e.g., tartaric acid, citric acid, vanillin, etc.) may be used to enhance the taste effect.

Exemplary embodiments of the inventionThe sweetener of (a) may include, but is not limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof. Artificial sweeteners include, for example, acesulfame and various salts thereof (e.g., potassium salts thereof, andpurchased), alitame, aspartame (to)Andcommercially available), aspartame-acesulfame (in orderCommercially available), neohesperidin dihydrochalcone, naringenin dihydrochalcone, dihydrochalcone compounds, neotame, cyclamate, saccharin and various salts thereof (e.g., sodium salt, and so forth) Commercially available), stevioside, chlorinated derivatives of sucrose (e.g., sucralose, toAndpurchased) and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizic acid, monoammonium glycyrrhizinateCommercially available), stevia rebaudiana (stevia), natural intense sweeteners (e.g., luo han guo), polyols (e.g., sorbitol, mannitol, xylitol, erythritol, etc.).

In some embodiments, the enteric shell composition and/or enteric soft gelatin capsule may be subjected to a disintegration test based on a 1000mL beaker-in-basket assembly NT-40H model instrument, conducted at a temperature of about 37 ℃ ± 2 ℃ (more details are shown below). According to this embodiment, the enteric soft gelatin capsule may be left intact for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or longer than about 1-5 hours in an acidic medium, and may disintegrate in intestinal fluid in about 30 minutes or less, about 20 minutes or less, about 10 minutes or less, about 5 minutes or less.

The disintegration test carried out by the invention accords with the monograph of European pharmacopoeia and American pharmacopoeia for preparing enteric coating. The apparatus used for disintegration test was a model instrument NT-40H (manufactured by Toyama Sangyo Co. Ltd.). The apparatus has a frame assembly, a low-profile beaker (1000-mL, height 139-160mm, internal diameter 97-115mm) containing the infusion, thermostatic means (heating the liquid to between 35 ℃ and 39 ℃), and means for raising and lowering the frame in the infusion (constant frequency of 29 to 32 cycles per minute, the cycle distance being not less than 53mm and not more than 57 mm). The volume of liquid in the vessel should be such that at the highest point of the upstroke the wire screen is still at least 15mm below the level of the liquid and on the downstroke it descends to no less than 25mm from the bottom of the vessel. The top of the basket assembly cannot be flooded at any time. The time required for the upstroke is equal to the time required for the downstroke and the change in stroke direction is a smooth transition rather than a sudden motion reversal. The basket assembly moves vertically along its axis. There is no significant horizontal or vertical axis motion. Disks may be added to the device as necessary.

The disintegration test disclosed herein was performed in a volume of 1000mL of fluid at about 37 ℃ ± 2 ℃. Disintegration test liquid 1 (also referred to as "artificial gastric juice" in the present invention) is a 2g/L sodium chloride-hydrochloric acid solution having a pH of 1.2. Disintegration test liquid 2 (also referred to as "artificial intestinal liquid" in the present invention) was a 0.2mol/L potassium dihydrogenphosphate-0.2 mol/L sodium hydroxide solution having a pH of 6.8.

The disintegration test using the first test liquid was conducted for about 120 minutes by placing a cell in each of the 6 basket tubes, immersing the basket (and the cells therein) into the first test liquid, and then lifting the basket from the test liquid to see if the cell disintegrated. Disintegration is defined as the breaking of a unit or the breaking or breaking of an enteric shell composition. If none of the six units disintegrated, the test requirements were met. Similar tests were carried out with the second disintegration test liquid for a selected duration.

In some embodiments, the disintegration test can be performed for 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.

Encapsulation of the fill material may be accomplished in any conventional manner. A rotary die capsule may be used as an example.

According to one embodiment, a process for the preparation of enteric soft gelatin capsules comprising the steps of: (a) preparing a fill material comprising at least one pharmaceutically active ingredient; and (b) encapsulating the filler material of step (a) in an enteric shell composition. The encapsulation process according to step (b) may further comprise the sub-step of preparing an enteric shell composition, e.g. by mixing gelatin, HPMC, low methoxyl pectin and a plasticizer, wherein the enteric shell composition is free of conventional enteric polymers.

In one embodiment, the enteric shell composition comprises: (a) gelatin, (b) a cellulose derivative (e.g., "HPMC"), (c) pectin (e.g., low methoxyl pectin), and (d) a plasticizer.

In one embodiment, the enteric shell composition consists essentially of: (a) gelatin, (b) a cellulose derivative (e.g., "HPMC"), (c) pectin (e.g., low methoxyl pectin), and (d) a plasticizer.

In one embodiment, the enteric shell composition consists of: (a) gelatin, (b) cellulose derivatives (e.g., "HPMC"), (c) pectins (e.g., low-methoxy pectins), and (d) plasticizers.

In one embodiment, the enteric shell composition comprises: (a) gelatin from about 40 wt% to about 80 wt%, from about 45 wt% to about 75 wt%, or from about 50 wt% to about 70 wt% (b) a cellulose derivative (e.g., "HPMC") from about 0.15 wt% to about 4 wt%, from about 0.2 wt% to about 2 wt%, or from about 0.25 wt% to about 1.4 wt%, (c) pectin (e.g., low methoxyl pectin) from about 2 wt% to about 20 wt%, from about 3 wt% to about 15 wt%, or from about 3 wt% to about 5.5 wt%, and (d) a plasticizer from about 15 wt% to about 40 wt%, from about 20 wt% to about 35 wt%, or from about 25 wt% to about 30 wt%.

In one embodiment, the enteric shell composition consists essentially of: (a) gelatin from about 40 wt% to about 80 wt%, from about 45 wt% to about 75 wt%, or from about 50 wt% to about 70 wt% (b) a cellulose derivative (e.g., "HPMC") from about 0.15 wt% to about 4 wt%, from about 0.2 wt% to about 2 wt%, or from about 0.25 wt% to about 1.4 wt%, (c) pectin (e.g., low methoxyl pectin) from about 2 wt% to about 20 wt%, from about 3 wt% to about 15 wt%, or from about 3 wt% to about 5.5 wt%, and (d) a plasticizer from about 15 wt% to about 40 wt%, from about 20 wt% to about 35 wt%, or from about 25 wt% to about 30 wt%.

In one embodiment, the enteric shell composition consists of: (a) gelatin from about 40 wt% to about 80 wt%, from about 45 wt% to about 75 wt%, or from about 50 wt% to about 70 wt% (b) a cellulose derivative (e.g., "HPMC") from about 0.15 wt% to about 4 wt%, from about 0.2 wt% to about 2 wt%, or from about 0.25 wt% to about 1.4 wt%, (c) pectin (e.g., low methoxyl pectin) from about 2 wt% to about 20 wt%, from about 3 wt% to about 15 wt%, or from about 3 wt% to about 5.5 wt%, and (d) a plasticizer from about 15 wt% to about 40 wt%, from about 20 wt% to about 35 wt%, or from about 25 wt% to about 30 wt%.

Examples

Specific embodiments of the present invention will now be described by reference to the following examples. It should be understood that the sole disclosure of these embodiments is illustrative only and is not intended to limit the scope of the invention in any way.