TW201311296A - Novel gelatin capsule compositions and methods of making - Google Patents

Abstract

A gelatin capsule composition that includes one or more first distinct regions comprising a gelatin and one or more second distinct regions comprising a water-insoluble rapid-release agent is provided.

Description

Novel gelatin capsule composition and preparation method thereof

Provided herein are gelatin capsule compositions comprising a gelatin component and a rapid release formulation. In particular, the present invention relates to novel gelatin capsule compositions comprising a fast release formulation dispersed throughout the gelatin component coating.

The development of compositions for the rapid release of active pharmaceutical compounds (APIs) is a challenge that is emerging in the pharmaceutical industry. Due to the various discomfort characteristics of many APIs (e.g., bitterness), some oral compositions incorporate the addition of flavoring agents to mask the taste of the API. In addition, other oral pharmaceutical compositions include encapsulating agents to separate the API during oral administration, alleviating other unpleasant properties of the API (eg, grit or stickiness), and enhancing other properties of the composition (eg, storage and/or Or stability during transportation). Encapsulated pharmaceutical compositions, such as gelatin-coated lozenges, hard capsules, and soft gelatin capsules, are widely used in therapeutic compositions for oral administration.

Although the encapsulation of the API alleviates many of the palatability and stability issues described above, the nature of the encapsulating material poses another problem with the rapid release of the API into the stomach cramps. Many existing methods use water soluble encapsulant materials, but many water soluble encapsulants tend to partially dissolve in the oral cavity or esophagus, causing adhesion during oral administration. Other ways use pH sensitive coatings that incorporate polymeric materials that are relatively insoluble in a relatively neutral pH environment (eg, oral cavity) but highly soluble in an acidic environment (eg, gastric fistula); however, pH sensitive polymer encapsulants Production usually requires specialized production techniques.

Other existing rapid release compositions incorporate various water soluble pore forming materials into the encapsulating material which dissolve in the gastric cavity and form pores in the remaining encapsulating material, Thereby allowing the API therein to dissolve and spread out into the gastric cavity. Still other existing rapid release compositions include multi-layer encapsulants wherein the waterproof porous outer layer directs gastric fluid to the swellable inner layer material which, upon swelling, ruptures the encapsulant and exposes the underlying API. Such encapsulant compositions require a great deal of effort to manufacture and require penetration of gastric fluid through the pores in the outer coating layer to effect release of the API, thereby producing a delayed release time of the API in the gastric cavity.

Gelatin is a well-known encapsulating material in the pharmaceutical industry. The material properties of the gelatin can be adjusted or controlled by gelatin treatment methods (e.g., cross-linking, deionization, and partial hydrolysis) to produce a gelatin coating having specified material properties (e.g., rigidity and solubility). The production of gelatin coatings, soft gelatin capsules and hard gelatin capsules typically utilizes an aqueous suspension of gelatin. Therefore, it is difficult to incorporate a water-soluble rapid release additive to enhance the rapid release properties of the resulting gel capsule sealant in the gastric cavity. In addition, the gelatin quick release additive can alter the chemical nature (e.g., pH) of the gelatin suspension, which can cause degradation or instability of the resulting gelatin matrix structure.

There is a need in the industry for a gelatin-based gelatin capsule composition that rapidly degrades in the acidic environment of the stomach sputum during oral administration of the API, but does not degrade in the pH neutral aqueous environment of the oral cavity and esophagus. In addition, there is a need in the industry for rapid release of additives to enhance the rapid release properties of gelatin or other polymeric encapsulants in the gastric cavity that do not degrade the encapsulant matrix structure during production. This rapid release additive can facilitate the production of gelatin capsules using accepted encapsulation techniques.

The presently claimed embodiments of the present invention generally provide gelatin having a compartmentalized area. Capsule formulations having variable dissolution and release profiles to rapidly dissolve and release the contents of the composition. Thus, in many aspects of the invention, a gelatin capsule composition comprising an outer surface coating and an inner core, the outer surface coating comprising: (a) one or more first compartment regions comprising a gelatin component; b) One or more second compartments comprising a rapid release formulation. In one embodiment, the one or more first compartments comprising the gelatin component and the one or more second compartments comprising the rapid release formulation further comprise an average molecular weight in the range of from about 100 to about 2000 Daltons. Gelatin hydrolysate. The gelatin component can have an average molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons.

In another embodiment, one or more second compartments comprising a rapid release formulation coat the depth from the proximal surface to the distal surface across the outer surface, and one or more second compartments comprising the rapid release formulation The regions can be dispersed throughout the gelatin capsule composition in a uniform or non-uniform pattern.

In another embodiment, the rapid release formulation can include water insoluble carbonates, water soluble carbonates, and combinations thereof. The water insoluble carbonate may include bismuth subcarbonate, calcium carbonate, cobalt carbonate, cesium carbonate, lead carbonate, lithium carbonate, magnesium carbonate, manganese carbonate, nickel (II) carbonate, silver carbonate, cesium carbonate, and combinations thereof. In yet another embodiment, the water insoluble carbonate can be substantially insoluble at a pH in the range of from about 6 to about 8, and can be dissociated at a pH in the range of from 0 to about 3. The water soluble carbonate salt can include sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium hydrogencarbonate, lithium carbonate, and combinations thereof, and can be at least partially soluble at a pH in the range of from about 0 to about 3. .

In another embodiment, the gelatin composition can include from about 1:1 to about 1:20 and about A quick release formulation and a gelatin component in a mass ratio ranging from 1:2 to about 1:9. In certain embodiments, the gelatin capsule composition is substantially completely degraded in less than 15 minutes at a pH in the range between 0 and about 3.

In addition, in another embodiment, the outer surface coating may also include a plasticizer comprising dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, sorbitol, red peony Alcohol, triacetin, triethyl citrate, water, and mixtures thereof. In one embodiment, the plasticizer can include a combination of sorbitol, sorbitan, glycerin, and water. The gelatin component incorporated into the outer surface coating may comprise a combination of gelatin, plasticizer and water. Specifically, in one embodiment, the one or more first compartments comprise from about 25% to about 55% gelatin by weight of one or more first compartments, in one or more first The compartments are from about 10% to about 30% by weight of the plasticizer and from about 15% to about 45% by weight of the weight of the one or more first compartments. In another embodiment, the gelatin component of the one or more first compartments comprises from about 35% to about 45% gelatin by weight of one or more first compartments, in one or more The weight of one zone ranges from about 16% to about 24% plasticizer and from about 20% to about 30% water by weight of one or more first compartments.

In an alternate embodiment, the gelatin component can comprise a combination of gelatin and water comprising from about 5% to about 30% gelatin and from about 70% to about 95% water. The gelatin component can also include from about 10% to about 20% gelatin and from about 80% to about 90% water. Moreover, in yet another embodiment, the outer surface coating can comprise a gelatin component and a gelatin hydrolysate in a mass ratio ranging from about 3:1 to about 99:1 and from about 4:1 to about 19:1.

In additional embodiments, one or more second compartments comprising a rapid release formulation may further comprise gelatin, a plasticizer, and water. In one embodiment Wherein the one or more second compartments comprise from about 20% to about 50% by weight of the weight of the one or more second compartments, about 1 by weight of the one or more second compartments % to about 25% of the quick release formulation, from about 10% to about 30% by weight of the one or more second compartments, and about 20% by weight of the one or more second compartments % to about 40% water. In another embodiment, the one or more second compartments comprise from about 30% to about 45% gelatin by weight of one or more second compartments, with one or more second compartments A quick release formulation of from about 4% to about 16% by weight, from about 16% to about 24% plasticizer by weight of one or more second compartments, and one or more second compartments The weight ranges from about 26% to about 34% water.

The inner core components of the presently claimed embodiments may include solid formulations, pastes or liquid formulations such as tablets, capsules, beads and granules. In addition, the inner core may comprise a pharmaceutically active ingredient and optionally one or more pharmaceutically acceptable excipients.

In another embodiment, the one or more first compartments may also comprise a rapid release formulation wherein the fast release formulation is present at a concentration less than the concentration of the fast release formulation of the one or more second compartments. In addition, the gelatin component can generally include Type A gelatin, Type B gelatin, and combinations thereof.

In additional embodiments, the one or more second compartments comprising the rapid release formulation are at about 30 minutes or less, about 20 minutes or less, about 15 minutes or less, about 12 minutes or less, about The solution is substantially dissolved in 10 minutes or less, about 8 minutes or less, about 6 minutes or less, and about 5 minutes or less, thereby releasing the contents of the inner core. In addition, one or more second compartments comprising a rapid release formulation may have the following appearance: strips, rods, strips, strips Traces, slats, columns, columns, spots, stripes, stripes, zones, strips, veins, short bars, ridges, twisted lines, and combinations thereof. The one or more second compartments may comprise a uniform and non-uniform shape. In one embodiment, the one or more second compartment regions comprise a uniform shape whereby the strips, rods, strips, etc. have a uniform appearance and length (eg, measured relative to the circumference along one axis of the composition) and width ( The measurement varies by no more than 10% with respect to each of the compartments as measured relative to the circumference of the alternate axis perpendicular to the axis for defining the length. In another embodiment, the one or more compartment regions comprise a non-uniform shape whereby the strips, rods, strips, etc. have different appearances and properties, and the length (eg, measured relative to the circumference along one axis of the composition) And the width (as measured relative to the circumference along an alternate axis perpendicular to the axis used to define the length) varies by no more than 10% relative to each of the compartments.

In another aspect, the presently claimed embodiments include a gelatin capsule composition comprising an outer surface coating and an inner core, the outer surface coating comprising: (a) one or more first comprising a gelatin component and a gelatin hydrolysate a compartmentalized area; and (b) one or more second compartments comprising a rapid release formulation, a gelatin component, and a gelatin hydrolysate, wherein one or more second compartments are coated across the outer surface from the proximal surface to The depth of the distal surface.

In yet another aspect, the presently claimed embodiments include a pharmaceutical gelatin capsule composition comprising an outer surface coating and an inner core, the outer surface coating comprising: (a) one or more first compartment regions, comprising one Or from about 35% to about 45% by weight of the plurality of first compartments, from about 3% to about 7% by weight of the one or more first compartments, having an average molecular weight of from about 100 to about 2,000. Gelatin hydrolysate in the range of Dalton, in one or more first compartments From about 18% to about 22% by weight of plasticizer and from about 20% to about 26% by weight of one or more first compartments; and (b) one or more second compartments And comprising from about 34% to about 40% gelatin by weight of one or more second compartments, and an average molecular weight of from about 3% to about 7% by weight of one or more second compartments a gelatin hydrolysate in the range of from about 100 to about 2000 Daltons, from about 5% to about 10% by weight of one or more second compartments, in one or more second compartments The weighting agent is from about 18% to about 22% by weight of the plasticizer and from about 28% to about 32% by weight of the weight of the one or more second compartments, wherein the inner core comprises a pharmaceutically active ingredient, one of which The plurality of second compartments span the outer surface from the proximal surface to the distal surface, and wherein the rapid release formulation comprises bismuth subcarbonate, calcium carbonate, cobalt carbonate, cesium carbonate, lead carbonate, lithium carbonate, magnesium carbonate, Manganese carbonate, nickel (II) carbonate, silver carbonate, barium carbonate, sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium hydrogencarbonate and combinations thereof

In still another aspect, embodiments of the presently claimed invention include a gelatin capsule composition comprising an outer surface coating, a subcoat, and an inner core, the outer surface coating comprising: (a) one or more gelatin containing components a compartment; and (b) one or more second compartments comprising a rapid release formulation, wherein the subcoat is applied to the distal portion of the core and surrounds a substantial portion of the core, and wherein the outer surface coating is applied to the subcoat The distal part. In one embodiment, the subcoat may generally comprise a gelatin component, a gelatin hydrolysate, a polymeric material, and combinations thereof. Moreover, in another embodiment, the subcoat may also include one or more channels for releasing the contents of the inner core. In yet another embodiment, the subcoat may include two Or more layers with different release and dissolution profiles. In one embodiment, the inner core comprises a pharmaceutically active ingredient.

In yet another aspect, the presently claimed embodiments encompass a gelatin capsule composition comprising an enteric coating, an inner core surface coating, and an inner core, the inner core surface coating comprising: (a) one or more gelatin-containing groups a first compartment; and (b) one or more second compartments comprising a rapid release formulation, wherein an enteric coating is applied to the distal portion of the inner core surface coating, wherein the inner core surface is coated Applied to the distal portion of the inner core, and wherein the enteric coating is insoluble at a pH in the range of from 0 to about 3 and is soluble at a pH greater than or equal to 5.5. In one embodiment, the enteric coating can include a gelatin component, a gelatin hydrolysate, a polymeric material, and combinations thereof. The internal core can also incorporate pharmaceutically active ingredients.

In yet another aspect, the presently claimed embodiments include a method of making a gelatin capsule composition comprising an outer surface coating and an inner core, wherein the outer surface coating comprises one or more first compartment regions comprising a gelatin component and Or a plurality of second compartments comprising a rapid release formulation, the method comprising: (a) dissolving the gelatin component in an aqueous medium to produce an aqueous gelatin solution; (b) incorporating a second formulation comprising a rapid release formulation into the gelatin aqueous solution The solution to produce one or more first compartments comprising a gelatin aqueous solution and one or more second compartments comprising a second solution comprising a rapid release formulation; and (c) encapsulating the pharmaceutically active ingredient while maintaining one Or a plurality of first compartments and one or more second compartments. In one embodiment, the encapsulation process of step (c) comprises an extrusion process. In another embodiment, the gelatin component of step (a) comprises gelatin having a molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons and a molecular weight of A combination of gelatin hydrolysate in the range of from about 100 Daltons to about 2000 Daltons.

In addition, step (a) may also include the addition of a plasticizer such as dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, sorbitol, erythritol, triacetin Ester and triethyl citrate, water, and mixtures thereof. In one embodiment, the plasticizer can include a combination of sorbitol, glycerin, and water. In another embodiment, the plasticizer component comprising a combination of sorbitol, sorbitan, glycerin, and water comprises 50 parts of a combination of sorbitol and sorbitan, 42.5 parts of glycerin, and 7.5 parts of water. In another embodiment, the gelatin component can comprise a combination of gelatin and a plasticizer.

In another embodiment, step (a) may comprise mixing from about 25% to about 55% gelatin by weight of the gelatin component, from about 15% to about 30% plasticizer by weight of the gelatin component, and From about 25% to about 40% water by weight of the gelatin component.

In additional embodiments, the second solution of step (b) can include a rapid release formulation, a gelatin component, a plasticizer, and an aqueous medium, such as water. The gelatin component can comprise a combination of gelatin having a molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons and a gelatin hydrolysate having a molecular weight in the range of from about 100 Daltons to about 2000 Daltons.

In yet another embodiment, the one or more first compartments comprising the aqueous gelatin solution and the one or more second compartments comprising the rapid release formulation are passed through a static mixer to feed the gelatin aqueous solution and comprise a rapid release A second solution of the formulation is produced.

In yet another aspect, the presently claimed embodiments include an outer surface coating comprising And an inner core gelatin composition wherein the outer surface coating comprises a quick release formulation and a gelatin component, wherein the fast release formulation is at least semi-dispersively dispersed throughout the outer surface coating without a zone of separation. The gelatin composition can further comprise a gelatin hydrolysate having a molecular weight in the range of from about 100 Daltons to about 2000 Daltons.

Moreover, in one embodiment, the fast release formulation comprises a water soluble carbonate, a water insoluble carbonate, and combinations thereof. The water-soluble rapid release formulation may generally include sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium hydrogencarbonate, and combinations thereof, and may be at least partially soluble in water, and wherein the rapid release formulation is from 0 to about Dissociation at pH within 3 ranges. Additionally, the water insoluble carbonates can generally include barium hypocarbonate, calcium carbonate, cobalt carbonate, barium carbonate, lead carbonate, lithium carbonate, magnesium carbonate, manganese carbonate, nickel (II) carbonate, silver carbonate, barium carbonate, and combinations thereof.

In certain embodiments, the composition can include a rapid release formulation with a mass ratio ranging from about 1:1 to about 1:20, from about 1:2 to about 1:15, and from about 1:4 to about 1:9. Gelatin component. Moreover, in another embodiment, the composition is substantially completely degraded in less than 15 minutes at a pH in the range between 0 and about 3.

In yet another embodiment, the composition may comprise a gelatin component in a mass ratio ranging from about 3:1 to about 99:1, from about 4:1 to about 19:1, and from about 5:1 to about 13:1. Gelatin hydrolysate.

In still another aspect, the presently claimed embodiments include a gelatin composition comprising: (a) a water soluble fast release formulation; (b) a gelatin component; and (c) a gelatin hydrolysate, wherein the composition comprises about Mass ratio in the range of 1:1 to about 1:20 a water soluble quick release formulation and a gelatin component, wherein the gelatin hydrolysate has a molecular weight in the range of from about 100 Daltons to about 2000 Daltons, and wherein the composition comprises from about 3:1 to about 99:1 The quality is better than the gelatin component and the gelatin hydrolysate.

In still another aspect, the presently claimed embodiments include a gelatin composition comprising a rapid release formulation and a gelatin component, which is prepared by the process comprising: (a) dissolving the gelatin component in an aqueous medium. Forming a gelatin aqueous solution; (b) mixing the quick release formulation with the gelatin aqueous solution prior to capsule formation; and (c) incorporating the gelatin aqueous solution and the water soluble quick release formulation into a gelatin capsule forming machine. Additionally, step (b), which may include mixing the rapid release formulation with the gelatin aqueous solution prior to capsule formation, comprises an in-line mixing process. In one embodiment, the rapid release composition can further comprise a gelatin hydrolysate having a molecular weight in the range of from about 100 Daltons to about 2000 Daltons.

In yet another aspect, the presently claimed embodiments include a method of making a gelatin composition comprising a rapid release formulation comprising the steps of: (a) dissolving the gelatin component in an aqueous medium; (b) prior to capsule formation Mixing the fast release formulation with an aqueous gelatin solution; and (c) incorporating the combination of the gelatin aqueous solution and the quick release formulation into a gelatin capsule forming machine. In one embodiment, step (b) can comprise mixing the rapid release formulation with an aqueous gelatin solution using an in-line mixing method prior to capsule formation. In another embodiment, the gelatin component of step (a) comprises gelatin having a molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons and having a molecular weight in the range of from about 100 Daltons to about 2000 Daltons. A combination of gelatin hydrolysate.

In a specific embodiment, step (a) of the method of preparing a composition comprises About 0.01% to about 30% of the gelatin component, by weight of the combined gelatin aqueous solution, is dissolved in an aqueous medium of from about 40% to about 99.9% by weight of the combined aqueous gelatin solution. In another embodiment, step (a) comprises dissolving from about 10% to about 20% of the gelatin component by weight of the combined gelatin aqueous solution in an aqueous medium of from about 70% to about 90% by weight of the combined aqueous gelatin solution. in. In still another embodiment, step (a) comprises from about 10% to about 20% by weight, based on the weight of the combined aqueous gelatin solution, of gelatin having a molecular weight of from about 50,000 Daltons to about 300,000 Daltons and about 1% by weight. To about 5% by weight of the gelatin hydrolysate having a molecular weight in the range of from about 100 Daltons to about 2000 Daltons is dissolved in from about 70% to about 90% by weight of the aqueous medium.

Other aspects and illustrations of the invention are described in detail below.

The drawings illustrate various aspects of the invention.

The term "composition" as used herein is suitable for any solid object, semi-solid or liquid composition designed to contain a particular predetermined amount (dosage) of a particular ingredient, such as an active ingredient as defined below. Suitable compositions can be pharmaceutical drug delivery systems, including oral administration, buccal administration, rectal administration, topical or mucosal delivery, or subcutaneous implants, or other delivery systems for implanted drug delivery systems; For the delivery of minerals, vitamins and other nutrients, oral care agents, flavoring agents and the like. In one embodiment of the invention, the composition is considered to be a solid; however, it may contain a liquid or semi-solid component. Typically, the dosage form is an oral administration system for delivering a pharmaceutically active ingredient to the human gastrointestinal tract.

Gelatin compositions typically include an outer surface coating and a core. Core (or substrate) It can be in any solid, semi-solid or liquid form. The core can be made by any suitable method, for example, as a core of a compression dosage form, or can be injected to provide a liquid-filled core. "Core" as used herein refers to a material that is at least partially encapsulated or surrounded by another material. In one embodiment, the core comprises a liquid-filled formulation that typically comprises a liquid, suspension or emulsion. In another embodiment, the core comprises a solid, for example, the core may be in the form of a compressed or molded lozenge, a hard or soft capsule, a suppository or a candy, such as a diamond lozenge, a fructose, a caramel, a fondant or a fat based combination.

The core can be in many different shapes. For example, in one embodiment, the core can be frustoconical in shape. In other embodiments, the core may be formed in a polyhedral shape, such as a cube, pyramid, cymbal or the like; or may have a geometry containing some non-planar spatial patterns, such as a cone, a cylinder, a sphere, an oval, an ellipse , torus or the like. In one embodiment where the core comprises a liquid formulation, the core is generally spherical or oval in shape. In another embodiment, if the core is a solid compressed tablet formulation, the core shape used is comprised by "The Elizabeth Companies Tablet Design Training Manual" (Elizabeth Carbide Die, Inc., page 7, McKeesport, Pa.) The manner of incorporating the shape of the tablet formed from the shape of the compression tool as described below (the shape of the tablet corresponds inversely to the shape of the compression tool): shallow concave, standard concave, deep concave, ultra deep Concave, modified spherical concave, Standard Concave Bisect, standard concave double bisector, Standard Concave European Bisect, standard concave partial bisector, Double radius, bevel and concave, plane, plane bevel edge (FFBE), FFBE bisector, FFBE double bisector, ring, dent, ellipse, oval, capsule, rectangle, square, triangle, hexagon, pentagon, octagon, diamond, arrow, warhead, cylinder, Half moon shape, shield shape, heart shape, almond shape, house shape / home plate shape, parallelogram, trapezoid, figure 8 / barbell shape, bow shape, irregular triangle.

The core may comprise a blend of suitable active ingredients and excipients, which may have their natural color, including white, or may be conveniently colored as needed to provide the core of any desired color.

In one embodiment, the core of the presently claimed gelatin composition may contain one or more active ingredients. The term "active ingredient" as used herein broadly includes, for example, pharmaceutical substances, minerals, vitamins and other nutrients, plant extracts, fatty acids, oral care agents, flavoring agents, and mixtures thereof. Suitable examples of pharmaceutically active ingredients include, but are not limited to, abortion drugs, ACE inhibitors, adrenocorticotropic hormone, alpha-adrenergic agonists, alpha-adrenergic blockers, alpha-glucosidase inhibitors, assimilation Steroids, narcotic analgesics, non-narcotic analgesics, anorectic agents, antacids, anthelmintics, anti-allergic agents, anti-pilling agents, anti-Ami worms, anti-pharyngeal drugs, anti-arrhythmia Medicine, anti-arthritis medicine, antiasthmatic agent, antibiotic, anticholinergic agent, antispasmodic agent, antidepressant, antidiabetic agent, antidiarrheal agent, antidote, antitrachyrrhea agent, antiemetic, antiestrogens , antifungal agents, antiglaucoma agents, anti-gout agents, antihistamines, antihypertensives, non-steroidal anti-inflammatory drugs, anti-malarial agents, anti-migraine agents, anti-muscarinic drugs, anti-nausea drugs, anti-drugs Tumor, antiparkinsonians, anti-pheochromocytoma agents, anti-pneumocystis drugs, anti-prostatic hyperplasia agents, anti-protozoal agents, antipruritic agents, anti-drying agents Agent, antipsychotic, antipyretic, anti-rickettsia, antispasmodic, anti-thrombotic, antithrombotic, anti-thyroid, anti-tuberculosis, cough, anti-ulcer, antiviral, Anxiolytics, aromatase inhibitors, autonomic drugs, barbiturates, benzodiazepine antagonists, beta-adrenergic antagonists, beta-adrenergic blockers, bradycardia Agent, bronchodilator, calcium channel blocker, carbonic anhydrase inhibitor, cardiac drug, cardiotonic, choleretic, cholinergic agent, cholinesterase inhibitor, cholinesterase re-activator, CNS stimulation Agent, cytoprotective agent, decongestant, diuretic, dopamine receptor agonist, dopamine receptor antagonist, ectoparasite, emetic, expectorant, fibrinogen receptor antagonist, stomach Secretion inhibitors, gastrointestinal drugs, gastric motility agents, genitourinary smooth muscle relaxants, heavy metal antagonists, hemostatic agents, histamine H2 receptor antagonists, sedatives, immunomodulators, immunosuppressive agents, iron preparations, exfoliating agents MAO Agent, viscous sputum, muscle relaxant, dilating agent, narcotic antagonist, nootropics, anaesthetic agonist, oxytocin, potassium channel activator, respiratory irritant, sedative, serenics, serum Receptor agonists, serotonin receptor antagonists, serotonin uptake inhibitors, stimulators, sympatholytic blockers, sympathomimetic drugs, thrombolytic agents, anti-delivery drugs, tranquilizers, vasodilators, vascular protection And vitamins.

In one embodiment, the pharmaceutically active ingredient (API) may be water soluble in an aqueous solution having a pH in the range of from 0 to about 9. Alternatively, the water soluble API can be water soluble in aqueous solutions (including but not limited to gastric juice) having a pH in the range of from 0 to about 3. Non-limiting examples of water soluble APIs include abacavir sulfate (abacavir sulfate), acebutolol, acetaminophen, acyclovir, albendazole, alendronate sodium, anthraquinone Allopurinol, amoxicillin, amantadine HCl, potassium amide, aminocaproic acid, aminoarone HCl, amitriptyline hydrochloride , amphetamine, aspirin, atenolol, atorvastatin calcium, atropine sulfate, azithromycin, balsalazide (balsalazide), benzepril hydrochloride, bepridil HCl, betaine HCl, bisoprolol fumarate, buformin, Bupropion HCl, calacyclovir, capecitabine, captopril, carisoprodol, cefdroxil, cephalosporin Cefdnir, cefixime, cefpod Cefpodoxime proxetil, cefprozil, cefuroxime axetil, celecoxib, cetizine hydrochloride, chondroitin, chlorathiazide , chlorpheniramine maleate, chlorpromazine HCl, chlorzoxazone, choline magnesium trisalicylate, cimetidine, Ciprofloxacin, clavulanate potassium, clin Clindamycin, clomipramine hydrochloride, clonidine hydrochloride, clopidogrel bisulfate, cloxacillin sodium, codeine phosphate ), colchicines, colsevelam HCl, creatine, cyclophosphamide, cyproheptadine, delavirdine mesylate ), demeclocycline HCl, diclofenac, didanosine, diethylcarbamazine citrate, diltiazem HCl, DL-methionine (DL) -methionine), doxepine HCl, doxycycline, efavirenz, eprosartan mesylate, entacapone, hydrochloride B Etembutol hydrochloride, eprosartan, erythromycin, ethosuximide, etidronate disodium, etodolac, sulphate iron , flecainide acetate, felbamate, fexofenadine HCl, firocoxib, fluconazole, fluoxetine hydrochloride Fluoxetine hydrochloride), fluriprofen, fluvastatin, fosonopril sodium, fumarate, gabapentine, gatifloxacin, ganciclovir Ganciclovir, guaifenesine, salt Hydralazine hydrochloride, hydrocodone bitartrate, hydroxychloroquine sulfate, (hydroxyurea), hydroxyzine hydrochloride, ibuprofen, barium sulfate Indinavir sulfate, irbesartan, isoflavone, isoniazid, isosorbide mononitrate, ketoprofen, lactobionate, lamiv Lamivudine, levamisole hydrochloride, levofloxacin, lisinopril, lithium carbonate, losartan potassium, mebendazole, meclofenamic acid (mefenamic acid), meperidine HCl, mesalamine, metaprolol tartrate, metaxalone, metformin HCl, and ursolic acid Methamine mandelate, methyldopa, methocarbamol, methylphenidate, methylphenidate hydrochloride, meditin Meyrosine, minocycline hydrochloride, modafinil, montelukast sodium, morphine sulfate, moxifloxacin HCl, wheat Mycophenolate mefetil, nabumetone, naproxen sodium, nefazodone HCl, nelfinavir meslyate, bromine Neostigmine bromide, niacin, nicotinamide, nitrofurantoin (nitrofurantoin), nifurtimox (nifurtimox), nizatidine, norfloxacin, nortriptyline hydrochloride, ofloxacin, olanzapine ( Olanzepine), orlistat, oxybytynin chloride, trypsin, pantothenic acid, penicillamine, penicillin V potassium, pentosan sulfate (pentosan) Polysulfate sodium), phenformin, phenylbutazone, phenytoin sodium, phytoestrogens, potassium chloride, pramipexole, pravastatin sodium, pyridine Praziquantel, primaquine phosphate, proanthocyanidin, procainamide, promethazine, promethazine hydrochloride, propafenone HCl (propafenone) HCl), propanolol HCl, propoxyphene hydrochloride, propoxyphene napsylate, prozosin, pseudophedrine hydroc Hloride), pseudoephedrine sulfate, psyllium, pycnogenol, pyrazinamide, pyridostigmine bromide, pyridoxine hydrochloride , pyruvate, quetiapine carafate, quinidine sulfate, quinapril hydrochloride, ramipril, ranitidine hydrochloride Ranitidine hydrochloride Reboxetine, rifabutin, rifampin, risedronate sodium, rofecoxib, rosiglitazone maleate, Salbutamol sulfate, saquinavir mesylate, sertraline HCl, sevelamer HCl, sildenafil, methotrexate (simethicone), sodium valproate, sotalol HCl, stavudine, succimer, sumanirole, succinic acid Sumatriptan succinate, suntheanine, terazosin hydrochloride, terbinafine HCl, tetracycline HCl, theophylline, thiobenzene Thiobendazole, ticlopidine HCl, timolol meleate, tocainide HCl, tolcapne, tolmetin Sodium), tramadol HCl (tramadol HCl), trovafloxacin trovafloxacin (trovafloxacin mes Ylate), valacyclovir HCl, valganciclovir HCl, valsartan, vancomycin, venlafaxine hydrochloride, dysphagia HCl (verapamil HCl), warfarin sodium, xylamine, zidovudine, and combinations thereof. Depending on the particular embodiment, the API can be in the form of a solid, powder, granule or liquid.

Suitable flavoring agents include, but are not limited to, methanol, mint, mint flavoring agents, Fruit flavors, chocolate, vanilla, bubble gum flavors, coffee flavors, liqueur flavors, combinations thereof, and the like.

Suitable vitamins and minerals include, but are not limited to, tricalcium phosphate or calcium acetate, dipotassium hydrogen phosphate, magnesium sulfate or magnesium oxide, salt (sodium chloride), potassium chloride or potassium acetate, ascorbic acid, iron orthophosphate, tobacco Indamine, zinc sulfate or zinc oxide, calcium pantothenate, copper gluconate, riboflavin, beta-carotene, pyridoxine hydrochloride, thiamine mononitrate, folic acid, biotin, chromium chloride or picolinic acid Chromium, potassium iodide, sodium selenate, sodium molybdate, chlorophyllin, vitamin D3, cyanocobalamin, sodium selenite, copper sulfate, vitamin A, vitamin C, inositol, potassium iodide and combinations thereof. Dosages suitable for vitamins and minerals can be obtained, for example, by reviewing the U.S. RDA guidelines. Additionally, non-limiting examples of minerals include iron, calcium, magnesium, potassium, copper, chromium, zinc, molybdenum, iodine, boron, selenium, manganese, derivatives thereof, or combinations thereof. Such vitamins and minerals may come from, but are not limited to, any source or combination of sources. Non-limiting exemplary B vitamins include, but are not limited to, thiamine, nicotinamide, pyridoxine, riboflavin, cyanocobalamin, biotin, pantothenic acid, or combinations thereof.

The term "nutrient agent" as used herein means a natural component of a food or other ingestible form that has been determined to be beneficial to the human body in preventing or treating one or more diseases or improving psychological performance. If an essential nutrient provides a benefit other than its essential role in the normal growth or maintenance of the human body, it can be considered a nutrient. A nutrient as used herein is defined as any substance that is administered to an individual in the form of a dietary supplement. Such supplements may be purified vitamins or minerals, herbs or plant extracts. Preferred nutritional supplements are extracts or concentrates of plants, including herbal plants. Range of such nutritional supplements that can be used in the present invention Examples include, but are not limited to, cherry extract, Ginkgo biloba extract, Kava Kava extract, Ginseng extract, Saw Palmetto extract, cranberry ( Cranberry) or blueberry extract, tomato extract, cordyceps sinensis extract, pomegranate, elderberries, and whole raspberry family (strawberry, raspberry, cherry, black raspberry) , Boysenberry, etc.), glucosamine sulfate, chromium picolinate, milk thistle extract, grape seed extract, Ma Huang extract, coenzyme Q10.

Suitable plants from which extracts can be prepared and isolated from natural materials include, but are not limited to, higher plants: Acanthopanax, Acanthopsis, Acanthosicyos, Acanthus , Achyranthes, Acokanthera, Aconitum, Acorus, Acronychia, Actaea, Actinidia, A. Adenia, Adhatoda, Aegle, Aesculus, Aframomum, Agastache, Agathosma, Coleus Genus (Alchemilla), Aleurites (Allium), Allium, Aloe, Alonsoa, Aloysia, Alphitonia, and Camellia Alpinia), Alternanthera, Amaranthus, Amomum, Amphipterygium, Amyris, Anchusa, Crotalaria (Ancistrocladus), Three White Grass (Anemopsis), Angelica, Annona, Anonidium, Anthemis, Antidesma, Apium, Aralia , Aristolochia, Artemisia, Artocarpus, Asarum, Asclepias, Asimina, and Asparta ( Aspalanthus), Asparagus, Aspidosperma, Astragalus, Astronium, Atropa, Avena, Azadirachta , Azara, Baccharis, Bacopa, Balantites, Bambusa, Barleria, cloth Barosma, Bauhinia, Belamcanda, Benincasa, Berberis, Berchemia, Bixa, and genus Bocconia), Borago, Boronia, Boswellia, Brosimum, Brucea, Brunfelsia, Bryoni a), Buddleja, Bulnesia, Bupleurum, Bursera, Byrsonima, Calamintha, Calea ), Calophyllum, Camellia, Camptotheca, Cananga, Canarium, Canella, Capparis, Capsicum (Capsicum), Carthamus, and Carum, Cassia, Cassine, Chestnut Seeds Castanospermum, Catalpa, Catha, Catharanthus, Cayaponia, Cecroopia, Centaurea, and Bacillus Gentipea, Centranthus, Cephaelis, Chiranthodendron, Chondrodendron, Chrysophyllum, Cimicifuga ), Cinchona, Cinnamomum, Cistus, Citrus, Clausena, Cnicus, Coccoloba, Codonopsis Codonopsis, Coffea, Coix, Cola, Coleus, Colletia, Combretum, Commiphora , Cordia, Coriaria, Correa, Corydalis, Costus, Crataegus, Croton, White Leaf Cryptolepis, Cudrania, Cuminum, Cuphea, Cucurma, Cycla. Nthera), Cymbopogon, Cynara, Cynoglossum, Cyperus, Cyrtocarpa, Dalbergia, Dalea, Danae, Daphne, Datura, Daucus, Decadon, Dendrocalamus, Dendropanax, Dessert (Dendropanax) Deppea), Derris, Desmos, Dichrostachys, Dictamnus, Digitalis, Dillenia, Dioscorea, Dioscoreophyllum, Diosma, Diospyros, Drimys, Duboisia, Dusit Genus (Duguetia), Dysoxylum, Echinacea, Eclipta, Ehretia, Ekebergia, Carassius Eleagnus), Elettaria, Eleutherococcus, Encelia, Entandrophragma, Ephedra, Epimedium, Eriobotrya ), Erodium, Eryngium, Erythrochiton, Erythroxylum, Escholzia, Bacillus (Esenbeckia), Euclea, Eucommia, Euodia, Eupatorium, Fabiana, Ferula, Afrika (Fevillea), Futonia, Flindersia, Foeniculum, (Gallesia), Galphimia, Garcinia ), (Gaudichaudia), Gaultheria, Gelsemium, Gentiana, Geranium, Gigantochloa, Gingko, Astragalus (Glochidion), Gloeospemum, Grewia, Greyia, Guaiacum, Gymnema, Haematoxylum ), Hamamelis, Hamelia, Harpagophytum, Hauya, Heimia, 嚏根 Helleborus, Hieracium, Hieroehloc, Hilleria, Hippophae, Houttuynia, Hovenia, Humulus, Huperzia, Hura, Hybanthus, Hydnocarpus, Hydnophytum, Hydrastis, Tianhu Hydrocotyle, Hymenaea, Hyoscamus, Hypericum, Hyptis, Hyssopus, Iboza, Osa Idyspermum, Ilex, Illicium, Indigofera, Inga, Inula, lochroma, blood scorpion Genus (Iresine), Iris, Jacaranda, Jatropha, Juniperus, Justicia, Kadsura, Hawthorn ( Kaempferia), Lactuca, Lagochilus, Larrea, Laurus, Lavandula, Lawsonia, Leonurus, Leucas, Ligusticum, Lindera, Lippia, Liriosma, Litsea, Lobelia Lobelia), Lonchocarpus, Lonicera, Lycium, Macfadyena, Maclura, Mangifera, Mansoa ), (Marcgravia), Marrubium, Martinella, Matricaria, Maytenus, Medicago, Melissa, Mentha, Mimosa, Mimusops, Mitragyna, Montanoa, horse Morkillia, Mouriri, Mucuna, Mutisia, Myrica, Myristica, Nardostachys , Nepeta, Nicotiana, Ocotea, Olea, Oncoba, Ophiopogon, Origanum ), Pachyrhizus, Panax, Papaver, Pappea, Parthenium, Passiflora, Paullinia , Pelargonium, Penstemon, Perezia, Perilla, Persea, Petiveria, Petroselinum, Peucedanum, Peumus, Pfaffia, Phoebe, Phyllanthus, Phytolacca, Prunus Genus (Pilocarpus), Pimenta, Pimpinella, Pinellia, Piper, Piqueria, Pithecellobium, Pitaya (Pittosporum), Plectranthus, Pleuropetalum, Podophyllum, Pogostemon, Polygala, Polygonum, Cup Polymnia, Psacalium, Psychotria, Pterygota, Secopatem (Ptychopetalum), Pueraria, Punica, Pycnanthemum, Pygeum, Quararibea, Quasisia, Soap Tree Quillaja), Randia, Ratibida, Rauvolfia, Rehmannia, Renealmia, Rheum, Luo Rollinia, Rorippa, Rosmarinus, Rudbeckia, Ruellia, Rumex, Ruscus , Ruta, Saccharum, Salix, Salvia, Sambucus, Sanguinaria, Sapium, Sassafras, Satureja, Sceletium, Schizandra, Securidaca, Securinega, Serenoa, Simon Simmondsia, Smilax, Stachytarpheta, Stachys, Staurogyne, Stelechocarpus, Stem Phania), Sterculia, Stevia, Strophanthus, Strychnos, Symphytum, Syzygium, Tabebuia, Tabemaemontana, Tabemanthe, Tanacetum, Taxus, Tecoma, Terminalia, Neisseria Teucrium), Thaumatococcus, Tribulus, Clover (Trifolium), Trigonella, Triplaris, Triumfetta, Tumera, Tussilago, Tylophora, Blue Tynnanthus, Uncaria, Urginea, Urtica, Uvaria, Vaccinium, Valeriana, tile Vallesia, Vangueria, Vanilla, Vellozia, Vepris, Verbascum, Verbena, Vetiveria, Virola, Viscum, Visism, Vitex, Voacanga, Warburgia , Withania, Zanthoxylum, Zingiber, Zizyphus, and Zygophyllum. In addition to the genus of higher plants listed above, compounds may also be recovered from biological sources (eg algae, bacteria, fungi, lichens, moss) and marine organisms (eg, polyps, sponges, tunicates) or other invertebrates Animal or vertebrate organism.

The term "fatty acid" as used herein is recognized in the art and includes long chain hydrocarbon based carboxylic acids. Fatty acids are components of many lipids including glycerides. The most common naturally occurring fatty acids are monocarboxylic acids having an even number of carbon atoms (16 or 18) and being saturated or unsaturated. "Unsaturated" fatty acids contain cis double bonds between carbon atoms. Suitable unsaturated fatty acids include, but are not limited to, unsaturated fatty acids, which may include, but are not limited to, gamma-linolenic acid (GLA), alpha-linolenic acid (ALA), stearidonic acid (SDA), Arachidonic acid (AA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), Twenty-two carbon six Oleic acid (DHA) and linoleic acid (LA).

Various other pharmaceutically acceptable excipients may be included in the translucent semi-solid fill material, such as preservatives (e.g., methyl or propyl paraben), colorants, flavors, lubricants, fluids. Enhancers, antioxidants, surfactants, plasticizers, filler auxiliaries and other compounds, reagents and components that produce attractive end products.

One or more active ingredients are usually present in the core in a therapeutically effective amount, which is the amount which produces the desired therapeutic response upon oral administration and can be readily determined by those skilled in the art. In determining such amounts, the particular active ingredient to be administered, the bioavailability characteristics of the active ingredient, the dosage regimen, the age and weight of the patient, and other factors must be considered, as is known in the art. In one embodiment, the dosage form comprises at least about 0.1% by weight (based on the weight of the core) of one or more active ingredients.

One or more of the active ingredients may be presented in any form. For example, one or more of the active ingredients may be dispersed at the molecular level, for example, melted or dissolved in a dosage form, or may be in the form of particles, which in turn may be coated or uncoated. If the active ingredient is in the form of particles, the average particle size of the particles (whether coated or uncoated) is typically from about 1 to about 2000 microns. In a preferred embodiment, the particles are crystals having an average particle size of from about 1 to about 300 microns. In another preferred embodiment, the particles are particles or pellets having an average particle size of from about 50 to about 2000 microns, preferably from about 50 to about 1000 microns, and most preferably from about 100 to about 800 microns.

In certain embodiments, at least a portion of one or more active ingredients may optionally be coated with a release modified coating, as is known in the art. This advantageously provides an additional tool for the release profile of the active ingredient in the modified dosage form. For example, The core may contain coated particles of one or more active ingredients, wherein the particle coating imparts improved release functionality, as is well known in the art. Examples of suitable release coatings for particles are described in U.S. Patent Nos. 4,173,626, 4,863,742, 4,980,170, 4,984,240, 5,86,497, 5,912,013, 6,270,805, and 6,322,819. Commercially available modified release coated active particles can also be used. Thus, all or a portion of one or more of the active ingredients in the core may be coated with a release modifying material.

In embodiments where it is desired to absorb at least one active ingredient into the systemic circulation of the animal, the one or more active ingredients are preferably soluble upon contact with a dissolution medium such as water, gastric juice, intestinal fluid or the like.

In one embodiment, the solubility characteristics of the at least one active ingredient meet the USP specification for a direct release formulation containing the active ingredient. Those skilled in the art will appreciate that certain USP specifications will vary depending on the active ingredient selected.

In another embodiment, the solubility characteristics of one or more active ingredients are modified: for example, controlled, sustained, extended, delayed, extended, delayed, and the like. In one embodiment in which one or more of the active ingredients are released in a modified manner, the modified release active is preferably included in the core. As used herein, the term "modified release" means the release of the active ingredient from the composition or a portion thereof in a manner that is not directly released (ie, not immediately after the composition or a portion thereof is contacted with the liquid medium). As is known in the art, the types of modified release include delayed or controlled release. Types of controlled release include delay, persistence, extension, delay, and the like. Modified release profiles incorporating delayed release profiles include pulses, repetitive effects, and the like. As is also known in the art, mechanisms suitable for achieving improved release of the active ingredient include diffusion, Corrosion, surface area control via geometry and/or impermeable or semi-permeable barriers and other known mechanisms.

In addition to the core, the gelatin compositions of the presently claimed embodiments typically also comprise an outer surface coating. The outer surface coating comprises a quick release formulation and a gelatin component and is typically applied to the distal surface of the core. The outer surface coating is exposed to the external environment and is typically designed to dissolve rapidly upon contact with gastric or intestinal fluid, thereby exposing all or a portion of the core to gastric or intestinal fluid.

The outer surface coating is generally used as a component of coated lozenges, soft gel caps and hard gelatin capsules. Other uses of the encapsulating composition embodiments can include, but are not limited to, a chewable composition comprising a capping active therapeutic compound and a chewing gum.

To inhibit the formation of a cross bridge within the encapsulation during storage including, but not limited to, high temperatures, elevated humidity, and combinations thereof, the gelatin composition may further comprise a hydrolysate of gelatin. Since the formation of a cross bridge within the encapsulation prevents dissolution of the encapsulation, the addition of gelatin hydrolysate maintains the initial dissolution characteristics of the gelatin composition even after prolonged storage periods. In an exemplary embodiment, the hydrolysate of gelatin included in the gelatin capsule composition has a molecular weight in the range of from about 100 to about 2000 Daltons.

Surface coatings outside the presently claimed embodiments are typically incorporated into the fast release formulations and gelatin components. Rapid release formulations typically function by releasing a gas including, but not limited to, carbon dioxide as a dissociative by-product of the rapid release formulation upon contact with gastric or intestinal fluids. Without being bound by any particular theory, the dissociation of the rapid release formulation releases air bubbles within the outer surface coating. The static pressure of the bubbles released by the dissociation of the rapid release formulation in the encapsulation exerts physical stress on the surrounding area, causing tearing and eventual rupture of the coating. With no quick release system The composition of the agent induces a significantly faster release of the active compound encapsulated by the outer surface coating as a result of the destructive force of the dissociated release of the free release formulation.

The outer surface coating can include varying thicknesses depending on the desired properties of the endoscopic formulation. In one embodiment, the thickness of the outer surface coating can vary from about 0.01 mm to about 10 mm, from about 0.1 mm to about 5 mm, and from about 0.5 mm to about 3 mm. In particular, the thickness of the outer surface coating may comprise about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm. About 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, and about 2.0 mm.

Suitable rapid release formulations can include, but are not limited to, water soluble and water insoluble bicarbonates and carbonates. The water soluble rapid release formulation can be selected to be any compound that is soluble in aqueous solution and at least partially soluble in water, except at a pH in the range of from 0 to about 3. The term "at least partially soluble" generally includes compounds having a solubility in water of at least 1% (1 gram in 100 ml of water at 20 ° C). Suitable water soluble rapid release formulations include, but are not limited to, sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium hydrogencarbonate, calcium hydrogencarbonate, and combinations thereof.

In another embodiment, the fast release formulation can include a water insoluble carbonate. Suitable water insoluble rapid release formulations may be selected from any compound which is substantially insoluble in aqueous solution at a pH in the range of from about 0 to about 3, soluble in aqueous solution at a pH in the range of from about 6 to about 8. The term "substantially insoluble" as used herein indicates a solubility in water of less than 1% (at 100 ° C at 20 ° C) 1 g in water). Suitable water-insoluble rapid release formulations include, but are not limited to, barium carbonate, calcium carbonate, cobalt carbonate, barium carbonate, lead carbonate, lithium carbonate, magnesium carbonate, manganese carbonate, nickel (II) carbonate, silver carbonate, barium carbonate and combination. In a particular embodiment, the water insoluble rapid release formulation can be calcium carbonate.

For various edible gelatin compositions including, but not limited to, foods, dietary supplements, and pharmaceutical products, the fast release formulations can have at least food grade qualities. More preferably, the fast release formulation may have GRAS and USP qualities.

The fast release formulation can be used in the form of fine particles having a size of less than about 0.152 mm (about 100 mesh). The fine particles may have a size of less than about 0.089 mm (about 170 mesh), less than about 0.075 mm (about 200 mesh), less than about 0.066 mm (about 230 mesh), or less than about 0.053 mm (about 270 mesh). In another embodiment, the rapid release formulation can be used in the form of fine particles having a size of less than about 0.075 mm (about 200 mesh).

The amount of the quick release formulation included in the gelatin capsule composition can be sufficiently high to induce the formation of bubbles such as carbon dioxide when the gelatin composition is exposed to an acidic solution such as gastric juice. The rapid release formulation can be included in the gelatin composition in an amount ranging from about 0.1% to about 50% by weight of the gelatin component. Alternatively, the amount of rapid release formulation included in the gelatin capsule composition can range from about 5% to about 13%, from about 9% to about 17%, from about 10% to about 18%, by total weight of the composition, From about 14% to about 22%, from about 18% to about 26%, from about 22% to about 30%, from about 26% to about 34%, from about 30% to about 36%, from about 34% to about 40%, from about 38% % to about 44%, about 42% to about 48% And about 46% to about 50%. In one embodiment, the amount of the quick release formulation included in the gelatin capsule composition is from about 1% to about 20% by weight based on the weight of the gelatin. In another embodiment, the amount of the quick release formulation included in the gelatin composition is from about 10% to about 30% by weight based on the weight of the gelatin. In yet another embodiment, the amount of the fast release formulation included in the gelatin capsule composition is from about 15% to about 20% by weight based on the weight of the gelatin.

Preferably, the amount of the quick release formulation included in the gelatin capsule composition is sufficient to induce bubbling upon contact of the composition with an acidic solution such as gastric juice. A higher ratio of rapid release formulations, such as calcium carbonate, can result in a gelatin composition having undesirable brittle material properties.

In addition to the rapid release formulation, the gelatin capsule composition also includes a gelatin component. The gelatin component can be derived from collagen or collagen-rich tissue including, but not limited to, the skin or bone of pig or cow. Non-limiting examples of gelatin include Type A gelatin, Type B gelatin, and combinations thereof. Type A gelatin is characterized by a plasma point in the range of from about 7 to about 10.0 and is typically derived from collagen using acid pretreatment methods known in the art. Type B gelatin is characterized by a plasma point in the range of from about 4.8 to about 5.8.

Gelatin may generally comprise from about 80% to about 90% protein by weight, from about 0.1% to about 2% by weight mineral salts, and from about 10% to 15% by weight water. The term "protein" as used herein, refers to an organic compound composed of a plurality of amino acids joined by a peptide bond between a carboxyl group of each adjacent amino acid and an amine group. The average molecular weight of the gelatin can range from about 50,000 Da to about 300,000 Da. In another embodiment, the average molecular weight of the gelatin ranges from about 70,000 Da to about 150,000 Da. In yet another embodiment, The gelatin has an average molecular weight in the range of from about 80,000 Da to about 120,000 Da. Additionally, gelatin typically has a Bloom value of from about 50 to about 300. In one embodiment, the gelatin has a Buren value in the range of from about 125 to about 200. In yet another embodiment, the Buren value can range from about 150 to about 175. The pH of the gelatin is typically from about 3.8 to about 7.5. In another embodiment, the pH of the gelatin ranges from about 6.2 to about 7.3. In yet another embodiment, the gelatin has a pH in the range of from about 6.6 to about 7.0. The gelatin may also have an isoelectric point of from about 4.7 to about 9.0, a viscosity of from about 15 mPas to about 75 mPas, and an ash ranging from about 0.1% to about 2.0% by weight.

If the gelatin is substantially a type A gelatin, the strength of the blubber may range from about 50 to about 300, the pH may generally range from about 3.8 to about 5.5, and the isoelectric point may range from about 7.0 to about 9.0, viscosity. It may range from about 15 mPas to about 75 mPas and the ash may range from about 0.1% to about 2.0% by weight.

If the gelatin is substantially B-type gelatin, the strength of the blubber may generally range from about 50 to about 300, the pH may generally range from about 5.0 to about 7.5, and the isoelectric point may range from about 4.7 to about 5.8. The viscosity may range from about 20 mPas to about 75 mPas and the ash may range from about 0.5% to about 2.0% by weight.

Gelatin can be ionized as appropriate prior to use by known methods including, but not limited to, particle exchange using a mixed bed of particle exchange resins. Gelatin may also include hydrolysates having a gelatin molecular weight ranging from about 100 Da to about 2000 Da. The gelatin hydrolysate and the method of producing the hydrolysate are described in U.S. Patent No. 7,485,323, the disclosure of which is incorporated herein in its entirety by reference.

The physical properties of gelatin can vary depending on its intended use. Used in gelatin In one embodiment of the manufacture of a hard capsule pharmaceutical product, the gelatin can have a Brent strength in the range of from about 200 to about 300, a viscosity in the range of from about 40 mPas to about 60 mPas, and a pH in the range of from about 4.5 to about 6.5. In another embodiment of gelatin for use in the manufacture of a soft shell capsule pharmaceutical product, the gelatin may have a Brent strength in the range of from about 125 to about 200, a viscosity in the range of from about 25 mPas to about 45 mPas, and from about 4.5 to about 6.5. The pH within the range.

The particular gelatin of the gelatin capsule composition can be selected to have an isoelectric point of less than about 7.5. Lower gelatin isoelectric points reduce harmful chemical processes (including but not limited to gelatin deamidamine) during the production of gelatin capsule compositions due to the addition of a fast release formulation that produces a composition having a significantly higher pH than previous encapsulated compositions. The possibility of emergence.

The viscosity of the gelatin suspension used to produce the gelatin capsule composition can be at a level that does not remain suspended during rapid release of the formulation during production. In such cases, additional thixotropic compounds (including but not limited to hydrocolloids such as hydroxyethyl cellulose or carboxymethyl cellulose) may be added to the gelatin capsule composition to provide during gelatin capsule composition production. Maintain a high enough viscosity of the gelatin suspension.

Additionally, the term gelatin or gelatin component can be interpreted to encompass a combination of gelatin and other formulation additives (e.g., plasticizers, aqueous solvents or media) and other components known in the art. The term plasticizer (also known as dispersant) is commonly used to describe additives that impart flexibility and flexibility to the gelatin component. Specifically, the plasticizer may be a hydrophilic substance (for example, triethyl citrate and polyethylene glycol) and/or a hydrophobic substance (for example, diethyl phthalate, dibutyl phthalate, sebacic acid). Dibutyl ester and tributyl citrate citrate). Familiar with this technology It will be appreciated that other materials may be substituted for the polymer/plasticizer, provided that it is capable of meeting the same function, i.e., imparting increased flexibility and flexibility to the gelatin formulation. Various hydrophobic materials including oils and waxes can also be used in this regard and can be found by routine experimentation or by reference to those known to those skilled in the art. In one embodiment, the plasticizer comprises dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, sorbitol, sorbitan, triacetin, citric acid Ethyl ester, water and mixtures thereof. In another embodiment, the plasticizer is selected from the group consisting of glycerin, sorbitol, erythritol, and combinations thereof. Those skilled in the art will appreciate that the various plasticizer compounds discussed herein and known in the art can encompass any commercially available product incorporating the plasticizers discussed herein. In one embodiment, the plasticizer may comprise a combination of sorbitol and one or more sorbitol anhydrides, such as those sold by Roquette under the trade name POLYSORB®.

In one embodiment, the plasticizer comprises glycerin in a weight ratio of from 10:1 to 1:10, from 6:1 to 1:6, from 3:1 to 1:3, and at a weight ratio of about 1:1. a mixture of sorbitol. In yet another embodiment, the plasticizer comprises a mixture of sorbitol and sorbitan, a combination of glycerin and water. The combination of sorbitol and sorbitan mixture, glycerin and water may generally comprise from about 5% to about 95% by weight of the plasticizer component of the sorbitol and sorbitan mixture, by weight of the plasticizer component. From about 5% to about 95% glycerol and from about 1% to about 25% water by weight of the plasticizer component. In one embodiment, the plasticizer comprises from about 40% to about 60% by weight of the plasticizer component of the sorbitol and sorbitan mixture, from about 35% to about 50 by weight of the plasticizer component. % glycerol and from about 2% to about 12% water by weight of the plasticizer component. In yet another embodiment, The combination of sorbitol, glycerin and water comprises about 50% sorbitol by weight of the plasticizer component, about 42.5% glycerol by weight of the plasticizer component, and about the weight of the plasticizer component. 7.5% water. In yet another embodiment, the plasticizer comprises a combination of 50% POLYSORB® and a 50% glycerol solution comprising 85% glycerin and 15% water.

The term aqueous solvent or aqueous medium can be interpreted to encompass any solvent capable of forming a gelatin composition. Aqueous media can include, but are not limited to, water.

Additionally, the presently claimed embodiments may further include a pH-changing compound that increases or decreases the pH of the gelatin component. In one embodiment, the gelatin composition may also include sodium hydroxide to increase the pH of the composition. Those skilled in the art will appreciate that other basic or acidic compounds may be added to form a composition having a particular pH, thereby affecting the dissolution profile of the rapid release formulation.

In one embodiment, the gelatin component of the gelatin capsule composition comprises a combination of gelatin, a plasticizer, and an aqueous medium comprising water. The gelatin component may comprise from about 25% to about 55% gelatin by weight of the gelatin component, from about 15% to about 30% plasticizer by weight of the gelatin component, and about 25 weight percent of the gelatin component. % to about 40% water. In yet another embodiment, the gelatin component comprises from about 35% to about 45% gelatin by weight of the gelatin component, from about 20% to about 25% plasticizer by weight of the gelatin component, and a gelatin group. The weight ranges from about 30% to about 35% by weight of water. In yet another embodiment, the gelatin component comprises about 40% gelatin by weight of the gelatin component, about 20% plasticizer by weight of the gelatin component, and about 23% by weight of the gelatin component. water.

In additional embodiments, the gelatin component of the gelatin capsule composition comprises a combination of gelatin and an aqueous medium comprising water. Gelatin components can include gelatin components The gelatin is from about 5% to about 30% by weight and from about 70% to about 95% by weight of the gelatin component. In another embodiment, the gelatin component comprises from about 10% to about 20% gelatin by weight of the gelatin component and from about 80% to about 90% water by weight of the gelatin component.

In another embodiment, the gelatin component can also include a gelatin hydrolysate having a molecular weight in the range of from about 100 Da to about 2000 Da. The weight ratio of gelatin to gelatin hydrolysate typically ranges from about 3:1 to about 99:1. In another embodiment, the weight ratio of gelatin to gelatin hydrolysate is in the range of from about 4:1 to about 49:1. In yet another embodiment, the weight ratio of gelatin to gelatin hydrolysate is in the range of from about 5:1 to about 19:1.

In one aspect of the presently claimed embodiment, the outer surface coating incorporates one or more first compartments comprising a gelatin component and one or more second compartments comprising a rapid release formulation. One or more second compartments comprising a rapid release formulation can generally span from the distal surface of the surface coating that is exposed to the exterior environment to the proximal surface of the outer coating of the contact core. One or more second compartments comprising a rapid release formulation are generally described as functional strips, rods, strips, streaks, slats, columns, columns, spots, stripes, stripes, zones, strips, veins, Short bars, ridges, twisted lines, etc., which are deposited on the distal surface of the outer surface coating and penetrate the transparent adhesive layer toward the proximal surface. It will be appreciated that one or more second regions may be coated across the outer surface from the distal surface to the entire depth of the proximal surface, or may extend only from the distal surface to a portion of the proximal surface across the outer surface coating. In one embodiment, one or more second compartments comprising a rapid release formulation penetrate the entire width of the outer surface coating surrounding the core to allow rapid dissolution of the rapid release formulation to the core The contents are emptied to the external environment without having to wait for the entire gelatin material of the outer surface coating to dissolve.

One or more second compartments may be evenly dispersed throughout the gelatin capsule (ie, a strip of uniform width, shape, strip, etc.) or may comprise a non-uniform through pattern (ie, strips or strips of uniform width, shape, or shape) Etc.), which is generally similar to the appearance of a stone on the outer surface coating. In one embodiment, as illustrated in Figure 1, the gelatin composition can include a compartment comprising a rapid release formulation (shown in white) and two compartments comprising a gelatin component in the absence of any rapid release formulation. A compartment containing a rapid release formulation having a uniform size and shape. As shown in Figure 1, the width and appearance of the compartment are variable.

In yet another embodiment, as illustrated in Figure 2, the gelatin composition can comprise a second compartment that extends only over a portion of the circumference of the gelatin composition. In the embodiment illustrated in Figure 2, the compartment containing the rapid release formulation (shown in white) extends over about half of the circumference of the gelatin composition to produce two compartments comprising the gelatin component and One half of the composition of one of the compartments of the rapid release formulation is formed, and the second half of the composition consists entirely of the gelatin component. Those skilled in the art will appreciate that the size, shape, orientation, etc. can be tailored to the needs of the manufacturer to provide a novel release profile.

The width of the one or more second compartments may range from about 0. (1) mm to about 5 mm. In particular, the thickness of the outer surface coating may comprise about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm. , about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, About 1.7 mm, about 1.8 mm, about 1.9 mm, and about 2.0 mm.

Typically, one or more second compartments provide a mechanism by which gelatin capsules can release core contents faster than other dosage forms. In particular, the rapid release formulation dissolves in the medium upon exposure to aqueous, acidic environmental conditions, thereby releasing the gas. Since the rapid release formulation is concentrated in a region that spans at least a portion of the distance from the distal surface of the outer surface coating to the proximal surface, rapid dissolution causes the gelatin capsule to tear and rupture, thereby causing rapid release of the core contents to the surrounding area. Environment. Unlike other formulations in which the rapid release formulation is dispersed throughout the core formulation (in combination with the active ingredient and excipients), the gelatin compositions of the presently claimed embodiments depend on one or more second compartments. The rapid degradation of the bread coat causes the gelatin capsule surface to tear and rupture rapidly.

In one embodiment, both the one or more first compartment regions and the one or more second compartment regions may comprise a gelatin component, but only one or more of the second compartment regions comprise a rapid release formulation. The relative amount of gelatin component between the first region and the second region may vary depending on the desired quality; however, those skilled in the art will appreciate that one or more of the first regions are compared to one or more first regions. More, less or equal amounts of gelatin components can be included in the second zone. In an alternate embodiment, the one or more first compartment regions and the one or more second compartment regions are both incorporated into the gelatin component and the rapid release formulation; however, in this embodiment, the rapid release formulation is The concentration in the one or more first compartments is typically less than the concentration of the rapid release formulation in one or more of the second compartments such that when one or more second compartments are exposed to gastric or intestinal fluids The gelatin composition ruptures or tears.

The one or more first compartment regions and the one or more second compartment regions may comprise a gelatin component including, but not limited to, gelatin, a plasticizer, and an aqueous medium comprising water. Specifically, the gelatin component of the one or more first compartments comprises from about 25% to about 55% gelatin by weight of one or more first compartments, separated by one or more first zones. The weight of the zone ranges from about 10% to about 30% plasticizer and from about 15% to about 45% water by weight of one or more first compartments. In another embodiment, the gelatin component of the one or more first compartments comprises from about 35% to about 45% gelatin by weight of one or more first compartments, in one or more The weight of one zone ranges from about 16% to about 24% plasticizer and from about 20% to about 30% water by weight of one or more first compartments. In yet another embodiment, the gelatin component of the one or more first compartments comprises about 40% gelatin, about 20% plasticizer, and about 23% water.

In yet another embodiment, the one or more second compartments comprise a combination of gelatin, a quick release formulation, a plasticizer, and water. The one or more second compartments may comprise from about 20% to about 50% gelatin by weight of one or more second compartments, about 1% by weight of one or more second compartments Up to about 25% of the quick release formulation, from about 10% to about 30% by weight of the one or more second compartments, and about 20% by weight of the one or more second compartments Up to about 40% water. In yet another embodiment, the one or more second compartments comprise from about 30% to about 45% gelatin by weight of one or more second compartments, with one or more second compartments A quick release formulation of from about 4% to about 16% by weight, from about 16% to about 24% plasticizer by weight of one or more second compartments, and one or more second compartments It About 26% to about 34% by weight of water. In still another embodiment, the one or more second compartments comprise about 37% gelatin by weight of the one or more second compartments, by weight of one or more second compartments 7.75% of one or more rapid release formulations, about 20% plasticizer by weight of one or more second compartments and about 30% water by weight of one or more second compartments.

One or more of the first or second compartments as described herein may further incorporate a gelatin hydrolysate as previously described. Gelatin hydrolysate helps prevent the formation of films (insoluble gelatin formulations) which tend to interfere with the release of the contents of the core, thereby affecting the efficacy of the gelatin composition. Incorporating gelatin hydrolysate into one or more first compartments will improve the solubility of the zone, thereby reducing the time required to dissolve the gelatin capsule. Similarly, the incorporation of gelatin hydrolysate into one or more second compartments provides a base that dissolves rapidly upon exposure to one or more of the second release zones of the rapid release formulation in an aqueous, acidic environment. Typically, the gelatin hydrolysate can be included in the gelatin component at a concentration ranging from about 0.1% to about 20% by weight of one or more first compartments or one or more second compartments. In one embodiment, the gelatin hydrolysate may be included in the gelatin component in an amount ranging from about 1% to about 15% by weight of the one or more first compartments or from one or more second compartments. In yet another embodiment, the gelatin hydrolysate may be included in the gelatin component in an amount ranging from about 5% to about 10% by weight of the one or more first compartments or from one or more second compartments. .

In certain embodiments in which the gelatin hydrolysate is included in the formulation, the one or more first compartments may comprise the weight of the one or more first compartments From about 25% to about 55% gelatin, from about 0.01% to about 20% by weight of one or more first compartments, of gelatin hydrolysate, by weight of one or more first compartments From 10% to about 30% plasticizer and from about 15% to about 45% water by weight of one or more first compartments. In another embodiment, the one or more first compartments comprise from about 35% to about 48% gelatin by weight of one or more first compartments, with one or more first compartments From about 1% to about 10% by weight of the gelatin hydrolysate, from about 16% to about 24% by weight of the one or more first compartments, and one or more first compartments The weight ranges from about 20% to about 30% water. In additional embodiments, the one or more first compartments comprise about 40% gelatin, about 5% gelatin hydrolysate, about 20% plasticizer, and about 23% water.

Additionally, the one or more second compartments may comprise from about 20% to about 50% gelatin by weight of one or more second compartments, by weight of one or more second compartments From 0.01% to about 20% of the gelatin hydrolysate, from about 1% to about 25% by weight of the one or more second compartments, of the quick release formulation, by weight of one or more second compartments From 10% to about 30% plasticizer and from about 20% to about 40% water by weight of one or more second compartments. In yet another embodiment, the one or more second compartments may comprise from about 30% to about 45% gelatin by weight of one or more second compartments, separated by one or more second zones The area is from about 1% to about 10% by weight of the gelatin hydrolysate, from about 4% to about 16% by weight of the one or more second compartments, of the quick release formulation, separated by one or more second zones. The weight of the zone ranges from about 16% to about 24% plasticizer and from about 26% to about 34% water by weight of one or more second compartments. In yet another embodiment, one or more The two compartments include about 37% gelatin, about 5% gelatin hydrolysate, about 7.75% rapid release formulation, about 20% plasticizer, and about 30% water.

Those skilled in the art will appreciate that the gelatin and gelatin hydrolysate components of the pharmaceutical compositions can be dissolved in the absence of acidic conditions; however, rapid release formulations will generally not dissociate and release gases unless exposed to acidic conditions. Thus, when the proposed pharmaceutical composition is exposed to an acid-base environment, the release of the core contents is greatest.

A gelatin composition having one or more first compartments comprising a gelatin component and one or more second compartments comprising a rapid release formulation can be produced by any method known in the art capable of producing a desired product. In one embodiment, components of one or more first compartments and one or more second compartments may be separately fed via a static mixer to produce desired strips, strips, and the like. In addition, gelatin capsules incorporating pharmaceutically active ingredients can be produced according to any method known in the art, including extrusion processes.

In another embodiment, the outer surface coating can comprise a uniform or semi-uniform distribution of the fast release formulation throughout the gelatin component such that no compartments comprising the rapid release formulation and a compartment comprising the gelatin component are present. In this embodiment, upon exposure to an aqueous, acidic environment, the entire surface of the outer surface coating is degraded such that there is no intervening region that degrades at an accelerated rate compared to the remainder of the coating, thereby allowing the contents of the core Released to the environment for absorption. Upon exposure to an acidic environment, the fast release formulation particles will dissociate from the gelatin, causing gas release. In addition to the dissolution of gelatin, the increased release of gas by the rapid release formulation results in faster degradation of gelatin and release of core contents. Since the gelatin composition degrades over the entire surface of the capsule, The solution caused the gelatin surface to eventually rupture.

In additional aspects, the presently claimed embodiments provide a method of making a gelatin composition comprising a gelatin component and a rapid release formulation. A gelatin composition comprising a rapid release formulation and a gelatin component can be made according to the following steps: (a) dissolving the gelatin component in an aqueous medium; (b) mixing the rapid release formulation with an aqueous gelatin solution prior to capsule formation; and (c) A combination of a gelatin aqueous solution and a fast release formulation is included to form a surface coating applied to the core. The step (a) comprising dissolving the gelatin component in an aqueous medium can be carried out by dissolving the gelatin in an aqueous medium by any method known in the art to form from about 5% by weight to about 60% by weight gelatin. An aqueous solution within the range. In other embodiments, the gelatin aqueous solution may be from about 5% by weight to about 15% by weight, from about 10% by weight to about 20% by weight, from about 15% by weight to about 25% by weight, from about 20% by weight to about 30% by weight, From about 25% by weight to about 35% by weight, from about 30% by weight to about 40% by weight, from about 35% by weight to about 45% by weight, from about 40% by weight to about 50% by weight, from about 45% by weight to about 55% by weight or From about 50% to about 60% by weight of gelatin. In particular, the aqueous solution can have about 15% by weight gelatin.

Gelatin may have a varying particle size prior to adding gelatin to the water to form an aqueous solution. In one embodiment, the gelatin particle size can vary from about 0.1 mm to about 10 mm. In other embodiments, the gelatin particle size may be from about 0.1 mm to about 0.3 mm, from about 0.2 mm to about 0.8 mm, from about 0.5 mm to about 1.5 mm, from about 1 mm to about 3 mm, from about 2 mm. Up to about 6 mm or from about 5 mm to about 10 mm. Without being bound by any particular theory, the particle size of gelatin can affect the amount of time required for gelatin to degrade in aqueous solution. Particle size is about 0.1 Gelatin in the range of mm to about 0.3 mm can swell in solution within a few minutes, and gelatin having a particle size in the range of about 0.3 mm to about 0.8 mm can swell in solution in about 8 minutes to about 12 minutes. Gelatin having a particle size greater than about 0.8 mm can swell in about 1 hour.

Gelatin solutions having a concentration ranging from about 10% by weight to about 20% by weight gelatin can be prepared using any gelatin particle size. In another embodiment having a more concentrated solution in the range of from about 30% to about 34% by weight gelatin, gelatin particles having a size greater than about 0.8 mm can be used to inhibit aggregation and bubble formation during processing.

In one embodiment, the pH of the aqueous gelatin solution can be adjusted to a pH in the range of from about 6 to about 11 by the addition of an acid or a base during or immediately after step (a). In another embodiment, the gelatin solution is adjusted to a pH in the range of from about 8 to about 10 prior to step (b). In yet another embodiment, the pH of the gelatin solution is adjusted to about 8.9 prior to step (b). In embodiments where the gelatin composition is intended for use in a pharmaceutical encapsulant, suitable acids may include food grade acids. Non-limiting examples of suitable food grade acids include sulfuric acid, tartaric acid, citric acid, acetic acid, and carbon dioxide gas from carbon dioxide sources including, but not limited to, dry ice, phosphoric acid, or combinations thereof. Non-limiting examples of suitable food grade bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, calcium oxide, or combinations thereof. Without being bound by any particular theory, pH adjustment can alter the crosslinking or ionic interaction of the gelatin molecules, thereby altering the material properties of the resulting gelatin capsule sealant material, including but not limited to hardness, from 0 to about 3 Solubility and combinations thereof in aqueous solutions of low pH within the range.

Step (b) of the process relates to mixing an aqueous solution of a rapid release formulation with gelatin prior to gelatin coating or capsule formation. The mixing process forms an outer surface coating composition wherein the composition typically comprises a fast release formulation and gelatin in a mass ratio ranging from about 1:1 to about 1:99. The mass ratio is defined as the ratio of the mass of the fast release formulation to the mass of the gelatin solution, wherein the gelatin solution comprises a combined mass of gelatin, an aqueous solution of dissolved gelatin, and any gelatin hydrolyzate incorporated into the solution. Alternatively, the mass ratio of the fast release formulation to gelatin present in the encapsulating composition can be in the range of from about 1:1 to about 1:8, from about 1:4 to about 1:10, from about 1:6 to about 1. :12, about 1:8 to about 1:14, about 1:10 to about 1:16, about 1:12 to about 1:18, about 1:14 to about 1:20, about 1:16 to about 1 :22, about 1:18 to about 1:24, about 1:20 to about 1:26, about 1:22 to about 1:28, about 1:24 to about 1:30, about 1:26 to about 1 : 32, about 1:28 to about 1:34, about 1:30 to about 1:36, about 1:32 to about 1:38, about 1:34 to about 1:40, about 1:36 to about 1 : 42, about 1:38 to about 1:44, about 1:40 to about 1:46, about 1:42 to about 1:48, and about 1:44 to about 1:50. In one embodiment, the mass ratio of the fast release formulation to gelatin present in the gelatin composition can range from about 1:2 to about 1:19. In yet another embodiment, the mass ratio of the fast release formulation to gelatin present in the gelatin composition can range from about 1:4 to about 1:9.

In one embodiment, the fast release formulation is mixed with an aqueous gelatin solution prior to or during step (c). The period of time before step (c) may be within a few hours immediately before the execution of step (c). In some embodiments, the rapid release formulation can slightly alter the pH of the gelatin solution, but not to a degree sufficient to cause excessive gelatinization of the gelatin to hydrolyze.

Additionally, the mixing process associated with step (b) can include any method known in the art to allow for the incorporation of a fast release formulation prior to or during the incorporation of a gelatin aqueous solution into a coating or capsule forming machine. In one embodiment, step (b) can be accomplished by mixing a rapid release formulation with an aqueous gelatin solution by means of an in-line mixing process. In another embodiment, the in-line mixing process of step (b) is accomplished by means of a static mixer. Static mixers typically consist of a series of alternating left-handed and right-handed helical elements. Non-limiting examples of static mixers include, but are not limited to, Kenics static mixers. The in-line mixing process introduces both the quick release formulation and the gelatin aqueous solution into the inline mixer, thereby feeding the combination of the fast release formulation and the gelatin aqueous solution to the coating or capsule making machine or equipment immediately after mixing. The time required for the rapid release formulation to raise the pH of the aqueous gelatin solution can be shortened before the combination is to be incorporated into the coating or capsule formation process or during the process of mixing the two components together. By minimizing the mixing time of the water-soluble quick release formulation with the gelatin aqueous solution, it is possible to minimize the viscosity of the gelatin aqueous solution. Thus, step (b) of the presently claimed embodiment avoids solution stability problems that occur with long-term combination of water-soluble rapid release formulations and gelatin solutions prior to coating or capsule formation.

Step (c) of the presently claimed embodiment comprises incorporating or feeding a combination of a water soluble fast release formulation and an aqueous gelatin solution into a coating or capsule forming machine. Those skilled in the art will appreciate that a variety of machines are available for producing rapid release encapsulating compositions.

In one embodiment, the gelatin composition comprises an aqueous solution in an aqueous solution containing about 15% by weight gelatin and from about 2% by weight to about 10% by weight sodium hydrogencarbonate. gum. Another exemplary gelatin capsule composition comprises gelatin in an aqueous solution containing about 15% by weight gelatin and from about 5% by weight to about 15% by weight calcium carbonate. In any of the exemplary embodiments, the particular composition of gelatin may vary depending on the intended use of the encapsulating composition.

In another embodiment, the gelatin composition comprises from about 10% to about 15% by weight gelatin, from about 5% to about 15% by weight calcium carbonate, and from about 1% to about 5% by weight gelatin hydrolysate. Gelatin in an aqueous solution. In any of the exemplary embodiments, the particular composition of gelatin may vary depending on the intended use of the encapsulating composition, as described in Section III above.

In yet another embodiment, the gelatin composition comprises from about 36% to about 42% by weight gelatin, from about 17% to about 22% by weight plasticizer, from about 26% to about 31% by weight water, and about Gelatin in an aqueous solution of 10% by weight to about 15% by weight calcium carbonate. In any of the exemplary embodiments, the particular composition of gelatin may vary depending on the intended use of the encapsulating composition.

In yet another embodiment, the gelatin composition comprises from about 32% to about 40% by weight gelatin, from about 17% to about 22% by weight plasticizer, from about 26% to about 31% by weight water, about Gelatin in an aqueous solution of 10% by weight to about 15% by weight of calcium carbonate and from about 2% by weight to about 6% by weight of gelatin hydrolysate. In any of the exemplary embodiments, the particular composition of gelatin may vary depending on the intended use of the encapsulating composition.

Any of the above gelatin compositions can be used to produce a variety of therapeutic compositions including gelatin capsule compositions. Non-limiting examples of therapeutic composition embodiments include fast release coated tablets, soft gel capsules, hard capsule shells, and chewable therapeutic compositions. In one embodiment, the presently claimed gelatin compositions comprise a quick release tablet composition wherein the outer surface coating is applied as a thin coating to the outer surface of the active ingredient forming the core in the form of a solid tablet. The outer surface coating can be applied to the active ingredient using any technique known in the art including, but not limited to, pan coating, roller coating, film coating, spray coating, and dip coating.

In yet another embodiment, the presently claimed gelatin compositions comprise a fast release soft gel capsule wherein the outer surface coating forms a continuous film encapsulating the active ingredient, which may be in liquid or powder form. The gelatin composition can be formed into a gel cap using any technique known in the art including, but not limited to, forming and filling individual gel caps in a mold, forming a gel cap using a rotary die, and using blow molding or Filled with Accogel type encapsulation technology. In such embodiments, the gelatin composition may further comprise a plasticizer including, but not limited to, glycerol, a mixture of sorbitol derivatives, or mixtures thereof.

In yet another embodiment, the presently claimed gelatin compositions include hard capsule compositions wherein the outer surface coating forms a rigid shell encapsulating the core of the active ingredient, which may be in the form of a liquid, granule or powder. The hard capsule composition can be in the form of, but not limited to, a continuous shell formed around the active ingredient, or a half shell that separately forms each half shell and inserts the two elastically bonded active ingredients prior to bonding the half shell. The gelatin composition can be formed into a hard capsule using any technique known in the art including, but not limited to, dipping a metal rod tip or injection molding.

The gelatin compositions of the presently claimed embodiments may further comprise a polymer incorporated into the outer surface coating, core or both. The term "polymer" as used herein shall be understood by those skilled in the art to generally encompass repeating monomers. Any molecule consisting of structural units including, but not limited to, homopolymers, copolymers, heteropolymers, branched polymers, branched copolymers, star copolymers, brush copolymers, comb copolymers, Graft copolymers and block copolymers. The polymer can include any suitable polymer known in the art including, but not limited to, synthetic polyvinyl polymers, synthetic polyethylene polymers, synthetic acrylic polymers, biopolymers, modified biopolymers, and combinations thereof. Suitable synthetic polyvinyl polymers include, but are not limited to, polyvinyl chloride, polyvinyl acetate and copolymers thereof, polyvinyl alcohol and polyvinylpyrrolidone. Synthetic polyethylene polymers can include, but are not limited to, polyethylene and polystyrene. Synthetic acrylic polymers can include, but are not limited to, copolymers of methyl methacrylate or acrylic monomers. Non-limiting examples of biopolymers and modified biopolymers include ethyl cellulose, cellulose acetate phthalate, cellulose acetate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose. , microcrystalline cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, shellac, gelatin, ethyl cellulose, cellulose ester, cellulose diester, cellulose triester, cellulose ether, cellulose ester - Ether, mercapto cellulose, dimercapto cellulose, tridecyl cellulose, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate and cellulose acetate butyrate. Other suitable polymers are described in U.S. Patent Nos. 3,845,770, 3,916,899, 4, 008, 719, 4, 036, 228, and 4, 612, 008, the disclosures of each of which are incorporated herein by reference.

In one embodiment, the water soluble polymer may be suitable for various embodiments for the purpose of making various gelatin composition embodiments using aqueous solutions, as many formulations (including but not limited to) tablet coatings, soft Gelatin capsules and hard gelatin The capsules are typically formed from a liquid polymer solution. The water soluble polymer is soluble in an aqueous solution at a pH in the range of from about 6 to about 8. Non-limiting examples of water soluble polymers include carboxymethyl cellulose, crosslinked polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, shellac, and gelatin. In particular, gelatin capsule compositions can include gelatin and carboxymethylcellulose.

In an alternative aspect of the presently claimed embodiment, the gelatin composition comprises a core, a subcoat, and an outer surface coating. In this embodiment, the subcoat is positioned at the distal end of the core but is coated adjacent to the surface exposed to the external environment. The use of a subcoat is well known in the art and is disclosed, for example, in U.S. Patent No. 5,234,099, the disclosure of which is incorporated herein by reference. Any composition suitable for a film-coated tablet can be used as the sub-coat of the present invention. Examples of suitable sub-coats are disclosed in U.S. Patent Nos. 4,683,256, 4,543,370, 4,643,894, 4,828,841, 4,725,441, 4,802,924, 5, 630, 871, and 6, 274, 162 Into this article. Compositions suitable for use as subcoats include those manufactured by Colorcon, marketed by Berwind Pharmaceutical Services, Inc. 415 Moyer Blvd., West Point, Pa. 19486 under the trade designation "OPADRY.RTM." (including film-forming polymers and, as appropriate) A water-soluble concentrate of plasticizers, colorants and other useful excipients).

Other suitable subcoats include one or more of the following ingredients: cellulose ethers such as hydroxypropyl methylcellulose, hydroxypropylcellulose and hydroxyethylcellulose; polycarbohydrates such as xanthan gum, starch and malt paste Fine; plasticizers, including, for example, glycerol, polyethylene glycol, propylene glycol, dibutyl sebacate, lemon Triethyl citrate; vegetable oils such as castor oil; surfactants such as polysorbate-80, sodium lauryl sulfate and sodium dioctylsulfosuccinate; polycarbohydrates, pigments and opacifiers. The subcoat can be applied in a clear, transparent coating to make the core visible.

Depending on the desired properties of the gelatin composition, the subcoat may be applied to the entire outer surface of the core or may be applied to a portion of the entire surface that is less than the core. In another embodiment, the subcoat may include one or more channels for controlled release of the contents of the core to the external environment after the outer surface coating dissolves and/or is separated from the subcoat. As used herein, the term "channel" includes pores, orifices, perforations, holes, weakened areas, or erosive elements (eg, gelatin plugs) that form channels for releasing the contents of the core of the dosage form. The passages used in the present invention are well known and described in U.S. Patent Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407, 4,783,337, and 5,071,607. In one embodiment, one or more channels include a laser bore in the subcoat.

In yet another aspect of the presently claimed embodiments, the gelatin composition comprises an enteric coating, an outer surface coating, and a core, wherein the enteric coating is applied to the distal surface of the outer surface coating and the outer surface coating is applied to the core. Distal surface. The term "enteric coating" as used herein refers to a coating that is insoluble in a low pH environment, such as the stomach, wherein the fluid has a pH of typically less than about 3.5, but dissolves rapidly or is sufficiently swollen to have a pH of typically greater than about 5.0. Values in a high pH environment (eg, intestinal fluid) disintegrate. Polymers commonly used in enteric coatings are well known in the art, such as U.S. Patent Nos. 3,391,135, 3,629,237, 4,017,647, 4,138,013, 4,960,814, and The entire text of all cases is incorporated herein by reference. Non-limiting examples of enteric polymers include, but are not limited to, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP). ), a copolymer of methacrylic acid and ethyl acrylate, cellulose hydroxypropyl methyl acetate succinate (HPMCAS) and polyvinyl acetate phthalate (PVAP).

The compounds and methods of the present invention are better understood by reference to the following examples, which are intended to illustrate and not to limit the scope of the invention. Each example illustrates at least one method of preparing various intermediate compounds and further illustrates each of the intermediates utilized throughout the process. The examples are for some preferred embodiments and are not intended to limit the scope of the invention. On the contrary, the invention is to cover all modifications, modifications and equivalents

Instance

The following examples illustrate various aspects of the invention.

Example 1. Effect of production method on the dissolution properties of gelatin compositions

To assess the effect of adding an acidic compound used to produce the gelatin capsule sealant composition to the solubility properties of the composition, the following experiment was performed.

600 grams of pig skin gelatin was dissolved in 3400 g of deionized water and the mixture was filtered through a mixed bed of particle exchange resin (pH > 9). The gelatin mixture was then divided into five portions and adjusted to a pH of 5.5 ± 0.1 using the following acids: sulfuric acid, tartaric acid, citric acid, acetic acid, and carbon dioxide. Sublimate by dry ice or carbon dioxide by using sodium bicarbonate. Each of the five mixtures was frozen overnight and then dried in a dehydrator. In the case of treatment with carbon dioxide, A pH of 5.5 was not obtained, but the pH was significantly reduced from pH 9.

The dried sample was ground and prepared as a coating. A 30% gelatin solution of each sample was prepared by weighing 50 grams of dry gelatin into a 250 ml beaker, adding 116.7 g of deionized water and stirring to mix. After mixing, the beaker was covered with a watch glass and swelled for about 1 hour at room temperature. The mixture was then melted at 60 ° C for about 4 hours, stirred for about 1 hour and then stirred and mixed. A series of glass plates were preheated to a temperature of about 60 ° C and loaded into an automated coating apparatus. After removing any skin or air bubbles from the surface of the molten gelatin mixture, the mixture is loaded into an automatic coating device and coated onto a series of preheated glass sheets. The membrane was stored overnight (about 17 hours) at 45% ± 5% RH and 70 °F ± 5 °F in a temperature and humidity control chamber.

For each of the five compositions, a coated sample weighing approximately 0.075 g was placed in each of six reaction vessels filled with 900 g of KH ₂ PO ₄ solution having a pH of 3.0 and heated. To 37 ° C. The coated sample was measured for dissolution over a period of about 15 minutes using the absorbance of the contents of the reaction vessel at a wavelength of 218 nm.

The results of the dissolution measurements are summarized in Figure 3. The dissolution profile of the coating composition incorporating carbon dioxide in the form of sodium bicarbonate or dry ice does not significantly affect the solubility properties of the composition relative to any of the other coating compositions. However, in this experiment, sodium bicarbonate was added to the coating composition in an amount sufficient to induce formation of CO ₂ bubbles during dissolution of the composition.

The results of this experiment confirmed that the dissolution rate of the coating composition tested in this experiment was sensitive to the composition of the coating. In particular, a coating composition incorporating carbon dioxide produced from dry ice or sodium bicarbonate in an amount specified by this experiment is included. The solubility properties were not significantly different from any of the other coating compositions tested.

Example 2: Effect of sodium bicarbonate added during the production of a gelatin capsule seal on dissolution properties

To assess the solubility properties of sodium bicarbonate added to the gelatin coating obtained during the production of the gelatin capsule composition, the following experiment was carried out.

600 grams of gelatin was dissolved in 3400 g of deionized water and the mixture was filtered through a mixed bed of particle exchange resin (pH > 9). The gelatin mixture was then adjusted to a pH of 5.5 ± 0.1 using sulfuric acid. The gelatin mixture was then divided into two halves and 2% by weight of sodium bicarbonate was added to the half gelatin mixture. Each of the two mixtures was frozen overnight and then dried in a dehydrator. Coated samples were formed from the two mixtures using the method set forth in Example 1.

A buffer solution having a pH of 1.0 was formed by adding 200 ml of 2 M HCl and 29.8 g of KCl to 1800 ml of deionized water. Coated samples from two gelatin mixtures were added to two groups of six reaction vessels containing 900 g of pH = 1 buffer solution and the dissolution of the coated samples was measured using the method previously described in Example 1.

The measured dissolution of the coated samples is summarized in Figure 4. The addition of sodium bicarbonate to the gelatin mixture during the production of the gelatin capsule sealant composition significantly increased the dissolution rate of the resulting gelatin coating relative to the same gelatin coating produced without any added sodium bicarbonate. In particular, the addition of sodium bicarbonate significantly increased the rate of membrane tearing during the procedure.

The results of this experiment demonstrate that the addition of sodium bicarbonate during the gelatin coating composition production significantly increases the dissolution rate of the resulting gelatin coating compared to the same gelatin coating composition without sodium carbonate, which is largely due to Program period Carbon dioxide bubbles formed from sodium carbonate and the film tear ratio increases.

Example 3. Effect of carbonate compound on pH of gelatin mixture

To assess the sensitivity of the pH of the deionized gelatin suspension to the addition of various carbonate compounds, the following experiments were conducted. A deionized gelatin suspension was formed using the method described in Example 1 and sulfuric acid was added to the gelatin suspension to adjust the pH of the suspension to about 4.7. The gelatin suspension is divided into three equal portions. 10% by weight of calcium carbonate was added to the first portion of the gelatin suspension. Sodium hydrogencarbonate in an amount of 5% by weight and 7.5% by weight was added to the second and third portions of the gelatin suspension, respectively. The pH of each gelatin suspension was measured before and after the addition of carbonate and is summarized in Table 1 below:

The addition of carbonate to the gelatin mixture generally increases the pH of the gelatin suspension as expected due to the basic nature of the carbonate present in the solution. However, despite the addition of higher amounts of calcium carbonate, the pH of the gelatin suspension added by the addition of calcium carbonate is significantly less than the addition of sodium bicarbonate. This is most likely due to the lower solubility of calcium carbonate compared to sodium bicarbonate at the initial pH of the gelatin suspension (pH = 4.7). Since less calcium carbonate undergoes dissociation in the gelatin mixture, the gelatin suspension is less neutralized, thereby maintaining a lower pH in the gelatin suspension after the addition of calcium carbonate. The results of this experiment confirmed that the pH of the gelatin suspension tested was sensitive to the amount and composition of the carbonate added to the suspension. Example 4. Long-term storage of high-temperature and humidity-soluble capsule sealing composition

Solution effect

To assess the sensitivity of the solubility properties of several clear capsule seal compositions to long term storage at elevated temperatures and humidity, the following experiments were performed. A deionized bone cement suspension was formed using a method similar to that described in Example 1 and used as an encapsulating composition. The gelatin suspension was divided into three equal portions and used to form three different encapsulating compositions. The first encapsulating composition included bone glue (control) without further modification. The second encapsulating composition included bone cement and 15% by weight CaCO ₃ (FD-rapid dissolution). The third encapsulating composition comprises bone cement, 15% by weight of CaCO ₃ and 10% by weight of hydrolyzed bone glue (FD+SH) having a molecular weight of about 500 Daltons. The dissolution of each of the three encapsulating compositions in deionized water and pH = 1 buffer solution was measured using the method described in Example 1. The dissolution of the encapsulating composition was measured immediately after the composition was produced, and after storage for 2 weeks, 5 weeks, and 11 weeks at 50 ° C and 80% relative humidity.

The dissolution results of the control, FD and FD+SH encapsulation compositions in a pH 1 buffer solution are summarized in Figures 5, 6 and 7, respectively. Both Figures 5 and 6 show a significant decrease in dissolution rate over a longer period of storage at 50 ° C and 80% relative humidity. Although Figure 6 presents a similar tendency for the dissolution rate of the FD+SH encapsulating composition to decrease after two weeks of storage, the dissolution rate returned to an extent similar to the initial dissolution rate after 5 and 11 weeks of storage. Figure 8 is a comparison of the dissolution results of three encapsulated compositions in a pH 1 buffer solution after 11 weeks of storage. The dissolution rate of the FD+SH composition is maintained to a significant extent to the control or FD composition.

The results of dissolution of the control, FD and FD+SH encapsulation compositions in deionized water are summarized in Figures 9, 10 and 11, respectively. Figures 9 and 10 are similar to Figure 5 The manner of degradation shown in and 6 shows the degradation of the dissolution rate of the control and FD compositions after long-term storage. As shown in Figure 11, the dissolution rate of the FD+SH composition in deionized water was substantially unaffected by the long term storage period at 50 ° C and 80% relative humidity. Figure 12 is a comparison of the dissolution results of the control, FD and FD+SH compositions in deionized water after 11 weeks of storage, clearly showing that the FD+SH composition maintained a higher dissolution rate even after 11 weeks of storage.

The reduced dissolution rate of the control and FD encapsulating compositions after storage under high temperature and humidity conditions may be due to the formation of transverse bridges in the gelatin in the encapsulating composition. The addition of a low molecular weight hydrolyzate having a molecular weight of from about 100 Daltons to about 2000 Daltons to the encapsulating composition can interfere with the formation of the cross bridge, thereby dissolving the dissolution characteristics of the gelatin capsule composition even after a long period of storage. Maintain at the initial level.

The results of this experiment confirmed that the solubility properties of the gelatin capsule sealing composition were degradable after storage under high temperature and humidity. This degradation is sensitive to a particular composition and can substantially eliminate degradation by adding a hydrolysate having a molecular weight of from about 100 Daltons to about 2000 Daltons to the gelatin capsule composition.

Example 5: Effect of long-term storage on solubility properties under high temperature and humidity

To further assess the solubility properties of the various gelatin formulations discussed herein after exposure to temperature and humidity conditions, the following soft capsule experiments were performed. A soft capsule encapsulating composition having a viscosity of about 10,000 mPas at 60 ° C was prepared. The first encapsulating composition comprises 43.00% by weight of bone cement without any further modification, 10.75% sorbitol, 10.75% glycerol and 35.5% water ("Standard Bone Glue"). Second encapsulating glue composition comprising 40.8%, 7.2% calcium carbonate (CaCO _3), 10.2% sorbitol, 10.2% glycerin and 31.6% water ( "RR only"). The third encapsulating composition comprises 38.35% bone cement, 2.45% hydrolyzed bone cement having a molecular weight of about 500 Daltons, 7.2% calcium carbonate (CaCO ₃ ), 10.2% sorbitol, 10.2% glycerol and 31.6% water ("RR RXL" ). Soft capsules were prepared on a modified Chan Sung soft capsule M3 machine using three encapsulating compositions with a dual chamber dye roll to prepare a 7.5 oval capsule and tumble dried at 2.5 rpm for 30 minutes, then at about 25 ° C and about Dry indoors for one week at 35% RH. The capsules were filled with a liquid formulation comprising 96.51% polyethylene-diol, 2.99% glycerol, and 0.50% bright blue dye (filled). Three formulations were tested to determine the dissolution profile over time for three different dissolution media. In each case, the dissolution medium was monitored spectrophotometrically to observe the appearance of the bright blue dye in the medium. The first test assessed the dissolution profile of fresh capsules of the three formulations in simulated gastric fluid (at a pH of about 1.3 and in the absence of any enzyme). The results of the first test are illustrated in Figure 13. The second test assesses the dissolution profile of the formulations in water (about neutral pH) after three weeks of storage at 40 ° C and 75% relative humidity. The results of this second test are illustrated in Figure 14. The third test assesses the dissolution of the formulations in simulated gastric fluid (at a pH of about 1.3 and in the absence of any enzyme) after storage of the three formulations at 40 ° C and 75% relative humidity for two weeks and four weeks. curve. The results of this test for two weeks of storage and four weeks of storage are illustrated in Figures 15 and 16, respectively.

Referring to the results of the first test illustrated in Figure 13, the graph shows minimal differences in the dissolution profiles of standard bone cement, RR only and RR RXL formulations. This result is expected to occur when the capsule is fresh after it has just been produced, since the capsule is easily released along the seam to release the dye. The results of the second test, illustrated in Figure 14, show the difference in dissolution profiles of the three formulations after two weeks of storage. In particular, Figure 14 shows that RR RXL exhibits a substantially faster and more complete dissolution profile than RR and standard bone cement formulations alone. The results in Figure 14 illustrate the effect of incorporating the hydrolyzed gelatin component, which improves dissolution even when the formulation is tested in a neutral aqueous solution. The RR only formulation showed some improvement over the dissolution profile of the standard bone cement formulation; however, the results were not as stable as the RR RXL formulation. This is not surprising since the dissolution medium is a neutral aqueous solution and therefore does not expose the calcium carbonate to a pH which causes it to foam and further promotes dissolution of the formulation. Importantly, it should be noted that the dissolution profile of the standard bone cement formulation showed a slower rate of dissolution and a reduced overall dissolution compared to the results of the first test. This is evidence of adversely affecting the solubility properties of standard gelatin formulations after storage at increased temperature (40 ° C) and humidity (75% relative humidity).

The results of the third test, illustrated in Figures 15 and 16, show that the dissolution profiles of RR RXL and RR-only formulations are improved compared to standard bone cement formulations. In particular, RR RXL and RR-only formulations exhibited faster dissolution rates and a more complete dissolution profile to achieve 100% dissolution at the end of the test period. These results illustrate the effect of inclusion of calcium carbonate (in RR RXL and RR only formulations) and hydrolyzed gelatin (in RR RXL formulations) on dissolution rate. It is also important to note that the dissolution profile of the standard bone cement formulation shows a slower rate of dissolution and a reduced overall dissolution compared to the results of the first test, which in particular illustrates the dissolution after four weeks of storage in Figure 16. This is evidence of adversely affecting the solubility properties of standard gelatin formulations after storage at increased temperature (40 ° C) and humidity (75% relative humidity).

Example 6: Production of gelatin capsules having a compartment containing a water insoluble rapid release formulation

A gelatin solution (referred to as Sample A) containing about 7.5% gelatin hydrolysate having an average molecular weight of less than 1,000 Daltons was prepared and the pH was adjusted to 6.8 using 50% sodium hydroxide. Specifically, a gelatin solution containing 1546.4 grams of gelatin (including 115.9 grams of gelatin hydrolysate) was formed. The solution was sterilized and a portion containing 895.4 g of the solution was dried to form Sample A. Sample B was prepared using the remainder of the gelatin solution (651 g). Specifically, the sample A is not included in the remaining 651 g of gelatin was added 434 g of calcium carbonate (Vicality ^TM medium, the average particle size of 1.9 micron, USP grade), to give the (dry) of gelatin and from about 3-2 (dry) ratio of calcium carbonate. The slurry was dried and the resulting combination was taken as sample B. It should be noted that the solution is sterilized using standard steam injection methods whereby the circulating filtered steam is injected into the product and the solution is maintained at a temperature of about 240 ° C for a period of about 8 seconds, thereby killing the solution. Any microorganisms.

After forming Sample A and Sample B, they were tested to determine the physical properties of each compound. Specifically, the strength, viscosity, moisture content, ash, and calcium concentration of the blubber were tested. The results are illustrated in Table 2 below.

After performing the tests of Sample A and Sample B to determine the physical properties of the two gelatin solutions, each sample is incorporated into the gel material solution for gelatin formation. Coating. Specifically, Sample A and Sample B were mixed with glycerin and water in the proportions shown in Table 3, and then bubbles were eliminated to remove any air particles from the sample.

After forming the gel material solutions of Samples A and B, each solution was simultaneously pumped through Kenics static with 4 orthogonal spiral mixing units and 3/8 inch pipe diameter at equal rates. A mixer is used to produce alternating strips of gelatin coating of the gel material solution of Sample A and Sample B. The resulting interlaced mixture was coated onto a polycarbonate plate using a coating bar having a coating gap of 500 μm. The resulting strip coating was dried and stored in a constant humidity chamber at 22 ° C and 50% R.H.

The gelatin coating was then tested to determine the rate of dissolution. Specifically, the strip coating was peeled off from the polycarbonate substrate and tested for solubility properties. A sample of the strip coating (usually about 1 cm x 1 cm) was cut from the coating and the sample was floated on the surface of the dissolution medium to simulate exposure of the coating side to the dissolution medium. The dissolution medium was prepared according to the following procedure to simulate gastric acid (no enzyme). 2 g of sodium chloride and 7.0 ml of concentrated HCl were dissolved in sufficient water to obtain 1000 ml. The pH of the dissolution medium is about 1.2. The dissolution medium was warmed to 37 ° C for dissolution testing.

Each time the dissolution rate of the strip coating is tested, the gelatin coating preferentially disintegrates along the "strip" constituting sample B (incorporated with calcium carbonate) and constitutes sample A (containing only gelatin and gelatin hydrolysate, no calcium carbonate) Gelatin coating dissolves at a slower rate solution. It was observed that the undissolved portions of the coating constituting the sample A were separated from each other at the time of disintegration of the strip, thereby causing the coating to be quickly separated in less than 2 minutes. This separation of the undissolved portion of Sample A is important because it mimics the ability of the strip coating to rapidly tear the gelatin coating, thereby rapidly releasing the internal contents of the capsule or coating, if any. The strip of gelatin coating is tested several times after it has been formed to determine if the extended storage period can affect the rate of dissolution. See Table 4 below for dissolution time.

Thus, as is apparent from Table 4, the extended storage of the strip of gelatin coating does not adversely affect the dissolution characteristics of the coating. The strip gelatin coating maintained a rapid dissolution time of less than 2 minutes at all time points after the formation of the test (including 1 day, 1 week, 2 weeks, 3 weeks, 6 weeks, and 11 weeks), indicating an extended storage period Does not affect the solubility characteristics.

For comparison, a gelatin coating containing only the sample A gel material solution was prepared and tested for dissolution after storage at 22 ° C and 50% R.H. for 2 weeks and 4 weeks. The pure sample A coating was immersed in the dissolution medium (contact with the dissolution medium) and about 66% of the gelatin dissolved within 3 minutes and no film disintegration or separation was observed until the coating completely dissolved in about 9 minutes. . Therefore, a strip of gelatin coating containing calcium carbonate "strips" confirms dissolution with a gelatin coating containing only gelatin and gelatin hydrolysate. The gelatin coating dissolves and separates more quickly than solution and separation.

Example 7: Effect of the addition of carbonate to bone cement on the pH of the composition

To assess the effect of adding a water soluble fast release formulation to the gelatin formulation on pH, the following experiment was performed. 600 grams of calcified bone cement was dissolved in 3400 ml of water. The mixture was formed at a temperature of 60 ° C, and the pH of the formulation before addition of any water-soluble carbonate was measured to be 5.468 ("initial pH"). Four aliquots of 1000 g of gelatin and an aqueous solution were formed, labeled A, B, C and D. For formulations A and B, a total of 6 grams and 12 grams of sodium bicarbonate were added to each formulation, respectively, and after bubbling attenuated, the pH of formulations A and B at 60 °C was recorded. Separately, for formulations C and D, a total of 6 grams and 12 grams of sodium carbonate were added to each formulation, respectively, and after bubbling was attenuated, the pH of formulations C and D at 60 ° C was recorded. The pH value measured immediately after blending and bubbling is marked as "pH immediately after blending". In addition, each of Formulations A, B, C, and D was stored overnight at room temperature, and the pH was again measured at 60 ° C on Day 2. The pH value measured on the second day is indicated as "pH after storage overnight".

As illustrated in Table 2, the addition of a water soluble carbonate to the gelatin formulation resulted in a significant increase in the pH of each of the formulations compared to the initial pH of 5.468 (before the introduction of the carbonate). Specifically, the formulations A and B of 6 g and 12 g of sodium bicarbonate, respectively, and the blending of 6 g and 12 g of sodium carbonate, respectively, were included. Both materials C and D confirmed a significant increase in pH after the incorporation of carbonate. The data in Table 2 also confirmed that the inclusion of larger amounts of carbonate (formulations B and D, respectively, containing 12 grams of sodium bicarbonate and sodium carbonate) confirmed a significant increase in pH.

Example 8: Production of a rapid release encapsulating composition comprising a water soluble fast release formulation

A gelatin solution (referred to as Sample A) containing about 7.5% gelatin hydrolysate having an average molecular weight of less than 1,000 Daltons was prepared and the pH was adjusted to 6.8 using 50% sodium hydroxide. Specifically, a gelatin solution containing 1546.4 grams of gelatin (including 115.9 grams of gelatin hydrolysate) was formed. The solution was sterilized and a portion containing 895.4 g of the solution was dried to form Sample A. Sample B was prepared using the remainder of the gelatin solution (651 g). Specifically, the sample A is not included in the remaining 651 g of gelatin was added 434 g of calcium carbonate (Vicality ^TM medium, the average particle size of 1.9 micron, USP grade), to give the (dry) of gelatin and from about 3-2 (dry) ratio of calcium carbonate. The slurry was dried and the resulting combination was taken as sample B. It should be noted that the solution is sterilized using standard steam injection methods whereby the circulating filtered steam is injected into the product and the solution is maintained at a temperature of about 240 ° C for a period of about 8 seconds, thereby killing the solution. Any microorganisms.

After forming Sample A and Sample B, they were tested to determine the physical properties of each compound. Specifically, the strength, viscosity, moisture content, ash, and calcium concentration of the blubber were tested. The results are illustrated in Table 2 below.

After performing the tests of Sample A and Sample B to determine the physical properties of the two gelatin solutions, each sample was incorporated into a gel material solution for forming a gelatin coating. Specifically, Sample A and Sample B were mixed with glycerin and water in the ratios shown in Table 3, and then bubbles were removed to remove any air particles from the sample.

A quick release formulation (sodium carbonate and calcium carbonate) component is added to the formulation by forming a strip on the gelatin layer comprising the fast release formulation. The gel material solution of the above sample A gelatin was further adjusted to pH 8.9 by adding 2 equivalents of sodium hydroxide (partially added). After each addition, a small aliquot of the gel material solution was taken and diluted to a concentration of 6.67 wt% and the pH of the aliquot was measured. This process was repeated until the measured pH was about 8.9. The gel material mixture was prepared using the pH-adjusted undiluted gel material using sodium carbonate and the gel material solution of sample B as follows:

It should be noted that some samples include different ratios of water insoluble (CaCO ₃ ) and water soluble (Na ₂ CO ₃ ) rapid release formulations, while some samples (No. 3 gelatin) include only water soluble rapid release formulations. Therefore, experiments were designed to determine the effect of increasing the amount of water-soluble rapid release formulation compared to water insoluble rapid release formulations. Each of the above samples was coated on a polycarbonate plate using a coating gap of 700 μ. The coated panels were dried in a constant humidity chamber at 22 ° C and 50% RH.

Subsequently, after the gelatin sample was prepared, the solubility of the four gelatin samples and the two control samples was tested. Specifically, after drying for 2 weeks, the strip coating sample (usually about 1 cm × 1 cm) is cut from the coating and the sample is dissolved by immersing the sample in the dissolution medium at 37 ° C and Disintegration. The dissolution medium was prepared according to the following procedure to simulate gastric fluid (no enzyme). 2 g of sodium chloride and 7.0 ml of concentrated HCl were dissolved in sufficient water to obtain 1000 ml. The pH of the dissolution medium is about 1.2. Gelatin samples 1, 2, 3 and 4 disintegrated in less than 30 seconds, while the control samples disintegrated quite slowly. The dissolution profile of each sample is provided in Figure 17 (Figure 17).

Figure 17 is a graph illustrating the dissolution times of four different gelatin compositions comprising: bright capsules containing calcium carbonate and sodium carbonate in a mass ratio of about 1:1 (6.4% and 6.2%, respectively) a sealing composition; a gelatin capsule sealing composition containing calcium carbonate and sodium carbonate in a mass ratio of about 2.4:1 (11.1% and 4.6%, respectively); a capsule sealing composition containing only sodium carbonate (concentration: 5.0%) And a clear capsule sealing composition containing calcium carbonate and sodium carbonate in a mass ratio of about 1.5:1 (7.1% and 4.8%, respectively). All four formulations dissolved significantly faster than the control film.

As shown in the graph, the greater the relative amount of water-soluble carbonate compared to the water-insoluble carbonate, the faster the dissolution profile. For example, gelatin No. ₃ , which contains only water-soluble Na ₂ CO ₃ without any CaCO ₃ , produces the fastest dissolution profile, followed by gelatin No. 1, which contains 1:1 calcium carbonate: sodium carbonate, and contains 1.5. : 1 calcium carbonate: sodium carbonate ratio of No. 4 gelatin and 2.4:1 calcium carbonate: sodium carbonate ratio of No. 2 gelatin. Therefore, the results in Fig. 17 indicate that the larger the ratio of sodium carbonate (water-soluble releasing agent) to calcium carbonate (water-insoluble releasing agent), the faster the dissolution curve.

Example 9: Dissolution test of soft gel capsules with rapid release formulations

To further assess the solubility properties of the various gelatin formulations discussed herein after exposure to temperature and humidity conditions, the following soft capsule experiments were performed. A soft capsule gelatin composition having a viscosity of between about 4,000 mPas and about 10,000 mPas at 60 °C was prepared. The first gelatin composition comprises 44.00% by weight of bone cement without any further modification, 11.00% polysorbate, 11.00% glycerol (85%) and 34.00% water ("standard bone glue"). The second gelatin composition comprises 37.67% bone cement, 4.96% hydrolyzed bone cement having a molecular weight of about 500 Daltons, 6.38% calcium carbonate (CaCO ₃ ), 10.02% polysorbate, 10.02% glycerol (85%), and 30.97% water. ("CaCO ₃ "). The third gelatin composition comprises 37.11% bone cement, 4.88% hydrolyzed bone cement having a molecular weight of about 500 Daltons, 6.28% calcium carbonate (CaCO ₃ ), 1.47% potassium hydrogencarbonate, 9.87% polysorbate, 9.87% glycerol (85). %) and 30.51% water ("belt"). The fourth gelatin composition comprises 40.23% bone cement, 5.08% hydrolyzed bone cement having a molecular weight of about 500 Daltons, 7.40% 1.0 equivalent sodium hydroxide solution, 9.87% polysorbate, 9.87% glycerol (85%) and 23.11% water. ("HipH").

Soft capsules were prepared on a modified Chan Sung soft capsule M3 machine using four gelatin compositions with a dual chamber dye roll to prepare a 7.5 oval capsule and tumble dried at 2.5 rpm for 30 minutes, then at about 25 ° C and about Dry indoors for one week at 35% RH. Using a precision metering pump to deliver the formulation to the nozzle of the applicator cartridge using the needle encapsulation machine, modify the configuration of some of the capsule shells so that most of the shell composition is incorporated into the capsule of the HipE formulation Produces a narrow area with a formulation. The flow rate of the formulation is adjusted to produce regions of different widths. A flow rate of 0.16 ml/min produces a narrow region ("narrow broadband") and a flow rate of 0.40 ml/min produces a wider region ("medium broadband"). In addition to the capsules, a formulation having only one type of gelatin composition (i.e., all standard standard bone glue, all CaCO ₃ and all series HipH) was prepared in a total of five capsule configurations.

All capsules were filled with a liquid formulation containing 96.51% polyethylene-diol, 2.99% glycerol, and 0.50% bright blue dye (filled). Five capsule shell configurations were tested to determine the dissolution profile over time in an acidic dissolution medium. In each case, the dissolution medium was monitored spectrophotometrically to observe the appearance of the bright blue dye in the medium. The test assessed the dissolution profile of five shell-configured fresh capsules in simulated gastric fluid (at a pH of about 1.3 and in the absence of any enzyme). The test results of the dried fresh capsules are illustrated in Figure 18.

The results illustrated in Figure 18 show that the "CaCO ₃ " formulation releases the dye more slowly than normal gelatin ("standard bone glue"). Narrow broadband and normal band formulations release dye faster than standard bone cement formulations, and the fastest release is observed for narrow broadband configurations.

Modifications and variations will be apparent from the Detailed Description of the invention. In view of the present invention, it will be understood by those skilled in the art that many changes can be made in the particular embodiments disclosed and the same or similar results can be obtained without departing from the spirit and scope of the invention. For illustration Interpretive rather than restrictive.

Figure 1 is a photograph of a gelatin composition of the presently claimed embodiment having a compartment comprising a rapid release formulation and two compartments comprising a gelatin component and in the absence of any rapid release formulation, wherein A compartment containing a rapid release formulation has a uniform size and shape. Both formulations provide examples of regions of different widths that can be incorporated into the claimed compositions.

Figure 2 is a photograph of a gelatin composition of the presently claimed embodiment, wherein half of the gelatin composition consists entirely of gelatin components, does not contain any of a plurality of rapid release formulations, and the other half comprises a compartment containing a rapid release formulation and Two compartments containing gelatin components and no free release formulation.

Figure 3 is a graph showing the measured dissolution of a gelatin composition comprising various acid compounds in a pH = 1 buffer solution.

Figure 4 is a graph showing the effect of the addition of sodium carbonate on the measured dissolution of the gelatin composition in a pH = 1 buffer solution. In particular, Figure 4 illustrates the dissolution profile of a composition comprising gelatin and sodium bicarbonate compared to a composition comprising only gelatin.

Figure 5 is a graph showing the effect of storing a gelatin composition on its measured solubility characteristics in a pH = 1 buffer solution.

Figure 6 is a graph showing the effect of storing a gelatin composition comprising calcium carbonate on its measured solubility characteristics in a pH = 1 buffer solution.

Figure 7 is a diagram showing the storage of a gelatin composition comprising calcium carbonate and gelatin hydrolysate. A graph of the effect of its measured solubility characteristics in a pH 1 buffer solution.

Figure 8 is a graph comparing the measured dissolution of three different gelatin compositions in a pH 1 buffer solution after 11 weeks of storage.

Figure 9 is a graph showing the effect of storing a gelatin composition comprising calcium carbonate on its measured solubility characteristics in deionized water.

Figure 10 is a graph showing the effect of storing a gelatin composition comprising calcium carbonate on its measured solubility characteristics in deionized water.

Figure 11 is a graph showing the effect of storing a gelatin composition comprising calcium carbonate and gelatin hydrolysate on its measured solubility characteristics in deionized water.

Figure 12 is a graph comparing the measured dissolution of three different gelatin compositions in deionized water after 11 weeks of storage.

Figure 13 illustrates the dissolution profiles of three gelatin formulations in simulated gastric fluid (at a pH of about 1.3 without the presence of any enzyme). Three gelatin formulations include bone glue without any further modification ("standard bone glue"); bone glue and 15% by weight calcium carbonate (CaCO ₃ ) ("RR only"); and bone glue, 15% by weight calcium carbonate (CaCO ₃ ) and 10% by weight of hydrolyzed bone cement having a molecular weight of about 500 Daltons ("RR RXL").

Figure 14 illustrates the dissolution profile of the formulations in water (about neutral pH) after storage for three gelatin formulations at 40 ° C and 75% relative humidity for two weeks. Three gelatin formulations include bone glue without any further modification ("standard bone glue"); bone glue and 15% by weight calcium carbonate (CaCO ₃ ) ("RR only"); and bone glue, 15% by weight calcium carbonate (CaCO ₃ ) and 10% by weight of hydrolyzed bone cement having a molecular weight of about 500 Daltons ("RR RXL").

Figure 15 illustrates the dissolution profiles of the formulations in simulated gastric fluid (at a pH of about 1.3 and in the absence of any enzyme) after storage of the three gelatin formulations at 40 ° C and 75% relative humidity for two weeks. Three gelatin formulations include bone glue without any further modification ("standard bone glue"); bone glue and 15% by weight calcium carbonate (CaCO ₃ ) ("RR only"); and bone glue, 15% by weight calcium carbonate (CaCO ₃ ) and 10% by weight of hydrolyzed bone cement having a molecular weight of about 500 Daltons ("RR RXL").

Figure 16 illustrates the dissolution profiles of the formulations in simulated gastric fluid (at a pH of about 1.3 and in the absence of any enzyme) after storage of the three gelatin formulations at 40 ° C and 75% relative humidity for four weeks. Three gelatin formulations include bone glue without any further modification ("standard bone glue"); bone glue and 15% by weight calcium carbonate (CaCO ₃ ) ("RR only"); and bone glue, 15% by weight calcium carbonate (CaCO ₃ ) and 10% by weight of hydrolyzed bone cement having a molecular weight of about 500 Daltons ("RR RXL").

Figure 17 is a graph illustrating the dissolution times of four different gelatin compositions comprising: bright capsules containing calcium carbonate and sodium carbonate in a mass ratio of about 1:1 (6.4% and 6.2%, respectively) a sealing composition; a gelatin capsule sealing composition containing calcium carbonate and sodium carbonate in a mass ratio of about 2.4:1 (11.1% and 4.6%, respectively); a capsule sealing composition containing only sodium carbonate (concentration: 5.0%) And a clear capsule sealing composition containing calcium carbonate and sodium carbonate in a mass ratio of about 1.5:1 (7.1% and 4.8%, respectively).

Figure 18 is a chart illustrating the dissolution profiles of five gelatin compositions comprising: a composition comprising standard bone cement, but without any rapid release formulation (standard bone glue); a composition comprising Standard bone cement and calcium carbonate ("CaCO ₃ ") as a rapid release formulation; a composition comprising a standard bone cement having an elevated pH due to the addition of sodium hydroxide ("HipH"); a composition comprising a narrow width band ("narrow broadband") of standard bone cement with elevated pH and standard bone glue mixed with calcium carbonate and potassium bicarbonate; and a composition comprising elevated pH due to the addition of sodium hydroxide The standard bone glue and standard bone glue are mixed with calcium carbonate and potassium bicarbonate in the middle width band ("medium broadband").

Claims (116)

A gelatin capsule composition comprising an outer surface coating and a core, the outer surface coating comprising: a. one or more first compartment regions comprising a gelatin component; and b. one or more second compartment regions It contains a rapid release formulation. The composition of claim 1, wherein the one or more first compartments comprising the gelatin component and the one or more second compartments comprising the rapid release formulation further comprise a gelatin hydrolysate. The composition of claim 2, wherein the gelatin hydrolysate has an average molecular weight in the range of from about 100 Daltons to about 2000 Daltons. The composition of claim 1 wherein the gelatin component has an average molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons. The composition of claim 1, wherein the one or more second compartments comprising the rapid release formulation span the depth of the outer surface coating from the proximal surface to the distal surface. The composition of claim 1, wherein the one or more second compartments comprising the rapid release formulation are dispersed in a uniform pattern throughout the gelatin capsule composition, wherein the length and width of each of the second compartments are Change relative to each other no more than 10%. The composition of claim 1, wherein the one or more second compartments comprising the rapid release formulation are dispersed in a non-uniform pattern throughout the gelatin capsule composition, wherein the length and width of each of the second compartments They vary relative to each other by more than 10%. The composition of claim 1 wherein the rapid release formulation comprises water insoluble Carbonates, water soluble carbonates, and combinations thereof. The composition of claim 8, wherein the water-insoluble carbonate comprises bismuth subcarbonate, calcium carbonate, cobalt carbonate, cesium carbonate, lead carbonate, lithium carbonate, magnesium carbonate, manganese carbonate, nickel (II) carbonate, silver carbonate, carbonic acid Bismuth, lithium carbonate and combinations thereof. The composition of claim 9, wherein the water insoluble quick release formulation consists of calcium carbonate. The composition of claim 8, wherein the water soluble carbonate comprises sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium hydrogencarbonate, lithium carbonate, and combinations thereof. The composition of claim 8 wherein the water insoluble carbonate is substantially insoluble at a pH in the range of from about 6 to about 8, and wherein the fast release formulation dissociates at a pH in the range of from 0 to about 3. The composition of claim 8, wherein the water soluble carbonate is at least partially soluble in water, and wherein the fast release formulation dissociates at a pH in the range of from 0 to about 3. The composition of claim 1 wherein the gelatin capsule composition is completely degraded in less than 15 minutes at a pH in the range between 0 and about 3. The composition of claim 1 wherein the outer surface coating further comprises a plasticizer. The composition of claim 15 wherein the plasticizer comprises dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, sorbitol, sorbitan, erythritol, glycerol Triacetate, triethyl citrate, water, and mixtures thereof. The composition of claim 1, wherein the gelatin component of the one or more first compartments comprises a combination of gelatin, a plasticizer, and water. The composition of claim 17, wherein the gelatin component of the one or more first compartments comprises from about 25% to about 55% by weight of the gelatin of the one or more first compartments, From about 10% to about 30% by weight of the one or more first compartments of the plasticizer and from about 15% to about 45% by weight of the one or more first compartments . The composition of claim 17, wherein the gelatin component of the one or more first compartments comprises from about 35% to about 45% of the gelatin, by weight of the one or more first compartments, From about 16% to about 24% by weight of the one or more first compartments of the plasticizer and from about 20% to about 30% by weight of the one or more first compartments water. The composition of claim 1 wherein the gelatin component comprises a combination of gelatin and water. The composition of claim 22, wherein the gelatin component comprises from about 5% to about 30% gelatin and from about 70% to about 95% water. The composition of claim 22, wherein the gelatin component comprises from about 10% to about 20% gelatin and from about 80% to about 90% water. The composition of claim 2, wherein the outer surface coating comprises the gelatin component and the gelatin hydrolysate in a mass ratio ranging from about 3:1 to about 99:1. The composition of claim 2, wherein the outer surface coating comprises the gelatin component and the gelatin hydrolysate in a mass ratio ranging from about 4:1 to about 19:1. The composition of claim 1, wherein the one or more second compartments comprising the rapid release formulation further comprise gelatin, a plasticizer, and water. The composition of claim 25, wherein the one or more second compartments comprise from about 20% to about 50% by weight of the one or more second compartments, the one or more The second release zone is from about 1% to about 25% by weight of the quick release formulation, from about 10% to about 30% by weight of the one or more second compartments, of the plasticizer and The one or more second compartments weigh from about 20% to about 40% by weight of water. The composition of claim 25, wherein the one or more second compartments comprise from about 30% to about 45% of the gelatin by weight of the one or more second compartments, the one or more The second zone is from about 4% to about 16% by weight of the quick release formulation, from about 16% to about 24% by weight of the one or more second zones, of the plasticizer and The one or more second compartments weigh from about 26% to about 34% by weight of water. The composition of claim 25, wherein the one or more second compartments comprise the rapid release formulation and the gelatin in a mass ratio ranging from about 1:1 to about 1:20. The composition of claim 25, wherein the one or more second compartments comprise the rapid release formulation and the gelatin in a mass ratio ranging from about 1:2 to about 1:9. The composition of claim 1 wherein the core comprises a solid formulation and a liquid formulation. The composition of claim 1 wherein the core comprises a pharmaceutically active ingredient and optionally one or more pharmaceutically acceptable excipients. The composition of claim 1, wherein the one or more first compartments further comprise a rapid release formulation, and The concentration of the rapid release formulation of the one or more first compartments is less than the concentration of the rapid release formulation of the one or more second compartments. The composition of claim 1, wherein the gelatin component comprises Type A gelatin, Type B gelatin, and combinations thereof. The composition of claim 1, wherein the one or more second compartments comprising the rapid release formulation have the appearance of: strips, rods, strips, streaks, slats, columns, columns, spots, streaks, stripes, Zones, strips, veins, short bars, ridges, twisted lines, and combinations thereof. A gelatin capsule composition comprising an outer surface coating and an inner core, the outer surface coating comprising: a. one or more first compartment regions comprising a gelatin component and a gelatin hydrolysate; and b. one or more A second compartment comprising a rapid release formulation, a gelatin component, and a gelatin hydrolysate, wherein the one or more second compartments span the depth of the outer surface coating from the proximal surface to the distal surface. The composition of claim 35, wherein the gelatin hydrolysate has an average molecular weight in the range of from about 100 Daltons to about 2000 Daltons. The composition of claim 35, wherein the gelatin component of the one or more first compartments and the one or more second compartments has a range of from about 50,000 Daltons to about 300,000 Daltons. Average molecular weight. The composition of claim 35, wherein the rapid release formulation comprises a water insoluble carbonate, a water soluble carbonate, and combinations thereof. The composition of claim 38, wherein the water-insoluble carbonate comprises bismuth subcarbonate, calcium carbonate, cobalt carbonate, cesium carbonate, lead carbonate, lithium carbonate, magnesium carbonate, manganese carbonate, nickel (II) carbonate, silver carbonate, carbonic acid Bismuth, lithium carbonate and combinations thereof. The composition of claim 39, wherein the water insoluble quick release formulation consists of calcium carbonate. The composition of claim 38, wherein the water soluble carbonate comprises sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium hydrogencarbonate, lithium carbonate, and combinations thereof. The composition of claim 38, wherein the water insoluble carbonate is substantially insoluble at a pH in the range of from about 6 to about 8, and wherein the fast release formulation dissociates at a pH in the range of from 0 to about 3. The composition of claim 38, wherein the water soluble carbonate is at least partially soluble in water, and wherein the fast release formulation dissociates at a pH in the range of from 0 to about 3. The composition of claim 35, wherein the gelatin component of the one or more first compartments and the one or more second compartments comprises a combination of gelatin, a plasticizer, and water. The composition of claim 44, wherein the one or more first compartments comprise from about 25% to about 55% by weight of the one or more first compartments of the gelatin, the one or more The first compartment is from about 0.01% to about 20% by weight of the gelatin hydrolysate, from about 10% to about 30% by weight of the one or more first compartments, of the plasticizer and The one or more first compartments weigh from about 15% to about 45% by weight of water. The composition of claim 44, wherein the one or more first compartments comprise from about 35% to about 48% by weight of the one or more first compartments of the gelatin, the one or more The first compartment is from about 1% to about 10% by weight of the gelatin hydrolysate, from about 16% to about 24% by weight of the one or more first compartments, of the plasticizer and The one or more first compartments weigh from about 20% to about 30% by weight of water. The composition of claim 44, wherein the one or more second compartments comprise from about 20% to about 50% by weight of the one or more second compartments, the one or more The weight of the second compartment is from about 0.01% to about 20% by weight of the gelatin hydrolysate, from about 1% to about 25% by weight of the one or more second compartments, to the rapid release formulation, The one or more second compartments are from about 10% to about 30% by weight of the plasticizer and from about 20% to about 40% by weight of the weight of the one or more second compartments. The composition of claim 25, wherein the one or more second compartments comprise from about 30% to about 45% of the gelatin by weight of the one or more second compartments, the one or more From about 1% to about 10% by weight of the second compartment, the gelatin hydrolysate, from about 4% to about 16% by weight of the one or more second compartments, of the quick release formulation, The one or more second compartments comprise from about 16% to about 24% by weight of the plasticizer and from about 26% to about 34% by weight of the weight of the one or more second compartments. The composition of claim 35, which further comprises a pharmaceutically active ingredient. A pharmaceutical gelatin capsule composition comprising an outer surface coating and a core, The outer surface coating comprises: a. one or more first compartments comprising from about 35% to about 45% gelatin by weight of the one or more first compartments, in the one or more The weight of the first compartment is from about 3% to about 7% of the gelatin hydrolysate having an average molecular weight in the range of from about 100 Daltons to about 2000 Daltons, by weight of the one or more first compartments From about 18% to about 22% plasticizer and from about 20% to about 26% water by weight of the one or more first compartments; and b. one or more second compartments, It comprises from about 34% to about 40% gelatin by weight of the one or more second compartments, and an average molecular weight of from about 3% to about 7% by weight of the one or more second compartments. a gelatin hydrolysate in the range of from about 100 Daltons to about 2000 Daltons, from about 5% to about 10% by weight of the one or more second compartments, in one or more The second compartment has a weight of from about 18% to about 22% plasticizer and from about 28% to about 32% water by weight of the one or more second compartments, wherein the core comprises medicinal Active ingredient, one of which Or a plurality of second compartments span the depth of the outer surface coating from the proximal surface to the distal surface, and wherein the rapid release formulation comprises bismuth subcarbonate, calcium carbonate, cobalt carbonate, cesium carbonate, lead carbonate, lithium carbonate, Magnesium carbonate, manganese carbonate, nickel (II) carbonate, silver carbonate, barium carbonate, sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium hydrogencarbonate, lithium carbonate, and combinations thereof. The composition of claim 50, wherein the one or more first compartments One step comprises a rapid release formulation, and wherein the concentration of the fast release formulation included in the one or more first compartments is less than the concentration of the rapid release formulation included in the one or more second compartments. A gelatin capsule composition comprising an outer surface coating, a subcoat and a core, the outer surface coating comprising: a. one or more first compartment regions comprising a gelatin component; and b. one or more second A compartmentalized region comprising a rapid release formulation, wherein the subcoat is applied to a distal surface of the core and encompasses a substantial portion of the core, and wherein the outer surface coating is applied to the distal surface of the substrate. The composition of claim 52, wherein the subcoat comprises a gelatin component, a gelatin hydrolysate, a polymeric material, and combinations thereof. The composition of claim 52, wherein the subcoat comprises one or more channels for releasing the contents of the core. The composition of claim 52, wherein the subcoat comprises two or more layers having different release profiles. The composition of claim 52, wherein the core comprises a pharmaceutically active ingredient. A gelatin capsule composition comprising an enteric coating, a core surface coating, and a core, the core surface coating comprising: a. one or more first compartment regions comprising a gelatin component; and b. a plurality of second compartments comprising a rapid release formulation, wherein the enteric coating is applied to a distal surface of the core surface coating, wherein the core surface coating is applied to the distal surface of the core, and Wherein the enteric coating is insoluble at a pH in the range of from 0 to about 3 and is soluble at a pH of greater than or equal to about 5.0. The composition of claim 57, wherein the enteric coating comprises a gelatin component, a gelatin hydrolysate, a polymeric material, and combinations thereof. The composition of claim 57, wherein the core comprises a pharmaceutically active ingredient. A method of making a gelatin capsule composition comprising an outer surface coating and a core comprising a pharmaceutically active ingredient, the outer surface coating comprising one or more first compartments comprising a gelatin component and one or more A second compartment comprising a rapid release formulation, the method comprising: a. dissolving the gelatin component in an aqueous medium to produce an aqueous gelatin solution; b. incorporating a second solution comprising the rapid release formulation into the gelatin aqueous solution to produce One or more first compartments comprising the aqueous gelatin solution and one or more second compartments comprising the second solution containing the rapid release formulation; and c. encapsulating the core comprising a pharmaceutically active ingredient, The one or more first compartments and the one or more second compartments are maintained simultaneously. The method of claim 60, wherein the encapsulating step comprises an extrusion process. The method of claim 60, wherein the gelatin component of step (a) comprises gelatin having a molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons and having a molecular weight in the range of from about 100 Daltons to about 2000 Daltons. A combination of gelatin hydrolysates. The method of claim 60, wherein the one or more second compartments further comprise a gelatin component and the mass ratio of the fast release formulation to the gelatin component is in the range of from about 1:1 to about 1:20. The method of claim 60, wherein step (a) further comprises adding a plasticizer. The method of claim 64, wherein the plasticizer comprises dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, sorbitol, erythritol, triacetin, Triethyl citrate, water and mixtures thereof. The method of claim 60, wherein the gelatin component comprises a combination of gelatin and a plasticizer. The method of claim 62, wherein the gelatin has a molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons and the gelatin hydrolysate has a molecular weight in the range of from about 100 Daltons to about 2000 Daltons. The ratio is in the range of about 3:1 to about 99:1. The method of claim 60, wherein the gelatin component of step (a) comprises a combination of gelatin, a plasticizer, and an aqueous medium, and wherein step (a) comprises mixing the weight of the one or more first compartments From about 30% to about 55% of the gelatin, from about 10% to about 30% by weight of the one or more first compartments, and from the one or more first compartments The aqueous medium is from about 15% to about 45% by weight. The method of claim 68, wherein the step (a) comprises mixing about 35% to about 45% of the gelatin by weight of the one or more first compartments, with the one or more first compartments From about 0.1% to about 20% by weight of the gelatin hydrolysate having an average molecular weight in the range of from about 100 Daltons to about 2000 Daltons, by weight of about 10% by weight of the one or more first compartments About 30% of the plasticizer and about the weight of the one or more first compartments 25% to about 45% of the aqueous medium. The method of claim 60, wherein the second solution of step (b) comprises a rapid release formulation, a gelatin component, a plasticizer, and an aqueous medium. The method of claim 70, wherein the gelatin component of step (b) comprises gelatin having a molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons and having a molecular weight in the range of from about 100 Daltons to about 2000 Daltons. A combination of gelatin hydrolysates. The method of claim 71, wherein the second solution of step (b) comprises from about 20% to about 50% by weight of the second solution of the gelatin, and about 0.01% to about the weight of the second solution. 20% of the gelatin hydrolysate, from about 1% to about 25% by weight of the second solution of the quick release formulation, from about 10% to about 30% by weight of the second solution of the plasticizer and About 20% to about 40% water by weight of the second solution. The method of claim 60, wherein the aqueous medium comprises water. The method of claim 60, wherein the one or more first compartments comprising a gelatin aqueous solution and the one or more second compartments comprising a rapid release formulation are fed to the gelatin aqueous solution via a static mixer and comprising The second solution of the rapid release formulation is produced. A gelatin composition comprising an outer surface coating and a core, wherein the outer surface coating comprises a quick release formulation and a gelatin component. The composition of claim 75, wherein the composition further comprises a gelatin hydrolysate having a molecular weight in the range of from about 100 Daltons to about 2000 Daltons. The composition of claim 75, wherein the rapid release formulation comprises a water soluble carbonate, a water insoluble carbonate, and combinations thereof. The composition of claim 77, wherein the water soluble quick release formulation comprises sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium hydrogencarbonate, lithium carbonate, and combinations thereof. The composition of claim 77, wherein the water soluble carbonate is at least partially soluble in water, and wherein the fast release formulation dissociates at a pH in the range of from 0 to about 3. The composition of claim 77, wherein the water-insoluble carbonate comprises bismuth subcarbonate, calcium carbonate, cobalt carbonate, cesium carbonate, lead carbonate, lithium carbonate, magnesium carbonate, manganese carbonate, nickel (II) carbonate, silver carbonate, carbonic acid Bismuth, lithium carbonate and combinations thereof. The composition of claim 80, wherein the water insoluble quick release formulation consists of calcium carbonate. The composition of claim 75, wherein the composition further comprises the quick release formulation and the gelatin component in a mass ratio ranging from about 1:1 to about 1:20. The composition of claim 82, wherein the mass ratio of the fast release formulation to the gelatin component is in the range of from about 1:2 to about 1:15. The composition of claim 82, wherein the mass ratio of the fast release formulation to the gelatin component is in the range of from about 1:4 to about 1:9. The composition of claim 75, wherein the contents of the core are released in less than 15 minutes at a pH in the range between 0 and about 3. The composition of claim 75, further comprising a plasticizer. The composition of claim 86, wherein the plasticizer comprises dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, mountain Pear alcohol, erythritol, triacetin, triethyl citrate, water, and mixtures thereof. The composition of claim 75, wherein the gelatin component comprises a combination of gelatin, a plasticizer, and water. The composition of claim 88, wherein the gelatin component comprises from about 25% to about 55% by weight of the gelatin component of the gelatin, and from about 15% to about 30% by weight of the gelatin component. The plasticizer and the water are from about 25% to about 40% by weight of the gelatin component. The composition of claim 88, wherein the gelatin component comprises from about 35% to about 45%, by weight of the gelatin component, of the gelatin, from about 20% to about 25% by weight of the gelatin component. The plasticizer and from about 30% to about 35% by weight of the gelatin component of the water. The composition of claim 75, wherein the gelatin component comprises a combination of gelatin and water. The composition of claim 91, wherein the gelatin component comprises from about 5% to about 30% gelatin and from about 70% to about 95% water. The composition of claim 91, wherein the gelatin component comprises from about 10% to about 20% gelatin and from about 80% to about 90% water. The composition of claim 76, wherein the composition further comprises the gelatin component and the gelatin hydrolysate in a mass ratio ranging from about 3:1 to about 99:1. The composition of claim 76, wherein the composition further comprises the gelatin component and the gelatin hydrolysate in a mass ratio ranging from about 4:1 to about 19:1. The composition of claim 76, wherein the composition further comprises the gelatin component and the gelatin hydrolysate in a mass ratio ranging from about 5:1 to about 13:1. A gelatin composition comprising an outer surface coating and a core, the outer surface coating comprising: a. a quick release formulation; b. a gelatin component; and c. a gelatin hydrolysate, wherein the composition comprises from about 1:1 to about 1 a mass ratio within the range of 20 to the fast release formulation and the gelatin component, wherein the gelatin hydrolysate has a molecular weight in the range of from about 100 Daltons to about 2000 Daltons, and wherein the composition comprises about 3:1 The mass ratio to the gelatin component and the gelatin hydrolysate are in the range of about 99:1. A gelatin composition comprising a quick release formulation and a gelatin component, the composition being prepared by the method comprising: a. dissolving the gelatin component in an aqueous medium to form an aqueous gelatin solution; b. forming in a capsule The rapid release formulation is previously mixed with the gelatin aqueous solution; and c. The gelatin aqueous solution and the quick release formulation are combined into a gelatin capsule forming machine. The gelatin composition of claim 98, wherein the step (b) of mixing the quick release formulation with the gelatin aqueous solution prior to capsule formation comprises an in-line mixing process. The gelatin composition of claim 99, wherein the in-line mixing process comprises using a static mixer. The gelatin composition of claim 98, wherein the composition further comprises a gelatin hydrolysate having a molecular weight in the range of from about 100 Daltons to about 2000 Daltons. The gelatin composition of claim 98, wherein the water-soluble rapid release formulation comprises bismuth subcarbonate, calcium carbonate, cobalt carbonate, cesium carbonate, lead carbonate, lithium carbonate, magnesium carbonate, manganese carbonate, nickel (II) carbonate, and silver carbonate. , cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium hydrogencarbonate, lithium carbonate, and combinations thereof. A method of making a gelatin composition comprising a rapid release formulation, the method comprising the steps of: a. dissolving a gelatin component in an aqueous medium to form an aqueous gelatin solution; b. mixing the rapid release formulation with the aqueous gelatin solution prior to capsule formation; And c. incorporating the gelatin aqueous solution and the quick release formulation into a gelatin capsule forming machine. The method of claim 103, wherein the step (b) of mixing the water-soluble quick release formulation with the gelatin aqueous solution prior to capsule formation comprises an in-line mixing process. The method of claim 103, wherein the gelatin component of step (a) comprises gelatin having a molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons and a molecular weight in the range of from about 100 Daltons to about 2000 Daltons. A combination of gelatin hydrolysates. The method of claim 103, wherein the rapid release formulation comprises bismuth subcarbonate, calcium carbonate, cobalt carbonate, cesium carbonate, lead carbonate, lithium carbonate, carbonic acid Magnesium, manganese carbonate, nickel (II) carbonate, silver carbonate, barium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium hydrogencarbonate, lithium carbonate, and combinations thereof. The method of claim 103, wherein the water soluble quick release formulation is at least partially soluble in water, and wherein the fast release formulation dissociates at a pH in the range of from 0 to about 3. The method of claim 103, wherein the mass ratio of the fast release formulation to the gelatin component is in the range of from about 1:1 to about 1:20. The method of claim 103, wherein the gelatin composition is substantially completely degraded in less than 15 minutes at a pH in the range between 0 and about 3. The method of claim 105, wherein the gelatin has a molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons and the gelatin hydrolysate has a molecular weight in the range of from about 100 Daltons to about 2000 Daltons. It is in the range of about 3:1 to about 99:1. The method of claim 105, wherein the gelatin has a molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons and the gelatin hydrolysate has a molecular weight in the range of from about 100 Daltons to about 2000 Daltons. The ratio is in the range of about 4:1 to about 19:1. The method of claim 105, wherein the gelatin has a molecular weight in the range of from about 50,000 Daltons to about 300,000 Daltons and the gelatin hydrolysate has a molecular weight in the range of from about 100 Daltons to about 2000 Daltons. The ratio is in the range of about 5:1 to about 13:1. The method of claim 103, wherein the step (a) comprises dissolving from about 0.01% to about 30% by weight of the gelatin aqueous solution of the gelatin component to the The weight of the aqueous solution of the gum is from about 40% to about 99.9% by weight of the aqueous medium. The method of claim 103, wherein the step (a) comprises dissolving from about 10% to about 20% by weight of the combined aqueous gelatin solution of the gelatin component from about 70% to about 90% by weight of the combined gelatin aqueous solution. % of this aqueous medium. The method of claim 105, wherein the step (a) comprises, by weight of the combined aqueous gelatin solution, from about 10% by weight to about 20% by weight of the gelatin having a molecular weight of from about 50,000 Daltons to about 300,000 Daltons and From about 1% to about 5% by weight of the gelatin hydrolysate having a molecular weight in the range of from about 100 Daltons to about 2000 Daltons is dissolved in from about 70% to about 90% by weight of the aqueous medium. The method of claim 103, wherein the aqueous medium comprises water.