Osmotic Pharmaceutical Capsules

Abstract

In certain embodiments, a capsule is disclosed that includes a liquid fill material that includes an osmogen and an active agent, and a semipermeable, collapse-resistant shell composition.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 443,142, filed February 3, 2023, the entire contents of which are incorporated herein by reference in their entirety. [Technical Field]

[0002] The present invention relates to a capsule (eg, a softgel) comprising a liquid fill material including an osmogen and an active agent, and a semipermeable, collapse-resistant shell composition. [Background technology]

[0003] Capsules, especially hard gelatin capsules or soft gelatin capsules (or soft gel capsules), provide a dosage form that is more acceptable to patients because the capsules are easy to swallow and do not need to be flavored to mask any unpleasant taste of the active agent.By encapsulating drugs in soft gel capsules, the bioavailability of the drug can also be improved.For example, as soon as the gelatin shell ruptures, the active ingredient can be rapidly released in liquid form.

[0004] Osmotic delivery systems exist that operate on the principle of osmotic pressure through a semipermeable membrane, forcing the active ingredient out of the device through pores or strategically placed holes. These osmotic delivery systems can offer clinical advantages such as controlled release of the active agent, minimized peak-to-trough fluctuations, reduced dosage, less frequent administration, reduced side effects, and improved patient compliance.

[0005] There is a need in the art for a drug delivery system that combines the advantages of both liquid-filled capsules and osmotic delivery systems. Summary of the Invention

[0006] It is an object of certain embodiments of the present invention to provide an osmotic capsule capable of delivering a liquid payload.

[0007] It is an object of a further embodiment of the present invention to provide a method for preparing the osmotic capsules disclosed herein.

[0008] It is an object of a further embodiment of the present invention to provide a method of treating a disease or condition comprising orally administering to a patient in need thereof an osmotic capsule as disclosed herein.

[0009] It is an object of a further embodiment of the present invention to provide a device that allows the osmotic capsules disclosed herein to be pierced prior to ingestion by a patient.

[0010] One or more of the above objects and other objects are achieved by the present invention, which in certain embodiments relates to a capsule comprising a liquid fill material comprising an osmogen and an active agent, and a semipermeable, collapse-resistant shell composition, hi certain embodiments, the capsule has an opening through the shell formed by the patient or caregiver during manufacture or prior to administration. [Brief explanation of the drawings]

[0011] [Figure 1] 1 shows a liquid-filled capsule being pierced by a stylus, then removed and placed in water, according to one embodiment of the present invention. [Figure 2] 1 shows multiple capsules in a penetrating drug delivery device in a carousel configuration. [Figure 3a] ~ [Figure 3c] 1 illustrates a cross section of a capsule according to various embodiments of the present disclosure. [Figure 4] 1 illustrates the preparation of a liquid-filled capsule according to another embodiment of the present invention. [Figure 5] 1 shows the effect of crosslinking level and pore size on the release profile. MODES FOR CARRYING OUT THE INVENTION

[0012] The present invention advances the state of the art by developing an osmotic dosage form capable of delivering a liquid payload, which combines the convenience of a pharmaceutical capsule (e.g., a softgel) with the clinical advantages of an osmotic dosage form. In certain embodiments, the capsule shell is semipermeable, such that the presence of an osmogen in the liquid fill allows water influx, thereby expelling the drug from the capsule through openings and / or pores formed in the shell and / or controlled rupture of the capsule due to the resulting pressure gradient.

[0013] Certain embodiments of the present invention address the potential problem of leakage of fill material from the opening during transportation and / or storage of the capsule after manufacture. In certain embodiments, the opening is created by the patient or caregiver immediately prior to administration (e.g., using a stylus or by a device that pierces the capsule when activated). In other embodiments, the opening is created at the time of manufacture and is blocked or covered with a material that erodes after administration, exposing the opening to the liquid environment of the gastrointestinal tract. In some embodiments, the opening may be created by perforating the capsule using a laser, stylus, or drill. The opening of the capsule may then be sealed using a piezoelectric spray, thereby blocking the opening. In some embodiments, the capsule may be sealed using any suitable sealing method. The capsule may then be further coated with a soluble coating. In some embodiments, the opening may be created by perforation, which may then be further coated with a soluble coating. In other embodiments, the opening may be created by perforation and not sealed or covered.

[0014] In certain embodiments, the capsule shell is insoluble in the gastric and intestinal environments, or at least resistant to disintegration for the time required to deliver the proposed dose of active agent. Thus, in certain embodiments, the shell may comprise an insoluble or disintegration-resistant material or be coated with a substance that provides this capability. The disintegration-resistant shell may also comprise cross-linked gelatin or other polymers, such as alginate or carrageenan. Such a cross-linking process may be carried out, for example, by adding a cross-linking additive to the gel mass after filling the capsule with a liquid fill or before capsule formation, where the cross-linking agent has a reaction time delay sufficient to allow encapsulation before excessive cross-linking occurs, rendering the gel mass unmachinable. In certain embodiments, one method of preparing the capsules disclosed herein is to mix the cross-linking agent and the gel mass in-line just before casting onto a drum. In certain embodiments, the insoluble or disintegration-resistant material may include a base-resistant polymer.

[0015] The release rate of the active agent can be controlled by the fill composition, the shell composition, the size of the opening, or a combination of any or all of these factors. In certain embodiments, the fill material has low permeability, which allows water to migrate into the capsule, thereby causing the contents of the capsule to migrate through the opening, resulting in a relatively constant period of active agent delivery that gradually decreases as the contents of the capsule are diluted.

[0016] In certain embodiments, fill materials that are not hypotonic, such as oils, may be modified by the inclusion of a suspension of a compatible salt or a water-swellable material, such that when water migrates to the interior of the capsule, the immiscible fill material is not diluted.

[0017] In certain embodiments, the present invention relates to a capsule comprising a liquid fill material comprising an osmogen and an active agent, and a semipermeable, collapse-resistant shell composition.

[0018] In certain embodiments, the shell comprises a film-forming material and a disintegration-resistant material. In certain embodiments, the shell comprises a film-forming material, a disintegration-resistant material, or a combination thereof. In certain embodiments, the film-forming material and the disintegration-resistant material may comprise the same components.

[0019] In certain embodiments, the film-forming material and the disintegration-resistant material are dispersed within one another.

[0020] In certain embodiments, the shell comprises an inner layer comprising a film-forming material and an outer layer comprising a disintegration-resistant material, in some embodiments, the inner layer is understood to be a soluble layer and the outer layer is understood to be an insoluble layer.

[0021] In some embodiments, the disintegration-resistant material may include gums, cellulose ethers, acrylic resins, protein-derived materials, waxes, shellac, and oils such as hydrogenated castor oil and hydrogenated vegetable oil. Other polymers include alkylcelluloses such as ethylcellulose, polymers and copolymers of acrylic acid and methacrylic acid, and cellulose ethers such as hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Other polymers and copolymers of acrylic acid and methacrylic acid include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonium ethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymers, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), glycidyl methacrylate copolymers, and combinations thereof. Acrylic polymers useful as the disintegration-resistant material include acrylic resins, including copolymers synthesized from acrylic and methacrylic esters (e.g., copolymers of lower alkyl acrylates and lower alkyl methacrylates), containing approximately 0.02 to 0.03 moles of tri(lower alkyl)ammonium groups per mole of acrylic and methacrylic monomers used. An example of a suitable acrylic resin is the polymer manufactured by Rohm Pharma GmbH and sold under the Eudragit® RS trademark. Eudragit RS30D may also be used. Eudragit® RS is a water-insoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM), and trimethylammonium ethyl methacrylate chloride (TAM), with a molar ratio of TAM to the remaining components (EA and MM) of 1:40. Acrylic resins such as Eudragit® RS may be used in the form of an aqueous suspension.

[0022] In some embodiments, the disintegration-resistant material may include a cellulose polymer selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate (low, medium, or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, and cellulose triacetate. An example of ethyl cellulose has an ethoxy content of 44-55%. Ethyl cellulose may be used in the form of an alcohol solution. In other specific embodiments, the hydrophobic material includes polylactic acid, polyglycolic acid, or a copolymer of polylactic acid and polyglycolic acid.

[0023] In certain embodiments, the disintegration-resistant material may include a cellulose polymer selected from the group consisting of cellulose ethers, cellulose esters, cellulose ester ethers, and cellulose. The cellulose-based polymer may have a degree of substitution (DS) of the anhydroglucose units greater than 0 and less than or equal to 3. Representative materials include polymers selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di-, and tricellulose alkanylates, mono-, di-, and tricellulose alloyates, and mono-, di-, and tricellulose alkenylates. Exemplary polymers include cellulose acetate with a DS and acetyl content of up to 21%, cellulose acetate with an acetyl content of up to 32-39.8%, cellulose acetate with a DS of 1-2 and an acetyl content of 21-35%, and cellulose acetate with a DS of 2-3 and an acetyl content of 35-44.8%.

[0024] Other cellulosic polymers include cellulose propionate having a DS of 1.8, a propyl content of 39.2-45, and a hydroxyl content of 2.8-5.4%; cellulose acetate butyrate having a DS of 1.8, an acetyl content of 13-15%, and a butyryl content of 34-39%; cellulose acetate butyrate having an acetyl content of 2-29%, a butyryl content of 17-53%, and a hydroxyl content of 0.5-4.7%; cellulose triacylate having a DS of 2.9-3, e.g., cellulose triacetate cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, and cellulose trioctanoate; cellulose diacylates having a DS of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulose, such as cellulose acetate butyrate, cellulose acetate octanoate butyrate, and cellulose acetate propionate.

[0025] Additional cellulose polymers useful as disintegration-resistant materials include acetaldehyde dimethyl cellulose acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, and cellulose acetate dimethylamino cellulose acetate.

[0026] In some embodiments, the disintegration-resistant material and / or film-forming material may include an osmopolymer. Examples of osmopolymers include, but are not limited to, poly(hydroxy-alkyl methacrylates) having a molecular weight of 30,000 to 5,000,000; polyvinylpyrrolidone (PVP) having a molecular weight of 10,000 to 360,000; anionic and cationic hydrogels; polyelectrolyte complexes; polyvinyl alcohols cross-linked with glyoxal, formaldehyde, or glutaraldehyde and having a low acetate residue and a degree of polymerization of 200 to 30,000; mixtures of methylcellulose, cross-linked agar, and carboxymethylcellulose; mixtures of hydroxypropylmethylcellulose and sodium carboxymethylcellulose; mixtures of hydroxypropylethylcellulose and sodium carboxymethylcellulose; sodium carboxymethylcellulose; and carboxymethylcellulose. water-insoluble, water-swellable copolymers formed from dispersions of finely divided copolymers of maleic anhydride and styrene, ethylene, propylene, butylene, or isobutylene, crosslinked with 0.001 to about 0.5 moles of saturated crosslinker per mole of maleic anhydride per copolymer; water-swellable polymers of N-vinyl lactams; polyoxyethylene-polyoxypropylene gels; polyoxybutylene-polyethylene block copolymer gels; carob gum; polyacrylic gels; polyester gels; polyurea gels; polyether gels; polyamide gels; polypeptide gels; polyamino acid gels; polycellulose gels; polygum gels; and hydrogels that are initially dry but that absorb and take up water which penetrates the glassy hydrogel and lowers its glass temperature.

[0027] Other examples of osmopolymers include, but are not limited to, CARBOPOL® (Noveon, Inc., Cleveland, Ohio), an acidic carboxypolymer (an acrylic polymer crosslinked with polyallylsucrose, also known as carboxypolymethylene and carboxyvinyl polymer, having a molecular weight of 250,000 to 4,000,000); cinnamer polyacrylamide; crosslinked water-swellable indene-maleic anhydride polymer; GOOD-RITE® (Noveon, Inc., Cleveland, Ohio), a polyacrylic acid having a molecular weight of 80,000 to 200,000; POLYOX® (Union Carbide Chemicals & Plastics Technology Corporation, Danbury, Conn.), a polyethylene oxide polymer having a molecular weight of 100,000 to 5,000,000 or more; starch graft copolymers, acrylate polymer polysaccharides composed of condensed glucose units such as diester-crosslinked polygululan, and the like.

[0028] The osmogen may include an osmotically effective solute. The osmotically effective solute may include inorganic and organic compounds that can generate an osmotic pressure gradient across a semipermeable membrane when the osmotic delivery system is placed in a fluid environment. Osmotically effective solutes or penetration enhancers (i.e., non-volatile species that dissolve in water and create an osmotic pressure gradient to promote the osmotic influx of water) useful in osmotic agent formulations include, but are not limited to, magnesium sulfate, magnesium chloride, sodium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, d-mannitol, urea, inositol, magnesium succinate, tartaric acid, inositol, carbohydrates, and various monosaccharides, oligosaccharides, and polysaccharides such as sucrose, glucose, lactose, fructose, raffinose, and dextran, as well as mixtures of any of these various species.

[0029] Osmotic agents such as sodium chloride (NaCl) with suitable excipients (lubricants and binders, such as cellulose binders and povidone binders), and viscosity adjusters such as sodium carboxymethylcellulose or sodium polyacrylate are examples of preferred osmotic agents.Other osmotic agents useful as water swelling agents include osmopolymers and osmagents, as described, for example, in U.S. Patent Application No. 5,413,572.

[0030] In certain embodiments, the shell composition comprises from about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, to about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, or about 10%, or any range or subvalue therein.

[0031] In certain embodiments, the shell composition comprises from about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, to about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, or about 10%, or any range or subvalue therein.

[0032] In certain embodiments, the capsule is a hard capsule, for example a two-piece capsule.

[0033] In certain embodiments, the capsule is a softgel capsule.

[0034] In certain embodiments, the semipermeable shell composition is permeable to the passage of water but impermeable to the passage of the active agent.

[0035] In certain embodiments, the semipermeable shell composition comprises at least one opening, hi certain embodiments, the semipermeable shell composition comprises one opening, two openings, three openings, four openings, five openings, or more openings.

[0036] In certain embodiments, a pressure gradient is created by imbibing a fluid, such as water, into the capsule through the shell composition, causing the active agent to be expelled through the opening. The active agent is expelled through the capsule's fill composition at a slow, steady rate through the opening. In certain embodiments, when water passes through the shell composition, releasing the fill composition, the fill composition is diluted as the active agent is released from the capsule. In certain embodiments, the pressure gradient and release rate of the fill composition can be controlled by the size of the opening and the amount of openings present in the shell composition. In certain embodiments, the size of the opening may be about 600 μm to about 1 mm, about 625 μm to about 975 μm, about 650 μm to about 950 μm, about 675 μm to about 925 μm, about 700 μm to about 900 μm, about 725 μm to about 875 μm, about 750 μm to about 850 μm, or about 775 μm to about 825 μm.

[0037] In certain embodiments, the capsule further comprises a soluble plug filling or covering the opening. The soluble plug filling may be made of a material that is water-soluble and dissolves when contacted with water.

[0038] In certain embodiments, the capsule further comprises an additional soluble coating covering the shell composition and the opening. The additional soluble coating may be made from a material that is water-soluble and dissolves when contacted with water.

[0039] In certain embodiments, the capsule further comprises a swelling component within the capsule adjacent to the fill material.

[0040] In certain embodiments, the capsule further comprises an expandable component layered around the fill material.

[0041] In certain embodiments, the filler material is adjacent to the opening.

[0042] In certain embodiments, the osmotic gradient causes water to be imbibed through the shell composition, causing the swelling component to expand and force the active agent through the opening.

[0043] In certain embodiments, the shell composition further comprises a pore-forming agent. The pore-forming agent may be organic or inorganic and may comprise a substance that can be dissolved, extracted, or leached from the shell in the environment of use. The pore-forming agent may comprise a cellulose material (e.g., hydroxypropylmethylcellulose), a polyalkylene glycol (e.g., polyethylene glycol), povidone, or any combination thereof. In some embodiments, the pore-forming agent may include alkali metal salts such as sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, alkaline earth metals such as calcium chloride and calcium nitrate, carbohydrates such as sucrose, glucose, fructose, mannose, lactose, sorbitol, mannitol, and diols or polyols such as polyhydric alcohols, polyethylene glycol, and polyvinylpyrrolidone.

[0044] In certain embodiments, the pore-forming agent is soluble at a selected pH in the gastrointestinal system.

[0045] In certain embodiments, the osmotic pressure gradient causes water to be imbibed through the shell composition, causing the swelling component to expand and extrude the active agent through the pores formed by the dissolution of the pore-forming agent.

[0046] In certain embodiments, the film-forming material comprises gelatin.

[0047] In certain embodiments, the gelatin is cross-linked.

[0048] In certain embodiments, the degree of cross-linking controls the release rate of the active agent from the capsule.

[0049] In certain embodiments, gelatin is cross-linked with an aldehyde, such as a bifunctional aldehyde, a reducing sugar, or a divalent ion. In certain embodiments, gelatin is cross-linked with a divalent ion without the presence of an aldehyde. In certain embodiments, gelatin is cross-linked with a reducing sugar without the use of an aldehyde. In some embodiments, when gelatin is cross-linked with a reducing sugar, the reducing sugar may form an aldehyde. In certain embodiments, the aldehyde is formaldehyde.

[0050] In certain embodiments, crosslinking is incorporated into the shell composition during capsule manufacturing. For example, if an encapsulation machine is used to prepare the capsules, a crosslinking agent, such as a reducing sugar, can be incorporated into the encapsulation machine and mixed with the shell composition.

[0051] In certain embodiments, crosslinks are incorporated into the shell composition after the capsule is manufactured.

[0052] In certain embodiments, the difunctional aldehyde is formaldehyde.

[0053] In certain embodiments, the film-forming material may be a polymer. In some embodiments, the film-forming material may be an animal-derived polymer, a non-animal-derived polymer, or a combination thereof. In some embodiments, the animal-derived material may include gelatin. Gelatin may include, but is not limited to, type A gelatin, type B gelatin, skin gelatin, fish gelatin, porcine gelatin, and / or bone gelatin, alone or in combination. In some embodiments, the gelatin may be type A medium-to-high bloom gelatin. In some embodiments, the gelatin may be type B medium-to-high bloom gelatin. Medium bloom refers to a bloom of about 70 grams to about 160 grams. High bloom refers to a bloom of about 175 grams or greater, or about 175 grams to about 300 grams. In some embodiments, the gelatin may be 250 bloom gelatin. In other embodiments, there is only one type of gelatin. In yet other embodiments, there is a combination of at least two types of gelatin. The non-animal derived polymer may include carrageenan.

[0054] In some embodiments, the collapse-resistant material may be the same as the film-forming material. In some embodiments, the collapse-resistant material may be different from the film-forming material. In certain embodiments, the collapse-resistant material may include cross-linked gelatin as described herein.

[0055] In certain embodiments, the osmogen comprises a polyalkylene oxide, such as polyethylene oxide, an osmotic salt, such as sodium chloride or potassium chloride, or a sugar alcohol, such as xylitol or sorbitol, or a combination of any of the foregoing. In certain embodiments, the active agent can act as an osmogen. In some embodiments, the osmogen can include an inorganic salt, a carbohydrate, an osmotic salt, a polyalkylene oxide, or a combination thereof. In some embodiments, the osmogen may include polyethylene oxide, sodium chloride, fructose-3, potassium chloride, sucrose, xylitol, sorbitol, dextrose, citric acid, tartaric acid, mannitol, potassium sulfate, lactose, fumaric acid, adipic acid, lactose-fructose, dextrose-fructose, sucrose-fructose, mannitol-fructose, sodium chloride, fructose, lactose-sucrose, potassium chloride, lactose-dextrose, mannitol-dextrose, dextrose-sucrose, mannitol-sucrose, sucrose, mannitol-lactose, dextrose, potassium sulfate, mannitol, tribasic sodium phosphate-12H2O, dibasic sodium phosphate-12H2O, dibasic sodium phosphate-7H2O, monobasic sodium phosphate-H2O, dibasic sodium phosphate anhydrous, or combinations thereof.

[0056] In certain embodiments, the active agent is an analgesic, antihistamine, decongestant, antitussive, or antiepileptic.

[0057] In certain embodiments, the active agent is acetaminophen or dronabinol.

[0058] In certain embodiments, the capsules disclosed herein are contained within a device that allows entry into the capsule through an opening.

[0059] In certain embodiments, the capsule releases the active agent for at least 6 hours, at least 8 hours, at least 12 hours, or at least 24 hours after oral administration.

[0060] In certain embodiments, the present invention relates to a dispensing device comprising a plurality of capsules as disclosed herein and a piercing element capable of piercing an opening and entering the capsules.

[0061] In certain embodiments, the capsules are housed within the device in a carousel configuration. In certain embodiments, the device includes multiple capsules. In some embodiments, the device may include at least two capsules, at least four capsules, at least six capsules, or at least eight capsules. In some embodiments, the device may include 2-20 capsules, 4-18 capsules, 6-16 capsules, 8-14 capsules, or 10-12 capsules. In some embodiments, the device may include 2 capsules, 4 capsules, 6 capsules, 8 capsules, 10 capsules, 12 capsules, 14 capsules, or more capsules.

[0062] In certain embodiments, the dispensing devices disclosed herein include an actuator that, upon actuation, moves a piercing element from a first, disengaged position relative to the capsule to a second, engaged position with the capsule to create an opening. In some embodiments, the piercing element can include a stylus, drill, or needle. The piercing element can include various sizes depending on the desired pressure gradient and / or release rate for releasing the liquid fill composition.

[0063] In certain embodiments, upon actuation, the pierced capsule is expelled from the device for administration.

[0064] In certain embodiments, upon actuation, the proximal capsule advances to a first, disengaged position after penetrating the previous capsule.

[0065] In certain embodiments, upon actuation, the capsule advances to a first, disengaged position and then moves to a second, engaged position.

[0066] In certain embodiments, the present invention relates to a method of treating a disease or condition (e.g., pain, fever, or epilepsy) comprising forming an opening in a capsule as disclosed herein and administering the dosage form to a patient in need thereof.

[0067] In certain embodiments, the capsule is orally administered within 30 minutes, within 15 minutes, within 5 minutes, within 1 minute, within 30 seconds, or immediately after forming the opening.

[0068] In certain embodiments, the present invention relates to a method of treating a disease or condition comprising administering the capsules disclosed herein to a patient in need thereof.

[0069] In certain embodiments, the present invention relates to a method of preparing a capsule comprising laser drilling a hole in the capsule disclosed herein.

[0070] In certain embodiments, the method of preparing the capsule comprises piercing a hole or opening in the capsule using a stylus or needle.

[0071] A capsule having an opening or hole may be further sealed to close the hole or opening. The sealing may be performed by applying a piezoelectric spray to the capsule. In some embodiments, the sealing may be performed using other suitable methods to close the hole or opening. During this process, the hole or opening is plugged with a soluble plug. The soluble plug may include a material that dissolves in water. Thus, the capsule can be stored and does not need to be immediately given to a patient in need.

[0072] The method of preparation may further comprise coating the capsule with a soluble coating, which may be made from a material that dissolves in water.

[0073] The term "condition(s)" refers to medical conditions that can be treated or prevented by administering to a subject an effective amount of an active agent.

[0074] As used herein, the term "active ingredient" refers to any substance intended to produce a therapeutic, preventative, or other intended effect, regardless of whether it has been approved for that purpose by a governmental agency. This term, with reference to a particular agent, includes the pharmaceutically active agent and all pharmaceutically acceptable salts, solvates, and crystalline forms thereof, where the salts, solvates, and crystalline forms are pharmaceutically active.

[0075] For the purposes of the present invention, any pharmaceutically active ingredient may be used, including those that are water-soluble and those that are sparingly soluble in water. Suitable pharmaceutically active ingredients include, but are not limited to, analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterial agents, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarials, antimigraine agents, antimuscarinics, antineoplastic and immunosuppressive agents, antiprotozoal agents, antirheumatic agents, antithyroid agents, antiviral agents, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropes, corticosteroids, antitussives, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritionals, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and combinations thereof.

[0076] In some embodiments, the active pharmaceutical ingredient may be selected from the group consisting of, but not limited to, acetaminophen, dronabinol, dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurin, asimadoline, beclomethasone, apremilast, sapacitabine, linsitinib, abiraterone, vitamin D analogs (e.g., calcifediol, calcitriol, paricalcitol, doxercalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, pharmaceutically acceptable salts thereof, and combinations thereof.

[0077] According to certain embodiments, active agents may include, but are not limited to, lipid-lowering agents including statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), fibrates (e.g., clofibrate, ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil), niacin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof, mixtures of any of the foregoing, and the like.

[0078] Suitable dietary supplement active agents may include, but are not limited to, 5-hydroxytryptophan, acetyl L-carnitine, alpha-lipoic acid, alpha-ketoglutaric acid, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin 812), dimethylaminoethanol, fumaric acid, germanium dioxide, glandular products, glucosamine hydrochloride, glucosamine sulfate, hydroxymethylbutyrate, immunoglobulins, lactic acid, L-carnitine, liver products, malic acid, maltose anhydrous, mannose (d-mannose), methylsulfonylmethane, phytosterols, picolinic acid, pyruvic acid, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0079] Suitable dietary supplement active agents may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, or combinations thereof.

[0080] Suitable vitamin active agents may include, but are not limited to, ascorbic acid (vitamin C), vitamin B, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbates, mixed tocopherols, niacin (vitamin B3), orotic acid, para-aminobenzoic acid, pantothenate, pantothenic acid (vitamin B5), pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamine (vitamin B1), tocotrienols, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oils, and oil-soluble vitamins.

[0081] Suitable herbal supplement active ingredients may include, but are not limited to, arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginkgo biloba, ginseng, goldenrod, hawthorn, kava kava, licorice, milk thistle, psyllium, rauwolfia, senna, soy, St. John's wort, saw palmetto, turmeric, and valerian.

[0082] Examples of other possible active agents include, but are not limited to, antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, dexchlorpheniramine maleate), nonsteroidal anti-inflammatory drugs (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, pyroprofen, carprofen, oxaprozin, pramoprofen, muroprofen), and the like. (muroprofen), trioxaprofen, suprofen, aminoprofen, fluprofen, bucloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprine, azapropazone, benoline ralte, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, phythramine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicylate, sulindac, sulfonamide pyrazone, tenoxicam, tiaprofenic acid, tolmetin, pharmaceutically acceptable salts thereof and mixtures thereof, acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., phenyloin, meprobamate, nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem, nicardipine), antitussives and expectorants (e.g., codeine phosphate), antiasthmatics (e.g., theophylline), antacids, antispasmodics (e.g., atropine, scopolamine), antidiabetic agents (e.g.,insulin), diuretics (e.g., ethacrynic acid, bendrofluthiazide), antihypertensives (e.g., propranolol, clonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), anti-hemorrhoid drugs, hypnotics, psychotropic drugs, antidiarrheals, mucolytics, sedatives, decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine), cannabinoids, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof.

[0083] The active agent may be a benzodiazepine, a barbiturate, a stimulant, or a mixture thereof.The term "benzodiazepine" refers to benzodiazepines and drugs that are derivatives of benzodiazepines and can depress the central nervous system.Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures.Benzodiazepine antagonists that can be used as the active agent include, but are not limited to, flumazenil, and its pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0084] The term "barbiturates" refers to sedative-hypnotic drugs derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures. Barbiturate antagonists that can be used as active agents include, but are not limited to, amphetamine, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0085] The term "stimulant" includes, but is not limited to, amphetamines such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof. Stimulant antagonists that can be used as active agents include, but are not limited to, benzodiazepines, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0086] The dosage forms of the present disclosure include various active agents and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc., organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, etc., sulfonate, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc., amino acid salts such as alginate, aspartate, glutamate, etc., metal salts such as sodium salt, potassium salt, cesium salt, etc., alkaline earth metal salts such as calcium salt, magnesium salt, etc., organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

[0087] As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount or rate of administration of an active agent necessary to produce the desired therapeutic result.

[0088] As used herein, "shell" or "shell composition" refers to the shell of a softgel capsule that encloses the fill material.

[0089] Throughout the specification and claims, all references to weight percent refer to the weight of the component based on the weight of the total composition, which may also be designated w / w.

[0090] As used herein, "fill material" or "fill" refers to the composition enclosed in the capsule shell and comprising at least one pharmaceutically active ingredient.

[0091] As used herein, "about" refers to any value within a ±10% variance, e.g., "about 10" would include 9 to 11. As used herein, "a," "an," or "the" refers to one or more unless otherwise specified. Thus, for example, reference to an "excipient" includes a single excipient as well as a mixture of two or more different excipients, etc.

[0092] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each individual value falling within the range, unless otherwise indicated herein, and each individual value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0093] Any examples or use of exemplary language (e.g., "such as") provided herein are intended only to describe particular materials and methods and are not intended to be limiting in scope. No language provided herein should be construed as indicating any non-claimed element essential to the practice of the disclosed materials and methods.

[0094] In addition to osmogens, other suitable filler materials include flavoring agents, sweeteners, coloring agents, and fillers, or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides. Suitable amounts of pharmaceutically active ingredients and pharmaceutically acceptable excipients can be readily determined by one of ordinary skill in the art.

[0095] In one embodiment, the gelatin in the shell composition can include type A gelatin, type B gelatin, skin gelatin, and / or bone gelatin, alone or in combination. In one embodiment, the gelatin is 250 Bloom gelatin (a higher molecular weight gelatin that forms more crosslinks; Bloom does not necessarily correlate with molecular weight). In another embodiment, there is only one type of gelatin. In yet another embodiment, the gelatin is a combination of at least two types of gelatin. In one embodiment, the amount of gelatin in the shell composition is about 40% to about 80% by weight, more preferably about 45% to about 75% by weight, and most preferably about 50% to about 70% by weight.

[0096] In one embodiment, the capsule shell composition includes hydroxypropyl methylcellulose ("HPMC"). In one embodiment, the amount of cellulose derivative (e.g., methylcellulose or HPMC) in the capsule shell composition is about 0.15% to about 4.0% by weight, more preferably about 0.20% to about 2.0% by weight, and most preferably about 0.25% to about 1.4% by weight. In some embodiments, the capsule shell composition may include HPMC, methylcellulose (MC), hydroxypropyl cellulose (HPC), or a combination thereof. A cellulose derivative may be added to the capsule shell to mitigate potential loss of gel strength. The concentration of the cellulose derivative in the shell composition may be an amount effective to improve gel strength, but not so high as to interfere with sealing.

[0097] In some embodiments, the shell composition may include pectin, such as low-methoxy pectin. In one embodiment, the low-methoxy pectin may be LM pectin (P-25), LM pectin (445C), LM pectin (100C), or a combination thereof. The addition of pectin contributes to the properties of the dosage form. However, too much pectin in the dosage form may reduce the gel strength of the softgel capsule, which may adversely affect the sealability of the softgel capsule. Therefore, pectin can be added to the dosage form at a concentration high enough to form the dosage form, yet low enough to mitigate the loss of gel strength. In one embodiment, the amount of low-methoxy pectin in the shell composition is about 2% to about 20% by weight, about 3% to about 15% by weight, about 3% to about 5.5% by weight, and about 5% to about 10% by weight. The degree of esterification of the pectin incorporated into the shell composition may be less than about 50%, or may range from about 10% to about 50%, from about 20% to about 40%, or from about 25% to about 35%. In certain embodiments, pectin may be present in combination with an acrylic polymer (e.g., from about 10% to about 30%), such as N,N-dimethylaminoethyl methacrylate (Eudragit EPO®), including methyl methacrylate and butyl methacrylate. In such embodiments, the pectin prevents dissolution under acidic conditions, and the acrylic polymer prevents dissolution under basic conditions.

[0098] In one embodiment, the plasticizer in the shell composition may include glycerol, glycerin, sorbitol, and combinations thereof.Other suitable plasticizers may include, but are not limited to, sugar alcohol plasticizers such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, mannitol, or polyol plasticizers such as diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine, and mixtures thereof. Other exemplary plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single-block polymers, citrate ester-type plasticizers, and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0099] In one embodiment, the amount of plasticizer in the shell composition is from about 15% to about 40% by weight, more preferably from about 20% to about 35% by weight, and most preferably from about 25% to about 30% by weight.

[0100] In some embodiments, the shell composition may include a soluble layer in combination with an insoluble coating. In some embodiments, the shell composition includes an insoluble layer. In some embodiments, the shell composition may include a soluble layer in contact with a filler material, or the insoluble layer may be in contact with a filler material. In some embodiments, the soluble layer may include a soluble polymer and additional excipients as described herein. In some embodiments, the insoluble layer may include a disintegration-resistant material, a base-resistant material, or a combination thereof, and additional excipients as described herein.

[0101] In some embodiments, the capsules described herein may have an opening in the shell composition with either an insoluble layer or a soluble layer in combination with an insoluble coating. The capsule may then be exposed to water, whereby water is absorbed through the shell composition and the fill material may be released through the opening by osmotic pressure. In some embodiments, since an active agent, including an osmogen, is released through the opening at any sustained release rate, water may mix with the fill material and dilute the fill material present in the capsule. Note that, depending on the active agent, mixing of water with the fill material may be undesirable. Therefore, to avoid mixing with the fill material, a separate osmogen layer may be present in the capsule, acting as a piston to drive the fill material through the opening, as shown in Figures 3b and 3c.

[0102] In other embodiments, the shell composition may optionally include additional agents such as colorants, flavorants, sweeteners, fillers, antioxidants, diluents, pH adjusters, or other pharmaceutically acceptable excipients or additives such as synthetic dyes and mineral oxides.

[0103] Examples of suitable colorants may include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown. In certain embodiments, the color of the dosage form can indicate the contents contained therein (e.g., one or more active ingredients).

[0104] Examples of suitable flavoring agents may include, but are not limited to, "flavor extracts" obtained by extracting parts of raw animal or plant material, frequently using solvents such as ethanol or water, natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from whole plants, and the like.

[0105] Additional exemplary flavoring agents that may be included in the dosage form include, but are not limited to, breath freshening compounds such as menthol, spearmint, cinnamon, and the like, other flavors or fragrances (particularly those used for oral hygiene) such as coffee bean, fruit flavors (e.g., cherry, orange, grape, etc.), and actives used in tooth and mouth rinses such as quaternary ammonium bases. Flavor enhancers such as tartaric acid, citric acid, vanillin, and the like may be used to improve the flavor effect.

[0106] Exemplary sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof.Artificial sweeteners include, for example, acesulfame and its various salts such as potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salt (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts such as sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucralose, etc. (available as Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin, monoammonium glycyrrhizinate (sold under the trademark MagnaSweet®), Stevia rebaudiana (stevioside), natural high-intensity sweeteners such as Monk Fruit, and polyols such as sorbitol, mannitol, xylitol, and erythritol. Some flavors may also be used as cross-linking agents.

[0107] Encapsulation of the fill material may be accomplished by any conventional method, for example, rotary die encapsulation.

[0108] According to one embodiment, the softgel capsule is prepared by a process comprising the steps of: (a) preparing a fill material comprising at least one pharmaceutically active ingredient and an osmogen; and (b) encapsulating the fill material of step (a) in a semipermeable shell composition disclosed herein.

[0109] Referring now to FIG. 1, the progression of a liquid-filled capsule according to an embodiment 100 of the present disclosure is shown. As seen in block A of FIG. 1, a capsule 110 was prepared having a fill material and a shell composition. In some embodiments, the shell composition may include a film-forming material and / or a collapse-resistant material as described herein. The shell composition may include an insoluble or collapse-resistant material, or may be coated with a substance that provides this functionality. For example, a collapse-resistant shell may include cross-linked gelatin or other polymers, such as alginate or carrageenan. In some embodiments, the film-forming material may include a polymer, gelatin, or a combination thereof. In some embodiments, the fill material may be low-permeable, allowing water to migrate into the capsule. In some embodiments, the fill material may not be low-permeable, such as an oil, so that if water migrates into the capsule, the fill material is not diluted. If the fill material is not low-permeable, an osmogen is included in the fill material. Alternatively, a two-component fill system may be used within the capsule, with the fill material filled at one end and the osmogen at the other end. Thus, when pressure is applied, the osmogen can migrate through the capsule and force the fill material out of the capsule.

[0110] In Block B, a stylus 1085 is used to pierce the capsule. It is understood that the capsule may be pierced using another tool, such as a needle or laser. The stylus may be a variety of sizes depending on the targeted delivery of the dose. In some embodiments, the stylus may have a size of 15 gauge to about 25 gauge. In Block C, the stylus 105 is removed from the capsule 110 to create an opening 115 in the capsule. It is understood that the size of the opening 115 corresponds to the size of the stylus.

[0111] After piercing, capsule 110 is placed in water at block D. As seen in block E, when capsule 110 is placed in water, fill material 120 moves through the opening and out of the capsule. For example, water may enter the capsule interior, forcing fill material 120 out of capsule 110. Thus, a relatively constant period of delivery of fill material 102 occurs, gradually decreasing as the capsule contents become diluted.

[0112] FIG. 2 illustrates a dispensing system 200 according to an embodiment of the present disclosure. In FIG. 2, eight capsules 210 are loaded onto a carousel 215. The carousel 215 can be rotated to a position aligned with the stylus 205. The stylus 205 can be depressed, thereby piercing the capsules 210. The capsules 210 are then ejected from the carousel 215. It is believed that such a dispensing system 200 can provide a convenient means for delivering a continuous delivery system of a liquid-filled system. That is, the dispensing system 200 can also ensure proper use by patients.

[0113] 3a shows a cross section of a capsule 300 according to an embodiment of the present disclosure. Capsule 300 includes a fill material 315. Fill material 315 includes an osmogen. In some embodiments, the osmogen can include an inorganic salt, a carbohydrate, an osmotic salt, a polyalkylene oxide, or a combination thereof. In some embodiments, the osmogen may include polyethylene oxide, sodium chloride, fructose-3, potassium chloride, sucrose, xylitol, sorbitol, dextrose, citric acid, tartaric acid, mannitol, potassium sulfate, lactose, fumaric acid, adipic acid, lactose-fructose, dextrose-fructose, sucrose-fructose, mannitol-fructose, sodium chloride, fructose, lactose-sucrose, potassium chloride, lactose-dextrose, mannitol-dextrose, dextrose-sucrose, mannitol-sucrose, sucrose, mannitol-lactose, dextrose, potassium sulfate, mannitol, tribasic sodium phosphate-12H2O, dibasic sodium phosphate-12H2O, dibasic sodium phosphate-7H2O, monobasic sodium phosphate-H2O, dibasic sodium phosphate anhydrous, or combinations thereof. In some embodiments, the filler material further comprises an active agent as described herein.

[0114] Capsule 300 further includes a shell composition comprising a soluble shell 310 encapsulating fill material 315. Capsule 300 also includes an insoluble coating 305 in direct contact with soluble shell 310. It should be understood that there is no gap between insoluble coating 305 and soluble shell 310. In some embodiments, soluble shell 310 may include a polymer, gelatin, a plasticizer, pectin, dextrose, or a combination thereof. In some embodiments, the polymer may include hydroxymethylcellulose. In some embodiments, the pectin may include amidated pectin or non-amidated pectin. In some embodiments, the plasticizer may include glycerol, glycerin, sorbitol, polyethylene sorbitan monooleate, or a combination thereof. Other suitable plasticizers may include, but are not limited to, sugar alcohol plasticizers such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, mannitol, or polyol plasticizers such as diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine, and mixtures thereof. Other exemplary plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single-block polymers, citrate ester-type plasticizers, and triacetin.Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof. In another embodiment, soluble shell 310 may be absent, with only insoluble shell 305 present, and insoluble shell 305 encapsulating fill material 315.

[0115] In some embodiments, the insoluble coating may include a cross-linked gelatin as described herein. Cross-linked gelatin may be formed using a reducing sugar, an aldehyde, a divalent ion, or an amine polymer. An amine polymer, such as polylysine, may be cross-linked with gelatin in the presence of an aldehyde, such as formaldehyde. In some embodiments, gelatin may be cross-linked in the presence of a reducing sugar without the use of an aldehyde. In some embodiments, the insoluble coating may include a disintegration-resistant material as described herein.

[0116] Another embodiment of capsule 300 is shown in Figures 3b and 3c. In Figures 3b and 3c, the shell composition can include a soluble layer 310 in combination with an insoluble layer 305. In some embodiments, the shell composition includes only insoluble layer 305. In capsule 300 of Figures 3b and 3c, fill material 315 is prepared in combination with osmogen 320. When capsule 300 is exposed to water, pressure is created, causing osmogen 320 to push against fill material 315 and be released from capsule 300, as described throughout this disclosure.

[0117] Referring to FIG. 4, in block A, a liquid-filled capsule 405 is prepared having a fill material 410, which may be the fill material described with reference to FIG. 1 or any fill material described herein. The liquid-filled capsule 405 further includes a shell composition, which may be the shell composition described in connection with FIG. 1. Between blocks A and B, the liquid-filled capsule 405 is drilled to form a hole or opening 415 in the shell composition. The capsule 405 may be drilled using a laser, drill, stylus, or needle to form the opening 415. The opening 415 may be formed to have a diameter of about 600 μm to about 1 mm, about 700 μm to about 900 μm, or about 750 μm to about 850 μm. After the opening 415 is formed, it is sealed in block C using a plug 420. A piezoelectric spray is then applied to the capsule to seal the opening. The spray then forms the plug 420, allowing the capsule 405 to be stored until it is exposed to water. Capsule 405 is optionally further coated with an additional soluble coating 425 in block D. In some embodiments, liquid-filled capsule 405 may not receive the sealing stop of block C, but is coated with an additional soluble coating 425 in block D. Thus, capsule 405 can be plugged, coated, or both plugged and coated.

[0118] As understood herein, the term "covering" may be interchangeable with "coat" or "coating" and refers to an encapsulation layer around the capsule. In accordance with the present disclosure, the encapsulation layer or coating 425 is soluble. The coating 425 is in direct contact with the plug 420 and the shell composition of the capsule 405. Thus, the capsule 405 can be stored and then exposed to water, which will result in the slow release of the fill material as described herein. If the sealing step of Block C is not performed, the capsule is perforated to prevent excessive leakage before the capsule is covered, while the covering process of Block D is performed continuously. [Example]

[0119] Specific embodiments of the present invention will now be described with reference to the following examples, which should be understood to be for illustrative purposes only and should not be construed as limiting the scope of the present invention.

[0120] Example 1 Softgel capsules were prepared using a capsule shell comprising gelatin, sorbitol, sorbitan, glycerin, and water and a fill material comprising acetaminophen, povidone, polyethylene glycol 600, potassium acetate, and water.

[0121] Crosslinking of the shell composition was achieved by incubating the capsules in a glass desiccator equilibrated with 37% aqueous formaldehyde for 24 hours before placing them in a plate. 80 capsules were transferred to the desiccator and placed in a single layer on a plate. After 3, 6, 12, and 24 hours, 20 capsules were removed from the desiccator and placed in a 60 cc glass bottle with a cap.

[0122] Disintegration studies were performed by placing capsules from each crosslinked group in 800 ml of simulated gastric fluid (SGF, pH 1.6) preheated to 37.4°C. Acetaminophen (APAP) release was measured in real time using Pion FiberOptic technology. After 30 minutes, concentrated fasting simulated intestinal fluid (FaSSIF) was added to a final pH of approximately 6. Release was measured for 5 to 12 hours from the start of the experiment.

[0123] Figure 5 shows the release rate over time for uncrosslinked capsules, 12-hour crosslinked capsules without an opening, 12-hour crosslinked capsules with an opening pierced with an 18-gauge needle, and 12-hour crosslinked capsules with an opening pierced with a 21-gauge needle. As can be seen in Figure 5, the uncrosslinked capsules exhibited immediate release. The capsules with an opening formed with an 18-gauge needle that were crosslinked for 12 hours exhibited a continuous release profile. The capsules with an opening formed with a 21-gauge needle that were crosslinked for 12 hours exhibited a pulsatile release profile due to the small opening and high viscosity of the fill material. That is, internal pressure builds, a release pulse occurs, pressure is released, and then pressure rises again, generating a second pulse. The capsules crosslinked for 12 hours without a hole exhibited a buildup of internal pressure, followed by the capsule rupturing, creating a large hole, resulting in a continuous release profile.

[0124] In summary, the inventors believe that the release profile is influenced by the osmogen, water permeability (eg, cross-linking), aperture size, shell elasticity, and fill viscosity.

Claims

1. a liquid fill material comprising an osmogen and an active agent; and a semipermeable, collapse-resistant shell composition.

2. 10. The capsule of claim 1, wherein the shell comprises a film-forming material, a disintegration-resistant material, or a combination thereof.

3. The capsule of claim 2 , wherein the film-forming material and the collapse-resistant material are interdispersed.

4. 3. The capsule of claim 2, wherein the shell comprises an inner layer comprising the film-forming substance and an outer layer comprising the collapse-resistant material.

5. The capsule according to any one of claims 1 to 4, wherein the capsule is a hard capsule.

6. 6. The capsule of claim 5, wherein the capsule is a two-piece hard capsule.

7. The capsule according to any one of claims 1 to 4, wherein the capsule is a soft gel capsule.

8. 8. The capsule of any one of claims 1 to 7, wherein the semipermeable shell composition is permeable to the passage of water but impermeable to the passage of the active agent.

9. The capsule of any one of claims 1 to 8, wherein the semipermeable shell composition comprises at least one opening.

10. 10. The capsule of claim 9, wherein a pressure gradient is created by imbibing a fluid into the capsule through the shell composition, causing the active agent to be expelled through the opening.

11. 11. The capsule of claim 9 or 10, further comprising a soluble plug filling or covering the opening.

12. 12. The capsule of any of claims 9 to 11, further comprising an additional soluble coating covering the shell composition and the opening.

13. The capsule of any preceding claim, further comprising a swelling component within the capsule adjacent to the fill material.

14. The capsule of any one of claims 1 to 12, further comprising an expanding component layered around the fill material.

15. 14. The capsule of claim 13, wherein the fill material is adjacent to the opening.

16. 16. The capsule of claim 15, wherein an osmotic pressure gradient causes water to be imbibed through the shell composition, causing the swelling component to expand and forcing the active agent through the opening.

17. 10. The capsule of any preceding claim, wherein the shell composition further comprises a pore-forming agent.

18. 18. The capsule of claim 17, wherein the pore-forming agent is soluble at a selected pH in the gastrointestinal system.

19. 20. The capsule of claim 18, wherein an osmotic pressure gradient causes water to be imbibed through the shell composition, causing the swelling component to expand and extruding the active agent through pores formed by dissolution of the pore-forming agent.

20. 10. A capsule according to any preceding claim, wherein the film-forming material comprises gelatin.

21. 21. The capsule of claim 20, wherein the gelatin is cross-linked.

22. 10. The capsule of claim 1, wherein the shell comprises an enteric material and a base-resistant polymer.

23. 23. The capsule of claim 22, wherein the enteric material comprises pectin and the base-resistant polymer comprises Eudragit EPO.

24. 22. The capsule of claim 21, wherein the degree of cross-linking controls the release rate of the active agent from the capsule.

25. 22. The capsule of claim 21, wherein the gelatin is cross-linked with an aldehyde, a reducing sugar, a divalent ion, or an amine-containing polymer that cross-links with gelatin in the presence of an aldehyde.

26. 26. The capsule of claim 25, wherein the aldehyde is a difunctional aldehyde.

27. 26. The capsule of claim 25, wherein the amine-containing polymer comprises polylysine.

28. 26. The capsule of claim 25, wherein the crosslinks are incorporated into the shell composition during manufacture of the capsule.

29. 26. The capsule of claim 25, wherein the crosslinks are incorporated into the shell composition after the capsule is manufactured.

30. 26. The capsule of claim 25, wherein the aldehyde is formaldehyde.

31. 10. The capsule of any preceding claim, wherein the osmogen comprises a polyalkylene oxide, an osmotic salt, a sugar alcohol, or a combination of any of the foregoing.

32. 32. The capsule of claim 31, wherein the polyalkylene oxide comprises polyethylene oxide, the osmotic salt comprises sodium chloride or potassium chloride, and the sugar alcohol comprises xylitol or sorbitol.

33. The capsule of claim 1 , wherein the active agent is an osmogen.

34. 10. A capsule according to any preceding claim, wherein the active agent is an analgesic, antihistamine, decongestant, antitussive, or antiepileptic.

35. 30. The capsule of claim 29, wherein the active agent is acetaminophen or dronabinol.

36. A capsule according to any preceding claim, wherein the capsule is contained within a device capable of piercing an opening into the capsule.

37. 36. The capsule of any of claims 1-35, wherein the capsule releases the active agent for at least 6 hours, at least 8 hours, at least 12 hours, or at least 24 hours after oral administration.

38. A dispensing device comprising a plurality of capsules according to any one of claims 1 to 37 and a piercing element capable of piercing the capsules through openings.

39. 39. The dispensing device of claim 38, wherein the capsules are housed in a carousel configuration.

40. 40. The dispensing device of claim 38 or 39, further comprising an actuator that, when actuated, moves the piercing element from a first disengaged position relative to the capsule to a second engaged position with the capsule to create an opening.

41. 41. A dispensing device according to claim 40, wherein upon actuation, the pierced capsule is expelled from the device for dispensing.

42. 42. A dispensing device according to claim 40 or 41, wherein upon actuation, the proximal capsule advances to a first disengaged position after piercing the previous capsule.

43. 42. A dispensing device according to claim 40 or 41, wherein upon actuation the capsule advances to the first disengaged position and then moves to the second engaged position.

44. 10. A method of treating a disease or condition comprising forming an opening in the capsule of claim 1 and administering the dosage form to a patient in need thereof.

45. 45. The method of claim 44, wherein the capsule is orally administered within 30 minutes, within 15 minutes, within 5 minutes, within 1 minute, within 30 seconds, or immediately after forming the opening.

46. 38. A method of treating a disease or condition comprising administering to a patient in need thereof a capsule according to any one of claims 1 to 37.

47. A method of preparing a capsule comprising laser drilling a hole in a capsule according to any one of claims 1 to 37.

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