Permeable medicinal capsule

Abstract

Disclosed in certain embodiments is a capsule comprising: a liquid filling material comprising an osmogen and an active agent; and a semipermeable anti-disintegration shell composition.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 443,142, filed on February 3, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to capsules (eg, soft gels) comprising a liquid fill material comprising an osmogen and an active agent; and a semipermeable disintegration-resistant shell composition. Background Art

[0004] Capsules, particularly hard or soft gelatin capsules (or softgel capsules), offer dosage forms that are more readily accepted by patients because the capsules are easy to swallow and do not require flavoring to mask any unpleasant taste of the active agent. Softgel encapsulation of drugs further offers the potential to improve the bioavailability of the drug. For example, once the gelatin shell is ruptured, the active ingredient can be rapidly released in liquid form.

[0005] There are many osmotic delivery systems available today that work by applying osmotic pressure across a semipermeable membrane, forcing the active substance to be released from the device through pores or intentionally placed holes. These osmotic delivery systems can offer clinical benefits such as controlled release of the active agent, minimization of "peak and valley" fluctuations, reduced dosage, decreased dosing frequency, reduced side effects, and improved patient compliance.

[0006] 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

[0007] It is an object of certain embodiments of the present invention to provide an osmotic capsule capable of delivering a liquid payload.

[0008] It is an object of other embodiments of the present invention to provide methods of making the osmotic capsules disclosed herein.

[0009] It is an object of other embodiments of the present invention to provide methods of treating a disease or condition comprising orally administering to a patient in need thereof an osmotic capsule disclosed herein.

[0010] It is an object of other embodiments of the present invention to provide a device capable of piercing the osmotic capsule disclosed herein prior to ingestion by a patient.

[0011] One or more of the above and other objects can be achieved by the present invention, which, in certain embodiments, is directed to a capsule comprising a liquid fill material comprising an osmogen and an active agent; and a semipermeable, disintegration-resistant shell composition. In certain embodiments, the capsule has an orifice through the shell, which is formed during manufacture or by the patient or caregiver prior to administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 The processing of a liquid-filled capsule in an embodiment of the present invention is shown as it is pierced by a stylus and then the stylus is removed and the pierced capsule is placed in water.

[0013] Figure 2 A plurality of capsules in a piercing drug delivery device are shown in a carousel configuration.

[0014] Figures 3a-3c A cross-section of a capsule according to various embodiments of the present disclosure is shown.

[0015] Figure 4 The preparation of a liquid-filled capsule according to another embodiment of the present invention is shown.

[0016] Figure 5 The effects of the degree of cross-linking and pore size on the release profile are shown. DETAILED DESCRIPTION

[0017] The present invention improves upon the current state of the art by developing osmotic dosage forms capable of delivering liquid payloads. This combines the convenience of pharmaceutical capsules (e.g., soft gels) with the clinical benefits of osmotic dosage forms. In certain embodiments, the capsule shell is semipermeable to provide for the influx of water due to the presence of an osmogen in the liquid fill. The resulting pressure gradient allows the drug to escape from the capsule through an orifice and / or through pores formed in the shell and / or by controlled rupture of the capsule.

[0018] Certain embodiments of the present invention address the potential problem of filler material leaking from the orifice during transport and / or storage after capsule manufacture. In certain embodiments, the orifice is created by the patient or caregiver immediately prior to administration (e.g., with a stylus or by a device that pierces the capsule upon actuation). In other embodiments, the orifice is blocked or coated with a material during manufacture that erodes after administration, exposing the orifice to the fluid environment of the gastrointestinal tract. In some embodiments, the orifice can be created by piercing the capsule with a laser, stylus, or drill. The capsule orifice can then be sealed using a piezoelectric spray, which in turn blocks the orifice. In some embodiments, the capsule can be sealed using any suitable sealing method. The capsule can then be further coated with a soluble coating. In some embodiments, the orifice can be created by puncture and subsequently further coated with a soluble coating. In other embodiments, the orifice can be created by puncture but not sealed or coated.

[0019] In certain embodiments, the capsule shell is insoluble in the gastric and intestinal environment, or at least resists disintegration for a period of time required to deliver the proposed dose of the active agent. Therefore, in certain embodiments, the shell comprises an insoluble or disintegration-resistant material, or can be coated with a substance that provides such properties. The disintegration-resistant shell can also comprise cross-linked gelatin or other polymers, such as alginate or carrageenan. Such a cross-linking process can be carried out, for example, after the liquid filler is filled into the capsule, or by adding a cross-linking additive to the gel material before forming the capsule, whereby the cross-linking agent should have sufficient reaction time delay to allow encapsulation before excessive cross-linking (which would render the gel material unprocessable) occurs. In certain embodiments, in-line blending of the cross-linking agent with the gel material before casting onto the drum is one way to prepare the capsules disclosed herein. In certain embodiments, the insoluble or disintegration-resistant material can include an alkali-resistant polymer.

[0020] The rate of release of the active agent can be controlled by the composition of the fill, the composition of the shell, the size of the orifice, or a combination of any or all of these factors. In certain embodiments, the fill material is hypotonic, which results in water migrating into the capsule, thereby expelling the contents of the capsule through the orifice, resulting in a relatively constant period of active agent delivery that slowly tapers off as the contents of the capsule are diluted.

[0021] In certain embodiments, non-hypotonic filler materials (e.g., oils) can be modified by suspending compatible salts or including water-swellable materials. In such embodiments, the immiscible filler material will not be diluted when water migrates into the capsule interior.

[0022] 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 disintegration-resistant shell composition.

[0023] In certain embodiments, the shell comprises a film-forming substance and an anti-disintegration material. In certain embodiments, the shell comprises a film-forming substance, an anti-disintegration material, or a combination thereof. In certain embodiments, the film-forming substance and the anti-disintegration material may comprise the same component.

[0024] In certain embodiments, the film-forming material and the anti-disintegration material are dispersed with each other.

[0025] In certain embodiments, the shell comprises an inner layer and an outer layer, the inner layer comprising a film-forming substance and the outer layer comprising an anti-disintegration material. In certain embodiments, the inner layer can be understood as a soluble layer, and the outer layer can be understood as an insoluble layer.

[0026] In some embodiments, the anti-disintegration material may include gums, cellulose ethers, acrylic resins, protein-derived materials, waxes, shellac, and oils such as hydrogenated castor oil and hydrogenated vegetable oils. Other polymers include alkylcelluloses (e.g., ethylcellulose), acrylic and methacrylic acid polymers and copolymers; and cellulose ethers such as hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Other acrylic and methacrylic acid polymers and copolymers include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, ethyl acrylate, trimethylammoniumethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), alkylamine methacrylate copolymers, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polymethacrylates, polyacrylamides, poly(methacrylic anhydride), glycidyl methacrylate copolymers, and combinations thereof. Acrylic polymers that can be used as anti-disintegration materials include acrylic resins comprising copolymers synthesized from acrylic acid esters and methacrylic acid esters (e.g., copolymers of lower alkyl acrylates and lower alkyl methacrylates) containing approximately 0.02-0.03 moles of tri(lower alkyl)ammonium groups per mole of acrylic acid and methacrylic acid monomers used. An example of a suitable acrylic resin is the polymer manufactured by Rohm Pharma GmbH and sold under the trademark Eudragit® RS. Eudragit RS30D can be used. Eudragit® RS is a water-insoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM), and methyl methacrylate trimethylammonium chloride (TAM), wherein the molar ratio of TAM to the remaining components (EA and MM) is 1:40. Acrylic resins such as Eudragit® RS can be used in the form of an aqueous suspension.

[0027] In some embodiments, the anti-disintegration material may include a cellulose polymer selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate and cellulose triacetate. An example of an ethyl cellulose is ethyl cellulose having an ethoxy content of 44% to 55%. The ethyl cellulose may be used in the form of an alcoholic solution. In certain other embodiments, the hydrophobic material comprises polylactic acid, polyglycolic acid or a copolymer of polylactic acid and polyglycolic acid.

[0028] In certain embodiments, the anti-disintegration material may include a cellulosic polymer selected from the group consisting of cellulose ethers, cellulose esters, cellulose ester ethers, and cellulose. The cellulosic polymer may have a degree of substitution (DS) on the anhydroglucose units greater than 0 and up to 3 (inclusive). Representative materials include polymers selected from the group consisting of acylcellulose, diacylcellulose, triacylcellulose, cellulose acetate, cellulose diacetate, cellulose triacetate, alkanylate monocellulose, alkanylate dicellulose, alkanylate tricellulose, aroyl monocellulose, aroyl dicellulose, and aroyl tricellulose, alkenyl monocellulose, alkenyl dicellulose, and alkenyl tricellulose. Exemplary polymers include: cellulose acetate having a DS and an acetyl content of up to 21%; cellulose acetate having an acetyl content of up to 32% to 39.8%; cellulose acetate having a DS of 1 to 2 and an acetyl content of 21% to 35%; and cellulose acetate having a DS of 2 to 3 and an acetyl content of 35% to 44.8%.

[0029] Other cellulosic polymers include: cellulose propionate, which has a DS of 1.8, a propyl content of 39.2 to 45, and a hydroxyl content of 2.8% to 5.4%; cellulose acetate butyrate, which has a DS of 1.8, an acetyl content of 13% to 15%, and a butyryl content of 34% to 39%; cellulose acetate butyrate, which has an acetyl content of 2% to 29%, a butyryl content of 17% to 53%, and a hydroxyl content of 0.5% to 4.7%; triacylcelluloses with a DS of 2.9 to 3, such as cellulose triacetate, cellulose tripalanate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, and cellulose trioctanoate; diacylcelluloses with a DS of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose divalerate; and cellulose copolymers, such as cellulose acetate butyrate, cellulose acetate octanoate butyrate, and cellulose acetate propionate.

[0030] Additional cellulosic polymers useful as anti-disintegration materials include cellulose acetate dimethyl cellulose, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, and cellulose acetate dimethyl amino cellulose acetate.

[0031] In some embodiments, the anti-disintegration material and / or the film-forming material may include an osmopolymer. Examples of osmopolymers include, but are not limited to, poly(hydroxyalkyl methacrylate) 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 alcohol having a low acetate residue, cross-linked with glyoxal, formaldehyde or glutaraldehyde and a degree of polymerization of 200 to 30,000; a mixture of methylcellulose, cross-linked agar and carboxymethylcellulose; a mixture of hydroxypropyl methylcellulose and sodium carboxymethylcellulose; a mixture of hydroxypropyl ethylcellulose and sodium carboxymethylcellulose; sodium carboxymethylcellulose; potassium carboxymethylcellulose; a mixture of Water-insoluble, water-swellable copolymers formed from dispersions of finely divided copolymers of maleic anhydride and styrene, ethylene, propylene, butylene, or isobutylene, crosslinked with from 0.001 to about 0.5 moles of saturated crosslinker per mole of maleic anhydride / copolymer; water-swellable polymers of N-vinyl lactams; polyoxyethylene-polyoxypropylene gels; polyoxybutylene-polyethylene block copolymer gels; carob bean gum; polyacrylic acid gels; polyester gels; polyurea gels; polyether gels; polyamide gels; polypeptide gels; polyamino acid gels; polycellulose gels; polygum gels; and initially dry hydrogels that absorb and adsorb water that penetrates into glassy hydrogels and lowers their glass transition temperature.

[0032] Other examples of osmopolymers include, but are not limited to, the following: hydrogel-forming polymers, such as CARBOPOL® (Noveon, Inc., Cleveland Ohio), an acidic carboxy polymer, a polymer composed of acrylic acid cross-linked with polyallylsucrose, also known as carboxypolymethylene and carboxyvinyl polymers, having a molecular weight of 250,000 to 4,000,000; cynamer polyacrylamide; cross-linked water-swellable indene-maleic anhydride polymers; GOOD-RITE® (Noveon, Inc., Cleveland Ohio) polyacrylic acid, having a molecular weight of 80,000 to 200,000; POLYOX® (Union Carbide Chemicals & Plastics Technology Corporation, Danbury Conn.) polyethylene oxide polymers, having a molecular weight of 100,000 to 5,000,000 and higher; starch graft copolymers; acrylate polymer polysaccharides composed of condensed glucose units, such as diester cross-linked polydextrose; and the like.

[0033] Osmogeneous substances can include osmotic effective solutes. Osmogeneous solutes can include inorganic and organic compounds that can exhibit an osmotic pressure gradient across a semipermeable membrane when the osmotic delivery system is placed in a fluid environment. Osmogeneous effective solutes or osmogenes (i.e., non-volatile substances that are soluble in water and produce an osmotic gradient that drives osmotic influx of water) that can be used 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 substances.

[0034] Osmotic agents such as sodium chloride (NaCl) with suitable excipients (lubricants and binders, such as cellulose and povidone binders) and viscosity modifiers such as sodium carboxymethylcellulose or sodium polyacrylate are examples of preferred osmotic agents. Other osmotic agents that can be used as water-swelling agents include osmopolymers and osmogens and are described, for example, in U.S. Pat. No. 5,413,572.

[0035] In certain embodiments, the shell composition includes disintegration-resistant material in an amount of 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% or 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 herein.

[0036] In certain embodiments, the shell composition includes film-forming material in an amount of 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%, or 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 herein.

[0037] In certain embodiments, the capsule is a hard capsule, such as a two-section hard capsule.

[0038] In certain embodiments, the capsule is a soft gel capsule.

[0039] In certain embodiments, the semipermeable shell composition is permeable to and passes through water, and is impermeable to and passes through the active agent.

[0040] In certain embodiments, the semipermeable shell composition comprises at least one orifice. In certain embodiments, the semipermeable shell composition comprises one orifice, two orifices, three orifices, four orifices, or five orifices or more.

[0041] In certain embodiments, a pressure gradient is generated by drawing a fluid (e.g., water) into the capsule via the shell composition, which causes the active agent to be discharged from the orifice. The active agent is discharged from the orifice at a slow and steady rate through the fill composition of the capsule. In certain embodiments, if water passes through the shell composition to release the fill composition, the fill composition will be 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 orifice and the amount of the orifice present in the shell composition. In certain embodiments, the size of the orifice can be from about 600 μm to about 1 mm, from about 625 μm to about 975 μm, from about 650 μm to about 950 μm, from about 675 μm to about 925 μm, from about 700 μm to about 900 μm, from about 725 μm to about 875 μm, from about 750 μm to about 850 μm, or from about 775 μm to about 825 μm.

[0042] In certain embodiments, the capsule further comprises a soluble plug that fills or covers the orifice. The soluble plug filler can be made of a material that is soluble in water and dissolves when in contact with water.

[0043] In certain embodiments, the capsule further comprises an additional soluble coating covering the shell composition and the orifice.The additional soluble coating can be made of a material that is soluble in water and dissolves upon contact with water.

[0044] In certain embodiments, the capsule further comprises an expansion component adjacent to the fill material in the capsule.

[0045] In certain embodiments, the capsule further comprises a layered expansion component surrounding the fill material.

[0046] In certain embodiments, the filler material is adjacent to the aperture.

[0047] In certain embodiments, the osmotic gradient causes water to be drawn through the shell composition, thereby causing the swelling component to swell and expel the active agent through the orifice.

[0048] In certain embodiments, the shell composition further comprises a pore former. The pore former can be organic or inorganic and includes materials that can be dissolved, extracted, or leached from the shell in the environment of use. The pore former can include a cellulosic material, such as hydroxypropyl methylcellulose; a polyalkylene glycol, such as polyethylene glycol; povidone; or a combination of any of the foregoing. In some embodiments, the pore former can include an alkali metal salt, such as sodium chloride, sodium bromide, potassium chloride, potassium sulfate, or potassium phosphate; an alkaline earth metal, such as calcium chloride or calcium nitrate; a carbohydrate, such as sucrose, glucose, fructose, mannose, lactose, sorbitol, or mannitol; and a diol or polyol, such as a polyol, polyethylene glycol, or polyvinyl pyrrolidone.

[0049] In certain embodiments, the pore former is soluble at the selected pH of the gastrointestinal system.

[0050] In certain embodiments, the osmotic gradient causes water to be imbibed through the shell composition, thereby causing the swelling component to swell and expel the active agent through the pores formed by the dissolution of the pore former.

[0051] In certain embodiments, the film-forming substance comprises gelatin.

[0052] In certain embodiments, the gelatin is cross-linked.

[0053] In certain embodiments, the degree of cross-linking controls the rate of release of the active agent from the capsule.

[0054] In certain embodiments, gelatin is cross-linked with an aldehyde (e.g., a bifunctional aldehyde), a reducing sugar, or a divalent ion. In certain embodiments, gelatin is cross-linked with a divalent ion in the absence of an aldehyde. In certain embodiments, gelatin is cross-linked with a reducing sugar without the use of an aldehyde. In certain embodiments, when gelatin is cross-linked with a reducing sugar, the reducing sugar may subsequently form an aldehyde. In certain embodiments, the aldehyde is formaldehyde.

[0055] In certain embodiments, crosslinking is performed in the shell composition during the manufacture of the capsule. For example, when an encapsulation machine is used to prepare the capsules, a crosslinking agent (such as a reducing sugar) can be incorporated into the encapsulation machine to mix with the shell composition.

[0056] In certain embodiments, cross-linking is performed in the shell composition after manufacture of the capsule.

[0057] In certain embodiments, the difunctional aldehyde is formaldehyde.

[0058] In certain embodiments, the film-forming substance may be a polymer. In some embodiments, the film-forming substance may be a polymer of animal origin, a polymer of non-animal origin, or a combination thereof. In some embodiments, the animal origin may include gelatin. Gelatin may include, but is not limited to, type A gelatin, type B gelatin, animal hide gelatin, fish gelatin, porcine gelatin, and / or bone gelatin, used alone or in combination. In some embodiments, the gelatin is type A medium to high bloom gelatin. In some embodiments, the gelatin is type B medium to high bloom gelatin. Medium bloom is when the bloom is about 70 grams to about 160 grams. High bloom is when the bloom is about 175 grams or more, or about 175 grams to about 300 grams. In some embodiments, the gelatin may be 250 bloom gelatin. In another embodiment, there is one type of gelatin. In yet another embodiment, there is a combination of at least two types of gelatin. The non-animal origin polymer may include carrageenan.

[0059] In some embodiments, the anti-disintegration material can be the same as the film-forming material. In some embodiments, the anti-disintegration material can be different from the film-forming material. In certain embodiments, the anti-disintegration material can include cross-linked gelatin as described herein.

[0060] 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 serve 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, 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, trisodium phosphate-12H2O, disodium hydrogen phosphate-12H2O, disodium hydrogen phosphate-7H2O, sodium dihydrogen phosphate-H2O, disodium hydrogen phosphate anhydrous, or a combination thereof.

[0061] In certain embodiments, the active agent is an analgesic, antihistamine, decongestant, antitussive, or anti-epileptic agent.

[0062] In certain embodiments, the active agent is acetaminophen or dronabinol.

[0063] In certain embodiments, the capsules disclosed herein are contained within a device capable of puncturing an aperture in the capsule.

[0064] 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.

[0065] In certain embodiments, the present invention relates to a drug delivery device comprising a plurality of capsules disclosed herein and a piercing element capable of piercing an orifice in the capsules.

[0066] In certain embodiments, the capsules are contained in a device in a turntable configuration. In certain embodiments, the device comprises a plurality of capsules. In some embodiments, the device may comprise at least 2 capsules, at least 4 capsules, at least 6 capsules, or at least 8 capsules. In some embodiments, the device may comprise 2 to 20 capsules, 4 to 18 capsules, 6 to 16 capsules, 8 to 14 capsules, or 10 to 12 capsules. In some embodiments, the device may comprise 2 capsules, 4 capsules, 6 capsules, 8 capsules, 10 capsules, 12 capsules, 14 capsules, or more.

[0067] In certain embodiments, the drug delivery devices disclosed herein comprise an actuator that, upon actuation, moves a piercing element from a first, non-engaged position relative to the capsule to a second, engaged position engaged with the capsule to create an orifice. In some embodiments, the piercing element may comprise a stylus, a drill bit, or a needle. Piercing elements of various sizes may be included depending on the desired pressure gradient and / or release rate for releasing the liquid-filled composition.

[0068] In certain embodiments, upon actuation, the pierced capsule is ejected from the device for administration.

[0069] In certain embodiments, upon actuation, an adjacent capsule is advanced to a first, non-engaged position after a previous capsule has been pierced.

[0070] In certain embodiments, upon actuation, the capsule is advanced to a first, non-engaged position and subsequently moved to a second, engaged position.

[0071] In certain embodiments, the present invention is directed to a method of treating a disease or condition (eg, pain, fever, or epilepsy) comprising forming an orifice in a capsule as disclosed herein and administering the dosage form to a patient in need thereof.

[0072] 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 the orifice is formed.

[0073] In certain embodiments, the present invention relates to a method of treating a disease or condition comprising administering to a patient in need thereof a capsule as disclosed herein.

[0074] In certain embodiments, the present invention relates to a method of making a capsule comprising laser drilling holes in a capsule as disclosed herein.

[0075] In certain embodiments, the method of making a capsule includes puncturing a hole or orifice in the capsule using a stylus or needle.

[0076] Capsules with orifices or holes can be further sealed to block the holes or holes. Sealing can be performed by applying a piezoelectric spray to the capsule. In some embodiments, other suitable methods can be used to perform sealing to block the holes or holes. In the process, the holes or holes are then blocked with a soluble plug. The soluble plug can include a water-soluble material. Therefore, the capsule can be stored and does not need to be immediately administered to a patient in need.

[0077] The preparation method may further comprise coating the capsule in a soluble coating. The soluble coating may be made of a material that is soluble in water.

[0078] The term "condition" or "conditions" refers to those medical conditions that can be treated or prevented by administering to a subject an effective amount of an active agent.

[0079] As used herein, the term "active ingredient" refers to any material intended to produce a therapeutic, prophylactic or other desired effect, whether or not approved by a governmental agency for that purpose. This term with respect to a specific 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.

[0080] Any pharmaceutically active ingredient can be used for the purpose of the present invention, including those that are water-soluble and those that are poorly water-soluble. Suitable pharmaceutically active ingredients include, but are not limited to, analgesics and anti-inflammatories, antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigouts, antihypertensives, antimalarials, antimigraines, antimuscarinics, antitumors and immunosuppressants, antiprotozoals, antirheumatic agents, antithyroid agents, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropes, corticosteroids, cough suppressants, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, lipid-regulating agents, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritional agents, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants and combinations thereof.

[0081] In some embodiments, the active pharmaceutical ingredient can be selected from, but is not limited to, the group consisting of: acetaminophen, dronabinol, dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurine, asimadoline, beclomethasone, apremilast, sapacitabine, linsitinib, abiraterone, vitamin D analogs (e.g., calcifediol, calcitriol, paricalcitol, doxorcalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, pharmaceutically acceptable salts thereof, and combinations thereof.

[0082] According to certain embodiments, the active agent may include a lipid-lowering agent, including but not limited to statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), fibrates (e.g., clofibrate, ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil), niacin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof, mixtures of any of the foregoing, and the like.

[0083] Suitable nutraceutical actives can include, but are not limited to, 5-hydroxytryptophan, acetyl L-carnitine, alpha-lipoic acid, alpha-ketoglutarate, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetearyl alcohol, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), dimethylaminoethanol, fumaric acid, germanium sesquioxide, glandular products, glucosamine HCI, glucosamine sulfate, hydroxymethylbutyrate, immunoglobulins, lactic acid, L-carnitine, liver products, malic acid, anhydrous maltose, mannose (d-mannose), methylsulfonylmethane, phytosterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0084] Suitable nutritional supplement actives may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, or combinations thereof.

[0085] Suitable vitamin actives may include, but are not limited to, the following: ascorbic acid (vitamin C), B vitamins, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbate, 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.

[0086] Suitable herbal supplement actives may include, but are not limited to, the following: arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginkgo biloba, ginseng, goldenrod, hawthorn, kava-kava, licorice, milk thistle, plantain, rauwolfia, senna, soy, St. John's wort, saw palmetto, turmeric, and valerian.

[0087] Examples of other possible active agents include, but are not limited to, antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), nonsteroidal anti-inflammatory agents (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, pirprofen, carprofen, oxaprozin, pramoprofen, muroprofen, suprofen, aminoprofen, fluprofen, bucloxic acid), and steroids. acid), indomethacin, sulindac, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam,Aceclofenac, aloxiprin, azapropazone, benolate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid acid), metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofen acid, tolmetin, its pharmaceutically acceptable salts and mixtures thereof) and acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., phenyloin, meprobamine and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardipine), antitussives and expectorants (e.g., codeine phosphate), antiasthmatics (e.g., theophylline), antacids, antispasmodics (e.g., atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid),The present invention also includes but is not limited to: antihistamines, analgesics, narcotics, steroids, bendrofluthiazide, analgesics, steroids, antihistamines, steroids (e.g., hydrocortisone, triamcinolone, prednisone), analgesics, steroids (e.g., tetracycline), analgesics, narcotics, steroids, antidiarrheals, mucolytics, sedatives, decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine), and cannabinoids, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof.

[0088] The active agent may also be a benzodiazepine, a barbiturate, a stimulant, or a mixture thereof.The term "benzodiazepine" refers to benzodiazepines and drugs that are derivatives of benzodiazepines that are capable of depressing 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 pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Benzodiazepine antagonists that may be used as active agents include, but are not limited to, flumazenil, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0089] The term "barbiturate" refers to a sedative-hypnotic drug derived from barbituric acid (2,4,6-trioxohexidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists that can be used as active agents include, but are not limited to, amphetamine, and pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0090] The term "stimulant" includes, but is not limited to, amphetamines, such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, and 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 pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

[0091] The dosage forms according to the present disclosure include various active agents and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts, such as hydrochlorides, hydrobromides, sulfates, phosphates, etc.; organic acid salts, such as formates, acetates, trifluoroacetates, maleates, tartrates, etc.; sulfonates, such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.; amino acid salts, such as arginine salts, aspartate salts, glutamate salts, etc.; and metal salts, such as sodium salts, potassium salts, cesium salts, etc.; alkaline earth metals, such as calcium salts, magnesium salts, etc.; organic amine salts, such as triethylamine salts, pyridinium salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N′-dibenzylethylenediamine salts, etc.

[0092] As used herein, the terms "therapeutically effective" and "effective amount" refer to the amount of an active agent, or the rate of administration thereof, required to produce the desired therapeutic result.

[0093] As used herein, "shell" or "shell composition" refers to the softgel capsule shell that encapsulates the fill material.

[0094] All references to wt% throughout the specification and claims refer to the weight of the component relative to the weight of the entire composition and may also be specified as w / w.

[0095] As used herein, "fill material" or "fill" refers to the composition encapsulated by the capsule shell and containing at least one pharmaceutically active ingredient.

[0096] As used herein, "about" refers to any value within a variation of ± 10%, such that "about 10" would include 9 to 11. As used herein, unless otherwise specified, "a," "an," or "the" refers to one or more. Thus, for example, a reference to "an excipient" includes a single excipient as well as a mixture of two or more different excipients, etc.

[0097] Recitation of ranges of values ​​herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0098] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to illustrate the particular materials and methods and does not limit the scope. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods.

[0099] In addition to osmotic agents, other suitable filler materials include flavorings, sweeteners, coloring agents, and fillers or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides. One of ordinary skill in the art can readily determine the appropriate amounts of the pharmaceutically active ingredient and the pharmaceutically acceptable excipient.

[0100] In one embodiment, the gelatin in the shell composition may include type A gelatin, type B gelatin, animal hide gelatin and / or bone gelatin, used alone or in combination. In one embodiment, the gelatin is 250 bloom gelatin (a high molecular weight gelatin that forms more cross-links, bloom not necessarily related to 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 wt% to about 80 wt%, more preferably about 45 wt% to about 75 wt%, and most preferably about 50 wt% to about 70 wt%.

[0101] In one embodiment, the capsule shell composition comprises hydroxypropyl methylcellulose ("HPMC"). In one embodiment, the amount of the cellulose derivative (e.g., methylcellulose or HPMC) in the capsule shell composition is from about 0.15 wt% to about 4.0 wt%, more preferably from about 0.20 wt% to about 2.0 wt%, and most preferably from about 0.25 wt% to about 1.4 wt%. In some embodiments, the capsule shell composition may comprise HPMC, methylcellulose (MC), hydroxypropyl cellulose (HPC), or a combination thereof. A cellulose derivative may be added to the capsule shell to mitigate potential gel strength degradation. The concentration of the cellulose derivative in the shell composition may be an effective amount to enhance gel strength, but not so high as to interfere with sealing.

[0102] In some embodiments, the shell composition may include pectin, such as low-methoxyl pectin. In one embodiment, the low-methoxyl 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, excessive pectin in the dosage form may reduce the gel strength of the soft gel capsule, which in turn may adversely affect the sealability of the soft gel capsule. Therefore, pectin may be added to the dosage form at a concentration high enough to form the dosage form but low enough to mitigate the reduction in gel strength. In one embodiment, the amount of low-methoxyl pectin in the shell composition is from about 2 wt% to about 20 wt%, from about 3 wt% to about 15 wt%, from about 3 wt% to about 5.5 wt%, and from about 5 wt% to about 10 wt%. 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 can be present in combination with an acrylic polymer (e.g., about 10% to about 30%), such as N,N-dimethylaminoethyl methacrylate with methyl methacrylate and butyl methacrylate (Eudragit EPO®). In such embodiments, the pectin prevents dissolution under acidic conditions, and the acrylic polymer prevents dissolution under alkaline conditions.

[0103] In one embodiment, the plasticizer in the shell composition can include glycerol, glycerol, sorbitol and combinations thereof. Other suitable plasticizers can include, but are not limited to, sugar alcohol plasticizers, such as isomalt, maltitol, xylitol, erythritol, adonitol, galactitol, pentaerythritol or mannitol; or polyol plasticizers, such as diglycerol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycol at the most 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propylene glycol, 2-methyl-1,3-propylene glycol, trimethylolpropane, polyether polyol, ethanolamine; and mixtures thereof. Other exemplary plasticizers may also include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyl groups, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single-block polymers, citrate-type plasticizers, and triacetin. Such plasticizers may include 1,2-butanediol, 2,3-butanediol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitan 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.

[0104] In one embodiment, the amount of plasticizer in the shell composition is from about 15 wt % to about 40 wt %, more preferably from about 20 wt % to about 35 wt %, and most preferably from about 25 wt % to about 30 wt %.

[0105] In some embodiments, the shell composition may include a soluble layer and 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 the filler material, or an insoluble layer in contact with the filler material. In some embodiments, the soluble layer may include a soluble polymer and another excipient as described herein. In some embodiments, the insoluble layer may include an anti-disintegration material, an alkali-resistant material, or a combination thereof and another excipient as described herein.

[0106] In some embodiments, a capsule as described herein may include an orifice in a shell composition having an insoluble layer, or an orifice in a shell composition having a soluble layer and an insoluble coating. The capsule is then exposed to water so that water can be drawn through the shell composition and generate osmotic pressure to release the fill material through the orifice. In some embodiments, when an active agent, including an osmogen, is released through the orifice at a slow release rate, water can mix with the fill material to dilute the fill material present in the capsule. It should be noted that, depending on the active agent, it may be undesirable for water to mix with the fill material. Thus, as Figure 3band 3c As shown, to avoid mixing with the fill material, a separate osmotic layer may be present in the capsule and act as a piston to drive the fill material through the orifice.

[0107] In other embodiments the shell composition may optionally contain additional agents such as colorants, flavorings, sweeteners, fillers, antioxidants, diluents, pH adjusters or other pharmaceutically acceptable excipients or additives, such as synthetic dyes and mineral oxides.

[0108] Exemplary suitable colorants can 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 (e.g., one or more active ingredients) contained therein.

[0109] Exemplary suitable flavoring agents may include, but are not limited to, "flavor extracts" obtained by extracting a portion of a raw material (e.g., animal or plant material), typically by using a solvent such as ethanol or water; natural flavors obtained by extracting essential oils from flowers, fruits, roots, etc., or from the entire plant.

[0110] Other exemplary flavoring agents that may be in dosage form may include, but are not limited to, breath freshening compounds such as menthol, spearmint, and cinnamon; coffee beans; other flavorings or spices, such as fruit flavors (e.g., cherry, orange, grape, etc.), especially those used for oral hygiene, and active agents for tooth and oral cleaning, such as quaternary ammonium bases. The effect of the flavoring agents may be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, and the like.

[0111] Exemplary sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Artificial sweeteners include, for example, acesulfame and its various salts, such as the potassium salt (available as Sunett®); alitame; aspartame (available as NutraSweet® and Equal®); salts of aspartame-acesulfame (available as Twinsweet®); neohesperidin dihydrochalcone; naringin dihydrochalcone; dihydrochalcone compounds; neotame; sodium cyclamate; saccharin and its various salts, such as the sodium salt (available as Sweet'N Low®); stevia; chlorinated derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®); and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); stevia (steviosides), natural intense sweeteners (e.g., monk fruit), polyols (e.g., sorbitol, mannitol, xylitol, erythritol, etc.). Some flavoring agents may also serve as cross-linking agents.

[0112] The encapsulation of the filler material can be accomplished in any conventional manner. As an example, rotary mold encapsulation can be used.

[0113] According to one embodiment, a soft gel capsule is prepared by a method comprising the following steps: (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.

[0114] Referring now to the accompanying drawings, Figure 1 FIG. 1 shows a process 100 for processing a liquid-filled capsule according to one embodiment of the present disclosure. Figure 1As shown in Block A of FIG, a capsule 110 having a filler material and a shell composition is prepared. In some embodiments, the shell composition may include a film-forming material and / or an anti-disintegration material as described herein. The shell composition may include an insoluble or anti-disintegration material, or may be coated with a substance that provides such properties. For example, the anti-disintegration 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 filler material may be hypotonic, which allows water to migrate into the capsule. In some embodiments, the filler material may be non-hypotonic (e.g., oil), where the filler material is not diluted when water migrates into the capsule. When the filler material is non-hypotonic, an osmogen is included in the filler material. Alternatively, a two-component filling system may be used in the capsule, where one end is filled with the filler material and the other end is filled with the osmogen. Thus, when pressure is applied, the osmogen can move through the capsule, forcing the filler material out of the capsule.

[0115] In Block B, the capsule is pierced using a stylus 1085. It should be understood that the capsule can be pierced using various tools, such as a needle or a laser. The stylus can be of various sizes, depending on the desired dose delivery. In some embodiments, the stylus can have a size of 15 to about 25 gauge. In Block C, the stylus 105 is removed from the capsule 110 to form an orifice 115 in the capsule. It should be understood that the size of the orifice 115 corresponds to the size of the stylus.

[0116] After being pierced, capsule 110 is then placed in water in Block D. As can be seen in Block E, when capsule 110 is placed in water, filler material 120 migrates through the orifice to the exterior of the capsule. For example, water can enter the interior of the capsule, forcing filler material 120 out of capsule 110. Consequently, there is a relatively constant delivery period of filler material 102, which then slowly decreases as the capsule contents are diluted.

[0117] exist Figure 2 In FIG, a dispensing system 200 according to an embodiment of the present disclosure is shown. Figure 2 In the embodiment of the present invention, eight capsules 210 are loaded into a turntable 215. The turntable 215 can be rotated to align with the stylus 205. The stylus 205 can be pressed, and then the stylus 205 will pierce the capsule 210. The capsule 210 is then ejected from the turntable 215. It is believed that this type of dispensing system 200 can provide a convenient way to provide a continuous delivery system for liquid-filled systems. In other words, the dispensing system 200 can also ensure correct use by the patient.

[0118] exist Figure 3a, a cross-section of a capsule 300 according to an embodiment of the present disclosure is provided. Capsule 300 includes a filler material 315. Filler material 315 includes an osmogen. In some embodiments, the osmogen may 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, 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, trisodium phosphate-12H2O, disodium hydrogen phosphate-12H2O, disodium hydrogen phosphate-7H2O, sodium dihydrogen phosphate-H2O, disodium hydrogen phosphate anhydrous, or a combination thereof. In some embodiments, the filler material further includes an active agent as described herein.

[0119] The capsule 300 also includes a shell composition comprising a soluble shell 310 encapsulating a filler material 315. The capsule 300 also includes an insoluble coating 305 in direct contact with the soluble shell 310. It should be understood that there is no gap between the insoluble coating 305 and the soluble shell 310. In some embodiments, the soluble shell 310 may include a polymer, gelatin, a plasticizer, pectin, dextrose, or a combination thereof. In some embodiments, the polymer may include hydroxymethyl cellulose. In some embodiments, the pectin may include amidated pectin or non-amidated pectin. In some embodiments, the plasticizer may include glycerol, glycerol, 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, galactitol, pentaerythritol, or mannitol; or polyol plasticizers such as diglycerol, 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, ethanolamines; and mixtures thereof. Other exemplary plasticizers may also include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyl groups, ester plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single-block polymers, citrate plasticizers, and triacetin. Such plasticizers may include 1,2-butanediol, 2,3-butanediol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitan 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, and only insoluble shell 305 may be present, wherein insoluble shell 305 encapsulates filler material 315.

[0120] In some embodiments, the insoluble coating may include cross-linked gelatin as described herein. Cross-linked gelatin can be formed using reducing sugars, aldehydes, divalent ions, or amine polymers. Amine polymers (e.g., polylysine) can be cross-linked with gelatin in the presence of an aldehyde (e.g., formaldehyde). In some embodiments, gelatin can be cross-linked in the presence of a reducing sugar without the use of an aldehyde. In some embodiments, the insoluble coating may include an anti-disintegration material as described herein.

[0121] exist Figure 3b and 3c In , an alternative embodiment of the capsule 300 is provided. Figure 3b and 3cIn some embodiments, the shell composition may include a soluble layer 310 and an insoluble layer 305. In some embodiments, the shell composition includes only the insoluble layer 305. Figure 3b and 3c In the capsule 300, the filler material 315 is prepared in combination with an osmogen 320. As described throughout this disclosure, when the capsule 300 is exposed to water, pressure is generated, which causes the osmogen 320 to push the filler material 315 to be released from the capsule 300.

[0122] refer to Figure 4 In block A, a liquid-filled capsule 405 having a filling material 410 is prepared, which may be a reference Figure 1 The liquid-filled capsule 405 also includes a shell composition that can be a fill material described herein or any fill material described herein. Figure 1 The shell composition described above is formed in a manner similar to that described above. A liquid-filled capsule 405 is pierced between blocks A and B to form a hole or orifice 415 in the shell composition. A laser, drill, stylus, or needle can be used to pierce the capsule 405 to form orifice 415. Orifice 415 can be formed to have a diameter ranging from about 600 μm to about 1 mm, from about 700 μm to about 900 μm, or from about 750 μm to about 850 μm. After orifice 415 is formed, it is then sealed with a plug 420 in block C. To plug the orifice, a piezoelectric spray is applied to the capsule. Plug 420 is then sprayed, allowing the capsule 405 to be stored until exposed to water. In block D, the capsule 405 is optionally further coated in an additional soluble coating 425. In some embodiments, the liquid-filled capsule 405 may not undergo the sealing step of block C but will be coated in the additional soluble coating 425 of block D. Thus, the capsule 405 may be plugged, coated, or plugged and coated.

[0123] As understood herein, the term "enrobe" is interchangeable with "coat" or "coating" and refers to the encapsulating layer surrounding the capsule. According to the present disclosure, encapsulating layer or coating 425 is soluble. Coating 425 is in direct contact with stopper 420 and the shell composition of capsule 405. Therefore, as discussed herein, capsule 405 can be stored and subsequently exposed to water, which will slowly release the fill material. If the sealing step of Block C is not performed, the encapsulation process of Block D will be performed continuously as the capsule is pierced to prevent excessive leakage before the capsule is encapsulated.

[0124] Examples

[0125] Specific embodiments of the present invention will now be presented with reference to the following examples. It should be understood that these examples are disclosed only by way of illustration of the present invention and should not limit the scope of the present invention in any way.

[0126] Example 1

[0127] Soft gel capsules are prepared with a capsule shell comprising gelatin, sorbitol sorbitan, glycerol and water and a fill material comprising acetaminophen, povidone, polyethylene glycol 600, potassium acetate and water.

[0128] The shell composition was crosslinked by incubating the capsules in a glass desiccator that had been equilibrated with a 37% aqueous formaldehyde solution for 24 hours before placement of the capsules. 80 capsules were transferred to the desiccator and placed in a single layer on a plate. At 3, 6, 12, and 24 hours, 20 capsules were removed from the desiccator and placed in a 60-cc glass bottle with a lid.

[0129] Disintegration testing was performed on capsules from each cross-linked group placed 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 fiber optic 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.

[0130] Figure 5 The percentage release over time is shown for uncrosslinked capsules, 12-hour crosslinked capsules without orifices, 12-hour crosslinked capsules with orifices (pierced with an 18G needle), and 12-hour crosslinked capsules with orifices (pierced with a 21G needle). Figure 5 As shown, the uncrosslinked capsules exhibited immediate release. The crosslinked 12-hour capsules with an orifice formed with an 18-gauge needle exhibited a sustained release profile. The crosslinked 12-hour capsules with an orifice formed with a 21-gauge needle exhibited a pulsatile release profile due to their smaller orifice and higher viscosity fill material. Internal pressure buildup resulted in a release pulse to relieve the pressure, followed by another pressure buildup and a second pulse, and so on. The 12-hour crosslinked capsules without an orifice exhibited internal pressure buildup followed by capsule rupture, resulting in a macroporous and sustained release profile.

[0131] In summary, the inventors believe that the release profile will be affected by the osmogen, the degree of water permeability (e.g., cross-linking), pore size, shell elasticity, and filler viscosity.

Claims

1. A capsule comprising: a liquid fill material comprising an osmogen and an active agent; and Semipermeable disintegration-resistant shell composition.

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

3. The capsule according to claim 2, wherein the film-forming substance and the anti-disintegration material are dispersed with each other.

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

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

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

8. The capsule according to any one of claims 1 to 7, wherein the semipermeable shell composition is permeable to and passes through water and is impermeable to and passes through the active agent.

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

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

11. The capsule according to claim 9 or 10, further comprising a dissolvable plug filling or covering the orifice.

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

13. The capsule of any one of claims 1 to 12, further comprising a swelling component adjacent to the fill material in the capsule.

14. The capsule of any one of claims 1 to 12, further comprising a layered expansion component surrounding the fill material.

15. The capsule of claim 13, wherein the filler material is adjacent to the orifice.

16. The capsule of claim 15, wherein an osmotic gradient causes water to be imbibed through the shell composition, thereby causing the swelling component to swell and expel the active agent through the orifice.

17. The capsule of any one of the preceding claims, wherein the shell composition further comprises a pore former.

18. The capsule of claim 17, wherein the pore former is soluble at a selected pH of the gastrointestinal system.

19. The capsule of claim 18, wherein an osmotic gradient causes water to be imbibed through the shell composition, thereby causing the swelling component to swell and expel the active agent through pores formed by dissolution of the pore former.

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

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

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

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

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

25. 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 will cross-link the gelatin in the presence of an aldehyde.

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

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

28. The capsule of claim 25, wherein the cross-linking is performed in the shell composition during manufacture of the capsule.

29. The capsule of claim 25, wherein the cross-linking is performed in the shell composition after manufacturing the capsule.

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

31. 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. 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. The capsule of any one of the preceding claims, wherein the active agent is an analgesic, antihistamine, decongestant, antitussive, or antiepileptic.

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

36. The capsule according to any one of claims 1 to 35, wherein the capsule is contained within a device capable of puncturing an aperture in the capsule.

37. The capsule of any one of claims 1 to 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 drug delivery device comprising a plurality of capsules according to any one of claims 1 to 37 and a piercing element capable of piercing holes in the capsules.

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

40. The drug delivery device of claim 38 or 39, further comprising an actuator which, when actuated, moves the piercing element from a first, non-engaged position relative to the capsule to a second, engaged position engaged with the capsule to create the orifice.

41. The drug delivery device of claim 40, wherein upon actuation, the pierced capsule is ejected from the device for administration.

42. A drug delivery device according to claim 40 or 41, wherein upon actuation an adjacent capsule is advanced to the first non-engaged position after a previous capsule has been pierced.

43. A drug delivery device according to claim 40 or 41, wherein upon actuation the capsule is advanced to the first non-engaged position and subsequently moved to the second engaged position.

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

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 orifice.

46. ​​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 making a capsule comprising laser drilling a hole in the capsule according to any one of claims 1 to 37.

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