Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
  • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

• the present invention relates to the field of pharmaceutical dosage forms that are resistant to tampering and abuse. Specifically, the present invention is directed to an immediate release solid oral dosage form that is abuse deterrent, its methods of preparation and use.
• opioid analgesic may be more potent when administered parenterally as compared to the same dose administered orally.
• Some formulations can be tampered with to facilitate illicit use of the opioid therein.
• a pattern of such abuse of opioid dosage forms may develop if the dosage form is easy to abuse and/or if the abuser likes the high obtained from the abuse, which stimulates the abuser to take the dosage form again.
• gelling agents has been contemplated in order to deter the abuse potential of immediate release dosage forms containing a drug susceptible to abuse, such as an opioid analgesic.
• a drug susceptible to abuse such as an opioid analgesic.
• One form of abuse is via the crushing of a dosage form in order to liberate the drug contained therein for illicit use such as parenteral administration or through absorption across an external mucosal surface.
• a viscosity is obtained which inhibits the drug from being drawn into a needle, thereby hindering parenteral abuse.
• the crushed dosage form is applied to a mucosal surface (e.g., the nasal cavity)
• the composition forms a gel upon contact with mucosal moisture, thereby inhibiting absorption.
• One problem to overcome when incorporating a gelling agent into an immediate release dosage form is the extended release characteristics that such an agent may impart to the immediate release dosage form when included in sufficient amounts to inhibit tampering.
• an immediate release solid oral dosage form containing an active agent susceptible to abuse such as an opioid analgesic, that is resistant to parenteral and nasal abuse. More specifically, there exists a need for an immediate release formulation containing a gelling agent that will maintain its abuse deterrence upon tampering, while maintaining the immediate release nature the active agent susceptible to abuse upon proper administration of the formulation.
• an immediate release solid oral dosage form comprising an active agent susceptible to abuse (e.g., an opioid analgesic), which is tamper-resistant.
• an active agent susceptible to abuse e.g., an opioid analgesic
• an immediate release solid oral dosage form comprising an active agent susceptible to abuse (e.g., an opioid analgesic), which is subject to less parenteral abuse than other dosage forms.
• an active agent susceptible to abuse e.g., an opioid analgesic
• an immediate release solid oral dosage form comprising an active agent susceptible to abuse (e.g., an opioid analgesic), which is subject to less intranasal abuse than other dosage forms.
• an active agent susceptible to abuse e.g., an opioid analgesic
• an active agent susceptible to abuse e.g., an opioid analgesic
• a disease or condition e.g., pain
• an active agent susceptible to abuse e.g., an opioid analgesic
• the present invention which in certain embodiments is directed to a solid oral dosage form comprising an immediate release active agent (e.g., an opioid analgesic) composition and a delayed release gelling agent composition, wherein the solid oral dosage form is free of or substantially free of an extended release active agent composition.
• an immediate release active agent e.g., an opioid analgesic
• a delayed release gelling agent composition wherein the solid oral dosage form is free of or substantially free of an extended release active agent composition.
• the present invention is directed to an immediate release active agent (e.g., an opioid analgesic) composition and a delayed release gelling agent composition, wherein the solid oral dosage form is free of or substantially free of an extended release active agent composition, wherein the delayed release gelling agent composition comprises a gelling agent and an enteric material.
• the enteric material may dissolve at a pH of 5.5 or higher and not dissolve below a pH of 5.5.
• the ratio of the viscosity of a solution obtained from an intact solid oral dosage form at 5 minutes in about 5 ml water at room temperature to the viscosity of a solution obtained from an intact solid oral dosage form at 5 minutes in about 5 ml 0. IN HC1 at room temperature is about 10: 1 or more.
• the opioid analgesic in the immediate release solid oral dosage forms disclosed herein may be in the form of one or more particles.
• Each opioid analgesic particle may comprise (i) an inert core coated with the opioid analgesic, or (ii) the opioid analgesic dispersed in a matrix material.
• the delayed release gelling agent composition in the immediate release solid oral dosage forms disclosed herein may be in the form of one or more particles.
• Each delayed release gelling agent particle may comprise (i) the gelling agent coated with an enteric material, (ii) an inert core coated with a gelling agent and overcoated with the enteric material, or (iii) the gelling agent dispersed in an enteric matrix material.
• the opioid analgesic in the immediate release solid oral dosage forms disclosed herein may be coated on the one or more delayed release gelling agent particles.
• the one or more delayed release gelling agent particles in the immediate release solid oral dosage forms disclosed herein may be dispersed in a matrix (e.g., a matrix tablet) comprising an opioid analgesic.
• one or more delayed release gelling agent particles and one or more immediate release opioid particles are contained in a pharmaceutically acceptable capsule.
• tampering with the immediate release solid oral dosage forms disclosed herein imparts a viscosity that makes the dosage form unsuitable for parenteral administration.
• the recovery of the opioid analgesic from the immediate release solid oral dosage forms disclosed herein is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% based on a syringeability test whereby a crushed or intact solid oral dosage form is dissolved with 5 ml or 10 ml of solvent with agitation or without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• obj ects may be achieved by the present invention which in certain embodiments is directed to a process for preparing a solid oral dosage form comprising (i) preparing a delayed release gelling agent composition; (ii) blending the delayed release gelling agent composition with an active agent (e.g., opioid analgesic); and (iii) compressing the blend into a tablet.
• the process for preparing the immediate release solid oral dosage forms disclosed herein comprises enteric coating the gelling agent by a method selected from the group consisting of rotor powder layering, fluid bed granulation, roller compaction, fluid bed coating (Wurster coating), and combination thereof.
• the process for preparing the immediate release solid oral dosage forms disclosed herein may comprise (i) preparing one or more delayed release gelling agent particles; and (ii) coating the one or more delayed release gelling agent particles with an opioid analgesic, wherein the solid oral dosage form comprises an immediate release opioid analgesic composition, and wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition.
• the process for preparing the immediate release solid oral dosage forms disclosed herein may comprise containing one or more delayed release gelling agent particles and one or more immediate release opioid particles in a pharmaceutically acceptable capsule.
• the process for preparing the immediate release solid oral dosage forms disclosed herein may comprise (i) preparing one or more particles; (ii) coating the one or more particles with an opioid analgesic composition; and (iii) blending the one or more particles coated with opioid analgesic composition with a delayed release gelling agent composition, wherein the solid oral dosage form comprises an immediate release opioid analgesic composition, and wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition.
• the process for preparing the immediate release solid oral dosage forms disclosed herein may comprise (i) preparing one or more delayed release gelling agent particles; and (ii) dispersing an opioid analgesic composition and the one or more delayed release gelling agent particles in a matrix, wherein the solid oral dosage form comprises an immediate release opioid analgesic composition, and wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition.
• the present invention is directed to a method of treating a disease or condition (e.g., pain) comprising administering to a patient in need thereof an immediate release solid oral dosage form as disclosed herein.
• a disease or condition e.g., pain
• FIG. 1 presents a process flow diagram for the manufacture of a solid oral dosage form according to a non-limiting embodiment disclosed herein comprising rotor layered and enteric coated pellets.
• FIG. 2 presents a process flow diagram for the manufacture of a solid oral dosage form according to a non-limiting embodiment disclosed herein comprising top sprayed granules.
• FIG. 3 presents a process flow diagram for the manufacture of a solid oral dosage form according to a non-limiting embodiment disclosed herein comprising roller compacted and bottom sprayed granules.
• FIG. 4 presents a chart showing the Active Agent volume aspirated after a syringeability test performed on intact tablets in tap water at room temperature (Example 8).
• FIG. 5 presents a chart showing the Active Agent volume aspirated after a syringeability test performed on crushed and intact tablets in tap water at room temperature (Example 8).
• FIG. 6 presents a chart showing the percent assay of Active Agent aspirated after a syringeability test performed on intact tablets in tap water at room temperature (Example 8).
• FIG. 7 presents a chart showing the percent assay of Active Agent aspirated after a syringeability test performed on crushed vs. intact tablets in tap water at room temperature (Example 8).
• FIG. 8 presents the dissolution profiles for tablet formulations disclosed in Table 4 of Example 2, Table 9 of Example 4, and Table 16 of Example 7.
• FIG. 9 presents the dissolution profiles for tablet formulations disclosed in Tables 9 and 10 of Example 4.
• FIG. 10 presents the dissolution profiles for tablet formulations disclosed in Tables 4 and 5 of Example 2.
• FIG. 11 presents the dissolution profiles for tablet formulations disclosed in Tables 16 and 17 of Example 7.
• the invention is directed to a solid oral dosage form, which comprises an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form, wherein the solid oral dosage form is free of or substantially free of the opioid analgesic composition in an extended release form.
• the opioid analgesic is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, dihydrocodeine, dihydromorphine, oxymorphone, fentanyl, buprenorphine, pharmaceutically acceptable salts thereof, solvates thereof, prodrugs thereof, and mixtures thereof.
• the solid oral dosage form comprises a therapeutically effective amount of the opioid analgesic. In another embodiment, the solid oral dosage form comprises an analgesically effective amount of the opioid analgesic. In certain embodiments, the solid oral dosage form contains about 0.1% to about 80% (w/w), about 0.5% to about 30% (w/w), or about 1% to about 10% (w/w), of the opioid analgesic.
• the solid oral dosage form of the invention releases at least about 80% of the opioid analgesic within 30 minutes, as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0.1N HC1 at room temperature. Under certain circumstances, the solid oral dosage form releases at least about 85%, at least about 90%, or at least about 95% of the opioid analgesic within 30 minutes, as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0. IN HC1 at room temperature.
• the solid oral dosage form of the invention releases at least about 80% of the opioid analgesic within 45 minutes, as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0.1N HC1 at room temperature. Under certain circumstances, the solid oral dosage form releases at least about 85%, at least about 90%, or at least about 95% of the opioid analgesic within 45 minutes, as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0. IN HC1 at room temperature.
• the solid oral dosage form of the invention releases at least about 80% of the opioid analgesic within 60 minutes, as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0.1N HC1 at room temperature. Under certain circumstances, the solid oral dosage form releases at least about 85%, at least about 90%, or at least about 95% of the opioid analgesic within 60 minutes, as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0. IN HC1 at room temperature.
• the delayed release gelling agent composition in the solid oral dosage form of the invention comprises a gelling agent and an enteric material.
• the gelling agent can be, for example, starch, starch derivatives, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, attapulgites, bentonites, dextrins, alginates, carrageenan, gum tragacanth, gum acacia, guar gum, xanthan gum, pectin, gelatin, kaolin, cross linked polyacrylic acid, polyvinylpyrrolidone, polyethylene oxide, or polyvinyl alcohol, or mixtures thereof.
• the gelling agent in the solid oral dosage form of the invention is selected from the group consisting of polyethylene oxide, xanthan gum, cross linked polyacrylic acid, polysaccharides, and mixtures thereof.
• the gelling agent comprises a polymer.
• the polymer may comprise a polysaccharide (e.g., a microbial polysaccharide) and/or an anionic polymer in a neutral pH aqueous solution.
• a microbial polysaccharide is a xanthan gum.
• An example of the anionic polymer comprises a polyacrylic acid or a carbomer homopolymer.
• the gelling agent of the solid oral dosage form of the invention comprises xanthan gum and carbomer homopolymer.
• the solid oral dosage form of the invention contains from about 0.1 % to about 50%, from about 0.5% to about 20%, or from about 1% to about 10%, gelling agent (w/w).
• the invention provides a solid oral dosage form, with the viscosity of a solution obtained from an intact solid oral dosage form at 5 minutes in about 0.5 ml to about 10 ml water at room temperature being about 50 cP or more, about 75 cP or more, about 100 cP or more, or about 125 cP or more, wherein the viscosity is measured by a rotational viscometer.
• the viscosity of a solution obtained from a tampered solid oral dosage form at 2 minutes in about 0.5 ml to about 10 ml water at room temperature is about 50 cP or more, about 75 cP or more, about 100 cP or more, or about 125 cP or more, wherein the viscosity is measured by a rotational viscometer.
• IN HCl at room temperature is about 50 cP or less, about 40 cP or less, about 30 cP or less, about 20 cP or less, about 10 cP or less, about 5 cP or less, or about 2 cP or less, wherein the viscosity is measured by a rotational viscometer.
• IN HCl at room temperature is about 50 cP or less, about 40 cP or less, about 30 cP or less, about 20 cP or less, about 10 cP or less, about 5 cP or less, or about 2 cP or less, wherein the viscosity is measured by a rotational viscometer.
• the viscosity of a solution obtained from an intact solid oral dosage form at 5 minutes in about 0.5 ml to about 10 ml of 0.1N HCl at room temperature is within about 30%, about 20%, about 10%, or about 5% of the viscosity of a solution obtained from a tampered solid oral dosage form at 5 minutes in about 0.5 ml to about 10 ml of 0. IN HCl at room temperature, wherein the viscosity is measured by a rotational viscometer.
• the invention provides a solid oral dosage form, wherein the ratio of the viscosity of a solution obtained from an intact solid oral dosage form at 5 minutes in about 5 ml water at room temperature to the viscosity of a solution obtained from an intact solid oral dosage form at 5 minutes in about 5 ml 0. IN HCl at room temperature is about 10: 1 or more, about 15 : 1 or more, about 20: 1 or more, about 25: 1 or more, or about 30: 1 or more, wherein the viscosity is measured by a rotational viscometer.
• the invention provides a solid oral dosage form, wherein the opioid analgesic composition is in the form of one or more particles.
• Each opioid analgesic particle may comprise the opioid analgesic coated on an inert core.
• each opioid analgesic particle comprises the opioid analgesic dispersed in a matrix material.
• the invention provides a solid oral dosage form, wherein the delayed release gelling agent composition is in the form of one or more particles.
• Each delayed release gelling agent particle for example, contains (i) the gelling agent coated with the enteric material, (ii) an inert core coated with the gelling agent and overcoated with the enteric material, or (iii) the gelling agent dispersed in matrix material.
• One embodiment of the invention provides a solid oral dosage form, in which the one or more opioid analgesic particles and the one or more delayed release gelling agent particles are contained in a pharmaceutically acceptable capsule.
• the one or more opioid analgesic particles and the one or more delayed release gelling agent particles are compressed into a tablet.
• One embodiment of the invention provides a solid oral dosage form, in which the opioid analgesic composition is coated on the one or more delayed release gelling agent particles.
• the one or more delayed release gelling agent particles are dispersed in a matrix comprising the opioid analgesic composition.
• the delayed release gelling agent composition comprises a gelling agent and an enteric material, wherein the enteric material dissolves above a pH of about 5.5.
• the enteric material does not dissolve below a pH of about 5.5; for example, the enteric material dissolves above a pH of about 5.5 and does not dissolve below a pH of about 5.5.
• the enteric material in accordance to the invention includes, such as, a cellulosic material, an acrylic polymer, a methacrylic polymer, and a mixture thereof.
• the enteric material can be methacrylic acid/methyl methacrylate, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl acrylate/methyl methacrylate copolymers, shellac, hydroxypropyl methylcellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose trimellitate, cellulose acetate phthalates, polyvinyl acetate phthalates, or mixtures thereof.
• each particle may comprise from about 10% to about 30% (w/w), from about 12% to about 25% (w/w), from about 0.1 % to about 50% (w/w), from about 1 % to about 20% (w/w), or from about 2% to about 15% (w/w), enteric material.
• the invention provides a solid oral dosage form further comprising an aversive agent.
• the aversive agent can be, for example, an emetic, an antagonist, a bittering agent, an irritant, or a mixture thereof.
• the emetics for example, can be methyl cephaeline, cephaeline, emetine hydrochloride, psychotrine, O-methylps chotrine, emetamine, ipecamine, hydro-ipecamine, ipecacunhic acid, ipecac, or mixtures thereof.
• the antagonists that can be used in the invention include, such as, naltrexone, naloxone, nalmefene, cyclazacine, levall orphan, pharmaceutically acceptable salts thereof, solvates thereof, prodrugs thereof, and combinations thereof.
• the bittering agent that can be used includes, such as, flavor oils, flavoring aromatics, oleoresins, plant extracts, leaf extracts, flower extracts, fruit extracts, sucrose derivatives, chlorosucrose derivatives, quinine sulphate, denatonium benzoate, or mixtures thereof.
• the aversive agent is a bittering agent selected from the group consisting of spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitter almonds, menthol, and mixtures thereof.
• the bittering agent is extracted from a fruit selected from the group consisting of lemon, orange, lime, grapefruit, and mixtures thereof.
• the irritant that can be used as an aversive agent include, such as, a surfactant, capsaicin, capsaicin analog, and mixtures thereof.
• the capsaicin analog can be resiniferatoxin, tinyatoxin, heptanoylisobutylamide, heptanoyl guaiacylamide, an isobutyl amide, a guaiacylamide, dihydrocapsaicin, homovanillyl oetylester, nonanoyl vanillylamide, or mixtures thereof.
• the surfactant can be a poioxamer, a sorbitan monoester, a glyceryl monooleate, sodium lauryl sulfate, or combinations thereof.
• the solid oral dosage form of the invention contains from about 0.1% to about 30% (w/w), or from about 0.5% to about 20% (w/w), or from about 1% to about 10% (w/w), irritant.
• compositions of the invention provide a solid oral dosage form, which further comprises a pharmaceutically acceptable excipient.
• pharmaceutically acceptable excipients can be, for example, plasticizers, colorants, lubricants, fillers, thermal lubricants, antioxidants, buffering agents, disintegrants, binding agents, diluent, glidant, anti-adherants, sweeteners, chelating agents, flavorants, surfactants, solubilizers, stabilizers, hydrophilic polymers, hydrophobic polymers, waxes, lipophilic materials, absorption enhancers, preservative, absorbent, cross-linking agents, bioadhesive polymers, pore formers, osmotic agents, polycarboxylic acids or combinations thereof.
• the pharmaceutically acceptable excipient can be present at from about 0.1% to about 99% (w/w), or from about 10% to about 80% (w/w), or from about 15% to about 70% (w/w), of the solid oral dosage form.
• the filler in accordance with the invention can be lactose, dextrose, mannitol, microcrystalline cellulose, or a mixture thereof.
• the glidant comprises silicon dioxide.
• the lubricant comprises magnesium stearate.
• Certain embodiments of the solid oral dosage form of the invention contain a delayed release gelling agent composition, which comprise one or more of rotor layered and enteric coated pellets, top sprayed granules, roller compacted pellets, bottom sprayed granules, or combinations thereof.
• the solid oral dosage form of the invention can be in the form of a unitary dosage form, or in the form of a plurality of particles, which can be contained in a pharmaceutically acceptable capsule. Also, the solid oral dosage form can be in the form of a tablet.
• the weight ratio of opioid analgesic to gelling agent in the solid oral dosage form is from about 1 : 30 to about 30: 1, or from about 1 : 15 to about 15 : 1, or from about 1 : 10 to about 10: 1, or from about 1 : 8 to about 8: 1, or from about 1 :5 to about 5 : 1, or from about 1 :3 to about 3: 1 , or from about 1 : 1.5 to about 1.5: 1.
• the solid oral dosage form contains a gelling agent and an enteric material, wherein the weight ratio of the gelling agent to the enteric material is from about 1 :30 to about 30: 1, or from about 1 : 15 to about 15 : 1, or from about 1 : 10 to about 10: 1 , or from about 1 : 8 to about 8: 1, or from about 1 :3 to about 3 : 1, or from about 1 : 1.5 to about 1.5: 1.
• the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%.
• Another embodiment provides that, in a syringeability test during which an intact solid oral dosage form of the invention is dissolved with 5 ml of solvent without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle, the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%.
• the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%.
• Another embodiment provides that after a syringeability test during which an intact solid oral dosage form of the invention is dissolved with 10 ml of solvent without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle, the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%.
• Certain embodiments of the invention provide that, in a syringeability test when a crushed solid oral dosage form is dissolved with 5 ml of solvent with agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle, the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%.
• Another embodiment of the invention provides that, in a syringeability test when a crushed solid oral dosage form is dissolved with 10 ml of solvent with agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle, the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%.
• a further embodiment of the invention provide that, in a syringeability test when a crushed solid oral dosage form is dissolved with 5 ml of solvent without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle, the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%.
• Yet another embodiment of the invention provide that, in a syringeability test when a crushed solid oral dosage form is dissolved with 10 ml of solvent without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle, the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%.
• the viscosity of the solid oral dosage form when mixed with from about 0.5 ml to about 10 ml of water, makes the opioid analgesic unsuitable for parenteral administration. In other embodiments, the viscosity of the solid oral dosage form of the invention, when mixed with from about 0.5 ml to about 10 ml of water, makes the opioid analgesic unsuitable for intravenous administration.
• the delayed release gelling agent composition includes rotor layered and enteric coated pellets, which comprise from about 5% to about 35% (w/w), or from about 5% to about 15% (w/w), or from about 15% to about 25% (w/w), or from about 25% to about 35% (w/w), enteric material based on total weight of the delayed release gelling agent composition.
• rotor layered and enteric coated pellets comprise about 10% (w/w) enteric coat based on total weight of the delayed release gelling agent composition.
• the rotor layered and enteric coated pellets comprise about 30% (w/w) enteric coat based on total weight of the delayed release gelling agent composition.
• the invention is also drawn to a solid oral dosage form comprising a delayed release gelling agent composition, which comprises top spray granules, with about 90% to about 100% (specifically, about 95% to about 100%; or more specifically, about 99% to about 100%) of the top spray granules incorporated into the solid oral dosage form retained in one or more of a 100 mesh screen, a 200 mesh screen, and a pan.
• a delayed release gelling agent composition which comprises top spray granules, with about 90% to about 100% (specifically, about 95% to about 100%; or more specifically, about 99% to about 100%) of the top spray granules incorporated into the solid oral dosage form retained in one or more of a 100 mesh screen, a 200 mesh screen, and a pan.
• the invention is drawn to a solid oral dosage form comprising a delayed release gelling agent composition, which comprises top spray granules, with about 20% to about 50% (specifically, about 30% to about 45%) of the top spray granules incorporated into the solid oral dosage form being retained in a 100 mesh screen.
• a delayed release gelling agent composition which comprises top spray granules, with about 20% to about 50% (specifically, about 30% to about 45%) of the top spray granules incorporated into the solid oral dosage form being retained in a 100 mesh screen.
• a delayed release gelling agent composition which comprises top spray granules, with about 20% to about 50% (specifically, about 30% to about 45%) of the top spray granules incorporated into the solid oral dosage form being retained in a 100 mesh screen.
• the invention is drawn to a solid oral dosage form comprising a delayed release gelling agent composition, which comprises top spray granules, with about 20% to about 50% (specifically, about 30% to about 45%) of the top spray granules incorporated into the solid oral dosage form being retained in a 200 mesh screen.
• a delayed release gelling agent composition which comprises top spray granules, with about 20% to about 50% (specifically, about 30% to about 45%) of the top spray granules incorporated into the solid oral dosage form being retained in a 200 mesh screen.
• a delayed release gelling agent composition which comprises top spray granules, with about 20% to about 50% (specifically, about 30% to about 45%) of the top spray granules incorporated into the solid oral dosage form being retained in a 200 mesh screen.
• the delayed release gelling agent composition comprises top spray granules, with about 10% to about 30% (or about 15% to about 25%) of the top spray granules incorporated into the solid oral dosage form being retained after sifting through a 200 mesh screen. In one instance, about 20% of the top spray granules incorporated into the solid oral dosage form are retained after sifting through a 200 mesh screen.
• the delayed release gelling agent composition in the solid oral dosage form of the invention may comprise roller compacted pellets having a bulk density ranging from about 0.4 g/ml to about 0.6 g/ml. Alternatively, the roller compacted pellets may have a tapped density ranging from about 0.55 g/ml to about 0.65 g/ml.
• the solid oral dosage form of the invention can be in the form of a compressed tablet. Certain embodiments are drawn to a compressed tablet having a hardness of about 2 Kp to about 20 Kp, or of about 5 Kp to about 18 Kp.
• a solid oral dosage form of the invention has a disintegration time in water ranging from about 10 seconds to about 30 minutes, or has a disintegration time in water ranging from about 1 minute to about 10 minutes, or has a disintegration time in water ranging from about 10 seconds to about 2 minutes.
• a solid oral dosage form of the invention has a disintegration time in SGF ranging from about 10 seconds to about 30 minutes, or from about 1 minute to about 10 minutes, or from about 10 seconds to about 2 minutes.
• Another aspect of the invention provides a solid oral dosage form comprising an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form.
• the gelling agent composition comprises a gelling agent and an enteric material coating the gelling agent, wherein the solid oral dosage form releases at least about 85% of the opioid analgesic within 45 minutes as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0. IN HC1 at room temperature.
• a further aspect of the invention is drawn to a solid oral dosage form, which comprises an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form,
• solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form
• the gelling agent composition comprises a gelling agent and an enteric material
• enteric material dissolves above a pH of about 5.5 and does not dissolve below a pH of about 5.5.
• the invention is also drawn to a solid oral dosage form comprising an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form,
• the solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form
• the gelling agent composition comprises rotor layered and enteric coated pellets comprising about 10% (w/w) enteric material based on total weight of the pellets
• the recovery of the opioid analgesic is less than about 15% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 5 ml to about 10 ml of tap water without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• a separate aspect of the invention provides a solid oral dosage form comprising an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form,
• solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form
• the gelling agent composition comprises rotor layered and enteric coated pellets comprising about 10% (w/w) enteric material based on total weight of the pellets, and
• recovery of the opioid analgesic is less than about 5% based on a syringeability test during which an intact solid oral dosage form is dissolved with about 5 ml to about 10 ml of tap water with agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the invention further includes a solid oral dosage form comprising an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form,
• solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form
• the gelling agent composition comprises rotor layered and enteric coated pellets comprising about 30% (w/w) enteric material based on total weight of the pellets, and
• recovery of the opioid analgesic is less than about 20% based on a syringeability test in which an intact solid oral dosage form is dissolved with about 10 ml of tap water with or without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the invention is further drawn to a solid oral dosage form comprising an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form,
• the solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form
• the gelling agent composition comprises rotor layered and enteric coated pellets comprising about 30% (w/w) enteric material based on total weight of the pellets
• recovery of the opioid analgesic is less than about 10% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 5 ml of tap water without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• a further separate aspect of the invention provides a solid oral dosage form comprising an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form,
• solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form
• the gelling agent composition comprises rotor layered and enteric coated pellets comprising about 30% (w/w) enteric material based on total weight of the pellets, and
• recovery of the opioid analgesic is less than about 5% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 5 ml of tap water with agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the invention is drawn to a solid oral dosage form comprising an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form,
• solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form
• the gelling agent composition comprises top spray granules
• recovery of the opioid analgesic is less than about 2% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 5 ml to about 10 ml of tap water with or without agitation at room temperature and the resultant solution is aspirated with a
• the invention provides a solid oral dosage form comprising an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form,
• solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form
• the gelling agent composition comprises roller compacted and bottom sprayed granules, wherein the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 10%, or less than about 8% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 5 ml to about 10 ml of tap water with or without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• compositions in an immediate release form comprising an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form,
• solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form
• the gelling agent composition comprises rotor layered and enteric coated pellets comprising about 30% (w/w) enteric material based on total weight of the pellets, and
• the recovery of the opioid analgesic is less than about 15%, less than about 10%, or less than about 5%, based on a syringeability test in which a crushed solid oral dosage form is dissolved with about 10 ml of tap water with or without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the invention also includes a solid oral dosage form comprising an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form,
• solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form
• gelling agent composition comprises roller compacted and bottom sprayed granules
• the recovery of the opioid analgesic is less than about 30%, less than about 25%, or less than about 5%, based on a syringeability test in which a crushed solid oral dosage form is dissolved with about 10 ml of tap water with or without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• a solid oral dosage form of the invention in a certain embodiment, comprises an active agent composition in an immediate release form and a gelling agent composition in delayed release form, wherein the solid oral dosage form is free of or substantially free of an active agent composition in an extended release form.
• the active agent can be a drug selected from the group consisting of opioid agonists, tranquilizers, CNS depressants, CNS stimulants, sedative hypnotics, and mixtures thereof.
• the invention is also drawn to a method of treating a disease or condition through administering a solid oral dosage form of the invention.
• the solid oral dosage form is suitable for use in treating pain.
• the invention is also drawn to a process for preparing a solid oral dosage form as above discussed, which comprises steps, such as (i) preparing a delayed release gelling agent composition; (ii) blending the delayed release gelling agent composition with an active agent composition; and (iii) compressing the blend into a tablet.
• the preparing step comprises enteric coating a gelling agent, which can be performed by a method including such as, rotor powder layering, fluid bed granulation, roller compaction, fluid bed coating, and combination thereof.
• the solid oral dosage form of the invention can also be prepared by a process comprising (i) preparing one or more particles; (ii) coating the one or more particles with an opioid analgesic composition; and (iii) blending the one or more particles coated with opioid analgesic composition with a delayed release gelling agent composition, wherein the solid oral dosage form comprises an opioid analgesic composition in an immediate release form, and wherein the solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form.
• the process further comprises a step of (iv) compressing the blend into a tablet.
• the solid oral dosage form of the invention can also be prepared by a process comprising (i) preparing one or more delayed release gelling agent composition particles; and (ii) coating the one or more delayed release gelling agent particles with an opioid analgesic composition, wherein the solid oral dosage form comprises an opioid analgesic in an immediate release form, and wherein the solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form.
• the process further comprises a step of (iii) compressing the one or more coated particles into a tablet.
• the invention provides a process of preparing a solid oral dosage form above discussed, which comprises steps such as: (i) preparing one or more delayed release gelling agent particles; and (ii) dispersing an opioid analgesic composition and the one or more delayed release gelling agent particles in a matrix, wherein the solid oral dosage form comprises an opioid analgesic composition in an immediate release form, and wherein the solid oral dosage form is free of or substantially free of an opioid analgesic composition in an extended release form.
• an active agent susceptible to abuse includes a single active agent as well as a mixture of two or more different active agents
• gelling agent includes a single gelling agent as well as a mixture of two or more different gelling agents, and the like.
• the term "about” in connection with a measured quantity refers to the normal variations in that measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment.
• the term “about” includes the recited number ⁇ 10%, such that "about 10" would include from 9 to 11.
• the terms “abuse-deterrent” and “tamper-resistant” refer to dosage forms that provide at least some physical and/or chemical barriers such as deterrence or resistance to, for example, crushing, chewing, cutting, grating or grinding of the dosage form, or extraction of the opioid from the dosage form using common solvents (e.g., water, simulated biological media, alcohol or organic solvents), or any combination thereof.
• the dosage forms may include agonist/antagonist combinations to interfere with, reduce or defeat the euphoria associated with abuse.
• the dosage forms may deter or be resistant to abuse even if they do not fully prevent abuse.
• recovery means the amount of drug obtained from the resultant solution of a tampered dosage form (e.g., crushing and mixing in 5 mL solvent) upon aspiration with a needle, e.g., a 27gauge needle.
• a tampered dosage form e.g., crushing and mixing in 5 mL solvent
• active agent active ingredient
• pharmaceutical agent pharmaceutically acceptable salts thereof, complexes, stereoisomers, crystalline forms, co-crystals, ether, esters, hydrates, solvates, and mixtures thereof, where the form is pharmaceutically active.
• the terms "therapeutically effective” refers to the amount of drug or the rate of drug administration needed to produce a desired therapeutic result.
• prophylactically effective refers to the amount of drug or the rate of drug administration needed to produce a desired prophylactic result.
• analgesically effective amount refers to an amount of a drug sufficient to provide analgesia.
• stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with one or more chiral centers that are not mirror images of one another (diastereomers).
• enantiomer or “enantiomeric” refers to a molecule that is non- superimposable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction by a certain degree, and its mirror image rotates the plane of polarized light by the same degree but in the opposite direction.
• chiral center refers to a carbon atom to which four different groups are attached.
• racemic refers to a mixture of enantiomers.
• resolution refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
• patient refers to a subject, particularly a human, who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated.
• subject is inclusive of the definition of the term “patient” and does not exclude individuals who are otherwise healthy.
• “Pharmaceutically acceptable salts” include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; amino acid salts such as arginate, asparaginate, glutamate and the like; metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, discyclohexylamine salt, ⁇ , ⁇ '-dibenzylethylenediamine salt and the like.
• inorganic acid salts such
• ppm means "parts per million”.
• compression refers to a tableting process where the tablet or any other compressed dosage form is made by a process including blending the components of the formulation and compressing the blend to form the formulation.
• dition refers to those medical conditions that can be treated or prevented by administration to a subject of an effective amount of an active agent (such as an opioid analgesic or pharmaceutically acceptable salt thereof), such as acute and chronic pain, pulmonary edema, cough, diarrhea, inflammation or inflammatory disease, etc.
• an active agent such as an opioid analgesic or pharmaceutically acceptable salt thereof
• treatment of and “treating” includes the lessening of the severity of or cessation of a Condition, e.g., pain.
• treating or “treatment of may include inhibiting, for example decreasing, the overall frequency of episodes of pain.
• prevention of and preventing includes the avoidance of the onset of a Condition, e.g., pain.
• the term "free or substantially free of an extended release opioid analgesic composition” or “free or substantially free of an extended release active agent composition” or “free or substantially free of an opioid analgesic composition in an extended release form” or “free or substantially free of an active agent composition in an extended release form” refers to solid oral dosage forms in which about 15% or less, about 10% or less, about 5% or less, of the opioid analgesic or active agent in the solid oral dosage form is released in accordance with an extended release profile (where an extended release profile may refer, e.g., to the amount of active agent released at a time period of greater than 4 hours as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0. IN HC1 at room temperature).
• an extended release profile may refer, e.g., to the amount of active agent released at a time period of greater than 4 hours as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900
• extended release refers to an active agent that is released over a period of time, e.g., to provide a once daily or twice daily dosage form.
• extended release active agent composition active agent composition in an extended release form
• extended release active agent active agent in an extended release form
• delayed release gelling agent composition and “gelling agent composition in a delayed release form” are used interchangeably. These terms refer to the gelling agent being released after the occurrence of an event.
• the event may be the passage of time, a trigger such as change in pH, or any other comparable event as understood by one of ordinary skill in the art.
• release as used with respect to the gelling agent refers to at least a partial release of the gelling agent that causes an increase in viscosity.
• immediate release refers to the release of at least 85%, at least 90%, or at least 95% of an active agent in a time from of 5 minutes, 15 minutes, 30 minutes, 45 minutes or 60 minutes, as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0. IN HC1 at room temperature.
• immediate release active agent composition and “active agent composition in an immediate release form” are used interchangeably.
• immediate release opioid analgesic composition and “opioid analgesic composition in an immediate release form” are used interchangeably.
• Viscosity measurements disclosed herein can be measured using a rotational viscometer (e.g. a Brookfield RV viscometer available from Brookfield Engineering, Middleboro, Mass. USA or equivalent) with the spindle number that corresponds to the viscosity range to be measured (e.g., spindle numbers 1-7 for viscosities ranging between 100-160,000 cP). Viscosity measurements can be measured in accordance with the United States Pharmacopeia (USP) monograph for Carbomer Homopolymer (USP40-NF35) as recited in the August 1, 2017 version (which is hereby incorporated by reference), or a comparable method as understood by one with ordinary skill in the art.
• USP United States Pharmacopeia
• Syringeability tests as used herein refer to tablets that are tested for syringeability of liquid post dissolution using 5 mL and 10 mL tap water at room temperature. Tablets were tested in an intact and in a crushed form. The aspiration is performed over a duration of about 1-60 minutes in an iterative process with a 18, 22, 25, or 27 gauge needle. Aspirated volumes of water are noted and assayed for content of active agent aspirated.
• Disintegration tests refer to tablets that are tested for active agent released in 0.1 N HC1 and in water in accordance with the United States Pharmacopeia (USP) disintegration test procedure described in the official version of April 1, 2006 (which is hereby incorporated by reference).
• USP United States Pharmacopeia
• the "in-vitro dissolution test in a USP Apparatus 1 (#40 mesh basket)" is used in a slightly modified form, by equipping the USP Apparatus 1 basket with a retaining spring placed in the upper part of the basket (above the dosage form), to reduce the propensity of the tested dosage forms, once hydrated in the dissolution medium, to stick to the solid underside of the top of the basket or the base of the shaft.
• a passivized stainless steel 316 spring 1.5 -cm outside diameter and 2-cm length can be used.
• the present disclosure is related to immediate release solid oral dosage forms comprising an immediate release opioid analgesic composition and a delayed release gelling agent composition.
• the delayed release gelling agent composition does not interfere with the immediate release characteristics of the active agent when the dosage form is orally administered intact as directed.
• the delayed release gelling agent composition, the opioid analgesic, or both may be in a form of one or more particles.
• the delayed release gelling agent composition may be in a form of one or more particles dispersed in a matrix material comprising an opioid analgesic.
• the opioid analgesic composition may be in a form of one or more particles dispersed in a matrix material comprising the delayed release gelling agent composition.
• the delayed release gelling agent composition may be in the form of one or more particles and the opioid analgesic composition may be in the form of one or more particles such that the various kinds of particles are dispersed in a matrix material.
• the delayed release gelling agent composition may be in a form of one or more particles and the opioid analgesic composition may be coated onto the one or more delayed release gelling agent particles.
• the active agent composition is in the form of one or more particles
• the active agent e.g., opioid analgesic
• the active agent composition may be coated over an inert particle or bead core to form an active agent layer on each particle in the dosage form.
• the core of the particles may be formed from a delayed release gelling agent composition, an aversive agent, an excipient or any combination thereof.
• Active agents may be present in any one or more of the layers of the multiparticulates.
• the one or more opioid analgesic particles and the one or more delayed release gelling agent particles may be compressed into a tablet, or may be contained in a pharmaceutically acceptable capsule.
• One or more aversive agents may also be included in the dosage form.
• the aversive agent may be included in one or more particles, which may be combined in a dosage form including the delayed release gelling agent composition and active agent composition.
• the one or more aversive agents may be included in the delayed release gelling agent composition, or with the active agent composition, or with both compositions.
• the immediate release solid oral dosage forms may release the active agent in accordance with the immediate release dissolution profile when the dosage form is taken as intended.
• the delayed release gelling agent composition may be at least partially released to increase the viscosity of the tampered dosage form, making the active agent (e.g., opioid analgesic) composition unsuitable for parenteral (e.g., intravenous) administration.
• the immediate release profile may be altered, for example, by varying the formulation of the dosage form, such as by altering the matrix material, by altering the types and amounts of excipients added, by altering the type and amount of aversive agents added, by the inclusion of additional ingredients, by altering the method of manufacture, etc.
• the immediate release profile may be influenced by the inclusion of release-modifying agents, which may function as pore-formers, may be organic or inorganic, and may include materials that can be dissolved, extracted or leached from the dosage form in the environment of use.
• the pore-formers may include one or more hydrophilic materials such as hydroxypropylmethylcellulose, lactose, and mixtures of any of the foregoing.
• the dosage form may include a hydrophobic material, including, but is not limited to, digestible, long chain (Cs-Cso, especially C12-C40), substituted or unsubstituted hydrocarbons, such as natural or synthetic waxes (such as beeswax, glycowax, castor wax and carnauba wax), fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, including, but not limited to, fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon backbones.
• Cs-Cso especially C12-C40
• substituted or unsubstituted hydrocarbons such as natural or synthetic waxes (such as beeswax, glycowax,
• the dosage form may also contain suitable quantities of other pharmaceutically acceptable excipients, e.g., diluents, lubricants, binders, granulating aids, and glidants that are known to those of ordinary skill in the art.
• excipients e.g., diluents, lubricants, binders, granulating aids, and glidants that are known to those of ordinary skill in the art.
• the immediate release solid oral dosage forms may have a hardness of about 2 Kp to about 20 Kp, or about 5 Kp to about 18 Kp.
• the immediate release solid oral dosage form may be in any suitable form for administration.
• the dosage form may be in the form of compressed tablets, gelcaps, capsules, caplets, granules, lozenges, bulk powders, film, or extrudate.
• a tablet may have any suitable shape including, but not limited to, a round shape, caplet shape, or a troche shape.
• the entire dosage form, including any additional ingredients besides the active agent composition and delayed release gelling agent composition may be in the form of a unitary dosage form such as a tablet.
• the tablet may be prepared by compression to form a compressed tablet.
• the tablet core may include the active agent composition dispersed in one or more excipients and/or aversive agents.
• the tablet core may also be formed from multiparticulates as described above that are compressed into a tablet shape.
• the entire dosage form including any additional ingredients besides the active agent composition and delayed release gelling agent composition, may be in the form of a plurality of particles.
• the plurality of particles may be contained in a pharmaceutically acceptable capsule, such as a gelatin capsule.
• such tablets may be compressed, tablet triturates, sugar-coated, film-coated, multiply compressed, or multi-layered.
• the unit dose of a multiparticulate dosage form of the present invention may include without limitation, from about 2 to about 75 particles; from about 10 to about 50 particles; from about 15 to about 25 particles; or from about 10 to about 50 particles.
• a unit dose of an immediate release dosage form of the present invention may include without limitation, from about 50 to about 500 particles; from about 75 to about 350 particles; from about 100 to about 300 particles; or from about 150 to about 250 particles.
• the solid oral dosage form may include a therapeutically effective amount, an antitussive amount, or an analgesically effective amount of the active agent (e.g., opioid analgesic).
• the active agent e.g., opioid analgesic
• the solid oral dosage forms disclosed herein can provide an immediate release of the active agent.
• the solid oral dosage forms disclosed herein provide an immediate release of an opioid analgesic and are free of or substantially free of an extended release of the opioid analgesic.
• the solid oral dosage forms disclosed herein release at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the opioid analgesic within 15 minutes as measured by in- vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0. IN HC1 at about 37 °C.
• the solid oral dosage forms disclosed herein release at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the opioid analgesic within 30 minutes as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0. IN HC1 at 37 °C.
• the solid oral dosage forms disclosed herein release at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the opioid analgesic within 45 minutes as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0. IN HC1 at 37 °C.
• the solid oral dosage forms disclosed herein release at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the opioid analgesic within 60 minutes as measured by in-vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml 0. IN HC1 at room temperature.
• the solid oral dosage forms disclosed herein comprise a gelling agent composition in a delayed release form, wherein the gelling agent composition comprises a gelling agent and an enteric coating.
• the gelling agent composition may be prepared by a method selected from the group consisting of rotor powder layering, fluid bed granulation, roller compaction, fluid bed coating (wurster coating), and combination thereof.
• the immediate release solid oral dosage form disclosed herein comprises an immediate release opioid analgesic composition and a delayed release gelling agent composition, wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition, wherein the delayed release gelling agent composition comprises rotor layered and enteric coated pellets comprising about 10% (w/w) enteric material based on total weight of the pellets, and wherein the recovery of the opioid analgesic is less than about 15% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 5 ml to about 10 ml of tap water without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the immediate release solid oral dosage form disclosed herein comprises an immediate release opioid analgesic composition and a delayed release gelling agent composition, wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition, wherein the delayed release gelling agent composition comprises rotor layered and enteric coated pellets comprising about 10% (w/w) enteric material based on total weight of the pellets, and wherein the recovery of the opioid analgesic is less than about 5% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 5 ml to about 10 ml of tap water with agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the immediate release solid oral dosage form disclosed herein comprises an immediate release opioid analgesic composition and a delayed release gelling agent composition, wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition, wherein the delayed release gelling agent composition comprises rotor layered and enteric coated pellets comprising about 30% (w/w) enteric material based on total weight of the pellets, and wherein the recovery of the opioid analgesic is less than about 20% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 10 ml of tap water with or without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the immediate release solid oral dosage form disclosed herein comprises an immediate release opioid analgesic composition and a delayed release gelling agent composition, wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition, wherein the delayed release gelling agent composition comprises rotor layered and enteric coated pellets comprising about 30% (w/w) enteric material based on total weight of the pellets, and wherein the recovery of the opioid analgesic is less than about 10% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 5 ml of tap water without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the immediate release solid oral dosage form disclosed herein comprises an immediate release opioid analgesic composition and a delayed release gelling agent composition, wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition, wherein the delayed release gelling agent composition comprises rotor layered and enteric coated pellets comprising about 30% (w/w) enteric material based on total weight of the pellets, and wherein the recovery of the opioid analgesic is less than about 5% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 5 ml of tap water with agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the immediate release solid oral dosage form disclosed herein comprises an immediate release opioid analgesic composition and a delayed release gelling agent composition, wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition, wherein the delayed release gelling agent composition comprises top sprayed granules, and wherein the recovery of the opioid analgesic is less than about 2% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 5 ml to about 10 ml of tap water with or without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the immediate release solid oral dosage form disclosed herein comprises an immediate release opioid analgesic composition and a delayed release gelling agent composition, wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition, wherein the delayed release gelling agent composition comprises roller compacted and bottom sprayed (enteric coated) granules, wherein the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 10%, or less than about 8% based on a syringeability test whereby an intact solid oral dosage form is dissolved with about 5 ml to about 10 ml of tap water with or without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the immediate release solid oral dosage form disclosed herein comprises an immediate release opioid analgesic composition and a delayed release gelling agent composition, wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition, wherein the delayed release gelling agent composition comprises rotor granulated and enteric coated pellets comprising about 30% (w/w) enteric material based on total weight of the pellets, and wherein the recovery of the opioid analgesic is less than about 15%, less than about 10%, or less than about 5% based on a syringeability test whereby a crushed solid oral dosage form is dissolved with about 10 ml of tap water with or without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the immediate release solid oral dosage form disclosed herein comprises an immediate release opioid analgesic composition and a delayed release gelling agent particles, wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition, wherein the delayed release gelling agent composition comprises roller compacted and bottom sprayed (enteric coated) granules, and wherein the recovery of the opioid analgesic is less than about 30%, less than about 25%, or less than about 5% based on a syringeability test whereby a crushed solid oral dosage form is dissolved with about 10 ml of tap water with or without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the immediate release solid oral dosage forms according to the disclosure include various active agents and their pharmaceutically acceptable salts thereof.
• Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like, and metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, ⁇ , ⁇ '-d
• any of the following active agents can be used in the immediate release solid oral dosage forms disclosed herein: ACE inhibitors, adenohypophoseal hormones, adrenergic neuron blocking agents, adrenocortical steroids, inhibitors of the biosynthesis of adrenocortical steroids, alpha-adrenergic agonists, alpha- adrenergic antagonists, selective alpha-two-adrenergic agonists, analgesics, anti-pyretics, antiinflammatory agents, androgens, local and general anesthetics, anti-addictive agents, anti- androgens, anti-arrhythmic agents, anti-cholinergic agents, anti-cholinesterase agents, anticoagulants, anti-diuretic, anti-emetic agents, pro-kinetic agents, anti-estrogens, anti-fungal agents, anti-microbial agents, anti-migraine agents, anti-muscarinic agents, anti -neoplastic agents, anti
• the active agent for the immediate release solid oral dosage forms disclosed herein is an active agent susceptible to abuse.
• the active agent may be selected from the group consisting of opioid agonists, tranquilizers, CNS depressants, CNS stimulants, sedative hypnotics, and mixtures thereof.
• active agents may include an opioid analgesic.
• opioid analgesics for the immediate release solid oral dosage forms disclosed herein include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives,
• the opioid analgesic for the immediate release solid oral dosage forms disclosed herein may be selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, dihydrocodeine, dihydromorphine, oxymorphone, fentanyl, buprenorphine pharmaceutically acceptable salts thereof, solvates thereof, prodrugs thereof, and mixtures thereof.
• antihistamines e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate
• non-steroidal anti-inflammatory agents e.g., aspirin, celecoxib, Cox-2 inhibitors, ibuprofen, indomethacin, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetaci
• anti-asthmatics e.g. theophylline
• antacids e.g. theophylline
• anti-spasmodics e.g. atropine, scopolamine
• antidiabetics e.g., insulin
• diuretics e.g., ethacrynic acid, bendrofluthiazide
• anti- hypotensives e.g., propranolol, clonidine
• antihypertensives e.g., clonidine, methyldopa
• bronchodilatiors e.g., albuterol
• steroids e.g., hydrocortisone, triamcinolone, prednisone
• antibiotics e.g., tetracycline
• antihemorrhoidals hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants (e.g
• the active agent that may also be a benzodiazepine, barbiturate, stimulants, or mixtures thereof.
• benzodiazepines refers to a benzodiazepine and drugs that are derivatives of a benzodiazepine that are able to 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 as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and mixtures thereof.
• Benzodiazepine antagonists that can be used as active agent include, but are not limited to, flumazenil as well as pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.
• 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 as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof.
• Barbiturate antagonists that can be used as active agent include, but are not limited to, amphetamines as well as pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.
• stimulants includes, but is not limited to, amphetamines such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, as well as pharmaceutically acceptable salts, hydrates, and solvates and mixtures thereof.
• Stimulant antagonists that can be used as active agent include, but are not limited to, benzodiazepines, as well as pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.
• the immediate release solid oral dosage forms disclosed herein may comprise from about 0.1 %, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, or about 7% to about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, or about 80% (w/w) active agent (e.g., opioid analgesic) per dosage form.
• active agent e.g., opioid analgesic
• the immediate release solid oral dosage forms disclosed herein may comprise from about 0.1% to about 80%, from about 0.5% to about 30%, or from about 1% to about 10% (w/w) of an active agent (e.g., opioid analgesic) per dosage form.
• an active agent e.g., opioid analgesic
• the delayed release gelling agent composition disclosed herein may comprise a gelling agent and an enteric material.
• the delayed release gelling agent composition may be in a form of one or more particles.
• Each delayed release gelling agent particle may comprise (i) the gelling agent coated with an enteric material, (ii) an inert core (e.g., bead) coated with the gelling agent and overcoated with an enteric material, or (iii) the gelling agent dispersed in an enteric matrix material.
• the dosage form in addition to the delayed release gelling agent composition, may include an amount of gelling agent in immediate release form that does not interfere with the immediate release characteristics of the dosage form.
• the gelling agent used in the immediate release solid oral dosage forms disclosed herein may include, but not be limited to, selected from, starch and starch derivatives, cellulose derivatives (e.g., sodium carboxymethyl cellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), attapulgites, bentonites, dextrins, alginates, carrageenan, gums (e.g., gum tragacanth, gum acacia, guar gum, and xanthan gum), pectin, gelatin, kaolin, high molecular weight polymer of acrylic acid cross- linked with allyl ethers of polyalcohols such as carbomers (also referred to as crosslinked polyacrylic acid), polyvinylpyrrolidone, polyethylene oxide, polyvinyl alcohol, curdlan, furcelleran, egg white powder, lacto albumin, soy protein, chitosan, surfactants, mixed surfactant
• the gelling agent may be selected from the group consisting of polyethylene oxide, xanthan gum, carbomers, polysaccharides, and mixtures thereof.
• the gelling agent may be a polymer (e.g., a gelling polymer), such as a polysaccharide, specifically a microbial polysaccharide such as xanthan gum.
• the gelling agent may be an anionic polymer in a neutral pH aqueous solution such as a polyacrylic acid, specifically a carbomer homopolymer.
• the gelling agent may be xanthan gum and a carbomer homopolymer.
• the gelling agent may be included in the immediate release solid oral dosage forms in an amount such that the viscosity of the dosage form mixed (crushed or intact) with from about 0.5 ml to about 10 ml of tap water at room temperature prevents or reduces the ability of the active agent (e.g., opioid analgesic) from being drawn up into a syringe, or from being systemically absorbed when administered by parenteral or nasal route.
• the viscosity of the tampered dosage form may make the dosage form unsuitable for parenteral or intravenous administration.
• the viscosity (e.g., measured from a rotational viscometer) of a solution obtained from an intact solid oral dosage form at 5 minutes in about 0.5 ml to about 10 ml water at room temperature is about 10 cP or more, about 25 cP or more, about 50 cP or more, about 75 cP or more, about 100 cP or more, about 125 cP or more to about 150 cP or more, about 175 cP or more, about 200 cP or more, about 300 cP or more, about 400 cP or more, about 500 cP or more, about 750 cP or more, about 1000 cP or more, about 2000 cP or more, about 3000 cP or more, about 4000 cP or more, about 5000 cP or more, about 7500 cP or more, about 10,000 cP or more, about 15,000 cP or more, about 20,000 cP or more, about 25,000 cP or more, about
• the viscosity (e.g., measured from a rotational viscometer) of a solution obtained from an intact solid oral dosage form at 5 minutes in about 0.5 ml to about 10 ml water at room temperature may be in the range of about 10-150,000 cP, about 25-10,000 cP, about 25-1000 cP, about 50-1000 cP, about 75-1000 cP, about 25-500 cP, about 50-500 cP, about 75-500 cP, about 25-200 cP, about 50-200 cP, or about 75-200 cP.
• the viscosity of a solution obtained from a tampered solid oral dosage form at 2 minutes in about 0.5 ml to about 10 ml water at room temperature is about 10 cP or more, about 25 cP or more, about 50 cP or more, about 75 cP or more, about 100 cP or more, or about 125 cP or more about 150 cP or more, about 175 cP or more, about 200 cP or more, about 300 cP or more, about 400 cP or more, about 500 cP or more, about 750 cP or more, about 1000 cP or more, about 2000 cP or more, about 3000 cP or more, about 4000 cP or more, about 5000 cP or more, about 7500 cP or more, about 10,000 cP or more, about 15,000 cP or more, about 20,000 cP or more, about 25,000 cP or more, about 50,000 cP or more, about 75,000 cP
• the viscosity obtained from an intact solid oral dosage form at 5 minutes in about 0.5 ml to about 10 ml 0. IN HCl at room temperature is about 50 cP or less, about 40 cP or less, about 30 cP or less, about 20 cP or less, about 10 cP or less, about 5 cP or less, or about 2 cP or less.
• the viscosity obtained from a tampered solid oral dosage form at 5 minutes in about 0.5 ml to about 10 ml 0. IN HCl at room temperature is 50 cP or less, about 40 cP or less, about 30 cP or less, about 20 cP or less, about 10 cP or less, about 5 cP or less, or about 2 cP or less.
• the viscosity of a solution obtained from an intact solid oral dosage form at 5 minutes in about 0.5 ml to about 10 ml of 0. IN HCl at room temperature is within about 30%, about 20%, about 10%, or about 5% of the viscosity of a solution obtained from a tampered solid oral dosage form at 5 minutes in about 0.5 ml to about 10 ml of 0. IN HCl at room temperature.
• the weight amount of gelling agent contained in the immediate release dosage form of the present invention is not more than the weight amount of active agent (e.g., opioid analgesic). In other embodiments, the weight amount of gelling agent contained in the immediate release dosage forms of the present invention is less than the weight amount of active agent. In further embodiments, the weight amount of gelling agent contained in the immediate release dosage forms of the present invention is more than the weight amount of active agent.
• active agent e.g., opioid analgesic
• the immediate release dosage forms of the present invention contain a weight ratio of active agent (e.g., opioid analgesic) to gelling agent from about 1:40 to about 40:1; from about 1:35 to about 35:1; from about 1:30 to about 30:1; from about 1:25 to about 25:1; from about 1:20 to about 20:1; from about 1:15 to about 15:1; from about 1:10 to about 10:1; from about 1:8 to about 8:1; from about 1:5 to about 5:1; from about 1:3 to about 3:1; from about 1:1.5 to about 1.5:1; from about 1:1.25 to about 1.25:1; 1:1 to about 40:1; from about 1:1 to about 35:1; from about 1:1 to about 30:1; from about 1:1 to about 25:1; from about 1:1 to about 20:1; from about 1:1 to about 15:1; from about 1:1 to about 10:1; from about 1:1 to about 8:1; from about 1 : 1 to about 5:1; from about 1 : 1 to
• the immediate release solid oral dosage forms disclosed herein may comprise from about 0.1 %, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, or about 7% to about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% (w/w) gelling agent based on the weight of the dosage form.
• the dosage form may contain from about 0.1% to about 60%, from about 0.5% to about 20%, or from about 1 % to about 10% (w/w) gelling agent based on the total weight of the dosage form.
• the delayed release gelling composition may comprise one or more of rotor layered and enteric coated pellets, top sprayed granules, roller compacted pellets, bottom sprayed granules (e.g., wurster coated granules), or combinations thereof.
• the delayed release gelling agent composition comprises top spray granules
• about 90% to about 100%, about 95% to about 100%, or about 99% to about 100% of the top spray granules incorporated into the immediate release solid oral dosage form may be retained in one or more of a 100 mesh screen, a 200 mesh screen, and a pan.
• when the delayed release gelling agent composition comprises top spray granules about 20% to about 50%, about 30% to about 45%, or about 40% of the top sprat granules incorporated into the immediate release solid oral dosage form may be retained in a 100 mesh screen.
• the delayed release gelling agent composition comprises top spray granules
• about 20% to about 50%, about 30% to about 45%, or about 40% of the top sprat granules incorporated into the immediate release solid oral dosage form may be retained in a 200 mesh screen.
• when the delayed release gelling agent composition comprises top spray granules about 10% to about 30%, about 15% to about 25%, or about 20% of the top spray granules incorporated into the immediate release solid oral dosage form may pass through a 200 mesh screen.
• the pellets when the delayed release gelling agent composition comprises roller compacted pellets, the pellets may have a bulk density ranging from about 0.4 g/ml to about 0.6 g/ml, or a tapped density ranging from about 0.55 g/ml to about 0.65 g/ml.
• tapped density refers to the increased bulk density attained after mechanically tapping the container containing the powder sample.
• the enteric material may overcoat the gelling agent(s) in one or more delayed release gelling agent particles.
• the enteric material may be part of a matrix material (unitary or multiparticulate) in which the delayed release gelling agent composition may be dispersed.
• the enteric material may (i) dissolve above a pH of about 5.5, (ii) not dissolve below a pH of about 5.5, or (iii) dissolve at a pH of 5.5 or higher and not dissolve below a pH of 5.5.
• the enteric material used to coat the gelling agent may be selected from the group consisting of a cellulosic material, an acrylic polymer, a methacrylic polymer and mixtures thereof.
• the enteric material may be selected from the group consisting of methacrylic acid/methyl methacrylate, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl acrylate/methyl methacrylate copolymers, shellac, hydroxypropyl methylcellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose trimellitate, cellulose acetate phthalates, polyvinyl acetate phthalates and mixtures thereof.
• the enteric material may be a methacrylic acid/ethyl acrylate copolymer.
• the dosage form may include from about 0.1 %, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% to about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% (w/w) enteric material based on the weight of the dosage form.
• the dosage form may contain from about 0. 1% to about 50%, from about 1 % to about 20%, or from about 2% to about 15% (w/w) enteric material based on the total weight of the dosage form.
• each delayed release gelling agent particle may comprise from about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% to about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 40%, about 50%, about 60%, about 70%, or about 80% (w/w) enteric material based on the weight of each delayed release gelling agent particle.
• the dosage form may contain from about 10% to about 30%, or from about 12% to about 25% (w/w) enteric material based on the weight of each delayed release gelling agent particle.
• the delayed release gelling agent composition comprises rotor layered and enteric coated pellets, the pellets comprising from about 5% to about 35%, from about 5% to about 15%, from about 15% to about 25%, from about 25% to about 35%, about 10%, or about 30% (w/w) enteric material based on total weight of the delayed release gelling agent composition.
• the immediate release solid oral dosage forms disclosed herein may have a weight ratio of gelling agent to enteric material of from about 1 :40 to about 40: 1, from about 1 :30 to about 30: 1, from about 1 :20 to about 20: 1, from about 1 : 15 to about 15: 1, from about 1: 10 to about 10: 1, from about 1:8 to about 8: 1, from about 1 :5 to about 5: 1, from about 1 :3 to about 3: 1, from about 1 : 1.5 to about 1.5: 1, from about 1: 1 to about 40: 1, from about 1: 1 to about 30: 1, from about 1 : 1 to about 20: 1, from about 1: 1 to about 15: 1, from about 1 : 1 to about 8: 1, from about 1 : 1 to about 5: 1, from about 1 : 1 to about 3: 1, from about 1 : 1 to about 1.5: 1, from about 1:40 to about 1 : 1, from about 1:30 to about 1 : 1, from about 1:20 to about 1: 1, from about 1 : 15 to about 1 :
• the immediate release solid oral dosage forms according to the disclosure may include one or more aversive agents to further deter illicit use of the active agent contained therein.
• aversive agents may be selected from the group consisting of emetics, antagonists, bittering agents, irritants, and mixtures thereof.
• the aversive agents may be incorporated into a matrix with the active agent (e.g., opioid analgesic) and delayed release gelling agent composition, or into particles, added separately within a capsule or as an additional tableting excipient.
• Exemplary emetics include, but are not limited to, methyl cephaeline, cephaeline, emetine hydrochloride, psychotrine, O-methylpsychotrine, emetamine, ipecamine, hydro- ipecamine, ipecacunhic acid and mixtures thereof.
• Exemplary antagonists include, but are not limited to, naltrexone, naloxone, nalmefene, cyclazacine, levallorphan, pharmaceutically acceptable salts thereof, solvates thereof, prodrugs thereof, and mixtures thereof.
• bittering agents include, but are not limited to, flavor oils, flavoring aromatics, oleoresins, plant extracts, leaf extracts, flower extracts, fruit extracts, sucrose derivatives, chlorosucrose derivatives, quinine sulphate, denatonium benzoate and mixtures thereof.
• the bittering agent may be selected from the group consisting of spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitter almonds, menthol and mixtures thereof.
• the fruit extract may be from a fruit including, but not limited to lemon, orange, lime, grapefruit, and mixtures thereof.
• Exemplary irritants include, but are not limited to, a surfactant, capsaicin or a capsaicin analog and mixtures thereof.
• the capsaicin analog may be selected from the group consisting of resiniferatoxin, tinyatoxin, heptanoylisobutylamide, heptanoyl guaiacylamide, an isobutylamide, a guaiacylamide, dihydrocapsaicin, homovanillyl octylester, nonanoyl vanillylamide, and mixtures thereof.
• Exemplary surfactants include, but are not limited to, a poloxamer, a sorbitan monoester, a glyceryl monooleate, sodium lauryl sulfate and combinations thereof.
• the surfactant may be sodium lauryl sulfate.
• the irritant may be included in the dosage form in an amount of, for example, from about 0.1 %, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% to about 1 1%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% (w/w) irritant based on the weight of the dosage form.
• the dosage form may contain from about 0. 1% to about 30%, from about 0.5% to about 20%, or from about 1 % to about 10% (w/w) irritant based on the total weight of the dosage form.
• the immediate release solid oral dosage forms according to the disclosure may include one or more pharmaceutically acceptable carriers and excipients.
• pharmaceutically acceptable carriers and excipients are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (6 th Edition, 2009 Publication), which is incorporated by reference herein.
• Suitable carriers and excipients include, but are not limited to, plasticizers, colorants, lubricants, fillers, thermal lubricants, antioxidants, buffering agents, disintegrants, binding agents, diluents, glidants, anti-adherants, sweeteners, chelating agents, flavorants, surfactants, solubilizers, stabilizers, hydrophilic polymers, hydrophobic polymers, waxes, lipophilic materials, absorption enhancers, preservative, absorbent, cross- linking agents, bioadhesive polymers, pore formers, osmotic agents, polycarboxylic acids or combinations thereof.
• the dosage forms may include a plasticizer.
• Plasticizers may interact with hydrophobic materials resulting in a lower viscosity of the mixture as compared to the mixture without the plasticizer when measured under the same conditions.
• Suitable plasticizers include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin.
• plasticizers may include ethylene glycol, 1,2- butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, 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, acetyltributylcitrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.
• the plasticizer may be in an amount of about 5% or less, or about 4% or less, or about 2% or less, or 0% (i.e., plasticizer free).
• An exemplary plasticizer may be a glyceryl monostearate based plasticizer such as PlasaACRYL ® HTP 20 obtained from Evonik Industries.
• the dosage form may include a glidant.
• a glidant is an excipient that improves the flow characteristics of a compressible powder such as tablet ingredients or granules.
• the glidant is silicon dioxide.
• Two exemplary glidants are colloidal silicon dioxide (CAB-O-SIL®) and Quso (also known as Phila Quartz). The amount of glidant that can be used ranges from about 0.1 wt% to about 5 wt%.
• Suitable diluents useful in the dosage forms according to the disclosure include, but are not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, directly compressible starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, dibasic calcium phosphate dihydrate NF, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granular NF, dextrates NF (e.g., EmdexTM), dextrose (e.g., CereloseTM), inositol, hydrolyzed cereal solids such as the MaltronsTM and Mor-RexTM, amylose, powdered cellulose (e.g., ElcemaTM), calcium carbonate, glycine, bentonite, polyvin
• Suitable lubricants include, but are not limited to, glyceryl behenate (CompritolTM 888), metallic stearates (e.g., magnesium, calcium and sodium stearates), stearic acid, hydrogenated vegetable oils (e.g., SterotexTM), talc, waxes such as beeswax and carnauba wax, silica, fumed silica, colloidal silica, calcium stearate, long chain fatty alcohols, boric acid, sodium benzoate and sodium acetate, sodium chloride, DL-Leucine, polyethylene glycols (e.g., CarbowaxTM 4000 and CarbowaxTM 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearyl fumarate (PruvTM), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin, micro crystalline cellulose,
• the dosage forms may include one or more lubricants in an amount of from about 0.1% to about 15%, or from about 0.25% to about 10%, or from about 1% to about 8%, of the total weight of the dosage form.
• Magnesium stearate is a preferred lubricant for use in certain embodiments of the dosage forms.
• Suitable anti-adherents include, but are not limited to, talc, cornstarch, colloidal silicone dioxide (Cab-O-SilTM), DL-Leucine, sodium lauryl sulfate, and metallic stearates.
• the dosage forms can include an anti-adherent in an amount from about 0.1% to about 15%, or from about 0.25% to about 10%, or from about 1% to about 8%, of the total weight of the dosage form.
• excipients such as colorants, flavors and sweeteners
• colorants such as colorants, flavors and sweeteners
• sweeteners can be utilized in embodiments of the dosage forms where they impart little to no deleterious effect on the stability of the dosage form.
• recovery of the active agent from the dosage form may be less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% based on a syringeability test whereby an intact solid oral dosage form is dissolved with 5 ml of solvent (such as tap water) with agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• the dissolution can be for a time from about 1 to about 60 minutes, e.g., about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes or about 45 minutes.
• the recovery of the active agent from the dosage form may be less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% based on a syringeability test whereby an intact solid oral dosage form is dissolved with 10 ml of solvent (such as tap water) with agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• solvent such as tap water
• the recovery of the active agent from the dosage form may be less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% based on a syringeability test whereby an intact solid oral dosage form is dissolved with 5 ml of solvent (such as tap water) without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• solvent such as tap water
• the recovery of the active agent from the dosage form may be less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% based on a syringeability test whereby an intact solid oral dosage form is dissolved with 10 ml of solvent (such as tap water) without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• solvent such as tap water
• the recovery of the active agent from the dosage form may be less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% based on a syringeability test whereby a crushed solid oral dosage form is dissolved with 10 ml of solvent (such as tap water) with agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• solvent such as tap water
• the recovery of the active agent from the dosage form may be less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% based on a syringeability test whereby a crushed solid oral dosage form is dissolved with 5 ml of solvent (such as tap water) with agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• solvent such as tap water
• the recovery of the active agent from the dosage form may be less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% based on a syringeability test whereby a crushed solid oral dosage form is dissolved with 10 ml of solvent (such as tap water) without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• solvent such as tap water
• the recovery of the active agent from the dosage form may be less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% based on a syringeability test whereby a crushed solid oral dosage form is dissolved with 5 ml of solvent (such as tap water) without agitation at room temperature and the resultant solution is aspirated with a 18, 22, 25, or 27 gauge needle.
• solvent such as tap water
• the ratio of the viscosity of a solution obtained from an intact solid oral dosage form at 5 minutes in about 5 ml water at room temperature to the viscosity of a solution obtained from an intact solid oral dosage form at 5 minutes in about 5 ml 0. IN HC1 at room temperature is about 10: 1 or more, about 15: 1 or more, about 20: 1 or more, about 25: 1 or more, or about 30: 1 or more.
• the intact immediate release solid oral dosage forms disclosed herein have a disintegration time in water ranging from about 10 second, 20 seconds, 30 seconds, 40 seconds, 50 seconds, or 1 minute to about 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes.
• the intact immediate release solid oral dosage forms disclosed herein have a disintegration time in water ranging from about 10 seconds to about 30 minutes, from about 1 minute to about 10 minutes, or from about 10 seconds to about 2 minutes.
• the intact immediate release solid oral dosage forms disclosed herein have a disintegration time in Simulated Gastric Fluid (SGF) ranging from about 10 second, 20 seconds, 30 seconds, 40 seconds, 50 seconds, or 1 minute to about 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes.
• SGF Simulated Gastric Fluid
• the intact immediate release solid oral dosage forms disclosed herein have a disintegration time in SGF ranging from about 10 seconds to about 30 minutes, from about 1 minute to about 10 minutes, or from about 10 seconds to about 2 minutes.
• condition or disease states that can be treated by the dosage forms described herein include, but are not limited to, a condition or symptom that is inhibited, reduced or alleviated by opioid receptor activation. This refers to conditions or symptoms that are associated with one or more of the nervous system, vascular system, gastrointestinal system, pulmonary system and heart. Examples of such conditions are pain, pulmonary edema, cough and diarrhea.
• a method of treating or preventing pain by administering a dosage form, for example, an immediate release solid oral dosage form as described herein, to a patient in need thereof.
• a dosage form for example, an immediate release solid oral dosage form as described herein
• the dosage forms described herein can be used to treat or prevent acute or chronic pain.
• the dosage forms can be used to treat or prevent pain, including, but not limited to, cancer pain, central pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post operative pain, headache pain, muscle pain, and pain associated with intensive care.
• the dosage forms described herein can also be used for treating or preventing pain associated with inflammation or with an inflammatory disease in a subject.
• the pain to be treated or prevented may be associated with inflammation associated with an inflammatory disease, which can arise where there is an inflammation of the body tissue, and which can be a local inflammatory response and/or a systemic inflammation.
• the dosage forms can be used to treat or prevent pain associated with inflammatory diseases including, but not limited to: organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grupp et al., Protection against Hypoxia-reoxygenation in the Absence of Poly (ADP-ribose) Synthetase in Isolated Working Hearts, J. Mol. Cell Cardiol.
• inflammatory diseases of the joints including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases, such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin, including sclerodermatitis, psoriasis and ec
• the dosage forms described herein can also be used for treating or preventing pain associated with inflammatory disease that can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
• inflammatory disease can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
• shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer.
• the present invention is directed to methods of preparing the immediate release solid oral dosage forms disclosed herein.
• Spheroids or beads coated with an active agent composition and/or with delayed release gelling agent composition may be prepared, for example, by rotor layering, by top spraying, by roller compacting, by bottom spraying (e.g., wurster coating), or by any conceivable combination of these methods.
• spheroids or beads coated with an active agent composition and/or with delayed release gelling agent composition may be prepared by roller compacting followed by milling and sieving.
• a process for preparing immediate release solid oral dosage forms according to the invention comprise (i) preparing a delayed release gelling agent composition; (ii) blending the delayed release gelling agent composition with an active agent composition; and (iii) compressing the blend into a tablet.
• preparing the delayed release gelling agent composition may comprise enteric coating a gelling agent.
• FIG. 1 presents a non-limiting process flow diagram for the manufacture of an immediate release solid oral dosage form by the rotor layering method.
• inert beads or cores e.g., microcrystalline cellulose spheres, MCC
• gelling agents e.g., carbopol 971 and xanthan gum in water.
• a coating dispersion comprising the enteric material (e.g., Eudragit® L30D-55) and plasticizer (e.g. PlasaACRYLTM HTP20) are mixed and screened through a #30 mesh screen.
• the coating dispersion from block 106 is rotor layered onto the coated gelling agents from block 104 to form rotor layered and enteric coated delayed release gelling agent composition.
• Blocks 110 through 126 describe the preparation of a compressed Naltrexone tablet by blending the various components (Naltrexone HC1, MCC, sodium lauryl sulfate, and croscarmellose in block 112, rotor layered and enteric coated delayed release gelling agent composition in block 116, colloidal silicon dioxide in block 120, and magnesium stearate in block 124) and ultimately compressing the blend from block 124 to form a compressed tablet in block 126.
• the compressed tablet of block 126 may undergo dissolution and syringeability testing as described in the examples below.
• FIG. 2 presents a process flow diagram for the manufacture of an immediate release solid oral dosage form by the top spray granulation method.
• inert beads or cores e.g, microcrystalline cellulose
• gelling agents e.g., Carbopol 971 and xanthan gum
• enteric material dispersion in water e.g., Eudragit® L30D-55
• plasticizer dispersion in water e.g. PlasaACRYLTM HTP20
• Blocks 210 through 222 describe the preparation of a compressed Naltrexone tablet by blending the various components (Naltrexone HC1, MCC, sodium lauryl sulfate, croscarmellose, and top spray delayed release gelling agent granules in block 212, colloidal silicon dioxide in block 216, and magnesium stearate in block 220) and ultimately compressing the blend from block 220 to form a compressed tablet in block 222.
• the compressed tablet of block 222 may undergo dissolution and syringeability testing, in accordance with block 224, as described in the examples below.
• FIGs. 3A-3B present a process flow diagram for the manufacture of an immediate release solid oral dosage form by the roller compaction/milling/sifting and bottom spray (wurster coating) method.
• inert beads or cores e.g, microcrystalline cellulose spheres, MCC
• gelling agents e.g., carbopol 971 and xanthan gum
• magnesium stearate enteric material dispersion in water (e.g., Eudragit® L30D-55) and plasticizer dispersion in water (e.g.
• Blocks 316 through 332 describe the preparation of a compressed Naltrexone tablet by blending the various components (Naltrexone HC1, MCC, sodium lauryl sulfate, and croscarmellose in block 318, bottom sprayed and roller compacted delayed release gelling agent granules in block 322, colloidal silicon dioxide in block 326, and magnesium stearate in block 330 and ultimately compressing the blend from block 330 to form a compressed tablet in block 332.
• the compressed tablet of block 332 may undergo dissolution and syringeability testing, in accordance with block 334, as described in the examples below.
• the process for preparing an immediate release solid oral dosage form may comprise (i) preparing one or more particles; (ii) coating the one or more particles with an opioid analgesic composition; and (iii) blending the one or more particles coated with opioid analgesic composition with a delayed release gelling agent composition, wherein the solid oral dosage form comprises an immediate release opioid analgesic composition, and wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition.
• the process may further comprise (iv) compressing the blend into a tablet.
• the process for preparing an immediate release solid oral dosage form may comprise (i) preparing one or more delayed release gelling agent particles; and (ii) coating the one or more delayed release gelling agent particles with an opioid analgesic composition, wherein the solid oral dosage form comprises an immediate release opioid analgesic composition, and wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition.
• the process may further comprise (iii) compressing the one or more coated particles into a tablet.
• the process for preparing an immediate release solid oral dosage form may comprise (i) preparing one or more delayed release gelling agent particles; and (ii) dispersing an opioid analgesic composition and the one or more delayed release gelling agent particles in a matrix, wherein the solid oral dosage form comprises an immediate release opioid analgesic composition, and wherein the solid oral dosage form is free of or substantially free of an extended release opioid analgesic composition.
• Example 1 Enteric Coated Pellets Prepared Through a Rotor Layering Process
• a gelling agent was layered on microcrystalline cellulose (MCC) spheres via rotor layering. Subsequently, an enteric coating was layered onto the pellets.
• MCC microcrystalline cellulose
• Eudragit® L 30D-55 is a 30% w/w dispersion
• PlasACRYLTM HTP20 is 20% w/w dispersion.
• Carbopol® 97 IP and Xantural® 75 were sifted together through # 30 mesh screen and mixed in a polybag for 5 minutes to form a powder blend.
• Vivapur® spheres were charged in rotor insert of VFC fluid bed equipment.
• the carbopol and xanthan gum powder blend was fed to the rotor using K-Tron powder feeder.
• the entire quantity of powder blend was layered on the MCC spheres to form powder layered pellets.
• the powder layered pellets were dried for 30 minutes in the rotor.
• Table 2 Process Parameters for Powder Layering of Gelling Agents
• An aqueous dispersion of Eudragit® L30D-55 was prepared by adding purified water and PlasACRYLTM HTP20 to Eudragit® L30D-55 while stirring with a propeller stirrer. The dispersion was mixed for at least 10 minutes. Dried powder layered pellets were coated with the enteric coating dispersion in a rotor process to form coated pellets. The coated pellets were dried for 20 minutes to form Rotor Layered Pellets. The process parameters for enteric coating layering are disclosed in Table 3 below.
• Example 2 Naltrexone Tablets Comprising Rotor Layered Pellets of Example 1
• Naltrexone tablets were made in two lots using Rotor Layered Pellets from Example 1 (Lot 2428-053A and Lot 2428-053B) as summarized in Table 4 below and in FIG. 1.
• Lot 2428- 053A had a higher content of gelling agents (carbopol 30 mg, xanthan gum 9 mg) and 10% enteric coating.
• Lot 2428-053B had a lower content of gelling agents (carbopol 25 mg, xanthan gum 7.5 mg) and 30% enteric coating.
• the percent enteric coating was calculated based on weight gain obtained from adding the Eudragit® L-30D-55 and PlasACRYLTM HTP 20 to the gelling agent composition comprising the MCC spheres, carbopol, and xanthan gum.
• Example 3 Enteric Coated Granules Prepared Through a Top Spray Fluid Bed Granulation Process
• enteric granules of gelling agents were prepared by top spray granulation.
• Eudragit® L 30D-55 is a 30% w/w dispersion
• PlasACRYLTM HTP 20 is 20% w/w dispersion.
• Microcrystalline Cellulose PH 101, Carbopol® 971P and Xantural® 75 (Xanthan Gum) were sifted together through # 30 mesh screen and collected and loaded into a Fluid Bed Granulator bowl.
• Purified Water and PlasACRYLTM HTP20 were added to Eudragit® L30D-55 while stirring with a propeller stirrer to form a dispersion. The dispersion was mixed for at least 10 minutes.
• the dispersion was screened through #30 mesh screen and was sprayed onto a bed of material using top spray gun assembly in accordance with the process parameters summarized in Table 7 below.
• the resulting enteric granules were screened through a #60, #80, #100, and a #200 mesh screens. There were some agglomerates formed during the process which were rejected. Granules retained on #60 and # 80 mesh screens were rejected as well. Tablets were made using composite granules of retains of #100 mesh, #200 mesh and Pan. The percentage of retained granules after sifting through the various mesh screens is summarized in Table 8 below.
• Example 4 Naltrexone Tablets Comprising Top Sprayed Granules of Example 3
• Naltrexone tablets were made in two lots using Top Sprayed Granules from Example 3 (Lot 2428-048A and Lot 2428-048B) as summarized in Table 9 below and in FIG. 2.
• Lot 2428- 048A had a higher content of gelling agents (carbopol 30 mg, xanthan gum 9 mg).
• Lot 2428-048B had a lower content of gelling agents (carbopol 25 mg, xanthan gum 7.5 mg).
• gelling agent particles were prepared through roller compaction followed by wurster coating (i.e., bottom spray fluid bed coating).
• roller compacted particles from Example 5 underwent Wurster coating as summarized below.
• Eudragit® L30D-55 is a 30% w/w dispersion
• PlasACRYLTM HTP 20 is 20% w/w dispersion.
• Coated granules were screened through #20 mesh, #30 mesh and #40 mesh screens. Portion above #20 mesh was agglomerates that were discarded. The Portion retained on #30 and #40 mesh screens, combined, were used to make the tablets of Example 7.
• Example 7 Naltrexone Tablets Comprising Roller Compacted and Bottom Sprayed Granules of Example 6
• Naltrexone tablets were made in two lots using Roller Compacted and Bottom Sprayed Granules from Example 6 (Lot 2428-069A and Lot 2428-069B) as summarized in Table 16 below and in FIGs. 3A-3B.
• Lot 2428-069A had a higher content of gelling agents (carbopol 30 mg, xanthan gum 9 mg).
• Lot 2428-069B had a lower content of gelling agents (carbopol 20 mg, xanthan gum 6 mg).
• Example 7 With roller compacted and bottom spray pellets of Example 7, the volume aspirated after dissolving intact Naltrexone HCl tablets in various volumes of tap water (5 ml and 10 ml) at room temperature with and without agitation was lower for pellets with high gelling agent content. The highest volume aspirated for the tablets containing high gelling agent content was 6.7 ml, and for the tablets containing low gelling agent content it was 7.3 ml.
• Roxicodone® (Oxycodone HCl tablets) was used as a comparator.
• the highest volume aspirated after dissolving of intact Roxicodone with tap water in room temperature was 9.9 ml.
• the volume aspirated from intact Roxicodone after dissolving in various volumes of tap water (5 ml and 10 ml) at room temperature with and without agitation is greater than the volume aspirated after manipulation of the tablets prepared in Examples 2, 4, and 7 under the same manipulation conditions.
• Table 19 The data of Table 19 is depicted in Figure 5. With rotor layered pellets of Example 2 (low gelling agent content), the highest volume aspirated for intact tablets dissolved with 10 ml of tap water at room temperature (with and without agitation) was 6.9 ml. The volume aspirated for crushed tablets dissolved with 10 ml of tap water at room temperature was lower after agitation.
• Example 7 With roller compacted and bottom spray pellets of Example 7, the volume aspirated for intact and crushed tablets dissolved with 10 ml of tap water at room temperature was lower after agitation for the tablets containing high gelling agent content.
• Roxicodone (Oxycodone HC1 tablets) was used as a comparator. The highest volume aspirated after dissolution of intact and crushed Roxicodone with tap water in room temperature was 9.9 ml. The volume aspirated from intact and crushed Roxicodone after dissolution in tap water at room temperature with and without agitation is greater than the volume aspirated after dissolution of the tablets prepared in Examples 2 (low gelling agent content) and 7 under the same conditions.
• Table 20 Percentage Assay of Active Agent in Aspirated Liquid After Dissolution of Intact Tablets in Tap
• gle number is listed in the table it means that a single tablet was tested
• the higher gelling agent lot performed better than the lower gelling agent content lot.
• the highest percentage of Naltrexone HCl aspirated from the higher gelling agent lot was 27.15% and for lower amount of gelling agent it was 36.5%.
• Roxicodone (Oxycodone HCl tablets) was used as a comparator. The highest percentage of Oxycodone aspirated was 44.2% of the label claim.
• Table 21 Percentage Assay of Active Agent in Aspirated Liquid After Dissolution of Tablets in Tap Water at Room Temperature for 5 Minutes (Intact vs. Crushed Tablet - FIG. 7)
• Example 2 The tablets of Examples 2, 4 and 7 were tested for Active Agent release in 0.1 N HCl using basket with spring.
• In-vitro dissolution testing of the tablets according to Examples 9 was performed as follows: tablets were tested in vitro using a USP Apparatus 1 (#40 mesh basket) in 900 ml 0.1N HCl at 37.0 ⁇ 0.5 °C. To reduce the propensity of the tablets, once hydrated in the dissolution medium, to stick to the solid underside of the top of the basket or the base of the shaft, a retaining spring (passivized stainless steel 316 spring, 1.5-cm outside diameter and 2-cm length) was placed in the upper part of the basket (above the tablet). Sampling time points included 5, 15, 30, 45, 60, and 90 minutes (or as indicated). Results are summarized in Tables 22 to 25 and Figures 8 through 11.
• Table 23 Effect of Hardness on Dissolution Profiles of Tablets Made With Top Sprayed Gelling Agent Granules (Example 4) in 0. IN HC1, 900 mL, using Basket With Spring
• Dissolution profile of tablets made with top spray fluid bed granulation approach (Example 4) was slower for tablets with a hardness value of 10 kP than for tablets with a hardness value of 17 kP. Additionally, the dissolution profile for tablets from Example 4 with low amounts of gelling agents were slower than for tablets from Example 4 with high amounts of gelling agents.
• Table 24 Effect of Hardness on Dissolution Profiles of Tablets Made With Rotor Layered Gelling Agent Pellets (Example 2) in 0. IN HC1, 900 mL, using Basket With Spring
• Table 24 The data of Table 24 is depicted in Figure 10. Dissolution profile of tablets made with Rotor Layered Gelling Agent Pellets approach (Example 2) was similar regardless of the hardness.
• Coating of gelling agent with Eudragit® L30D-55 and incorporating in an immediate release dosage form affords an immediate release of drug from the dosage form in acidic pH ( ⁇ pH 5.5) found in stomach.
• the Eudragit coating dissolves in water having pH greater than 5.5.
• All three techniques used to cover gelling agents with Eudragit® L30D-55 show reduction in the amount of drug that can be syringed upon dissolving in water. With top spray fluid bed granulation approach, the dissolution profile of drug was slower.
• X includes A or B is intended to mean any of the natural inclusive permutations. That is, if X includes A; X includes B; or X includes both A and B, then "X includes A or B" is satisfied under any of the foregoing instances.
• Reference throughout this specification to "an embodiment”, “certain embodiments”, or “one embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase “an embodiment”, “certain embodiments”, or “one embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment.

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